Decreased Interleukin-1 Family Cytokine Production in Patients with Nontuberculous Mycobacterial Lung Disease.

Nontuberculous mycobacteria (NTM) cause pulmonary disease in individuals without obvious immunodeficiency. This study was initiated to gain insight into the immunological factors that predispose persons to NTM pulmonary disease (NTMPD). Blood was obtained from 15 pairs of NTMPD patients and their healthy household contacts. Peripheral blood mononuclear cells (PBMCs) were stimulated with the Mycobacterium avium complex (MAC). A total of 34 cytokines and chemokines were evaluated in plasma and PBMC culture supernatants using multiplex immunoassays, and gene expression in the PBMCs was determined using real-time PCR. PBMCs from NTMPD patients produced significantly less interleukin-1ß (IL-1ß), IL-18, IL-1α, and IL-10 than PBMCs from their healthy household contacts in response to MAC. Although plasma RANTES levels were high in NTMPD patients, they had no effect on IL-1ß production by macrophages infected with MAC. Toll-like receptor 2 (TLR2) and TWIK2 (a two-pore domain K+ channel) were impaired in response to MAC in PBMCs of NTMPD patients. A TLR2 inhibitor decreased all four cytokines, whereas a two-pore domain K+ channel inhibitor decreased the production of IL-1ß, IL-18, and IL-1α, but not IL-10, by MAC-stimulated PBMCs and monocytes. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. A reduced monocyte ratio might contribute to the attenuated production of IL-1 family cytokines by PBMCs of NTMPD patients in response to MAC stimulations. Collectively, our findings suggest that the attenuated IL-1 response may increase susceptibility to NTM pulmonary infection through multiple factors, including impaired expression of the TLR2 and TWIK2 and reduced monocyte ratio. IMPORTANCE Upon MAC stimulation, the production of IL-1 family cytokines and IL-10 by PBMCs of NTMPD patients was attenuated compared with that of healthy household contacts. Upon MAC stimulation, the expression of TLR2 and TWIK2 (one of the two-pore domain K+ channels) was attenuated in PBMCs of NTMPD patients compared with that of healthy household contacts. The production of IL-1 family cytokines by MAC-stimulated PBMCs and MAC-infected monocytes of healthy donors was reduced by a TLR2 inhibitor and two-pore domain K+ channel inhibitor. The ratio of monocytes was reduced in whole blood of NTMPD patients compared with that of healthy household contacts. Collectively, our data suggest that defects in the expression of TLR2 and TWIK2 in human PBMCs or monocytes and reduced monocyte ratio are involved in the reduced production of IL-1 family cytokines, and it may increase susceptibility to NTM pulmonary infection.

Early IL-17A production helps establish Mycobacterium intracellulare infection in mice.

Nontuberculous mycobacteria (NTM) infection is common in patients with structural lung damage. To address how NTM infection is established and causes lung damage, we established an NTM mouse model by intranasal inoculation of clinical isolates of M. intracellulare. During the 39-week course of infection, the bacteria persistently grew in the lung and caused progressive granulomatous and fibrotic lung damage with mortality exceeding 50%. Lung neutrophils were significantly increased at 1 week postinfection, reduced at 2 weeks postinfection and increased again at 39 weeks postinfection. IL-17A was increased in the lungs at 1-2 weeks of infection and reduced at 3 weeks postinfection. Depletion of neutrophils during early (0-2 weeks) and late (32-34 weeks) infection had no effect on mortality or lung damage in chronically infected mice. However, neutralization of IL-17A during early infection significantly reduced bacterial burden, fibrotic lung damage, and mortality in chronically infected mice. Since it is known that IL-17A regulates matrix metalloproteinases (MMPs) and that MMPs contribute to the pathogenesis of pulmonary fibrosis, we determined the levels of MMPs in the lungs of M. intracellulare-infected mice. Interestingly, MMP-3 was significantly reduced by anti-IL-17A neutralizing antibody. Moreover, in vitro data showed that exogenous IL-17A exaggerated the production of MMP-3 by lung epithelial cells upon M. intracellulare infection. Collectively, our findings suggest that early IL-17A production precedes and promotes organized pulmonary M. intracellulare infection in mice, at least in part through MMP-3 production.

Geographic variability of antibiotic prescribing for acute respiratory tract infections within a direct-to-consumer telemedicine practice.

In this retrospective cohort study of patients presenting to a national direct-to-consumer medical practice, we found that provider geographic location is a stronger driver of antibiotic prescribing than patient location. Physicians in the Northeast and South are significantly more likely than physicians in the West to prescribe antibiotics for upper respiratory infection and bronchitis.

Effective Access to Care in a Crisis Period: Hypertension Control During the COVID-19 Pandemic by Telemedicine.

OBJECTIVE: To assess the effectiveness of telemedicine video visits in the management of hypertensive patients at home during the first year of the COVID-19 pandemic. METHODS: A quantitative analysis was performed of all home video visits coded with a diagnosis of essential hypertension during the first 12 months of the COVID-19 pandemic (March 2020 through February 2021). A total of 10,634 patients with 16,194 hypertension visits were present in our national telemedicine practice database during this time. Among this population, a total of 569 patients who had 1785 hypertension visits met the criteria of having 2 or more blood pressure (BP) readings, with the last BP reading occurring in the report period. We analyzed baseline characteristics and BP trends of these 569 patients during the study period. Voluntarily submitted patient satisfaction ratings, which were systematically requested at the end of each visit, were also analyzed. RESULTS: The mean age of the patients in this study cohort of 569 patients was 43.9 years, and 48.3% (275) were women. More than 62% (355) of the patients had an initial systolic BP (SBP) above 140 mm Hg, and 25.3% (144) had an initial SBP of greater than 160 mm Hg. The average number of visits during the study period was 3.1 visits per patient; an average of 6.4 BP measurements per patient were available. During the study period, 77% (438) of the patients experienced an improvement in either SBP or diastolic BP (DBP), with mean reductions of -9.7 mm Hg and -6.8 mm Hg in SBP and DBP, respectively. A total of 416 patients in the cohort started with a BP above 140/90 mm Hg. For this subset of patients, 55.7% (232) achieved a BP of 140/90 mm Hg or lower by the end of the study period, and the average reductions in SBP and DBP were -17.9 mm Hg and -12.8 mm Hg, respectively, which corresponded to improvements of 11.2% and 12.4%. These improvements did not vary significantly when patients were stratified by age, sex, or geographic region of residence (rural vs urban/suburban). Voluntarily submitted patient surveys indicated a high degree of patient satisfaction, with a mean satisfaction score of 4.94 (5-point scale). CONCLUSION: Clinician-patient relationships established in a video-first telemedicine model were broadly effective for addressing suboptimally controlled hypertension. Patient satisfaction with these visits was high.

Genomic features of rapid versus late relapse in triple negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. METHODS: Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as 'rapid relapse' (rrTNBC; distant relapse or death ≤2 years of diagnosis), 'late relapse' (lrTNBC; > 2 years) or 'no relapse' (nrTNBC: > 5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome (n = 453), and whole genome copy number and mutation data for 171 cancer-related genes (n = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. RESULTS: Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training (n = 63 patients), testing (n = 63) and independent validation (n = 34) cohorts, although performance of all models were overall modest. CONCLUSIONS: We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.

Morbidity and cost burden of prenatal myelomeningocele repair.

OBJECTIVE: This study compared the morbidities and financial burden associated with prenatal open myelomeningocele repair versus postnatal repair. MATERIALS AND METHODS: The retrospective study cohort included 23 mother-infant dyads undergoing prenatal repair and 30 with postnatal repair. Financial, demographic, and medical information were obtained for mother-infant dyads from each infant's birth through the first year of life. RESULTS: Infants in the prenatal repair group were significantly affected by sequelae of prematurity, including apnea, bronchopulmonary dysplasia, and retinopathy of prematurity. Importantly, fewer of these infants required ventriculoperitoneal shunt procedures and the overall improved composite outcome of shunting or death. Infants in the postnatal repair group required more hospital readmissions in the first year of life. Financial costs for mother-infant dyads in the prenatal repair group were higher, driven by the length of stay in the neonatal intensive care unit and maternal hospital admissions. Kaplan-Meier curves analyzing the relative contributions of the length of stay and total charges in the population were constructed. The maternal contribution was markedly different between groups due to postoperative hospitalization, readmission, and close fetal surveillance required. Though these differences did not reach statistical significance, it highlights an important burden on families and the medical system. CONCLUSIONS: This is the first study to report the contributions of prematurity in relation to maternal and infant morbidity and financial costs. The benefits of prenatal myelomeningocele repair include lower risk for ventriculoperitoneal shunting and fewer hospital readmissions. The risk of preterm birth and its neonatal sequelae continue to be a significant burden.

Education vs Clinician Feedback on Antibiotic Prescriptions for Acute Respiratory Infections in Telemedicine: a Randomized Controlled Trial.

BACKGROUND: Antibiotics prescribed for acute respiratory tract infections in the telemedicine setting are often unwarranted. OBJECTIVE: We hypothesized that education plus individualized feedback, compared with education alone, would significantly reduce antibiotic prescription rates for upper respiratory infections, bronchitis, sinusitis, and pharyngitis in a telemedicine setting. DESIGN: Two-arm, parallel-group randomized controlled trial conducted at a telemedicine practice from January 1, 2018, to November 30, 2018. PARTICIPANTS: Clinicians employed at the practice on or after January 1, 2017 (n = 45). INTERVENTIONS: The control group received education (treatment guideline presentation and online course) in April 2018. The intervention group received education plus individualized feedback via an online dashboard with monthly rates of personal and practice-wide antibiotic prescription rates starting May 2018. MAIN MEASURES: Antibiotic prescription for any visit with at least one target condition: upper respiratory tract infection, bronchitis, sinusitis, and pharyngitis. KEY RESULTS: Baseline antibiotic prescription rates in control and intervention groups across conditions were as follows: upper respiratory infection (URI): 626/3410 (18.4%), 413/2752 (15.0%), bronchitis: 689/1471 (46.8%), 742/1162 (64.0%), sinusitis: 5154/6131 (84.1%), 4250/4876 (87.2%), pharyngitis: 2308/2838 (81.3%), 1593/2126 (74.9%). Antibiotic prescriptions for all conditions decreased in the post-intervention period compared with those in the pre-intervention period, for both control and intervention groups. Reduction of antibiotic prescriptions for URI and bronchitis was greater for the group receiving education plus individualized feedback compared with that for the group receiving education alone (interaction term ratio 0.60, 95% CI 0.47 to 0.77 for URI; and interaction term ratio 0.42, 95% CI 0.32 to 0.55 for bronchitis), but not sinusitis and pharyngitis. CONCLUSION: Education plus individualized feedback in a telemedicine practice significantly decreased antibiotic prescription rates for upper respiratory tract infections and bronchitis, compared with education alone. Future studies should focus on tailoring antibiotic stewardship programs based on underlying conditions, and the maintenance of early reductions in antibiotic prescription.

Where Virtual Care Was Already a Reality: Experiences of a Nationwide Telehealth Service Provider During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic has led to an increase in the use of and demand for telehealth services. OBJECTIVE: Here, we describe the utilization of telehealth services provided by Doctor On Demand, Inc., a well-known telehealth company in the United States, before and during the COVID-19 pandemic. We also explore how the number of virtual visits, reasons for visits, and patients served changed over time. METHODS: We reported data as a percentage change from the baseline week during 2 distinct time periods: February-June 2019 and February-June 2020 based on 4 categories of visits: respiratory illness, unscheduled behavioral health, scheduled behavioral health, and chronic illness. RESULTS: In 2020, the total visit volume increased considerably from March through April 7, 2020 (59% above the baseline) and then declined through the week of June 2 (15% above the baseline). Visits for respiratory illnesses increased through the week of March 24 (30% above the baseline) and then steadily declined through the week of June 2 (65% below the baseline). Higher relative increases were observed for unscheduled behavioral health and chronic illness visits through April (109% and 131% above the baseline, respectively) before a decline through the week of June 2 (69% and 37% above the baseline, respectively). Increases in visit volume among rural residents were slightly higher than those among urban residents (peak at 64% vs 58% above the baseline, respectively). CONCLUSIONS: Although this telehealth service provider observed a substantial increase in the volume of visits during the COVID-19 pandemic, it is interesting to note that this growth was not fueled by COVID-19 concerns but by visits for behavioral health and chronic illness. Telehealth services may play a role as a "safety valve" for patients who have difficulty accessing care during a public health emergency.

Statewide implementation of an evidence-based trauma intervention in schools.

The goal of the current article is to describe the implementation and outcomes of an innovative statewide dissemination approach of the evidence-based trauma intervention Cognitive Behavioral Intervention for Trauma in Schools (CBITS). In the context of a 2-year statewide learning collaborative effort, 73 CBITS groups led by 20 clinicians from 5 different school-based mental health provider organizations served a total of 350 racially and ethnically diverse (66.9% Hispanic, 26.2% Black/African American, 43.7% White, and 30.1% Other), majority female (61%) children, averaging 12.2 years (SD = 2.4, range 8-19). Of the 350 children who began CBITS, 316 (90.3%) successfully completed treatment. Children demonstrated significant reductions in child posttraumatic stress disorder (PTSD) symptoms (42% reduction, d = .879) and problem severity (25% reduction, d = .396), and increases in child functioning, t(287) = -3.75, p < .001 (5% increase, d = .223). Findings point to the need, feasibility, and positive impact of implementing and scaling up school-based interventions for students suffering from posttraumatic stress. (PsycINFO Database Record

A method to optimize the response range while maintaining Rorschach Comprehensive System validity.

Brief and lengthy Rorschach records have been identified as common problems in protocol administration. Clinicians have debated how to prevent overly short and long records, but they have been reluctant to alter standardized administration for fear of introducing bias. The present study examines a nonintrusive method for constraining responses by prompting for an extra response when only one is offered per card and by removing the card after four responses are given. Among patients who typically produce brief records, consisting of a residential sample of civil and forensic patients with a range of disordered thinking, the alternative administration method demonstrated improved Comprehensive System validity in assessing thought disorder and eliminated the need to readminister the test due to fewer than 14 responses. The findings have clinical implications for protocol administration with thought-disordered populations that typically produce brief records.