Time to be blunt: Substance use in cystic fibrosis.

BACKGROUND: As the population of people with cystic fibrosis (pwCF) continues to age, attention is shifting towards addressing the unique challenges teenagers and adults face, including substance use. Changing attitudes and legality regarding marijuana and cannabidiol (CBD) may influence their use among pwCF, but data on the rate of use, reasons for use, and administration methods are lacking. OBJECTIVE: Investigate marijuana, CBD, e-cigarette, and cigarette usage among pwCF and explore differences in demographics, disease severity, and cystic fibrosis transmembrane receptor (CFTR) modulator use between recent users and nonusers. METHODS: This cross-sectional study used a one-time electronic survey to assess marijuana, CBD, e-cigarette, and cigarette use in pwCF aged >13 years. Demographic and clinical characteristics were compared between recent users and nonusers. The association between recent substance use and CFTR modulator use was analyzed using logistic regressions. RESULTS: Among 226 participants, 29% used marijuana, 22% used CBD, 27% used e-cigarettes, and 22% used cigarettes in the last 12 months. Users of all substances were more likely to be college-educated or aged 29-39 years than nonusers. E-cigarette users were 2.9 times more likely to use CFTR modulators (95% confidence interval [95% CI]: 0.98-11.00, p = .08) and marijuana users were 2.5 times more likely to use CFTR modulators compared to nonusers, adjusted for confounders. CBD, e-cigarettes, and cigarettes users were more likely to have an abnormal mental health screen compared to nonusers. A high proportion of never-users of marijuana and CBD expressed interest in using. CONCLUSION: Substance use is more prevalent among pwCF than previously reported and needs to be addressed by healthcare providers.

Food insecurity and mental health during the COVID-19 pandemic in cystic fibrosis households.

BACKGROUND: The COVID-19 pandemic impacted many households due to shelter-in-place orders and economic hardship. People with cystic fibrosis (CF) experienced increased food insecurity compared to the general population before the pandemic, even though adequate food access is needed to maintain nutrition goals associated with improved health-related outcomes. Little is known about the impact the pandemic had on the food insecurity of people with CF and their families. OBJECTIVE: To investigate how the COVID-19 pandemic impacted food insecurity, mental health, and self-care in people with CF. METHODS: Adults with CF and parents/guardians of children with CF were recruited via social media to complete online questionnaires from May 2020 to February 2021. Questionnaires in English and Spanish included USDA 2-question food insecurity screening, Patient Health Questionnaire-4 for mental health screening, and directed questions on the impact of the pandemic. RESULTS: Of 372 respondents, 21.8% of the households experienced food insecurity during the pandemic compared to 18.8% prepandemic (p < .001). More food insecure patients with CF reported weight loss (32.1% vs. 13.1%, p < .001), worse airway clearance adherence (13.6% vs. 5.8%, p < .01), and worse medication adherence (12.4% vs. 1.7%, p < .01) compared to food secure patients. Food insecure subjects were more likely to have an abnormal mental health screen compared to food secure subjects (53.1% vs. 16.2%, p < .001). CONCLUSION: Food insecurity increased in the CF population during the COVID-19 pandemic. Food insecure subjects reported worse mental health and self-care during the pandemic compared to food secure subjects.

Pulmonary Metagenomic Sequencing Suggests Missed Infections in Immunocompromised Children.

BACKGROUND: Despite improved diagnostics, pulmonary pathogens in immunocompromised children frequently evade detection, leading to significant mortality. Therefore, we aimed to develop a highly sensitive metagenomic next-generation sequencing (mNGS) assay capable of evaluating the pulmonary microbiome and identifying diverse pathogens in the lungs of immunocompromised children. METHODS: We collected 41 lower respiratory specimens from 34 immunocompromised children undergoing evaluation for pulmonary disease at 3 children's hospitals from 2014-2016. Samples underwent mechanical homogenization, parallel RNA/DNA extraction, and metagenomic sequencing. Sequencing reads were aligned to the National Center for Biotechnology Information nucleotide reference database to determine taxonomic identities. Statistical outliers were determined based on abundance within each sample and relative to other samples in the cohort. RESULTS: We identified a rich cross-domain pulmonary microbiome that contained bacteria, fungi, RNA viruses, and DNA viruses in each patient. Potentially pathogenic bacteria were ubiquitous among samples but could be distinguished as possible causes of disease by parsing for outlier organisms. Samples with bacterial outliers had significantly depressed alpha-diversity (median, 0.61; interquartile range [IQR], 0.33-0.72 vs median, 0.96; IQR, 0.94-0.96; P < .001). Potential pathogens were detected in half of samples previously negative by clinical diagnostics, demonstrating increased sensitivity for missed pulmonary pathogens (P < .001). CONCLUSIONS: An optimized mNGS assay for pulmonary microbes demonstrates significant inoculation of the lower airways of immunocompromised children with diverse bacteria, fungi, and viruses. Potential pathogens can be identified based on absolute and relative abundance. Ongoing investigation is needed to determine the pathogenic significance of outlier microbes in the lungs of immunocompromised children with pulmonary disease.

Mycobacterium abscessus complex lung infection in a toddler with a tracheostomy.

Mycobacterium abscessus complex and other non-tuberculous mycobacteria are infrequently encountered respiratory pathogens in patients with tracheostomies. We report a 4-year-old girl with a tracheostomy, placed during infancy for management of severe bronchopulmonary dysplasia and laryngeal stenosis, who developed a M. abscessus complex lung infection. There was clear evidence of parenchymal involvement and true infection beyond colonization. She demonstrated dramatic clinical, laboratory, and radiographic improvement after prolonged anti-mycobacterial therapy.

Urban particulate matter induces pro-remodeling factors by airway epithelial cells from healthy and asthmatic children.

CONTEXT: Chronic exposure to ambient particulate matter pollution during childhood is associated with decreased lung function growth and increased prevalence of reported respiratory symptoms. The role of airway epithelium-derived factors has not been well determined. OBJECTIVE: To determine if urban particulate matter (UPM) stimulates production of vascular endothelial growth factor (VEGF) and transforming growth factor-ß2 (TGF-ß2), and gene expression of mucin 5AC (MUC5AC) and interleukin-(IL)-8 by primary airway epithelial cells (AECs) obtained from carefully phenotyped healthy and atopic asthmatic school-aged children. METHODS: Primary AECs from 9 healthy and 14 asthmatic children were differentiated in air--liquid interface (ALI) culture. The apical surface was exposed to UPM suspension or phosphate buffered saline (PBS) vehicle control for 96 h. VEGF and TGF-ß2 concentrations in cell media at baseline, 48 and 96 h were measured via ELISA. MUC5AC and IL-8 expression by AECs at 96 h was measured via quantitative polymerase chain reaction. RESULTS: Baseline concentrations of VEGF, but not TGF-ß2, were significantly higher in asthmatic versus healthy cultures. UPM stimulated production of VEGF, but not TGF-ß2, at 48 and 96 h; the magnitude of change was comparable across groups. At 96 h there was greater MUC5AC and IL-8 expression by UPM exposed compared to PBS exposed AECs. CONCLUSIONS: Induction of the pro-remodeling cytokine VEGF may be a potential mechanism by which UPM influences lung function growth in children irrespective of asthma status. Respiratory morbidity associated with UPM exposure in children may be related to increased expression of MUC5AC and IL-8.

Inflammatory and growth mediators in growing preterm infants.

Little is understood about the optimal balance between IGF-I and antagonistic inflammatory mediators, such as IL-6, in growing preterm infants. Using a prospective cohort study, we investigated the relationship between postnatal growth of preterm infants and key growth and inflammatory mediators. We studied 51 stable, growing preterm infants (mean gestational age: 27.8 +/- 0.4 weeks, mean birth weight: 1,032.8 +/- 50.6 g). IL-6 and IL-1ra (reflecting stress/ inflammation) and IGF-I and GHBP (reflecting anabolic activity and GH sensitivity) were measured at enrollment and discharge using ELISA. During the observation period (mean 6.1 +/- 0.34 weeks) there was a significant increase in weight (1,396 +/- 81 g, p < 0.0001). IGF-I increased from 46.6 +/- 4.1 to 88.7 +/- 5.2 ng/ml (p < 0.001). In contrast, IL-6 decreased from 9.5 +/- 1.0 to 2.3 +/- 0.34 pg/ml (p <0.001) and IL-1ra from 6,042 +/- 362 to 4,851 +/- 365 ng/ml (p = 0.007). GHBP increased from 65.8 +/- 6.7 to 82.5 +/- 7.9 ng/ml (p = 0.003). IL-6 was inversely correlated with IGF-I (p < 0.001). In addition, a multiple regression model showed IGF-I levels correlated positively and IL-6 levels inversely with various parameters of growth. Growth in preterm infants is characterized by increases in IGF-I and GHBP with simultaneous decreases in IL-6 and IL-1ra. Efforts to optimally balance inflammatory and growth mediators may benefit somatic growth in infants very early in life.

Effect of a high-fat meal on the growth hormone response to exercise in children.

Exercise-induced growth hormone (GH) secretion may significantly modulate growth and development in children. Altered physiological GH responses, therefore, may reduce the beneficial effects of exercise. High-fat food ingestion before exercise blunts the GH response in adults, but it is unknown whether this occurs in children. We therefore performed standard exercise tests, following a high-fat meal or placebo, in 12 children, age 11-15 (6 M, 6 F). GH, insulin-like growth factor-I, glucose, insulin, glucagon, cortisol, epinephrine and interleukin-6 samples were drawn at baseline, end-exercise, and 30 and 60 min post-exercise. While GH was similar at baseline in all experiments, the exercise-induced GH peak was lower after the high-fat meal (6.7 +/- 1.6 ng/l vs 11.8 +/- 2.4 ng/l, p <0.02). Other exercise responses were not affected by prior fat ingestion. A high-fat meal before exercise, therefore (a common event in Western societies), may reduce the growth factor response to exercise in children, with potential implications for growth and development.

Inflammatory cytokine, growth factor and counterregulatory responses to exercise in children with type 1 diabetes and healthy controls.

In children with type 1 diabetes (T1DM), altered adaptive responses to exercise (secretion of growth factors, inflammatory cytokines, and glucoregulatory mediators) may have potential implications in growth and development, early onset of disease complications, and incidence of hypoglycemia. We therefore measured a broad spectrum of exercise responses in 12 children with T1DM (seven males and five females) and 12 controls (six males / six females) aged 11-15 yr, during a 30-min exercise challenge @ 80% VO(2)max. Euglycemia was strictly controlled during exercise, and in diabetic patients a basal rate of i.v. insulin was allowed to maintain baseline insulin concentrations. Throughout the experiment, interleukin-6 (IL-6) concentrations (pg/mL) were markedly higher in T1DM vs. controls (preexercise: 5.0+/-1.3 vs. 1.9+/-0.6, p<0.02; end-exercise 5.3+/-1.2 vs. 2.7+/-1.0, p<0.05; 30-min postexercise: 8.2+/-2.2 vs. 3.9+/-0.8, p<0.05). A similar pattern was also observed with norepinephrine. Growth hormone (GH) concentration was similar in both groups at baseline and end-exercise, but in T1DM the exercise-induced GH remained significantly elevated 30 min after exercise (9.2+/-2.2 vs. 3.1+/-0.9 ng/L, p<0.01). The exercise-induced increase in glucagon elicited by exercise in controls was similar to that previously observed in healthy adults (10+/-3 pg/mL); however, it was significantly blunted in T1DM children (2+/-2 pg/mL, p<0.05). In conclusion, T1DM children displayed significant alterations in multiple aspects of their adaptive response to intense exercise.

Clinical significance of occult metastatic melanoma in sentinel lymph nodes and other high-risk factors based on long-term follow-up.

Selective sentinel lymphadenectomy (SSL) following preoperative lymphoscintigraphy is the most significant recent advance in the management of patients with primary melanoma. This study evaluates the prognostic value of sentinel lymph node (SLN) status and other risk factors in predicting survival and recurrence in patients with primary cutaneous melanoma. From October 1993 to July 1998 a series of 412 patients with primary invasive melanoma underwent SSL at the UCSF/ Mt. Zion Melanoma Center. The outcome of 363 evaluable patients is summarized in this study. The factors related to survival and disease recurrence were analyzed by Cox proportional hazard regression models. The overall incidence of patients with positive SLNs was 18%. Over a median follow-up of 4.8 years, the overall mortality rate in patients with primary cutaneous melanoma was 18.7%, and 74 recurrences occurred (20.4%). Mortality was significantly related to SLN status [HR = 2.06; 95% Confidence interval (CI) 1.18, 3.58], angiolymphatic invasion (HR = 2.21; 95% CI 1.08, 4.55), ulceration (HR = 1.79; 95% CI 1.02, 3.15), mitotic index (HR =1.38; 95% CI 1.01, 1.90), and tumor thickness (HR = 2.20, 95% CI 1.21, 3.99). Factors significantly related to disease-free survival included SLN status (HR = 2.09; 95% CI 1.31, 3.34), tumor thickness (HR = 1.89; 95%. CI 1.20,2.98), and age (HR= 1.26 95% CI 1.08, 1.47). SLN status was the most significant factor for melanoma recurrence and death. Other important predictors include tumor thickness, ulceration, lymphatic invasion, and mitotic index.

Internal mammary sentinel lymph node mapping for invasive breast cancer: implications for staging and treatment.

The optimal staging and treatment of the internal mammary nodes (IMNs) among patients with invasive breast cancer (IBC) is controversial. Although medial tumors have been reported to more commonly drain to IMNs, other variables predictive for IMN drainage may help identify those patients who may benefit from further IMN assessment. Factors associated with IMN drainage were analyzed among 141 patients who underwent lymphatic mapping and selective sentinel lymphadenectomy using intradermal injection (ID) or peritumoral (PT) injection. Fourteen of 83 patients (17%) receiving PT injections had IMN drainage, compared to none among the 58 patients who underwent ID injection alone (p = 0.0004). There were no differences in patient or tumor variables detected between the two groups. Among patients receiving PT injections, no factors examined were significantly associated with IMN drainage on univariate analysis. Using the multivariate logistic regression model, palpable disease was the most important factor associated with IMN drainage (risk ratio [RR] = 6.02; 95% confidence interval [CI] 0.64-56.34; p = 0.05). In addition, lymphatic/vascular invasion (LVI) and age less than 50 years were associated with IMN drainage (RR = 6.17; 95% CI 1.02-37.50; p = 0.09 and RR = 2.94; 95% CI 0.82-10.49; p = 0.09, respectively). IMN drainage occurred in a significant proportion of patients after PT injection, but not ID injection. In the final model, palpable disease was the most important factor associated with IMN drainage; LVI and age less than 50 years were of borderline significance. These factors may aid in the selection of patients who might benefit from further staging or treatment of the IMNs.