A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. Exposure to noxious stimuli such as hyperoxia, volutrauma, and infection in infancy can have long-reaching impacts on lung health and predispose towards the development of conditions such as chronic obstructive pulmonary disease (COPD) in adulthood. BPD and COPD are both marked by lung tissue degradation, neutrophil influx, and decreased lung function. Both diseases also express a change in microbial signature characterized by firmicute depletion. However, the relationship between pulmonary bacteria and the mechanisms of downstream disease development has yet to be elucidated. We hypothesized that murine models of BPD would show heightened acetylated proline-glycine-proline (Ac-PGP) pathway and neutrophil activity, and through gain- and loss-of-function studies we show that Ac-PGP plays a critical role in driving BPD development. We further test a inhaled live biotherapeutic (LBP) using active Lactobacillus strains in in vitro and in vivo models of BPD and COPD. The Lactobacillus-based LBP is effective in improving lung structure and function, mitigating neutrophil influx, and reducing a broad swath of pro-inflammatory markers in these models of chronic pulmonary disease via the MMP-9/PGP (matrix metalloproteinase/proline-glycine-proline) pathway. Inhaled LBPs show promise in addressing common pathways of disease progression that in the future can be targeted in a variety of chronic lung diseases.

Clinical trial of a probiotic and herbal supplement for lung health.

Introduction: Dysbiosis of the gut microbiome may augment lung disease via the gut-lung axis. Proteobacteria may contribute to tissue proteolysis followed by neutrophil recruitment, lung tissue injury, and perpetuation of chronic inflammation. To study the effects of probiotics across the gut-lung axis, we sought to determine if a Lactobacillus probiotic and herbal blend was safe and well-tolerated in healthy volunteers and asthmatic patients. Methods: We conducted a 1-month randomized, open-label clinical trial in Cork, Ireland with healthy and asthmatic patients who took the blend twice a day. The primary endpoint was safety with exploratory endpoints including quality of life, lung function, gut microbiome ecology, and inflammatory biomarkers. Results: All subjects tolerated the blend without adverse events. Asthmatic subjects who took the blend showed significant improvements in lung function as measured by forced expiratory volume and serum short chain fatty acid levels from baseline to Week 4. The gut microbiome of asthmatic subjects differed significantly from controls, with the most prominent difference in the relative abundance of the proteobacteria Escherichia coli. Administration of the probiotic maintained overall microbial community architecture with the only significant difference being an increase in absolute abundance of the probiotic strains measured by strain-specific PCR. Conclusion: This study supports the safety and efficacy potential of a Lactobacillus probiotic plus herbal blend to act on the gut-lung axis. However, due to the lack of a control group, a longer blinded, placebo-controlled study will be warranted to confirm the efficacy improvements observed in this trial. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT05173168.

Impact of elexacaftor-tezacaftor-ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor-tezacaftor-ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF). METHODS: Lung function (FEV1 ), body mass index (BMI) and microbiologic data were collected at initiation and 3-month intervals for 1 year. Blood was analyzed at baseline and 6 months for cytokines and immune cell populations via flow cytometry and compared to non-CF controls. RESULTS: Sample size was 48 pwCF, 28 (58.3%) males with a mean age of 28.8 ± 10.7 years. Significant increases in %predicted FEV1 and BMI were observed through 6 months of ETI therapy with no change thereafter. Changes in FEV1 and BMI at 3 months were significantly correlated (r = 57.2, p < 0.01). There were significant reductions in Pseudomonas and Staphylococcus positivity (percent of total samples) in pwCF through 12 months of ETI treatment. Healthy controls (n = 20) had significantly lower levels of circulating neutrophils, interleukin (IL)-6, IL-8, and IL-17A and higher levels of IL-13 compared to pwCF at baseline (n = 48). After 6 months of ETI, pwCF had significant decreases in IL-8, IL-6, and IL-17A levels and normalization of peripheral blood immune cell composition. CONCLUSIONS: In pwCF, ETI significantly improved clinical outcomes, reduced systemic pro-inflammatory cytokines, and restored circulating immune cell composition after 6 months of therapy.

Microbial-induced Redox Imbalance in the Neonatal Lung Is Ameliorated by Live Biotherapeutics.

Bronchopulmonary dysplasia (BPD) is a common lung disease of premature infants. Hyperoxia exposure and microbial dysbiosis are contributors to BPD development. However, the mechanisms linking pulmonary microbial dysbiosis to worsening lung injury are unknown. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates oxidative stress responses and modulates hyperoxia-induced lung injury. We hypothesized that airway dysbiosis would attenuate Nrf2-dependent antioxidant function, resulting in a more severe phenotype of BPD. Here, we show that preterm infants with a Gammaproteobacteria-predominant dysbiosis have increased endotoxin in tracheal aspirates, and mice monocolonized with the representative Gammaproteobacteria Escherichia coli show increased tissue damage compared with germ-free (GF) control mice. Furthermore, we show Nrf2-deficient mice have worse lung structure and function after exposure to hyperoxia when the airway microbiome is augmented with E. coli. To confirm the disease-initiating potential of airway dysbiosis, we developed a novel humanized mouse model by colonizing GF mice with tracheal aspirates from human infants with or without severe BPD, producing gnotobiotic mice with BPD-associated and non-BPD-associated lung microbiomes. After hyperoxia exposure, BPD-associated mice demonstrated a more severe BPD phenotype and increased expression of Nrf2-regulated genes, compared with GF and non-BPD-associated mice. Furthermore, augmenting Nrf2-mediated antioxidant activity by supporting colonization with Lactobacillus species improved dysbiotic-augmented lung injury. Our results demonstrate that a lack of protective pulmonary microbiome signature attenuates an Nrf2-mediated antioxidant response, which is augmented by a respiratory probiotic blend. We anticipate antioxidant pathways will be major targets of future microbiome-based therapeutics for respiratory disease.

Efficacy of a Probiotic and Herbal Supplement in Models of Lung Inflammation.

BACKGROUND: Gut microbiome dysbiosis is associated with lung disease through the gut-lung axis. Abundant proteobacteria increase MMP-9 and contribute to tissue proteolysis followed by neutrophil recruitment, lung tissue injury, and perpetuation of chronic lung disease. We sought to determine if a scientifically formulated probiotic and herbal supplement could attenuate neutrophilic inflammation and improve lung structure and function in models of lung inflammation. METHODS: For in vitro experiments, epithelial cells exposed to proteobacteria were treated with resB-a blend of three probiotic Lactobacillus strains and turmeric, holy basil, and vasaka herbal extracts. For in vivo experimentation, mice exposed to pulmonary proteobacteria-derived lipopolysaccharide were treated by gavage with resB. RESULTS: In vitro, the bacterial and herbal components of resB decreased activity of the MMP-9 pathway. Mice exposed to LPS and pre- and post-treated with resB had decreased neutrophil recruitment and inflammatory biomarkers in bronchoalveolar lavage fluid, serum, and lung tissue compared to untreated mice. CONCLUSIONS: This study describes the mechanisms and efficacy of probiotic and herbal blend in pre-clinical models of lung injury and inflammation.

U.S. active-duty service women's urogenital health and operational readiness through the lens of the IBM-WASH model: A systematic integrative review.

AIM: Identify literature regarding urogenital health and hygiene practices/behaviors of U.S. active-duty service women (ADSW) with attention to environmental conditions; access to water, sanitation, and hygiene (WASH) resources in austere environments. Synthesize relationships among the 3-dimensions and 5-levels of the Integrated Behavioral Model for Water, Sanitation, and Hygiene (IBM-WASH). BACKGROUND: ADSW face sex-specific urogenital health challenges due to decreased access to WASH resources in austere environments, leading to increased risk for urogenital infection-related outcomes (urinary tract infections, vulvovaginal candidiasis, and bacterial vaginosis). During military conflicts in Afghanistan and Iraq, urogenital infections in ADSW were reported as one of the top five medical encounters, and one of the top seven reasons for medical evacuation. METHODS: A systematic review was performed in MEDLINE, CINAHL, Embase, and ClinicalTrials.gov databases, between January 2007-November 2021, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses as a reporting guideline. Eligible literature was evaluated utilizing the Johns Hopkins Research Evidence Appraisal Tool. WASH interactions were mapped using the IBM-WASH interactive matrix. RESULTS: Evidence gaps include shifting focus from "deployment" to environmental austerity; lack of training/education; shifting male-centric culture; and innovative technologies for safety/security. CONCLUSIONS: The IBM-WASH framework allowed for quantification and interpretation of complex interactions occurring in real world austere environments. Some could be overcome individually, but in aggregate they lead to progressive urogenital conditions and potential mission failure. Prevention, diagnosis, and treatment can mitigate disease sequelae. Preventive knowledge and access to innovative technologies designed for ease and private use are critical to preserve operational readiness.

Impact of type of health care provider on long term asthma control.

OBJECTIVE: Asthma prevalence is high and adherence to asthma guidelines is still less than adequate. The main objective of this study was to determine if there were significant differences in outcome measures if asthma care was provided per guidelines either by physicians (pediatric pulmonologists) or specialty trained advance practice nurses (APNs). METHODS: This was a three-year, prospective cohort study of children referred by their primary care providers to a tertiary care center for better asthma control. Patients were provided asthma care per NAEPP guidelines including asthma education. Results were compared over time and between patients followed by physicians or APNs. Alpha level of significance was ≤0.05. RESULTS: The sample included 471 children, ages 2-17 years (mean = 6.4 ± 2.4 years). Physicians and APN's provided asthma care. Of the 471 children enrolled in the study, 176 (37%) were followed for the full three-year study period. At the initial visit, physician group reported more short courses of oral steroids and more unscheduled visits to PCP for acute asthma care in the past 6 months compared to those followed by APNs (<0.05 for all). Among the total cohort and both subgroups, there were significant improvements in mean Asthma Control Test (ACT), acute care need and mean days/month with asthma symptoms over a three-year period (p < 0.05). There was significantly more improvement in use of oral steroids and urgent care visits in physician group (p < 0.05). CONCLUSION: When asthma guidelines are followed, improvements in asthma control are achieved in children in both the MD and APN groups.

Lessons learned in the development of a nurse-led family centered approach to developing a holistic comprehensive clinic and integrative holistic care plan for children with cerebral palsy.

CLINICAL PROBLEM: Children with cerebral palsy (CP) typically receive care from multiple specialty providers including Developmental Pediatrics, Orthopedics, Physical Medicine, Occupational Therapy, Physical Therapy, Speech Therapy, Clinical Social Work, Clinical Nutrition, Nursing and Orthotists, which often require many individual visits to the hospital annually. The potential for conflicting plans of care is increased by this fragmented approach, which may lead to duplication of services and increased healthcare costs. SOLUTION: To address the problem and alleviate burden for families, the Comprehensive Cerebral Palsy Program implemented a nurse-led comprehensive interdisciplinary team approach to provide optimal care coordination to patients and families, using an Integrative Holistic Care Plan (IHCP). During an annual 3-4 hour Comprehensive CP Clinic appointment, a team of specialists meets with the family, and a holistic, evidence-based plan of care is developed. The family-centered care plan includes summaries of each discipline's plan of care with individualized goals, recommendations, and evidence-based outcomes. After the visit, the plan of care is communicated with the family, primary care provider, and other community providers to ensure continuity of care. RESULTS: Early in the program and electronic IHCP development stage, clinical, and financial outcomes were improved. In addition to significant cost savings, family satisfaction surveys showed continuous improvement in the areas of access, communication, and coordination of care. PRACTICE IMPLICATIONS: Nurses working in interdisciplinary clinics are in a position to facilitate improved outcomes by developing and implementing a family-centered care plan that provides a comprehensive holistic approach to impacting the areas of quality, effectiveness, and efficiency of care delivery. The use of an IHCP decreases fragmentation of care and duplication of services leading to healthcare cost savings and enhanced patient satisfaction.

Impact of guideline adherence and race on asthma control in children.

BACKGROUND: Asthma control in African Americans (AA) is considered more difficult to achieve than in Caucasian Americans (CA). The aim of this study was to compare asthma control over time among AA and CA children whose asthma is managed per NAEPP (EPR-3) guidelines. METHODS: This was a one-year prospective study of children referred by their primary care physicians for better asthma care in a specialty asthma clinic. All children received asthma care per NAEPP guidelines. Results were compared between CA and AA children at baseline and then at three-month intervals for one year. RESULTS: Of the 345 children, ages 2-17 years (mean = 6.2 ± 4), 220 (63.8%) were CA and 125 (36.2%) were AA. There were no significant differences in demographics other than greater pet ownership in CA families. At baseline, AA children had significantly more visits to the Emergency Department for acute asthma symptoms (mean = 2.3 [Formula: see text] compared to CA (1.4 ± 2.3, P = 0.003). There were no other significant differences in acute care utilization, asthma symptoms (mean days/month), or mean asthma control test (ACT) scores at baseline. Within 3-6 months, in both groups, mean ACT scores, asthma symptoms and acute care utilization significantly improved (P < 0.05 for all) and change over time in both groups was comparable except for a significantly greater decrease in ED visits in AA children compared to CA children (P = 002). CONCLUSION: Overall, improvement in asthma control during longitudinal assessment was similar between AA and CA children because of  consistent use of NAEPP asthma care guidelines.

Use of a Pediatric Obesity Fall-risk Scale (POFS) in 301 hospitalized obese children and adolescents.

PURPOSE: Falls are a significant safety risk in hospitalized patients, but little evidence regarding their significance in obese children are available to date. Aim of the study was to determine whether the Pediatric Obesity Fall-risk Scale (POFS) is able to discriminate between hospitalized obese pediatric patients at high or low risk of falling, to evaluate its sensitivity and specificity and to analyze if the risk factors considered were actually related to the falling event. DESIGN AND METHODS: The sample consisted of 301 children and adolescents hospitalized for a body weight reduction program. In this 12-month study, 14.6% of patients experienced a fall during hospitalization, the fall rate per 1000 patient days being 5.33 for the first and 4.36 for the second 6-month of the year. The components of the POFS included chronological age, history of falls, body mass index standard deviation score (BMI-SDS), and the ability to maintain equilibrium. RESULTS: No differences were observed between fallers and nonfallers as far as BMI and BMI-SDS are concerned. Compared with patients who did not fall, those who fell were significantly younger and shorter and their weights were lower. The POFS identified 85 patients with high and 216 with low falling risk, the two subgroups being comparable for BMI and BMI-SDS. Compared with patients with low fall-risk, those with high fall-risk were significantly younger and shorter and their weights were lower. The sensitivity of the POFS was 61.4%, while the specificity was 77.4%. The positive predictive value of the POFS was 31.8%, while the negative predictive value was 92.1%. The analyses of each POFS component did not show significant differences between fallers and non-fallers in terms of BMI-SDS and equilibrium test. Compared with patients who did not fall, those who fell were significantly younger, experienced a fall during the 3 months prior the admission in hospital and their total POFS score was higher. PRACTICE IMPLICATIONS: Preventing falls in hospitalized obese pediatric patients is challenging due to the markedly increased risk of this population and specific fall-risk assessment tools are required to early identify patients who needs more care, attention, and specific nursing/medical interventions.

Impact of asthma severity on long-term asthma control.

Background: Asthma is a common childhood disease with significant morbidity. Severe asthma accounts for just 4-6% of patients, but this group is more difficult to treat and is responsible for up to 40% of asthma expenses.Objective: The relationship between asthma severity and control is not well characterized. The main objective of this study was to determine impact of asthma severity on asthma control over time.Methods: This was a three year, prospective observational cohort study at a tertiary care children's hospital. Results were compared over time and between patients with severe and non-severe persistent asthma. Intervention included therapy based on severity and control, accompanied by a NAEPP (EPR-3) guidelines based structured asthma education program.Results: The sample included 471 children referred from primary care offices with the diagnosis of persistent asthma, mean age 6.4 ± 2.4 years. Forty-one children (8.7%) had severe persistent asthma and 430 (91.3%) children had non-severe persistent asthma (mild-moderate persistent). Our sample size decreased over the three-year period and the number of patients completing the third year were 176 (38%) and among them 20 (11.4%) had severe asthma. At the initial visit, children with severe persistent asthma had significantly more acute care needs, more daily symptoms, and lower mean Asthma Control Test™ scores compared to children with non-severe persistent asthma. Differences between groups decreased within six months with significant improvements in most indicators persisting throughout three-year follow up in both groups (p < 0.05).Conclusion: Asthma control improves independent of severity if asthma guidelines are followed.

Transplantation and Adherence: Evaluating Tacrolimus Usage in Pediatric Patients With Cancer.

BACKGROUND: Researchers have estimated that about 50% of pediatric patients with chronic illness adhere to tacrolimus therapy, a medication responsible for preventing critical side effects in patients undergoing hematopoietic stem cell transplantation (HSCT). OBJECTIVES: The purpose of this study was to describe patient adherence to tacrolimus by reviewing documentation from the electronic health record and therapeutic drug levels. METHODS: This retrospective descriptive study examined 357 clinic visits by 57 patients undergoing HSCT. Direct (tacrolimus levels) and indirect (subjective reporting) measures were evaluated. FINDINGS: The authors found that, in 51% of visits, adherence was not documented. The overall nontherapeutic drug level rate was 60%. Because of the small sample size, nonadherence did not statistically correlate with nontherapeutic levels. The findings highlight the need for adherence awareness, assessment, and documentation in clinical practice.

Patterns of Growth and Nutrition From Birth to 6 Months in Infants With Complex Congenital Cardiac Defects.

BACKGROUND: Infants with complex congenital heart defects (CCHDs) experience alterations in growth that develop following surgical intervention and persist throughout early infancy, but the roles of nutritional intake and method of feeding require further exploration as their roles are not fully explained. OBJECTIVES: The purpose of this study was to characterize trends in growth and nutritional intake during the first 6 months of life in infants with CCHD. METHODS: We conducted a secondary analysis of growth and nutritional data from a pilot study designed to test the feasibility of nurse-guided participatory intervention with parents of infants with CCHD. Measures included demographic data, anthropometric data at birth, hospital discharge, and 6 months of age, nutritional intake at 2 and 6 months of age from parent-completed 24-hour nutrition diaries, and assessment of oral-motor skills between 1 and 2 months of age. Descriptive statistics and correlation and group differences were examined. RESULTS: Data for 28 infants were analyzed. Infants demonstrated a decrease in weight-for-age z score (WAZ) and length-for-age z score (LAZ) from birth to hospital discharge and an increase in WAZ and LAZ by 6 months of age. Many of the infants developed failure to thrive. Across the study period, one third of the infants were receiving enteral nutrition. Infants who were orally fed had better growth WAZ and LAZ at 6 months of age when compared to infants who were enterally fed. DISCUSSION: Infants with CCHD exhibit growth faltering throughout early infancy. Reliance on enteral nutrition did not improve growth outcomes in these infants. Findings suggest nutritional intake may not be enough to meet the nutrient requirements to stimulate catch-up growth.

The Medication Level Variability Index (MLVI) as a potential predictive biomarker of graft-versus-host disease in pediatric hematopoietic stem cell transplant patients.

The purpose of this study was to examine the potential predictive value of the Medication Level Variability Index (MLVI) biomarker with graft-versus-host disease (GVHD) in the pediatric hematopoietic stem cell transplant (HSCT) patient during the acute phase post-transplant. This retrospective descriptive study evaluated a total of 406 tacrolimus levels in 64 patients over a varying number of weeks per participant (median = 8, min = 3, max = 11). Patients were followed until Day 100 post-transplant or tacrolimus taper began. A total of 72 episodes of non-therapeutic levels occurred during the acute phase. Of those, 40 (56%) were <5, while 32 (44%) were >15. Approximately 39% (n = 25 of 64) of the participants in the study developed GVHD post-discharge. Those with GVHD had a statistically significantly higher MLVI than those that did not (median = 3.1, IQR = 2.5-4.7 vs 2.3, IQR = 1.6-3.4, respectively, P = 0.024). Using a criterion of MLVI > 3, there was a statistically significant increased likelihood of GVHD (OR = 3.82, 95% CI=1.32 = 11.04, P = 0.013). Area under the curve (AUC) calculation for the sensitivity and specificity of using the MLVI for GVHD was also conducted. The AUC of 0.67 was statistically significant (95% CI 0.53-0.81, P = 0.024). This is the first-known study to report the use of the MLVI in HSCT patients. The MLVI is associated with a main adverse outcome related to HSCT, GVHD. These results are encouraging of a new potential biomarker to evaluate tacrolimus serum assay levels and identify patients at risk for developing GVHD.

A Novel Approach to Assessing Head Injury Severity in Pediatric Patient Falls.

INTRODUCTION: Pediatric patient falls with head-to-floor impact have the greatest potential for injury. METHODS: An objective measure of head injury severity, the Head Injury Criterion (HIC15), was calculated from anthropometric and biomechanical components of patient falls. A secondary aim was to compare HIC15 levels with the hospital's subjective assignment of level of harm (1-9 scale) used for regulatory reports. RESULTS: Adverse event reports yielded a sample of 49 falls from heights of 72.5 to 1793.0 cm by children ages 11 months through 17 years. Contact velocity from beginning to end was 2.81 to 6.16 ms. Mean acceleration was 19.5 to 95.3g. HIC15 levels of impact ranged from 26.4 to 1,330.0, and mean force upon contact was 2.0 to 9.8 N/kg body mass. Seven (14.3%) children's HIC15 levels exceeded age-specific thresholds, with no follow-up scheduled. Hospital-assigned levels of harm were not correlated with HIC15 levels (r = .23, R2 = .05, p = .12). DISCUSSION: A point-of-care computerized HIC15 algorithm would be useful for diagnostic and follow-up decisions.

Erratum to: Racial differences in pet ownership in families of children with asthma.

In the article by Sheikh SI, et al, "Racial differences in pet ownership in families of children with asthma" in World Journal of Pediatrics 2016;12(3):343-346 (doi: 10.1007/s12519-016-0027-9), the last author's name was incorrectly listed as "Don Hayes". His name should have read "Don Hayes Jr".