Estimating seasonal onsets and peaks of bronchiolitis with spatially and temporally uncertain data.

RSV bronchiolitis (an acute lower respiratory tract viral infection in infants) is the most common cause of infant hospitalizations in the United States (US). The only preventive intervention currently available is monthly injections of immunoprophylaxis. However, this treatment is expensive and needs to be administered simultaneously with seasonal bronchiolitis cycles in order to be effective. To increase our understanding of bronchiolitis timing, this research focuses on identifying seasonal bronchiolitis cycles (start times, peaks, and declinations) throughout the continental US using data on infant bronchiolitis cases from the US Military Health System Data Repository. Because this data involved highly personal information, the bronchiolitis dates in the dataset were "jittered" in the sense that the recorded dates were randomized within a time window of the true date. Hence, we develop a statistical change point model that estimates spatially varying seasonal bronchiolitis cycles while accounting for the purposefully introduced jittering in the data. Additionally, by including temperature and humidity data as regressors, we identify a relationship between bronchiolitis seasonality and climate. We found that, in general, bronchiolitis seasons begin earlier and are longer in the southeastern states compared to the western states with peak times lasting approximately 1 month nationwide.

Seasonal patterns of Asthma medication fills among diverse populations of the United States.

OBJECTIVE: Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity. METHODS: We conducted a retrospective cohort study of asthmatics 4-50 years of age and enrolled in three diverse health insurance plans. Seasonal patterns of medications were reported by monthly prescription fill rates per 1000 individuals with asthma from 1998 to 2013, and stratified by healthcare plan, sex, and age. RESULTS: There was a distinct and consistent seasonal fill pattern for all asthma medications. The lowest fill rate was observed in the month of July. Fills increased in the autumn and remained high throughout the winter and spring. Compared with the month of May with high medication fills, July represented a relative decrease of fills ranging from 13% (rate ratio, RR: 0.87, 95% confidence interval, 95%CI: 0.72-1.04) for the combination of inhaled corticosteroids (ICS) + long acting beta agonists (LABA) to 45% (RR: 0.55, 95%CI: 0.49-0.61) for oral corticosteroids. Such a seasonal pattern was observed each year across the 16-year study period, among healthcare plans, sexes, and ages. LABA containing control medication (ICS+LABA and LABA) fill rates were more prevalent in older asthmatics, while leukotriene receptor antagonists were more prevalent in the younger population. CONCLUSIONS: A seasonal pattern of asthma medication fill rates likely represents a reactive response to a loss of disease control and increased symptoms. Adherence to and consistent use of asthma medications among individuals who use medications in reaction to seasonal exacerbations might be a key component in reducing the risk of asthma exacerbations.

Validation of International Classification of Diseases criteria to identify severe influenza hospitalizations.

In this cohort study of hospitalized patients with linked medical record data, we developed International Classification of Diseases (ICD) criteria that accurately identified laboratory-confirmed, severe influenza hospitalizations (positive predictive value [PPV] 80%, 95% confidence interval [CI] 71-87%), which we validated through medical record documentation. These criteria identify patients with clinically important influenza illness outcomes to inform evaluation of preventive and therapeutic interventions and public health policy recommendations.

Risks from Breathing Elevated Oxygen.

INTRODUCTION: Effects of breathing gas with elevated oxygen partial pressure (Po2) and/or elevated inspired oxygen fraction (FIo2) at sea level or higher is discussed. High FIo2 is associated with absorption problems in the lungs, middle ear, and paranasal sinuses, particularly if FIo2 > 80% and small airways, Eustachian tubes, or sinus passages are blocked. Absorption becomes faster as cabin altitude increases. Pulmonary oxygen toxicity and direct oxidative injuries, related to elevated Po2, are improbable in flight; no pulmonary oxygen toxicity has been found when Po2 < 55 kPa [418 Torr; 100% O2 higher than 15,000 ft (4570 m)]. Symptoms with Po2 of 75 kPa [520 Torr; 100% O2 at 10,000 ft (3050 m)] were reported after 24 h and the earliest signs at Po2 of 100 kPa (760 Torr, 100% O2 at sea level) occurred after 6 h. However, treatment for decompression sickness entails a risk of pulmonary oxygen toxicity. Elevated Po2 also constricts blood vessels, changes blood pressure control, and reduces the response to low blood sugar. With healthy lungs, gas transport and oxygen delivery are not improved by increasing Po2. Near zero humidity of the breathing gas in which oxygen is delivered may predispose susceptible individuals to bronchoconstriction.Shykoff BE, Lee RL. Risks from breathing elevated oxygen. Aerosp Med Hum Perform. 2019; 90(12):1041-1049.

Reduced thioredoxin increases proinflammatory cytokines and neutrophil influx in rat airways: modulation by airway mucus.

Thioredoxin (Trx) decreases viscosity of cystic fibrosis (CF) sputum. In this study reduced Trx increased the solubility and decreased the size of MUC5B glycoprotein while reducing disulfide bonds in sputum. Because Trx used as a mucolytic would enter airways, this study determined the effects of intratracheal instillation of reduced recombinant human thioredoxin (rhTrx) in naïve rat airways. Reduced rhTrx increased neutrophils and the cytokines TNFalpha, CINC2beta, and MIP3alpha in airways after 4 h. The effect of rhTrx was concentration-dependent. Exposure to saline, human serum albumin, or oxidized rhTrx at equal molarities did not increase airway neutrophils or cytokines. Instilling CF sputum (50 microl) into the lung before reduced rhTrx delivery attenuated these responses. This suggests that rhTrx reduces disulfide bonds present in CF sputum, limiting the reduction of other lung constituents. Together these findings indicate that the chemotactic and cytokine responses are due to the reducing potential of rhTrx and that the potential for inflammation in non-CF and CF patients given aerosolized rhTrx may differ. In parallel studies, increased amounts of the p65 subunit of NF-kappaB were present in nuclear extracts from rat lungs administered reduced rhTrx, suggesting a role for NF-kappaB in these proinflammatory responses.

The economic burden of spinal muscular atrophy.

AIM: To evaluate the economic burden of spinal muscular atrophy (SMA). MATERIALS AND METHODS: This study used Department of Defense Military Healthcare System (MHS) data from 2003-2012. Healthcare costs were determined for patients with at least one inpatient or three outpatient claims with a diagnosis of SMA before 18 years of age and who had ≥ 6 months of data after first SMA diagnosis or expired within 6 months of initial diagnosis. A comparator cohort was selected using a 3:1 match based on age and gender. RESULTS: A total of 239 individuals with SMA diagnosis met the inclusion criteria along with 717 matched comparator patients. More patients with SMA had hospitalizations (69.5%) compared to the comparator cohort (17.2%, p < 0.001). Median total expenditures across all years of data for patients with SMA were $83 652 (25-75th percentile = $29 620-228 754) vs the comparator group of $4329 (25-75(th) percentile = $1229-10 062 (p < 0.001)) over an average (SD) of 6.9 ± 3.6 years. The annualized mean costs of total healthcare expenditures were significantly higher for the SMA cases than the comparison cohort, $47 862 ± 88 607 compared to $1861 ± 6374, respectively (p < 0.001). The sub-group of patients with early diagnosis (n = 45) had 4.3 ± 2.9 years of observation with a median cost of $167 921 ($53 349-678 412). Mean age (SD) at first observed SMA diagnosis was 7.5 ± 6.4 years. Mean (SD) duration of follow-up after initial SMA diagnosis was 4.8 ± 3.3 years, with a median post-diagnosis cost of $60 213 ($18 229-192 559). The major costs for all patients were outpatient visits [median = $53 152 ($23 902-136 150)], followed by inpatient costs [median = $11 258 ($0-51 987)] and total prescription costs [median = $3167 ($943-13 283)]. LIMITATIONS: The analysis is limited to the data available and may under-estimate the total cost of SMA. CONCLUSIONS: Individuals with SMA have a high degree of morbidity, particularly those diagnosed during infancy. SMA patients have significant medical expenditures and high utilization of healthcare services.

Thioredoxin and dihydrolipoic acid inhibit elastase activity in cystic fibrosis sputum.

Excessive neutrophil elastase activity within airways of cystic fibrosis (CF) patients results in progressive lung damage. Disruption of disulfide bonds on elastase by reducing agents may modify its enzymatic activity. Three naturally occurring dithiol reducing systems were examined for their effects on elastase activity: 1) Escherichia coli thioredoxin (Trx) system, 2) recombinant human thioredoxin (rhTrx) system, and 3) dihydrolipoic acid (DHLA). The Trx systems consisted of Trx, Trx reductase, and NADPH. As shown by spectrophotometric assay of elastase activity, the two Trx systems and DHLA inhibited purified human neutrophil elastase as well as the elastolytic activity present in the soluble phase (sol) of CF sputum. Removal of any of the three Trx system constituents prevented inhibition. Compared with the monothiols N-acetylcysteine and reduced glutathione, the dithiols displayed greater elastase inhibition. To streamline Trx as an investigational tool, a stable reduced form of rhTrx was synthesized and used as a single component. Reduced rhTrx inhibited purified elastase and CF sputum sol elastase without NADPH or Trx reductase. Because Trx and DHLA have mucolytic effects, we investigated changes in elastase activity after mucolytic treatment. Unprocessed CF sputum was directly treated with reduced rhTrx, the Trx system, DHLA, or DNase. The Trx system and DHLA did not increase elastase activity, whereas reduced rhTrx treatment increased sol elastase activity by 60%. By contrast, the elastase activity after DNase treatment increased by 190%. The ability of Trx and DHLA to limit elastase activity combined with their mucolytic effects makes these compounds potential therapies for CF.