Dose-response Slope Research Articles

How Much Physical Activity Is Needed for 75 Year and Older Adults: Using NHANES Datasets

<i>Targets</i>: To examine the amount/level of Physical Activity (PA) needed to generate the most health benefits in noninstitutionalized 75 year and older U.S. resident adults. Intervention description: A total of 598 sample participants aged 75 year and above from National Health And Nutrition Examination Survey (NHANES) 2005-2006 datasets were included. Actigraph-monitored daily step counts, self-reported PA duration (time spent in weekly PA) and weekly energy expenditure were used to describe PA level/amount. Functional ability was expressed using the total levels of difficulties in doing twenty-one types of daily activities. PRISM Dose-response Curves Stimulation Variable slope model was applied to examine the needed PA level/amount in the population. <i>Mechanisms of action</i>: PA benefits functional health in 75 year and older adults. Older females aged 75- 84 year need at least 150 mins/ 800 kcal energy expenditure per week or 5,800 daily steps to reach the most functional benefits. Older men aged 75-84 year need walk about 5,800 steps/day to achieve higher level of functionality. Older adults aged 85 years and above need to spend about 240 minutes/week on PA to gain health benefits. <i>Outcomes</i>: Older males generally need/engage in more amount of PA compared to their female counterparts. Between 75-84 year old male and female adults, PA intensity is more important/reflective in male for expressing PA amount, while time spent in PA is more meaningful to older females. There is no difference in needed PA amount between different genders in 85 year and older adults.

Bronchial reactivity and asthma at school age after early-life metapneumovirus infection.

The association between early-life lower respiratory tract infection (LRTI) and asthma is well established. Knowledge about bronchial hyperresponsiveness (BHR) and asthma after metapneumovirus (MPV) LRTI is scarce. The aim of this study was to assess BHR and current asthma in school-aged children after hospital admission for early-life LRTI with MPV, and to compare with more well-known viruses, rhinovirus (RV) and respiratory syncytial virus (RSV), and with controls. A cohort consisting of children admitted for LRTI and controls was followed-up at school age with a clinical research assessment and lung function tests, including a methacholine provocation test. Current asthma was defined based on objective variable airway obstruction and clinical symptoms. BHR and asthma were compared according to viral groups. 135 children (median age 9.3 years) were included (16 MPV, 34 RV, 51 RSV, 13 mixed infections and 21 controls). Compared with controls there was increased BHR after MPV and RV LRTI (provocative dose causing a 20% fall in forced expiratory volume in 1 s and dose-response slope; p<0.05). Using Kaplan-Meier statistics, BHR was increased for MPV compared with both controls and RSV (p=0.02 and p=0.01). The proportion of children with current asthma at follow-up was higher in the LRTI children compared with the controls (46% versus 24%; p=0.06). Among children who had undergone MPV and RV infection, 50% fulfilled the asthma criteria compared with 43% in the RSV group (p=0.37). We found increased BHR and a high prevalence of asthma in school-aged children after early-life MPV infection, and findings were similar to RV, and less to RSV, compared with controls.

The metabolic cost of inspiratory muscle training in mechanically ventilated patients in critical care

BackgroundDiaphragmatic dysfunction is well documented in patients receiving mechanical ventilation. Inspiratory muscle training (IMT) has been used to facilitate weaning by strengthening the inspiratory muscles, yet the optimal approach remains uncertain. Whilst some data on the metabolic response to whole body exercise in critical care exist, the metabolic response to IMT in critical care is yet to be investigated. This study aimed to quantify the metabolic response to IMT in critical care and its relationship to physiological variables.MethodsWe conducted a prospective observational study on mechanically ventilated patients ventilated for ≥ 72 h and able to participate in IMT in a medical, surgical, and cardiothoracic intensive care unit. 76 measurements were taken on 26 patients performing IMT using an inspiratory threshold loading device at 4 cmH2O, and at 30, 50 and 80% of their negative inspiratory force (NIF). Oxygen consumption (VO2) was measured continuously using indirect calorimetry.ResultsFirst session mean (SD) VO2 was 276 (86) ml/min at baseline, significantly increasing to 321 (93) ml/min, 333 (92) ml/min, 351(101) ml/min and 388 (98) ml/min after IMT at 4 cmH2O and 30, 50 and 80% NIF, respectively (p = 0.003). Post hoc comparisons revealed significant differences in VO2 between baseline and 50% NIF and baseline and 80% NIF (p = 0.048 and p = 0.001, respectively). VO2 increased by 9.3 ml/min for every 1 cmH2O increase in inspiratory load from IMT. Every increase in P/F ratio of 1 decreased the intercept VO2 by 0.41 ml/min (CI − 0.58 to − 0.24 p < 0.001). NIF had a significant effect on the intercept and slope, with every 1 cmH2O increase in NIF increasing intercept VO2 by 3.28 ml/min (CI 1.98–4.59 p < 0.001) and decreasing the dose–response slope by 0.15 ml/min/cmH2O (CI − 0.24 to − 0.05 p = 0.002).ConclusionsIMT causes a significant load-dependent increase in VO2. P/F ratio and NIF impact baseline VO2. The dose–response relationship of the applied respiratory load during IMT is modulated by respiratory strength. These data may offer a novel approach to prescription of IMT.Take home messageThe optimal approach to IMT in ICU is uncertain; we measured VO2 at different applied respiratory loads to assess whether VO2 increased proportionally with load and found VO2 increased by 9.3 ml/min for every 1 cmH2O increase in inspiratory load from IMT. Baseline NIF has a significant effect on the intercept and slope, participants with a higher baseline NIF have a higher resting VO2 but a less pronounced increase in VO2 as the inspiratory load increases; this may offer a novel approach to IMT prescription.Trial registration ClinicalTrials.gov, registration number: NCT05101850. Registered on 28 September 2021, https://clinicaltrials.gov/ct2/show/NCT05101850

Monitoring Direct Thrombin Inhibitors With Calibrated Diluted Thrombin Time vs Activated Partial Thromboplastin Time in Pediatric Patients.

Activated partial thromboplastin time (aPTT) is the primary test used to monitor intravenous (IV) direct thrombin inhibitors (DTIs) but has many limitations. The plasma diluted thrombin time (dTT) has shown better correlation with DTI levels than aPTT. This study compared dose-response curves for dTT and aPTT in pediatric patients receiving argatroban and bivalirudin. A retrospective review of pediatric patients treated with argatroban (n = 45) or bivalirudin (n = 14) monitored with dTT and aPTT. The dTT assay was calibrated to report DTI concentrations in µg/mL for argatroban and bivalirudin with good analytic sensitivity and specificity. The dTT was fivefold more likely to show a stable dose-response slope than the aPTT (P < .0002; odds ratio, 4.9). For patients in whom both dTT and aPTT showed a significant correlation between dose and assay results, dTT had a higher average correlation factor compared with aPTT (P = .007). Argatroban dose-response slopes showed more inter- and intrapatient variation than bivalirudin (dose-response slope coefficient of variation, 132% vs 52%). The dTT assay was more likely to show a stable dose response and have a stronger correlation with DTI dose than aPTT. Argatroban shows more variation in dose response than bivalirudin.

Abstract 11237: Dose Response and Long QT Genotype During Exercise Stress Testing in Children

Introduction: Beta-blockers (BB) are first-line therapy for long QT syndrome (LQTS). Many physicians rely on repeated exercise stress tests (ESTs) to establish the optimal dose in each patient. Hypothesis: Increased BB dose is associated with a decrease in maximum heart rate, influenced by precision-medicine factors including genotype. Methods: Retrospective chart review of treadmill ESTs with the outcome variable “% predicted heart rate (HR)” = (maximum HR achieved/(220-age))*100. Genotype positive patients had pathogenic or likely pathogenic variants, re-adjudicated in 2022. Doses of BB other than nadolol were converted to nadolol equivalents using an established methodology. Results: We evaluated 345 ESTs in 132 LQTS patients (58% genotype positive) from 2003-21. The mean age at first EST was 12.5 years (standard deviation 4.0 years). Most patients were prescribed nadolol (59%) or atenolol (28%). When controlled for person-level fixed effects, we observed an inverse relationship between BB dose and % predicted HR. The dose-response slope was steeper in genotype positive patients than genotype negative patients (-4.8 vs. -3.3, Figure , p&lt;0.01). We observed mild decreases in blood pressure as BB dose increased, (mean 5 mmHg decrease in systolic blood pressure per 1 mg/kg increase in BB). However, neither maximum VO2 nor maximum respiratory exchange ratio were affected by increased BB dose (the slope of each was indistinguishable from 0 in person-level fixed effects models). Conclusion: In children with LQTS, genotype positive patients were more sensitive to BB than genotype negative patients. We developed a multivariate model to predict the dose of BB required to achieve therapeutic beta-blockade, conditional on individual patient demographics and genotype. The model may decrease the need for serial ESTs. BB dose did not affect maximum VO2 or respiratory exchange ratio, which is reassuring for children and adolescents with LQTS who exercise.

Functional MRI radiomics-based assessment of pelvic bone marrow changes after concurrent chemoradiotherapy for cervical cancer

ObjectivesTo quantify the dose-response relationship of changes in pelvic bone marrow (PBM) functional MR radiomic features (RF) during concurrent chemoradiotherapy (CCRT) for patients with cervical cancer and establish the correlation with hematologic toxicity to provide a basis for PBM sparing.MethodsA total of 54 cervical cancer patients who received CCRT were studied retrospectively. Patients underwent MRI IDEAL IQ and T2 fat suppression (T2fs) scanning pre- and post-CCRT. The PBM RFs were extracted from each region of interest at dose gradients of 5–10 Gy, 10–15 Gy, 15–20 Gy, 20–30 Gy, 30–40 Gy, 40–50 Gy, and > 50 Gy, and changes in peripheral blood cell (PBC) counts during radiotherapy were assessed. The dose-response relationship of RF changes and their correlation with PBC changes were investigated.ResultsWhite blood cell, neutrophils (ANC) and lymphocyte counts during treatment were decreased by 49.4%, 41.4%, and 76.3%, respectively. Most firstorder features exhibited a significant dose-response relationship, particularly FatFrac IDEAL IQ, which had a maximum dose-response curve slope of 10.09, and WATER IDEAL IQ had a slope of − 7.93. The firstorder-Range in FAT IDEAL IQ and firstorder-10Percentile in T2fs, showed a significant correlation between the changes in ANC counts under the low dose gradient of 5–10 Gy (r = 0.744, -0.654, respectively, p < 0.05).ConclusionFunctional MR radiomics can detect microscopic changes in PBM at various dose gradients and provide an objective reference for bone marrow sparing and dose limitation in cervical cancer CCRT.

Risk of Cerebrovascular Events among Childhood and Adolescent Patients Receiving Cranial Radiotherapy: A PENTEC Normal Tissue Outcomes Comprehensive Review

<h3>Purpose/Objective(s)</h3> Radiation (RT)-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. Although multiple retrospective series and case reports discuss the association between cranial RT in children and subsequent cerebral vasculopathy, useful dose-response data to guide practitioners in the counseling or prevention of these events is lacking. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial RT. This report presents our updated modeling results which will be the basis for our PENTEC publication. <h3>Materials/Methods</h3> A literature search was performed for studies reporting pediatric RT associated cerebral vasculopathy. When available, we utilized individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose. <h3>Results</h3> The search identified 766 abstracts, five of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack (TIA), stroke, <i>Moyamoya</i>, or arteriopathy. Logistic model parameters with 95% confidence intervals were: dose for 50% response (D50 = 75.6 Gy; 68.4-89.4 Gy) and normalized dose-response slope at D50 (γ50 = 2.69; 2.05–3.60). For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9-1.3%, 1.8-2.7%, and 2.8-4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared to a baseline risk of 0.2-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1-4.2%, 4.5-8.6%, and 6.7-13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared to a baseline risk of 0.5-1.0%). <h3>Conclusion</h3> The risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. Further, since the stroke hazard was based on prescribed dose rather than CW dose our reported stroke risk is likely underestimated. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population.

Altered Insulin Clearance after Gastric Bypass and Sleeve Gastrectomy in the Fasting and Prandial Conditions.

Background: The liver has the capacity to regulate glucose metabolism by altering the insulin clearance rate (ICR). The decreased fasting insulin concentrations and enhanced prandial hyperinsulinemia after Roux-en-Y gastric-bypass (GB) surgery and sleeve gastrectomy (SG) are well documented. Here, we investigated the effect of GB or SG on insulin kinetics in the fasting and fed states. Method: ICR was measured (i) during a mixed-meal test (MMT) in obese non-diabetic GB (n = 9) and SG (n = 7) subjects and (ii) during a MMT combined with a hyperinsulinemic hypoglycemic clamp in the same GB and SG subjects. Five BMI-matched and non-diabetic subjects served as age-matched non-operated controls (CN). Results: The enhanced ICR during the fasting state after GB and SC compared with CN (p < 0.05) was mainly attributed to augmented hepatic insulin clearance rather than non-liver organs. The dose-response slope of the total insulin extraction rate (InsExt) of exogenous insulin per circulatory insulin value was greater in the GB and SG subjects than in the CN subjects, despite the similar peripheral insulin sensitivity among the three groups. Compared to the SG or the CN subjects, the GB subjects had greater prandial insulin secretion (ISR), independent of glycemic levels. The larger post-meal ISR following GB compared with SG was associated with a greater InsExt until it reached a plateau, leading to a similar reduction in meal-induced ICR among the GB and SG subjects. Conclusions: GB and SG alter ICR in the presence or absence of meal stimulus. Further, altered ICR after bariatric surgery results from changes in hepatic insulin clearance and not from a change in peripheral insulin sensitivity.

Current status of resistance to ivermectin in Rhipicephalus sanguineus sensu stricto infesting dogs in three provinces in Argentina.

Intensive use of macrocyclic lactones for parasite control exerts strong selective pressure for arthropods such as ticks to become resistant to them. Rhipicephalus sanguineus sensu stricto is a tick and disease vector of significant public health and veterinary importance worldwide. We assessed the toxicological response to the macrocyclic lactone ivermectin (IVM) in R. sanguineus s.s. infesting dogs in Argentina. Samples of nine tick populations were obtained by inspecting dogs at veterinary clinics, hospitals, or rural areas in the provinces of San Luis, Rio Negro, and Buenos Aires. Pet owners were interviewed to gather data on the history of dog treatment with ectoparasiticides. The larval immersion test was used to assess the toxicological response of R. sanguineus s.s. to IVM. Dose-response mortality regressions, lethal concentrations (LC), and slope were calculated by probit analysis. The lowest LC concentrations were used to designate the reference susceptible population because a laboratory reference strain of R. sanguineus s.s. does not exist in Argentina. Compared with the most susceptible tick population in this study, six populations (66.66%) were classified as resistant to IVM. A clear interpopulation variation in the level of IVM resistance was present (resistance ratios at LC50% ranged from 1.0 to 18.33 and at LC99% ranged from 1.0 to 8.96). In San Luis Province, all tick populations were classified as resistant. The highest level of IVM resistance (resistance ratio at LC50%:18.83 and LC99%:8.96) was found in a population of R. sanguineus s.s. from a rural area in the province of Buenos Aires. It is concluded that populations of R. sanguineus s.s. from dogs in three provinces of Argentina were resistant to IVM. Clear interpopulation variation in the level of IVM resistance was present.

Asthma Phenotypes and Host Risk Factors Associated With Various Asthma-Related Outcomes in Health Workers.

Background: Work-related asthma phenotypes in health workers (HWs) exposed to cleaning agents have not been investigated extensively as other occupational exposures. This study aimed to describe asthma phenotypes and to identify important host risk factors associated with various asthma-related outcomes.Methods: A cross-sectional study of 699 HWs was conducted in two large tertiary hospitals. A total of 697 HWs completed questionnaire interviews. Sera collected from 682 HWs were analyzed for atopy (Phadiatop) and IgE to occupational allergens (NRL—Hev b5, Hev b6.02; chlorhexidine and ortho-phthalaldehyde—OPA). Methacholine (MCT), bronchodilator challenge (BDR) and fractional exhaled nitric oxide (FeNO) were performed. An asthma symptom score (ASS) used five asthma-related symptoms reported in the past 12 months. Current asthma was based on use of asthma medication or an asthma attack or being woken up by an attack of shortness of breath in the past 12 months. Nonspecific bronchial hyperresponsiveness (NSBH) was defined as having either a positive MCT or a significant bronchodilator response. Two continuous indices of NSBH [continuous index of responsiveness (CIR) and dose-response slope (DRS)] were calculated.Results: The prevalence of current asthma was 10%, atopic asthma (6%) and non-atopic asthma (4%). Overall, 2% of subjects had work-related asthma. There was a weak positive association between NSBH and FeNO [CIR: Beta coefficient (β) = 0.12; CI: 0.03–0.22 and DRS: β = 0.07; CI: 0.03–0.12]. Combining FeNO ≥ 50 ppb with a BDR [mean ratio (MR) = 5.89; CI: 1.02–34.14] or with NSBH (MR = 4.62; CI: 1.16–18.46) correlated better with ASS than FeNO alone (MR = 2.23; CI: 1.30–3.85). HWs with current asthma were twice as likely to be atopic. FeNO was positively associated with atopy (OR = 3.19; CI: 1.59–6.39) but negatively associated with smoking status (GMR = 0.76; CI: 0.62–0.94). Most HWs sensitized to occupational allergens were atopic.Conclusion: Atopic asthma was more prevalent than non-atopic asthma in HWs. Most asthma-related outcomes were positively associated with allergic predictors suggesting a dominant role for IgE mechanisms for work-related symptoms and asthma associated with sensitization to OPA or chlorhexidine.

How safe are gloves and masks used for protection against Legionella longbeachae infection when gardening?

Legionella longbeachae has been frequently identified in composted plant material and can cause Legionnaires' disease (LD). We wanted to determine how frequently L. longbeachae DNA was present on gardeners' gloves, and how long L. longbeachae could persist on inoculated gloves and masks. Volunteers completed a survey of gardening practices and their gardening gloves were tested for L. longbeachae DNA by qPCR. The persistence of viable L. longbeachae was assessed by timed subcultures after inoculation of gardening gloves and masks. Gloves but not masks were used regularly. L. longbeachae was detected on 11 (14%; 95% CI 8-24%) gloves. Viable organisms were recovered from 25-50% of inoculated cotton, leather and PU coated gloves but not rubber gloves after 8h incubation. There was a difference in dose-response curve slopes by glove material (P=0·001) and time to 50% sterility (P=0·036). There were differences in persistence of L. longbeachae between mask types from analysis of the slopes and 50% sterility on the decay curves (P=0·042, P<0·001 respectively). Gardening gloves and masks may act as a vector for transmission of L. longbeachae during gardening. Washing gardening gloves and prompt disposal of masks could reduce risk of LD.

A New Bitterness Evaluation Index Obtained Using the Taste Sensor for 48 Active Pharmaceutical Ingredients of Pediatric Medicines.

The aim of this study was to evaluate bitterness by using "CCDP; Change in concentration-dependent potential" considering dose-dependency of active pharmaceutical ingredients (APIs) as new and useful bitterness evaluation index compared with bitter sensor output value which is conventional bitterness evaluation index for 48 pediatric medicines from the recent edition of the WHO model list of essential medicines for children (7th edn, 2019). Solutions (0.01, 0.03, 0.1 mM) of the compounds were evaluated by an artificial taste sensor using membranes sensitive to bitterness. The dose-response slope of the sensor outputs was defined as CCDP. On the basis of principal component analysis of CCDPs, chlorpromazine hydrochloride, amitriptyline hydrochloride, propranolol hydrochloride, primaquine phosphate and haloperidol were predicted to express the strongest levels of basic bitterness, surpassing that of quinine hydrochloride. Correlation analysis (Fisher's exact tests and multiple regression analysis) was performed to determine the relation between CCDPs and various physicochemical properties participated in hydrophilicity and hydrophobicity. It is revealed that contribution physicochemical factors are different by individual basic bitterness sensor (AC0, AN0 or BT0), and this result becomes the criterion of the sensor choice to evaluate basic bitterness intensity using basic bitterness sensors. Hydrophobic and hydrophilic interactions could be simulated by ligand docking modeling for haloperidol, miconazole and quinine hydrochloride. The pharmaceutical products need a bitterness evaluation in consideration of concentration-dependency to vary in a dose depending on a patient individual. Thus, it was concluded that CCDP correlated to hydrophilicity and hydrophobicity is useful as a bitterness evaluation index of APIs in pediatric medicines.

Effects of encapsulation on the chemical inhibition of anaerobic hydrogen- and methane-producing microbial cells

Encapsulating microbial cells in an alginate matrix enables high-rate anaerobic biological treatment and resource recovery by increasing cell concentration and retention time. To determine whether encapsulation protected microbial cells from inhibitors, copper(II), chromium(VI) (as dichromate), ammonium, and chloroform were amended to hydrogen-producing anaerobic microbial cells that were either suspended or encapsulated in a composite-coated alginate matrix. Encapsulation mitigated dichromate inhibition by 36% based on the dose-response curve slope but increased ammonium inhibition by 210% and had no effect on inhibition by chloroform. This was explained by effective concentrations in the beads after measuring partition coefficients. Encapsulation rendered copper(II) unavailable through apparent chelation because it protected both the hydrogen-producing and a methane-producing community from copper(II) despite its high effective concentration in encapsulation. Understanding the effects that the encapsulation of microbial cells has on chemical inhibition can help expand the application conditions of wastewater treatment or resource recovery and avoid unanticipated toxicity.

The effect of deep inhalation on mannitol responsiveness.

Mannitol inhalation testing is specific for asthmatics with eosinophilic airway inflammation, a factor that has been negatively correlated with the development of deep inhalation bronchoprotection. To evaluate the effect of deep inhalations on responsiveness to inhaled mannitol in correlation with the degree of airway inflammation. Twenty participants with stable asthma completed this randomized, crossover study. A screening visit assessed responsiveness to methacholine and airway inflammation through fractional exhaled nitric oxide (FeNO) measures and sputum induction. Participants next completed two mannitol challenges, one with deep inhalations (standard method) and one with inhalations to half of total lung capacity, and two methacholine challenges, one with tidal breathing (standard method) and one with deep inhalations. Only the inhalation technique for dose administration differed between repeat mannitol or methacholine challenges. Deep inhalations did not significantly influence the provocative dose of mannitol causing a 15% fall in forced expiratory volume in 1second ((P=.73; n=7) or the mannitol dose-response slope (P=.26; n=20). Deep inhalations produced significant bronchoprotection against methacholine (P=.03; n=20). FeNO levels were significantly correlated to sputum eosinophilia (P=.02; n=15), responsiveness to deep inhalation methacholine (P=.005; n=20), the dose-response slopes from deep inhalation mannitol (P=.01; n=20), and the dose-response slope from non-deep inhalation mannitol (P=.005; n=20). Deep inhalations did not produce significant bronchoprotection against inhaled mannitol. This result is in agreement with past findings linking airway inflammation with loss of deep inhalation bronchoprotection. This study was prospectively registered on clinicaltrials.gov (NCT03505489).

Lung function and bronchial hyper-reactivity from 11 to 18years in children with bronchiolitis in infancy.

Various trajectories for lung function and bronchial hyper-reactivity (BHR) from early childhood to adulthood are described, including puberty as a period with excessive lung growth. Bronchiolitis in infancy may be associated with increased risk of developing chronic obstructive pulmonary disease, but the development of respiratory patterns during puberty is poorly characterized for these children. We aimed to study the development and trajectories of lung function and BHR from 11 to 18years of age in children hospitalized for bronchiolitis in infancy. Infants hospitalized for bronchiolitis at the University Hospitals in Stavanger and Bergen, Norway, during 1997-1998, and an age-matched control group, were included in a longitudinal follow-up study and examined at 11 and 18years of age with spirometry and methacholine provocation test (MPT). The MPT data were managed as dose-response slope (DRS) in the statistical analyses. Changes in lung function and DRS from 11 to 18years of age were analyzed by generalized estimating equations, including interaction terms. z-scores for forced vital capacity (FVC), forced expiratory volume in first second (FEV1 ), FEV1 /FVC ratio, and DRS were not different from 11 to 18years of age in both the post-bronchiolitis and the control group. The trajectories from 11 to 18years did not differ between the two groups. BHR at age 11 was independently associated with asthma at age 18. Children hospitalized for bronchiolitis had stable predicted lung function and BHR from 11 to 18years of age. The lung function trajectories were not different from controls.

Airway hyperresponsiveness in young children with respiratory symptoms: A five-year follow-up

BackgroundRecurrent wheezing in early life is transient in most children. The significance of airway hyperresponsiveness (AHR) in persistence of respiratory symptoms from infancy to early childhood is controversial. ObjectiveWe evaluated whether AHR in wheezy infants predicts doctor-diagnosed asthma (DDA) or AHR at the age of 6 years. MethodsSixty-one wheezy infants (age 6-24 months) were followed up to the median age of 6 years. Lung function and AHR with methacholine challenge test were assessed at infancy and 6 years. The exercise challenge test was performed at the age of 6 years. Atopy was assessed with skin prick tests. ResultsAt 6 years, 21 (34%) of the children had DDA. Children with DDA had higher logarithmic transformed dose-response slope (LOGDRS) to methacholine in infancy than children without DDA (0.047 vs 0.025; P = .033). Furthermore, AHR to methacholine in infancy and at 6 years were associated with each other (r = 0.324, P = .011). Children with exercise-induced bronchoconstriction (EIB) at 6 years were more reactive to methacholine in infancy than those without EIB (P = .019). ConclusionIncreased AHR in symptomatic infants was associated with increased AHR, DDA, and EIB at median the age of 6 years, suggesting early establishment of AHR.

BMI but not central obesity predisposes to airway closure during bronchoconstriction.

Obesity produces restrictive effects on lung function. We previously reported that obese patients with asthma exhibit a propensity towards small airway closure during methacholine challenge which improved with weight loss. We hypothesized that increased abdominal adiposity, a key contributor to the restrictive effects of obesity on the lung, mediates this response. This study investigates the effect of body mass index (BMI) versus waist circumference (WC) on spirometric lung function, sensitivity to airway narrowing and closure, and airway closure during bronchoconstriction in patients with asthma. Participants underwent spirometry and methacholine challenge. Sensitivity to airway closure and narrowing was assessed from the dose-response slopes of the forced vital capacity (FVC) and the ratio of forced expiratory volume in 1 s (FEV1 ) to FVC, respectively. Airway closure during bronchoconstriction (closing index) was computed as the percent reduction in FVC divided by the percent reduction in FEV1 at maximal bronchoconstriction. A total of 116 asthmatic patients (56 obese) underwent methacholine challenge. Spirometric lung function was inversely related to WC (P < 0.05), rather than BMI. Closing index increased significantly during bronchoconstriction in obese patients and was related to increasing BMI (P = 0.01), but not to WC. Sensitivity to airway closure and narrowing was not associated with BMI or WC. Although WC is associated with restrictive effects on baseline lung function, increased BMI, rather than WC, predisposes to airway closure during bronchoconstriction. These findings suggest that obesity predisposes to airway closure during bronchoconstriction through mechanisms other than simple mass loading.

Use of Apoptotic Biomarkers to Predict Response to Radiotherapy in Breast Cancer Patients

Introduction: To enhance radiation therapy efficiency it is crucial to implement an individual-based treatment. The aim of present study was to identify the mechanism of intrinsic apoptosis pathway on radiosensitivity and normal tissue complications caused by the radiotherapy. Materials and Methods: radiation-induced apoptosis in peripheral blood mononuclear cells derived from unselected breast cancer (BC) patients was examined using the relative quantitative RT-PCR. Expression levels of Bax, Bcl-2, and Bax/Bcl-2 ratio (as an in-vitro radiosensitivity index (RSI)) were examined in in-vitro irradiated (1 and 2 Gy) cells. All the patients received similar tangential irradiation of the whole breast and conventional fractionation and then, Clinical radiosensitivity (as a clinical radiosensitivity index) was determined using the acute reactions to radiotherapy of the skin according to RTOG score. All statistical analyses were performed using GraphPad Prism, version 7.01. Results: The notable result was a significant correlation between dose-response curve slope (in-vitro RSI) and acute skin toxicity score following irradiation (clinical RSI). Conclusion: These data suggest that Bax/Bcl-2 ratio determination before radiation therapy can be used as a potential biomarker to identify radiosensitive individuals. However, further studies are required to validate radiation-induced apoptotic biomarkers.

A power law function describes the time- and dose-dependency of Vγ9Vδ2 T cell activation by phosphoantigens

Phosphoantigens stimulate Vγ9Vδ2 T cells after binding to BTN3A1 in target cells and cell–cell contact. We evaluated phosphoantigens including diphosphates, bisphosphonates, and prodrugs for ability to induce leukemia cells to stimulate Vγ9Vδ2 T cell interferon-γ secretion. Most compounds displayed time-dependent activity at exposure times between 15 and 240 min. Potency (EC50 values) ranged between 8.4 nM and >100 µM. The diphosphate C-HMBPP displayed a shallow dose–response slope (Hill slope = 0.71), while the bisphosphonate slopes were steep (Hill slopes > 2), and the prodrugs intermediate. The bis-acyloxyalkyl POM2-C-HMBP showed low nanomolar potency even at an exposure time of 1 min. Mixed aryl-POM prodrugs also retained excellent potency at 15 min, while aryl-amidates were time dependent below 240 min. The sum of the dose and time logarithms is often constant, while a power law function fits most compounds. Collectively, these findings illustrate the exquisite activity of prodrugs relative to diphosphates and bisphosphonates.

Modeling the Risk of Neurocognitive Effects from Radiation Therapy in Childhood Cancer Survivors: Initial Results From the Pediatric Normal Tissue Effects in the Clinic (PENTEC) CNS Task Force

Brain injury from radiation therapy (RT) includes necrosis and neurocognitive (NC) impairment that can affect childhood cancer survivors’ quality-of-life. PENTEC seeks to quantitate RT dose-dependence of adverse effects and the risk modification by age and other factors. The PENTEC CNS task force reports preliminary results of RT related NC outcomes. A literature search for studies reporting incidence of RT associated NC sequelae (impaired IQ, NC function, or need for special education) was performed. Prescribed doses were converted to equivalent 2 Gy/fraction (EQD2). The Lyman-Kutcher-Burman formalism with generalized equivalent uniform dose (gEUD) was used for modeling normal tissue complication probability (NTCP) of NC effects. For whole brain (WB)/craniospinal or partial brain (PB) RT it was assumed that the prescribed dose uniformly irradiated the entire brain or 1/8 of the brain, respectively. In this analysis, a simple composite variable reflecting various NC endpoints was used. The model was fitted using a weighted least squares method and corrected for the patient number in each study. Best-fit parameter confidence intervals were determined using a bootstrap resampling technique. The search identified 1173 abstracts; each was evaluated by 2 reviewers. Two hundred nineteen studies with useful information were short-listed. The 62 highest scored articles were abstracted and the 19 studies (21 data sets, 1498 patients) with objective NC testing and RT data were analyzed (Table). Preliminary results show a sigmoidal dose-response for NC impairments: D50 corresponding to 50% risk of complication of 26.6 Gy (68% CI 25.5-27.9 Gy); slope of dose response 0.35 (0.31-0.40) and volume parameter 0.46 (0.40-0.59). The model indicates a 5% NC risk associated with 11.3 Gy WB and 29.8 Gy PB RT.Abstract 1032; TableStudyYearPtsWB/CS Dose (Gy)Focal Dose (Gy)Neurocognitive Function DeclineIncidence of Endpoint %Fouladi200331-52.2IQ0Fouladi Focal200538-54IQ < 7023.6Fouladi CSI20051418-3051.9IQ71.4Waber19952718-IQ0Krull201310224-IQ52Vern-Gross201434-59.4IQ0Agbahiwe2017483656IQ54.1Merchant2000823.4-3250.4IQ12.5Merchant200488-23.4-32IQ0Merchant200978-54IQ100Merchant201477-52.13IQ0Merchant20145823.4-39.655.8NC100Edelstein20112418-General50Waber200412518-General0Christopherson20143928.854General49Krull 18 Gy201316718-General12.3Krull 24 Gy201318624-General27Jakacki200461854Status50Cheng20162223.440Process Speed33.3Van Dijk201228521-24.849.3-51.3Disorder14.4Yeom20134118-39.654Special Ed70 Open table in a new tab The initial results of this meta-analysis confirm a RT dose and volume relationship to NC injury risk. Further model refinement will include the effect of age, chemotherapy and include a formal evaluation of heterogeneity across studies.