Exhaled metabolite patterns to identify recent asthma exacerbations

Asthma is a chronic respiratory disease that can lead to exacerbations, defined as acute episodes of worsening respiratory symptoms and lung function. Predicting the occurrence of these exacerbations is an important goal in asthma management. The measurement of exhaled breath by electronic nose (eNose) may allow for the monitoring of clinically unstable asthma and exacerbations. However, data on its ability to perform this is lacking. We aimed to evaluate whether eNose could identify patients that recently had asthma exacerbations. We performed a cross-sectional study, measuring exhaled breath using the SpiroNose in adults with a physician-reported diagnosis of asthma. Patients were randomly divided into a training (n = 252) and validation (n = 109) set. For the analysis of eNose signals, principal component (PC) and linear discriminant analysis (LDA) were performed. LDA, based on PC1-4, reliably discriminated between patients who had a recent exacerbation from those who had not (training receiver operating characteristic (ROC)–area under the curve (AUC) = 0.76,95% CI 0.69–0.82), (validation AUC = 0.76, 95% CI 0.64–0.87). Our study showed that, exhaled breath analysis using eNose could accurately identify asthma patients who recently had an exacerbation, and could indicate that asthma exacerbations have a specific exhaled breath pattern detectable by eNose

Severe CTE and TDP-43 pathology in a former professional soccer player with dementia: a clinicopathological case report and review of the literature

In the last decades, numerous post-mortem case series have documented chronic traumatic encephalopathy (CTE) in former contact-sport athletes, though reports of CTE pathology in former soccer players are scarce. This study presents a clinicopathological case of a former professional soccer player with young-onset dementia. The patient experienced early onset progressive cognitive decline and developed dementia in his mid-50 s, after playing soccer for 12 years at a professional level. While the clinical picture mimicked Alzheimer's disease, amyloid PET imaging did not provide evidence of elevated beta-amyloid plaque density. After he died in his mid-60 s, brain autopsy showed severe phosphorylated tau (p-tau) abnormalities fulfilling the neuropathological criteria for high-stage CTE, as well as astrocytic and oligodendroglial tau pathology in terms of tufted astrocytes, thorn-shaped astrocytes, and coiled bodies. Additionally, there were TAR DNA-binding protein 43 (TDP-43) positive cytoplasmic inclusions in the frontal lobe and hippocampus, and Amyloid Precursor Protein (APP) positivity in the axons of the white matter. A systematic review of the literature revealed only 13 other soccer players with postmortem diagnosis of CTE. Our report illustrates the complex clinicopathological correlation of CTE and the need for disease-specific biomarkers

Persistent pulmonary hypertension in neonates with perinatal asphyxia and therapeutic hypothermia: a frequent and perilous combination

Therapeutic hypothermia in neonates with perinatal asphyxia may increase the risk of PPHN. This potentially affects outcome.Objectives(1) To investigate whether neonates with perinatal asphyxia and therapeutic hypothermia more often developed PPHN compared to a control group with perinatal asphyxia not treated with hypothermia; (2) To identify risk factors for severe PPHN during hypothermia and evaluate short-term outcome.MethodsThis single-center retrospective cohort study included (near-)term neonates with perinatal asphyxia admitted between 2004 and 2016. Neonates with perinatal asphyxia and hypothermia were compared to a historical control group without hypothermia. Primary outcome was PPHN, defined as severe hypoxemia requiring mechanical ventilation and inhaled nitric oxide, confirmed by echocardiography. Short-term adverse outcome was defined as mortality within one month and/or severe brain injury on MRI.ResultsIncidence of PPHN was 23% (26/114) in the hypothermia group and 11% (8/70) in controls. In multivariate analysis, PPHN was 2.5 times more common among neonates with hypothermia. Neonates developing PPHN during hypothermia often had higher fraction of inspired oxygen at baseline. PPHN was not associated with a higher risk of severe brain injury. However, early mortality was higher and three infants died due to severe refractory PPHN during hypothermia.ConclusionsIn this study PPHN occurred more often since the introduction of therapeutic hypothermia. This was usually reversible and did not lead to overall increased adverse outcome. However, in individual cases with PPHN deterioration occurred rapidly. In such cases the benefits of hypothermia should be weighed against the risk of a complicated, fatal course.Developmen

Persistence of parental-reported asthma at early ages:A longitudinal twin study

Background: Currently, we cannot predict whether a pre-school child with asthma-like symptoms will have asthma at school age. Whether genetic information can help in this prediction depends on the role of genetic factors in persistence of pre-school to school-age asthma. We examined to what extent genetic and environmental factors contribute to persistence of asthma-like symptoms at ages 3 to asthma at age 7 using a bivariate genetic model for longitudinal twin data. Methods: We performed a cohort study in monozygotic and dizygotic twins from the Netherlands Twin Register (NTR, n = 21,541 twin pairs). Bivariate genetic models were fitted to longitudinal data on asthma-like symptoms reported by parents at age 3 and 7 years to estimate the contribution of genetic and environmental factors. Results: Bivariate genetic modeling showed a correlation on the liability scale between asthma-like symptoms at age 3 and asthma at age 7 of 0.746 and the contribution of genetics was estimated to be 0.917. The genetic analyses indicated a substantial influence of genetic factors on asthma-like symptoms at ages 3 and 7 (heritability 80% and 90%, respectively); hence, contribution of environmental factors was low. Persistence was explained by a high (rg = 0.807) genetic correlation. Conclusion: Parental-reported asthma-like symptoms at age 3 and asthma at age 7 are highly heritably. The phenotype of asthma-like symptoms at age 3 and 7 was highly correlated and mainly due to heritable factors, indicating high persistence of asthma development over ages 3 and 7

Early-life antibiotic use and risk of attention-deficit hyperactivity disorder and autism spectrum disorder:results of a discordant twin study

Background Development of the gut-brain axis in early life may be disturbed by antibiotic use. It has been hypothesized that this disturbance may contribute to development of neurodevelopmental disorders, including autism spectrum disorder and attention-deficit hyperactivity disorder. We aimed to assess the association between antibiotic use in early life and the risk of developing attention-deficit hyperactivity disorder or autism spectrum disorder, while controlling for shared genetic and environmental factors in a discordant twin design. Methods We conducted a cohort study in twins (7–12 years; 25 781 twins) from the Netherlands Twin Register (NTR) and a replication study in the Childhood and Adolescent Twin Study in Sweden (CATSS; 7946 9-year-old twins). Antibiotic use was recorded before age 2 years. Attention-deficit hyperactivity disorder and autism spectrum disorder were parent-reported in the Netherlands Twin Register and register-based in the Childhood and Adolescent Twin Study in Sweden. Results Early-life antibiotic use was associated with increased risk of attention-deficit hyperactivity disorder development [pooled odds ratio (OR) 1.10, 95% confidence interval (CI) 1.02-1.17] and autism spectrum disorder (pooled OR 1.15, 95% CI 1.06-1.25) in a case-control design. When restricting to monozygotic twin pairs discordant for the outcome, associations disappeared for both disorders in both cohorts (attention-deficit hyperactivity disorder OR 0.90, 95% CI 0.48-1.69 and OR 0.80, 95% CI 0.37-1.76, and autism spectrum disorder OR 0.66, 95% CI 0.38-1.16 and OR 0.29, 95% CI 0.02-4.50, respectively). Conclusions Our findings suggest that the association between early-life antibiotic use and risk of attention-deficit hyperactivity and autism spectrum disorder may be confounded by shared familial environment and genetics

Early-life antibiotic use and risk of asthma and eczema:results of a discordant twin study

RATIONALE: Early-life antibiotic use has been associated with development of atopic diseases, but the aetiology remains unclear. To elucidate aetiology, we used a discordant twin design to control for genetic and environmental confounding. METHODS: We conducted a retrospective cohort study in twins (3-10 years) from the Netherlands Twin Register (NTR, n=34 352) and a replication study at age 9 in the Childhood and Adolescent Twin Study in Sweden (CATSS, n=7906). Antibiotic use was recorded at 0-2 years. Doctor diagnosed asthma and eczema were reported by parents when children were 3-12 years in both cohorts. Individuals were included in unmatched analyses and in co-twin control analyses with disease discordant twin pairs. RESULTS: Early-life antibiotic use was associated with increased risk of asthma (NTR OR 1.34 95%CI 1.28-1.41; CATSS 1.45 95%CI 1.34-1.56) and eczema (NTR OR 1.08 95%CI 1.03-1.13; CATSS 1.07 95%CI 1.01-1.14) in unmatched analyses. Co-twin analyses in mono- and dizygotic twin pairs showed similar results for asthma (NTR 1.54 95%CI 1.20-1.98 and CATSS 2.00 95%CI 1.28-3.13), but opposing results for eczema in NTR (0.99 95%CI 0.80-1.25) and CATSS (1.67 95%CI 1.12-2.49). The risk of asthma increased for antibiotics prescribed for respiratory infections (CATSS 1.45 95%CI 1.34-1.56), but not for antibiotics commonly used for urinary tract/skin infections (CATSS 1.02 95%CI 0.88-1.17). CONCLUSION: Children exposed to early-life antibiotic use, particularly prescribed for respiratory infections, may be at higher risk of asthma. This risk can still be observed, when correcting for genetic and environmental factors. Our results could not elucidate whether the relationship between early-life antibiotic use and eczema is confounded by familial and genetic factors

Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial

Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989

The role of grass volatiles on oviposition site selection by Anopheles arabiensis and Anopheles coluzzii

Background: The reproductive success and population dynamics, of Anopheles malaria mosquitoes is strongly influenced by the oviposition site selection of gravid females. Mosquitoes select oviposition sites at different spatial scales, starting with selecting a habitat in which to search. This study utilizes the association of larval abundance in the field with natural breeding habitats, dominated by various types of wild grasses, as a proxy for oviposition site selection by gravid mosquitoes. Moreover, the role of olfactory cues emanating from these habitats in the attraction and oviposition stimulation of females was analysed. Methods: The density of Anopheles larvae in breeding sites associated with Echinochloa pyramidalis, Echinochloa stagnina, Typha latifolia and Cyperus papyrus, was sampled and the larvae identified to species level. Headspace volatile extracts of the grasses were collected and used to assess behavioural attraction and oviposition stimulation of gravid Anopheles arabiensis and Anopheles coluzzii mosquitoes in wind tunnel and two-choice oviposition assays, respectively. The ability of the mosquitoes to differentiate among the grass volatile extracts was tested in multi-choice tent assays. Results: Anopheles arabiensis larvae were the most abundant species found in the various grass-associated habitats. The larval densities described a hierarchical distribution, with Poaceae (Echinochloa pyramidalis and Echinochloa stagnina)-associated habitat sites demonstrating higher densities than that of Typha-associated sites, and where larvae were absent from Cyperus-associated sites. This hierarchy was maintained by gravid An. arabiensis and An. coluzzii mosquitoes in attraction, oviposition and multi-choice assays to grass volatile extracts. Conclusions: The demonstrated hierarchical preference of gravid An. coluzzii and An. arabiensis for grass volatiles indicates that vegetation cues associated with larval habitats are instrumental in the oviposition site choice of the malaria mosquitoes. Identifying volatile cues from grasses that modulate gravid malaria mosquito behaviours has distinct potential for the development of tools to be used in future monitoring and control methods