Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising. The planar cell polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly because of the perinatal lethality of many PCP mouse mutant lines. Here, we investigate heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin-modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage, including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in emphysema. In vitro, disruption of VANGL2 impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking on lung function. Finally, we show that PCP genes VANGL2 and SCRIB are significantly downregulated in lung tissue from patients with emphysema. Our data reveal an important novel role for the PCP pathway in adult lung homeostasis and repair and shed new light on the genetic factors which may modify destructive lung diseases such as emphysema.

BackgroundObservational studies on pubertal timing and asthma, mainly performed in females, have provided conflicting results about a possible association of early puberty with higher risk of adult asthma, possibly due to residual confounding. To overcome issues of confounding, we used Mendelian randomisation (MR), i.e., genetic variants were used as instrumental variables to estimate causal effects of early puberty on post-pubertal asthma in both females and males.Methods and findingsMR analyses were performed in UK Biobank on 243,316 women using 254 genetic variants for age at menarche, and on 192,067 men using 46 variants for age at voice breaking. Age at menarche, recorded in years, was categorised as early (<12), normal (12–14), or late (>14); age at voice breaking was recorded and analysed as early (younger than average), normal (about average age), or late (older than average). In females, we found evidence for a causal effect of pubertal timing on asthma, with an 8% increase in asthma risk for early menarche (odds ratio [OR] 1.08; 95% CI 1.04 to 1.12; p = 8.7 × 10−5) and an 8% decrease for late menarche (OR 0.92; 95% CI 0.89 to 0.97; p = 3.4 × 10−4), suggesting a continuous protective effect of increasing age at puberty. In males, we found very similar estimates of causal effects, although with wider confidence intervals (early voice breaking: OR 1.07; 95% CI 1.00 to 1.16; p = 0.06; late voice breaking: OR 0.93; 95% CI 0.87 to 0.99; p = 0.03). We detected only modest pleiotropy, and our findings showed robustness when different methods to account for pleiotropy were applied. BMI may either introduce pleiotropy or lie on the causal pathway; secondary analyses excluding variants associated with BMI yielded similar results to those of the main analyses. Our study relies on self-reported exposures and outcomes, which may have particularly affected the power of the analyses on age at voice breaking.ConclusionsThis large MR study provides evidence for a causal detrimental effect of early puberty on asthma, and does not support previous observational findings of a U-shaped relationship between pubertal timing and asthma. Common biological or psychological mechanisms associated with early puberty might explain the similarity of our results in females and males, but further research is needed to investigate this. Taken together with evidence for other detrimental effects of early puberty on health, our study emphasises the need to further investigate and address the causes of the secular shift towards earlier puberty observed worldwide.

RESUMOIntrodução: O Mini-Mental State Examination é o teste de rastreio de défice cognitivo/demência mais difundido. No nosso país têm-se utilizado pontuações de corte definidas por grupos de literacia, mas existem novas propostas sustentadas por estudos mais representativos. Propomo-nos confirmar a influência da idade e da escolaridade no desempenho, avaliar a capacidade discriminativa dos novos dados normativos e testar a acuidade diagnóstica das pontuações de corte validadas para o défice cognitivo ligeiro e para as formas mais prevalentes de demência. The Mini-Mental State Examination is the most commonly used cognitive screening test. In Portugal, the cut-off scores are defined according to literacy groups, but different proposals have been recommended by more representative studies. We therefore propose to confirm the influence of demographical variables, such as age and education, in the subject's performance; evaluating the discriminant ability of the new normative data; and to further examine the diagnostic acuity of the validated cut-off scoring for mild cognitive impairment and for the most prevalent types of dementia. Material and Methods: Our study includes 1 441 educated subjects, divided into seven subgroups: Mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, vascular dementia, dementia with Lewy bodies, community-controls and memory cliniccontrols. Results: Altogether age and education explain 10.4% of the Mini-Mental State Examination results variance, with both variables contributing significantly to the results' prediction. The diagnostic acuity based on the most recent normative data was always higher than the one obtained through the validation cut-off scoring, revealing an overall excellent specificity (superior to 90%) and different sensitivity values: excellent for mild Alzheimer's disease (91%), good for dementia with Lewy Bodies (78%) and low for mild cognitive impairment (65%), frontotemporal dementia and vascular dementia (55%). Discussion and Conclusions:The performance on the Mini-Mental State Examination is influenced by age and education, supporting the use of normative data that consider those variables. With this approach, the Mini-Mental State Examination could be a sensitive and specific instrument for the Alzheimer's disease screening among all healthcare levels. Nevertheless, its diagnostic acuity is limited in other conditions frequently seen in memory clinics, such as Mild Cognitive Impairment and other types of dementia.

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In observational studies, early menopause is associated with lower forced vital capacity (FVC) and a higher risk of spirometric restriction, but not airflow obstruction. It is, however, unclear if this association is causal. We therefore used a Mendelian randomisation (MR) approach, which is not affected by classical confounding, to assess the effect of age at natural menopause on lung function.We included 94 742 naturally post-menopausal women from the UK Biobank and performed MR analyses on the effect of age at menopause on forced expiratory volume in 1 s (FEV1), FVC, FEV1/FVC, spirometric restriction (FVC<lower limit of normal (LLN)) and airflow obstruction (FEV1/FVC<LLN). We used the inverse variance-weighted method, as well as methods that adjust for pleiotropy, and compared MR with observational analyses.The MR analyses showed higher FEV1/FVC and a 15% lower risk of airflow obstruction for women with early (<45 years) compared to normal (45–55 years) menopause. Despite some evidence of pleiotropy, the results were consistent when using MR methods robust to pleiotropy. Similar results were found among never- and ever-smokers, while the protective effect seemed less strong in women who had ever used menopause hormone treatment and in overweight women. There was no strong evidence of an association with FVC or spirometric restriction. In observational analyses of the same dataset, early menopause was associated with a pronounced reduction in FVC and a 13% higher risk of spirometric restriction.Our MR results suggest that early menopause has a protective effect on airflow obstruction. Further studies are warranted to better understand the inconsistency with observational findings, and to investigate the underlying mechanisms and role of female sex hormones.

Rationale: Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors. Objectives: To systematically investigate the effects of lung development genes on adult lung function. Methods: Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV 1 /FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger subset to select the most promising signals and the smaller subset for replication. Measurements and Main Results: We identified 55 genes, of which 36 (16 for FVC, 19 for FEV 1 /FVC, and one for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 replicated at nominal significance level. Of the 55 genes, 53 fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-to-cell adhesion; extracellular matrix), suggesting that these specific processes are important for adult lung health. Conclusions: Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.

A preliminary assessment of the occupational dose to the intervention radiologist received in fluoroscopy computerised tomography (CT) used to guide the collection of lung and bone biopsies is presented. The main aim of this work was to evaluate the capability of the reading system as well as of the available whole-body (WB) and extremity dosemeters used in routine monthly monitoring periods to measure per procedure dose values. The intervention radiologist was allocated 10 WB detectors (LiF: Mg, Ti, TLD-100) placed at chest and abdomen levels above and below the lead apron, and at both right and left arms, knees and feet. A special glove was developed with casings for the insertion of 11 extremity detectors (LiF:Mg, Cu, P, TLD-100H) for the identification of the most highly exposed fingers. The H(p)(10) dose values received above the lead apron (ranged 0.20-0.02 mSv) depend mainly on the duration of the examination and on the placement of physician relative to the beam, while values below the apron are relatively low. The left arm seems to receive a higher dose value. H(p)(0.07) values to the hand (ranged 36.30-0.06 mSv) show that the index, middle and ring fingers are the most highly exposed. In this study, the wrist dose was negligible compared with the finger dose. These results are preliminary and further studies are needed to better characterise the dose assessment in CT fluoroscopy.

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