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Introduction: Percutaneous thermal ablation of inconspicuous lesions can be challenging. Fusion ultrasound (FUS) allows the use of previously performed diagnostic imaging like computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET–CT) to localise hepatocellular carcinoma (HCC) for treatment. This paper illustrates FUS case studies of pre-, intra- and post-ablation imaging of inconspicuous HCC, supplemented by use of contrast-enhanced ultrasound (CEUS). Method: Four prospective cases during September 2014 to October 2018, with HCC amenable to ablation, which were poorly identified on ultrasound, underwent FUS. FUS pre-screening was scheduled within three months of the previous CT or MRI, and between one to four weeks prior to the scheduled ablation date. Post-ablation imaging with FUS was performed between four to six weeks to coincide with their routine follow-up CT or MRI. Findings: There were potential benefits observed in the cases with combined techniques of FUS and CEUS for limiting circumstances such as heat sink effect, multiple lesions targeting, inconspicuous lesion detection and pre-ablation technical feasibility assessment. Discussion: The combined use of FUS and CEUS improves tumour visibility, increases operator imaging confidence and reduces heat sink effect during percutaneous thermal ablation. Conclusion: FUS imaging is helpful in targeting poor conspicuity lesions that cannot be detected on grey-scale ultrasound. It facilitates in ensuring optimal treatment of hepatic lesions for improvement of patient prognosis and follow-up imaging. [ABSTRACT FROM AUTHOR]

Preventing childhood obesity from early life is considered essential. However, evidence from recent systematic reviews has highlighted inconsistent results and limited effectiveness of preconception and pregnancy lifestyle interventions regarding offspring weight outcomes and adiposity. Therefore, to improve our understanding regarding the mixed success of these early life interventions, we conducted a scoping review examining intervention complexity, process evaluation components, and authors' statements. Eligible articles (preconception or pregnancy lifestyle trials with offspring data beyond 1 month of age) were identified by searching databases (PubMed, Embase, and CENTRAL), previous reviews, and performing CLUSTER searches. The Intervention Complexity Assessment Tool for Systematic Reviews (iCAT_SR) was used to evaluate intervention complexity. A thematic analysis provided insight into process evaluation components and authors' interpretations. Finally, an expert consultation on the results was conducted. We identified 40 eligible publications corresponding to 27 trials. Only two trials started before conception. Potential reasons for interventions' limited success included the late intervention initiation, short intervention duration, and insufficient sample size. Few studies reported process evaluations and included stakeholder involvement, which are essential according to the expert group. We discuss current limitations and outline suggestions for future interventions in this field of research., (© 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Adolescence is a critical period for mental health and social exclusion, a key social determinant of mental health. Early intervention approaches are key to mitigating the impact of mental ill-health during adolescence, however social exclusion can create additional barriers to accessing care., Aim: We aimed to better understand help-seeking experiences of adolescents facing co-occurring social exclusion and mental ill-health, including sources of support, barriers and preferences for service provision., Method: Cross-sectional data were analysed, from the 2022 Mission Australia Youth Survey ( N  = 18,800). Adolescents aged 15 to 19 years were recruited from around Australia, through schools, community organisations and digital platforms. Indices of four domains of social exclusion (housing, finances, relational and education/employment) were created using existing Youth Survey variables, and supplemented with demographic characteristics, psychological distress and help-seeking behaviours (perceived need, mental health supports, barriers to access and preferences). Relationships between social exclusion domains, mental health concerns and help-seeking behaviours were explored using logistic regression models., Results: A total of 9,743 young people reported having needed mental health support, yet only 58.1% reportedly sought support ( n  = 5,565). Social exclusion domains were associated with different help-seeking behaviours: housing challenges with higher help-seeking (OR = 1.28; 95% CI [1.15, 1.42]); relational difficulties and edu-employment issues with lower (OR = 0.75; 95% CI [0.68, 0.83] and OR = 0.82; 95% CI [0.75, 0.89]). Stigma, confidentiality concerns, cost and not knowing where to seek help were common barriers to help-seeking; those experiencing social exclusion more likely to report these. Participants reported a strong preference for face-to-face support., Conclusions: This study highlights the additional needs and challenges faced by adolescents dealing with both social exclusion and mental ill-health. With greater barriers to help-seeking, concerted efforts are needed to reduce stigma, improve mental health literacy and increase access to trusted information sources. Further initiatives should focus on structural factors that socially exclude young people and exacerbate inequitable access to mental healthcare.

Aims: Most lifetime mental health disorders begin by age 25 years, and the prevalence among young people has been increasing over recent years. We sought to understand what impact, if any, social determinants have had on this increase through the analysis of an Australian longitudinal dataset (with data from 2007 to 2021)., Methods: The analysis focused on five social determinants: loneliness and lack of social support, family relationships, participation in education and employment, receipt of government benefits and relative socio-economic status. We analysed cross-sectional changes in self-reported psychological distress between 2007 and 2021 (using the Kessler-10 item; K10 scores) and examined the effects of these five social determinants on psychological distress using weighted linear regression models., Results: We identified a significant increase in psychological distress among Australians from 2007 to 2021, with the sharpest rise among those aged 15 to 25 years, who saw more than doubling in the percentage of high and very high K10. This period also saw an increase in the prevalence of social determinants such as loneliness and lack of social support, as well as poor family relationships, particularly in 2021 post COVID-19 pandemic. Regression models suggest loneliness and lack of social support had the most pronounced and increasing impact on psychological distress, followed by poor family relationships., Discussion: The observed significant and steady increases in psychological distress and related social determinant factors, particularly loneliness and lack of social support among young people, highlight the urgent need for comprehensive actions. Coordinated research and community-based initiatives are needed to deliver intrapersonal, interpersonal and socially-focused interventions with a holistic approach to support psychosocial wellbeing. Policymakers must adopt a comprehensive shift in political commitment and a whole-of-government approach to address these challenges., Competing Interests: Conflict of interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: rygen is funded by the Australian Government Department of Health and Aged Care to provide technical advice and policy direction on a number of youth mental health topics, including social determinants. This is relevant for DB, RM and VB.

Background and Aims: Since the onset of the COVID-19 pandemic, a significant rise in mental ill health has been observed globally in young people, particularly those in their final years of secondary school. Students' negative experiences coincide with a critical transitional period which can disrupt milestones in social and educational development. This study aimed to use innovative population-level data to map the impact of the pandemic on students entering higher education., Methods: Pre-pandemic (2019/2020) and pandemic (2020/2021) tertiary education application data were obtained from the Victorian Tertiary Admissions Centre. Prevalence of applications for special consideration related to mental ill health were compared between cohorts across various geographical areas and applicant demographic subgroups. Relative risk regression models were used to understand the role of different risk factors., Results: Rates of mental health-related special consideration applications increased by 38% among all applications (pre-pandemic: 7.8%, n = 56 916; pandemic: 10.8%, n = 58 260). Highest increases were observed among students in areas with both extended and close-quarter lockdown experiences, and areas impacted by 2019/2020 black summer bushfires. The increases were higher among Year 12 students and students with other special consideration needs (e.g., physical condition, learning disability). Slightly higher increases were observed in areas with higher socio-economic status, which may potentially be related to inequality in mental health service access., Conclusion: As consequences of mental health difficulties and academic disruption in youth can be long lasting, it is critical to establish a mental health support framework both in and outside of higher education to facilitate young people's recovery from the pandemic., (© 2024 The Author(s). Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

High-frequency US, with a linear transducer and gray-scale, color, and spectral Doppler US techniques, is the primary imaging modality for evaluation of the penis. It can allow delineation of anatomy and assessment of dynamic blood flow; it is easily available and noninvasive or minimally invasive; it is cost effective; and it is well tolerated by patients. US assessment after pharmacologic induction of erection is an additional tool in assessing patients with suspected vasculogenic impotence, and also in selected patients with penile trauma and suspected Peyronie disease. Penile injuries, life-threatening infections, and vascular conditions such as priapism warrant rapid diagnosis to prevent long-term morbidities due to clinical misdiagnosis or delayed treatment. US can facilitate a timely diagnosis in these emergency conditions, even at the point of care such as the emergency department, which can facilitate timely treatment. In addition, color and spectral Doppler US are valuable applications in the follow-up of patients treated with endovascular revascularization procedures for vasculogenic erectile dysfunction. Image optimization and attention to meticulous techniques including Doppler US is vital to improve diagnostic accuracy. Radiologists should be familiar with the detailed US anatomy, pathophysiologic characteristics, scanning techniques, potential pitfalls, and US manifestations of a wide spectrum of vascular and nonvascular penile conditions to suggest an accurate diagnosis and direct further management. The authors review a range of common and uncommon abnormalities of the penis, highlight their key US features, discuss differential diagnosis considerations, and briefly review management. © RSNA, 2024 Supplemental material is available for this article.

Introduction: Maternal social disadvantage adversely affects maternal and offspring health, with limited research on placental outcomes. Therefore, we examined maternal sociodemographic factor associations with placental and birth outcomes in general (Lifeways Cross-Generation Cohort) and at-risk (PEARS Study of mothers with overweight or obesity) populations of pregnant women., Methods: TwoStep cluster analysis profiled Lifeways mothers (n = 250) based on their age, parity, marital status, household income, private healthcare insurance, homeowner status, and education. Differences in placental and birth outcomes (untrimmed placental weight (PW), birthweight (BW) and BW:PW ratio) between clusters were assessed using one-way ANOVA and chi-square tests. Partial least squares regression analysed individual effects of sociodemographic factors on placental and birth outcomes in Lifeways and PEARS mothers (n = 461)., Results: Clusters were classified as "Married Homeowners" (n = 140, 56 %), "Highest Income" (n = 58, 23.2 %) and "Renters" (n = 52, 20.8 %) in the Lifeways Cohort. Renters were younger, more likely to smoke, have a means-tested medical card and more pro-inflammatory diets compared to other clusters (p < 0.01). Compared to Married Homeowners, renters' offspring had lower BW (-259.26 g, p < 0.01), shorter birth length (-1.31 cm, p < 0.01) and smaller head circumference (-0.59 cm, p = 0.02). PLS regression analyses identified nulliparity as having the greatest negative effect on PW (Lifeways and PEARS) while being a homeowner had the greatest positive effect on PW (Lifeways)., Conclusion: Certain combinations of sociodemographic factors (particularly homeownership) were associated with less favourable lifestyle factors, and with birth, but not placental outcomes. When explored individually, parity contributed to the prediction of placental and birth outcomes in both cohorts of pregnant women., Competing Interests: Declaration of competing interest None, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Multiomics has shown promise in noninvasive risk profiling and early detection of various common diseases. In the present study, in a prospective population-based cohort with ~18 years of e-health record follow-up, we investigated the incremental and combined value of genomic and gut metagenomic risk assessment compared with conventional risk factors for predicting incident coronary artery disease (CAD), type 2 diabetes (T2D), Alzheimer disease and prostate cancer. We found that polygenic risk scores (PRSs) improved prediction over conventional risk factors for all diseases. Gut microbiome scores improved predictive capacity over baseline age for CAD, T2D and prostate cancer. Integrated risk models of PRSs, gut microbiome scores and conventional risk factors achieved the highest predictive performance for all diseases studied compared with models based on conventional risk factors alone. The present study demonstrates that integrated PRSs and gut metagenomic risk models improve the predictive value over conventional risk factors for common chronic diseases., (© 2024. The Author(s).)

Introduction: The influence of maternal lifestyle behaviours on placental growth have been investigated individually, but with conflicting results, and their combined effect is under-researched. Therefore, we examined associations between a composite maternal healthy lifestyle score (HLS), and its individual components, during early pregnancy with placental outcomes., Methods: Participants included Lifeways Cross-Generational Cohort mother-child pairs (n = 202). A composite HLS based on a less inflammatory diet (bottom 40% of the energy-adjusted Dietary Inflammatory Index (E-DII™)), moderate-to-vigorous physical activity (MVPA), healthy pre-pregnancy BMI (18.5-24.9 kg/m 2 ), never smoking, and non-/moderate alcohol intake was calculated. Quantile regression analysed HLS (and individual components) associations with measures of placental development (untrimmed placental weight (PW)) and function (birth weight:placental weight (BW:PW) ratio) at the 10th, 25th, 50th, 75th and 90th centiles., Results: A more pro-inflammatory diet was positively, and smoking and heavy alcohol consumption were negatively, associated with PW at median centiles (B: 41.97 g, CI: 3.71, 80.22, p < 0.05; B: -58.51 g, CI: -116.24, -0.77, p < 0.05; B: -120.20 g, CI: -177.97, -62.43, p < 0.05 respectively). Low MVPA was inversely associated with BW:PW ratio at the 10th and 90th centiles (B: -0.36, CI: -0.132, -0.29, p < 0.01 and B: -0.45, CI: -0.728, -0.182, p < 0.01, respectively). Heavy alcohol intake was positively associated with BW:PW ratio at the 10th centile (B: 0.54, CI: 0.24, 0.85, p < 0.01). Results of sex-stratified analysis provide evidence of sexual dimorphism., Discussion: Associations of certain lifestyle factors, but not the composite HLS, during early pregnancy with measures of placental development (PW) and function (BW:PW ratio) varied by quantiles and by sex., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The gut-lung axis is generally recognized, but there are few large studies of the gut microbiome and incident respiratory disease in adults., Objective: We sought to investigate the association and predictive capacity of the gut microbiome for incident asthma and chronic obstructive pulmonary disease (COPD)., Methods: Shallow metagenomic sequencing was performed for stool samples from a prospective, population-based cohort (FINRISK02; N = 7115 adults) with linked national administrative health register-derived classifications for incident asthma and COPD up to 15 years after baseline. Generalized linear models and Cox regressions were used to assess associations of microbial taxa and diversity with disease occurrence. Predictive models were constructed using machine learning with extreme gradient boosting. Models considered taxa abundances individually and in combination with other risk factors, including sex, age, body mass index, and smoking status., Results: A total of 695 and 392 statistically significant associations were found between baseline taxonomic groups and incident asthma and COPD, respectively. Gradient boosting decision trees of baseline gut microbiome abundance predicted incident asthma and COPD in the validation data sets with mean area under the curves of 0.608 and 0.780, respectively. Cox analysis showed that the baseline gut microbiome achieved higher predictive performance than individual conventional risk factors, with C-indices of 0.623 for asthma and 0.817 for COPD. The integration of the gut microbiome and conventional risk factors further improved prediction capacities., Conclusions: The gut microbiome is a significant risk factor for incident asthma and incident COPD and is largely independent of conventional risk factors., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Individual macronutrient and micronutrient effects on placental growth have been widely investigated. However, the influence of overall maternal diet is relatively unknown. Therefore, the aim of this study is to examine associations between a range of maternal dietary scores during early pregnancy with placental outcomes, and to investigate whether there is evidence of sexual dimorphism., Methods: This analysis of the Lifeways Cross-Generational Cohort includes 276 mother-child pairs. A validated 148-item semi-quantitative food frequency questionnaire assessed maternal diet in early pregnancy. Dietary scores reflecting dietary quality [Healthy Eating Index (HEI-2015), Dietary Approaches to Stop Hypertension (DASH)], dietary inflammatory potential [Dietary Inflammatory Index (DII) and the energy adjusted DII (E-DII)], dietary antioxidant status [Dietary Antioxidant Quality (DAQ)], and glycemic and insulinemic loads/indices (GL/GI, IL/II) were calculated. Linear regression analyses assessed maternal dietary score relationships with untrimmed placental weight (PW) and birth weight:placental weight (BW:PW) ratio., Results: In fully adjusted models, maternal E-DII and GI were positively associated, and HEI-2015 and DAQ were negatively associated with PW (B: 12.31, 95% CI: 0.41, 24.20, p  = 0.04, B: 4.13, 95% CI: 0.10, 8.17, p  = 0.04, B: -2.70, 95% CI: -5.03, -0.35, p  = 0.02 and B: -15.03, 95% CI: -28.08, -1.98, p  = 0.02, for E-DII, GI, HEI-2015 and DAQ respectively). Maternal DAQ associations with BW:PW ratio were attenuated. When stratified by sex, maternal GI and pregnancy-specific DAQ were associated with PW in female offspring (B: 5.61, 95% CI: 0.27, 10.96, p  = 0.04 and B: -15.31, 95% CI: -30.35, -0.27, p  = 0.046). Maternal E-DII and HEI-2015 were associated with PW in males (B: 24.31, 95% CI: 5.66, 42.96, p  = 0.01 and B: -3.85, 95% CI: -7.47, -0.35, p  = 0.03 respectively)., Conclusion: The results of this novel investigation suggest that maternal diet may influence placental development. Female fetuses may be more sensitive to increased glucose levels whereas male fetuses may be more susceptible to in-utero stresses that are regulated by inflammatory pathways and overall diet quality. Hence, early pregnancy offers an opportune time for a mother to prioritize dietary changes that focus on reducing inflammatory and glycemic responses., Competing Interests: We wish to disclose that JH owns controlling interest in Connecting Health Innovations LLC (CHI), a company that has licensed the right to his invention of the dietary inflammatory index (DII) from the University of South Carolina to develop computer and smartphone applications for patient counseling and dietary intervention in clinical settings. The subject matter of this paper will not have any direct bearing on that work, nor has that activity exerted any influence on this project.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Teo, Murrin, Mehegan, Douglas, Hébert, Segurado, Kelleher and Phillips.)

Purpose: Robust biomarkers that predict disease outcomes amongst COVID-19 patients are necessary for both patient triage and resource prioritisation. Numerous candidate biomarkers have been proposed for COVID-19. However, at present, there is no consensus on the best diagnostic approach to predict outcomes in infected patients. Moreover, it is not clear whether such tools would apply to other potentially pandemic pathogens and therefore of use as stockpile for future pandemic preparedness., Methods: We conducted a multi-cohort observational study to investigate the biology and the prognostic role of interferon alpha-inducible protein 27 ( IFI27 ) in COVID-19 patients., Results: We show that IFI27 is expressed in the respiratory tract of COVID-19 patients and elevated IFI27 expression in the lower respiratory tract is associated with the presence of a high viral load. We further demonstrate that the systemic host response, as measured by blood IFI27 expression, is associated with COVID-19 infection. For clinical outcome prediction (e.g., respiratory failure), IFI27 expression displays a high sensitivity (0.95) and specificity (0.83), outperforming other known predictors of COVID-19 outcomes. Furthermore, IFI27 is upregulated in the blood of infected patients in response to other respiratory viruses. For example, in the pandemic H1N1/09 influenza virus infection, IFI27- like genes were highly upregulated in the blood samples of severely infected patients., Conclusion: These data suggest that prognostic biomarkers targeting the family of IFI27 genes could potentially supplement conventional diagnostic tools in future virus pandemics, independent of whether such pandemics are caused by a coronavirus, an influenza virus or another as yet-to-be discovered respiratory virus., Competing Interests: FS-F-G is a consultant for Biotheus Inc. KS is a consultant for Sanofi, Roche and NovoNordisk. The opinions and data presented in this manuscript are of the authors and are independent of these relationships. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shojaei, Shamshirian, Monkman, Grice, Tran, Tan, Teo, Rodrigues Rossi, McCulloch, Nalos, Raei, Razavi, Ghasemian, Gheibi, Roozbeh, Sly, Spann, Chew, Zhu, Xia, Wells, Senegaglia, Kuniyoshi, Franck, dos Santos, Noronha, Motamen, Valadan, Amjadi, Gogna, Madan, Alizadeh-Navaei, Lamperti, Zuñiga, Nova-Lamperti, Labarca, Knippenberg, Herwanto, Wang, Phu, Chew, Kwan, Kim, Teoh, Pelaia, Kuan, Jee, Iredell, O’Byrne, Fraser, Davis, Belz, Warkiani, Gallo, Souza-Fonseca-Guimaraes, Nguyen, Mclean, Kulasinghe, Short and Tang.)

The gut microbiome has shown promise as a predictive biomarker for various diseases. However, the potential of gut microbiota for prospective risk prediction of liver disease has not been assessed. Here, we utilized shallow shotgun metagenomic sequencing of a large population-based cohort (N > 7,000) with ∼15 years of follow-up in combination with machine learning to investigate the predictive capacity of gut microbial predictors individually and in conjunction with conventional risk factors for incident liver disease. Separately, conventional and microbial factors showed comparable predictive capacity. However, microbiome augmentation of conventional risk factors using machine learning significantly improved the performance. Similarly, disease-free survival analysis showed significantly improved stratification using microbiome-augmented models. Investigation of predictive microbial signatures revealed previously unknown taxa for liver disease, as well as those previously associated with hepatic function and disease. This study supports the potential clinical validity of gut metagenomic sequencing to complement conventional risk factors for prediction of liver diseases., Competing Interests: Declaration of interests V.S. has received honoraria for consulting from Novo Nordisk and Sanofi and travel support from Novo Nordisk. He also has ongoing research collaboration with Bayer Ltd (all unrelated to the present study). R.L. serves as a consultant or advisory board member for Anylam/Regeneron, Arrowhead Pharmaceuticals, Astra Zeneca, Bird Rock Bio, Boehringer Ingelheim, Bristol-Myer Squibb, Celgene, Cirius, CohBar, Conatus, Eli Lilly, Galmed, Gemphire, Gilead, Glympse Bio, GNI, GRI Bio, Inipharm, Intercept, Ionis, Janssen, Inc., Merck, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Prometheus, Promethera, Sanofi, Siemens, and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Cirius, Eli Lilly and Company, Galectin Therapeutics, Galmed Pharmaceuticals, GE, Genfit, Gilead, Intercept, Grail, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, NuSirt, Pfizer, pH Pharma, Prometheus, and Siemens. He is also co-founder of Liponexus, Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome 1-3 . Polygenic scores (PGS) aggregate these into a metric representing an individual's genetic predisposition to disease. PGS have shown promise for early risk prediction 4-7 and there is an open question as to whether PGS can also be used to understand disease biology 8 . Here, we demonstrate that cardiometabolic disease PGS can be used to elucidate the proteins underlying disease pathogenesis. In 3,087 healthy individuals, we found that PGS for coronary artery disease, type 2 diabetes, chronic kidney disease and ischaemic stroke are associated with the levels of 49 plasma proteins. Associations were polygenic in architecture, largely independent of cis and trans protein quantitative trait loci and present for proteins without quantitative trait loci. Over a follow-up of 7.7 years, 28 of these proteins associated with future myocardial infarction or type 2 diabetes events, 16 of which were mediators between polygenic risk and incident disease. Twelve of these were druggable targets with therapeutic potential. Our results demonstrate the potential for PGS to uncover causal disease biology and targets with therapeutic potential, including those that may be missed by approaches utilizing information at a single locus., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Studies indicate that the nasal microbiome may correlate strongly with the presence or future risk of childhood asthma., Objectives: In this study, we tested whether developmental trajectories of the nasopharyngeal microbiome in early life and the composition of the microbiome during illnesses were related to risk of childhood asthma., Methods: Children participating in the Childhood Origins of Asthma study (N = 285) provided nasopharyngeal mucus samples in the first 2 years of life, during routine healthy study visits (at 2, 4, 6, 9, 12, 18, and 24 months of age), and during episodes of respiratory illnesses, all of which were analyzed for respiratory viruses and bacteria. We identified developmental trajectories of early-life microbiome composition, as well as predominant bacteria during respiratory illnesses, and we correlated these with presence of asthma at 6, 8, 11, 13, and 18 years of age., Results: Of the 4 microbiome trajectories identified, a Staphylococcus-dominant microbiome in the first 6 months of life was associated with increased risk of recurrent wheezing by age 3 years and asthma that persisted throughout childhood. In addition, this trajectory was associated with the early onset of allergic sensitization. During wheezing illnesses, detection of rhinoviruses and predominance of Moraxella were associated with asthma that persisted throughout later childhood., Conclusion: In infancy, the developmental composition of the microbiome during healthy periods and the predominant microbes during acute wheezing illnesses are both associated with the subsequent risk of developing persistent childhood asthma., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In asthma, a significant portion of the interaction between genetics and environment occurs through microbiota. The proposed mechanisms behind this interaction are complex and at times contradictory. This review covers recent developments in our understanding of this interaction: the "microbial hypothesis" and the "farm effect"; the role of endotoxin and genetic variation in pattern recognition systems; the interaction with allergen exposure; the additional involvement of host gut and airway microbiota; the role of viral respiratory infections in interaction with the 17q21 and CDHR3 genetic loci; and the importance of in utero and early-life timing of exposures. We propose a unified framework for understanding how all these phenomena interact to drive asthma pathogenesis. Finally, we point out some future challenges for continued research in this field, in particular the need for multiomic integration, as well as the potential utility of asthma endotyping., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Microbial factors are likely to be involved in the recurrence of Crohn's disease (CD) after bowel resection. We investigated the luminal microbiota before and longitudinally after surgery, in relation to disease recurrence, using 16S metagenomic techniques., Methods: In the prospective Post-Operative Crohn's Endoscopic Recurrence (POCER) study, fecal samples were obtained before surgery and 6, 12, and 18 months after surgery from 130 CD patients. Endoscopy was undertaken to detect disease recurrence, defined as Rutgeerts score ≥i2, at 6 months in two-thirds of patients and all patients at 18 months after surgery. The V2 region of the 16S rRNA gene was sequenced using Illumina MiSeq. Cluster analysis was performed at family level, assessing microbiome community differences between patients with and without recurrence., Results: Six microbial cluster groups were identified. The cluster associated with maintenance of remission was enriched for the Lachnospiraceae family [adjusted OR 0.47 (0.27-0.82), P = .007]. The OTU diversity of Lachnospiraceae within this cluster was significantly greater than in all other clusters. The cluster enriched for Enterobacteriaceae was associated with an increased risk of disease recurrence [adjusted OR 6.35 (1.24-32.44), P = .026]. OTU diversity of Enterobacteriaceae within this cluster was significantly greater than in other clusters., Conclusions: Luminal bacterial communities are associated with protection from, and the occurrence of, Crohn's disease recurrence after surgery. Recurrence may relate to a higher abundance of facultatively anaerobic pathobionts from the Enterobacteriaceae family. The ecologic change of depleted Lachnospiraceae , a genus of butyrate-producing bacteria, may permit expansion of Enterobacteriaceae through luminal environmental perturbation.

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4 + T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases.

Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Events in early life contribute to subsequent risk of asthma; however, the causes and trajectories of childhood wheeze are heterogeneous and do not always result in asthma. Similarly, not all atopic individuals develop wheeze, and vice versa. The reasons for these differences are unclear. Using unsupervised model-based cluster analysis, we identified latent clusters within a prospective birth cohort with deep immunological and respiratory phenotyping. We characterised each cluster in terms of immunological profile and disease risk, and replicated our results in external cohorts from the UK and USA. We discovered three distinct trajectories, one of which is a high-risk 'atopic' cluster with increased propensity for allergic diseases throughout childhood. Atopy contributes varyingly to later wheeze depending on cluster membership. Our findings demonstrate the utility of unsupervised analysis in elucidating heterogeneity in asthma pathogenesis and provide a foundation for improving management and prevention of childhood asthma., Competing Interests: HT, ST, DB, ME, DJ, MB, MK, SJ, JG, RL, AS, AC, PS, PH, KH, MI No competing interests declared, (© 2018, Tang et al.)

Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. In this study, the occurrence of acute respiratory tract illnesses (ARIs) and the nasopharyngeal microbiome (NPM) were characterized in 244 infants through their first five years of life. Through this analysis, we demonstrate that >80% of infectious events involve viral pathogens, but are accompanied by a shift in the NPM toward dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change frequently precedes the detection of viral pathogens and acute symptoms. Colonization of illness-associated bacteria coupled with early allergic sensitization is associated with persistent wheeze in school-aged children, which is the hallmark of the asthma phenotype. In contrast, these bacterial genera are associated with "transient wheeze" that resolves after age 3 years in non-sensitized children. Thus, to complement early allergic sensitization, monitoring NPM composition may enable early detection and intervention in high-risk children., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rationale: In infants and young children with cystic fibrosis, lower airway infection and inflammation are associated with adverse respiratory outcomes. However, the role of lower airway microbiota in the pathogenesis of early cystic fibrosis lung disease remains uncertain., Objectives: To assess the development of the lower airway microbiota over time in infants and young children with cystic fibrosis, and to explore its association with airway inflammation and pulmonary function at age 6 years., Methods: Serial, semi-annual bronchoscopies and bronchoalveolar lavage (BAL) procedures were performed in infants newly diagnosed with cystic fibrosis following newborn screening. Quantitative microbiological cultures and inflammatory marker (interleukin 8 and neutrophil elastase) measurements were undertaken contemporaneously. 16S ribosomal RNA gene sequencing was conducted on stored BAL samples. Spirometry results recorded at 6 years of age were extracted from medical records., Measurements and Main Results: Ninety-five BAL samples provided 16S ribosomal RNA gene data. These were collected from 48 subjects aged 1.2-78.3 months, including longitudinal samples from 27 subjects and 13 before age 6 months. The lower airway microbiota varied, but diversity decreased with advancing age. Detection of recognised cystic fibrosis bacterial pathogens was associated with reduced microbial diversity and greater lower airway inflammation. There was no association between the lower airway microbiota and pulmonary function at age 6 years., Conclusions: In infants with cystic fibrosis, the lower airway microbiota is dynamic. Dominance of the microbiota by recognised cystic fibrosis bacterial pathogens is associated with increased lower airway inflammation, however early microbial diversity is not associated with pulmonary function at 6 years of age., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background and Aims: The intestinal microbiota is a key antigenic driver in Crohn's disease [CD]. We aimed to identify changes in the gut microbiome associated with, and predictive of, disease recurrence and remission., Methods: A total of 141 mucosal biopsy samples from 34 CD patients were obtained at surgical resection and at colonoscopy 6 and/or 18 months postoperatively; 28 control samples were obtained: 12 from healthy patients [healthy controls] and 16 from hemicolectomy patients [surgical controls]. Bacterial 16S ribosomal profiling was performed using the Illumina MiSeq platform., Results: CD was associated with reduced alpha diversity when compared with healthy controls but not surgical controls [p < 0.001 and p = 0.666, respectively]. Beta diversity [composition] differed significantly between CD and both healthy [p < 0.001] and surgical [p = 0.022] controls, but did not differ significantly between those with and without endoscopic recurrence. There were significant taxonomic differences between recurrence and remission. Patients experiencing recurrence demonstrated elevated Proteus genera [p = 0.008] and reduced Faecalibacterium [p< 0.001]. Active smoking was associated with elevated levels of Proteus [p = 0.013] postoperatively. Low abundance of Faecalibacterium [< 0.1%] and detectable Proteus in the postoperative ileal mucosa was associated with a higher risk of recurrence (odds ratio [OR] 14 [1.7-110], p = 0.013 and 13 [1.1-150], p = 0.039, respectively) when corrected for smoking. A model of recurrence comprising the presence of Proteus, abundance of Faecalibacterium, and smoking status showed moderate accuracy (area under the curve [AUC] 0.740, 95% confidence interval [CI] [0.69-0.79])., Conclusions: CD is associated with a microbial signature distinct from health. Microbial factors and smoking independently influence postoperative CD recurrence. The genus Proteus may play a role in the development of CD., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Vitamin D (25(OH)D) deficiency has been implicated as a possible risk factor for asthma development, but studies at selected time points measuring 25(OH)D levels during childhood have yielded conflicting findings. Prospective studies tracking 25(OH)D levels during the initiation phase of asthma in early childhood have not been reported., Objective: We sought to elucidate relationships between 25(OH)D levels from birth to age 10 years and susceptibility to allergic sensitization, respiratory tract infections, and asthma., Methods: Asthma-, allergy-, and respiratory tract infection-associated phenotypes (including pathogen identification) were characterized in a high-risk birth cohort. Plasma 25(OH)D concentrations were quantified at birth and at clinical follow-ups at the ages of 0.5, 1, 2, 3, 4, 5, and 10 years, and relationships with clinical outcomes were examined., Results: Cross-sectional analyses demonstrated inverse associations between 25(OH)D concentrations and the risk for concurrent sensitization at age 0.5, 2, and 3 years, and mixed-effects regression demonstrated inverse longitudinal associations of 25(OH)D levels with both sensitization and eczema. Multivariate regression modeling suggested that the number of 25(OH)D-deficient follow-ups was positively associated with risk for asthma/wheeze, eczema, and sensitization at 10 years; adjustment for sensitization (particularly by 2 years) in the asthma/wheeze models reduced 25(OH)D associations with these latter outcomes. 25(OH)D levels were also inversely associated with early nasopharyngeal colonization with Streptococcus species and age of first febrile lower respiratory illness, both of which are known asthma risk factors., Conclusion: 25(OH)D deficiency in early childhood is associated with increased risk for persistent asthma, potentially through modulating susceptibility to early allergic sensitization, upper respiratory tract colonization with bacterial pathogens, or both. These relationships are only evident if 25(OH)D status is monitored prospectively and longitudinally., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment., Methods: Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy-Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates., Results: Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08-0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12-0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15-0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism., Conclusions: This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

We explored the use of the optically transparent semiconductor indium tin oxide (ITO) as an alternative to optically opaque metals for the fabrication of photonic structures in terahertz (THz) near-field studies. Using the polaritonics platform, we confirmed the ability to clearly image both bound and leaky electric fields underneath an ITO layer. We observed good agreement between measured waveguide dispersion and analytical theory of an asymmetric metal-clad planar waveguide with TE and TM polarizations. Further characterization of the ITO revealed that even moderately conductive samples provided sufficiently high quality factors for studying guided and leaky wave behaviors in individual transparent THz resonant structures such as antennas or split ring resonators. However, without higher conductive ITO, the limited reflection efficiency and high radiation damping measured here both diminish the applicability of ITO for high-reflecting, arrayed, or long path-length elements.

Background: The intestinal microbiota is involved in the pathogenesis of inflammatory bowel disease. A reduction in the diversity of the intestinal microbiota as well as specific taxonomic and functional shifts have been reported in Crohn's disease and may play a central role in the inflammatory process. The aim was to systematically review recent developments in the structural and functional changes observed in the gastrointestinal microbiome in patients with Crohn's Disease., Results: Seventy-two abstracts were included in this review. The effects of host genetics, disease phenotype, and inflammatory bowel disease treatment on the gastrointestinal microbiome in Crohn's disease were reviewed, and taxonomic shifts in patients with early and established disease were described. The relative abundance of Bacteroidetes is increased and Firmicutes decreased in Crohn's disease compared with healthy controls. Enterobacteriaceae, specifically Eschericia coli, is enriched in Crohn's disease. Faecalibacterium prausnitzii is found at lower abundance in Crohn's disease and in those with postoperative recurrence. Observed functional changes include major shifts in oxidative stress pathways, a decrease in butanoate and propanoate metabolism gene expression, lower levels of butyrate, and other short-chain fatty acids, decreased carbohydrate metabolism, and decreased amino acid biosynthesis., Conclusions: Changes in microbial composition and function have been described, although a causative role remains to be established. Larger, prospective, and longitudinal studies are required with deep interrogation of the microbiome if causality is to be determined, and refined microbial manipulation is to emerge as a focused therapy.

The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. In the absence of effective anti-viral therapies, targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Multidimensional spectroscopy at visible and infrared frequencies has opened a window into the transfer of energy and quantum coherences at ultrafast time scales. For these measurements to be performed in a manageable amount of time, one spectral axis is typically recorded in a single laser shot. An analogous rapid-scanning capability for THz measurements will unlock the multidimensional toolkit in this frequency range. Here, we first review the merits of existing single-shot THz schemes and discuss their potential in multidimensional THz spectroscopy. We then introduce improved experimental designs and noise suppression techniques for the two most promising methods: frequency-to-time encoding with linear spectral interferometry and angle-to-time encoding with dual echelons. Both methods, each using electro-optic detection in the linear regime, were able to reproduce the THz temporal waveform acquired with a traditional scanning delay line. Although spectral interferometry had mediocre performance in terms of signal-to-noise, the dual echelon method was easily implemented and achieved the same level of signal-to-noise as the scanning delay line in only 4.5% of the laser pulses otherwise required (or 22 times faster). This reduction in acquisition time will compress day-long scans to hours and hence provides a practical technique for multidimensional THz measurements.

Asthma is a genetically complex, chronic lung disease defined clinically as episodic airflow limitation and breathlessness that is at least partially reversible, either spontaneously or in response to therapy. Whereas asthma was rare in the late 1800s and early 1900s, the marked increase in its incidence and prevalence since the 1960s points to substantial gene × environment interactions occurring over a period of years, but these interactions are very poorly understood (1-6). It is widely believed that the majority of asthma begins during childhood and manifests first as intermittent wheeze. However, wheeze is also very common in infancy and only a subset of wheezy children progress to persistent asthma for reasons that are largely obscure. Here, we review the current literature regarding causal pathways leading to early asthma development and chronicity. Given the complex interactions of many risk factors over time eventually leading to apparently multiple asthma phenotypes, we suggest that deeply phenotyped cohort studies combined with sophisticated network models will be required to derive the next generation of biological and clinical insights in asthma pathogenesis.

Whole-genome sequencing across multiple samples in a population provides an unprecedented opportunity for comprehensively characterizing the polymorphic variants in the population. Although the 1000 Genomes Project (1KGP) has offered brief insights into the value of population-level sequencing, the low coverage has compromised the ability to confidently detect rare and low-frequency variants. In addition, the composition of populations in the 1KGP is not complete, despite the fact that the study design has been extended to more than 2,500 samples from more than 20 population groups. The Malays are one of the Austronesian groups predominantly present in Southeast Asia and Oceania, and the Singapore Sequencing Malay Project (SSMP) aims to perform deep whole-genome sequencing of 100 healthy Malays. By sequencing at a minimum of 30× coverage, we have illustrated the higher sensitivity at detecting low-frequency and rare variants and the ability to investigate the presence of hotspots of functional mutations. Compared to the low-pass sequencing in the 1KGP, the deeper coverage allows more functional variants to be identified for each person. A comparison of the fidelity of genotype imputation of Malays indicated that a population-specific reference panel, such as the SSMP, outperforms a cosmopolitan panel with larger number of individuals for common SNPs. For lower-frequency (<5%) markers, a larger number of individuals might have to be whole-genome sequenced so that the accuracy currently afforded by the 1KGP can be achieved. The SSMP data are expected to be the benchmark for evaluating the value of deep population-level sequencing versus low-pass sequencing, especially in populations that are poorly represented in population-genetics studies., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Motivation: Analysing next-generation sequencing (NGS) data for copy number variations (CNVs) detection is a relatively new and challenging field, with no accepted standard protocols or quality control measures so far. There are by now several algorithms developed for each of the four broad methods for CNV detection using NGS, namely the depth of coverage (DOC), read-pair, split-read and assembly-based methods. However, because of the complexity of the genome and the short read lengths from NGS technology, there are still many challenges associated with the analysis of NGS data for CNVs, no matter which method or algorithm is used., Results: In this review, we describe and discuss areas of potential biases in CNV detection for each of the four methods. In particular, we focus on issues pertaining to (i) mappability, (ii) GC-content bias, (iii) quality control measures of reads and (iv) difficulty in identifying duplications. To gain insights to some of the issues discussed, we also download real data from the 1000 Genomes Project and analyse its DOC data. We show examples of how reads in repeated regions can affect CNV detection, demonstrate current GC-correction algorithms, investigate sensitivity of DOC algorithm before and after quality control of reads and discuss reasons for which duplications are harder to detect than deletions.

We investigate the interaction between terahertz waves and resonant antennas with sub-cycle temporal and λ/100 spatial resolution. Depositing antennas on a LiNbO₃ waveguide enables non-invasive electro-optic imaging, quantitative field characterization, and direct measurement of field enhancement (up to 40-fold). The spectral response is determined over a bandwidth spanning from DC across multiple resonances, and distinct behavior is observed in the near- and far-field. The scaling of enhancement and resonant frequency with gap size and antenna length agrees well with simulations.

The genomes of outbred populations were first shown in 2006 to contain regions of homozygosity (ROHs) of several megabases. Further studies have also investigated the characteristics of ROHs in healthy individuals in various populations but there are no studies on Singapore populations to date. This study aims to identify and investigate the characteristics of ROHs in three Singapore populations. A total of 268 samples (96 Chinese, 89 Malays and 83 Indians) are genotyped on Illumina Human 1 M Beadchip and Affymetrix Genome-Wide Human SNP Array 6.0. We use the PennCNV algorithm to detect ROHs. We report an abundance of ROHs (≥500 kb), with an average of more than one hundred regions per individual. On average, the Indian population has the lowest number of ROHs and smallest total length of ROHs per individual compared with the Chinese and Malay populations. We further investigate the relationship between the occurrence of ROHs and haplotype frequency, regional linkage disequilibrium (LD) and positive selection. Based on the results of this data set, we find that the frequency of occurrence of ROHs is positively associated with haplotype frequency and regional LD. The majority of regions detected for recent positive selection and regions with differential LD between populations overlap with the ROH loci. When we consider both the location of the ROHs and the allelic form of the ROHs, we are able to separate the populations by principal component analysis, demonstrating that ROHs contain information on population structure and the demographic history of a population.

A photodiode and data acquisition card whose sampling clock is synchronized to the repetition rate of a laser are used to measure the energy of each laser pulse. Simple analysis of the data yields the noise spectrum from very low frequencies up to half the repetition rate and quantifies the pulse energy distribution. When two photodiodes for balanced detection are used in combination with an optical modulator, the technique is capable of detecting very weak pump-probe signals (ΔI/I(0) ~ 10(-5) at 1 kHz), with a sensitivity that is competitive with a lock-in amplifier. Detection with the data acquisition card is versatile and offers many advantages including full quantification of noise during each stage of signal processing, arbitrary digital filtering in silico after data collection is complete, direct readout of percent signal modulation, and easy adaptation for fast scanning of delay between pump and probe.