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Sio Teng Lam,1,2,* He Huang,1,* Xiaojie Fang,1 Zhao Wang,1 Huangming Hong,3 Quanguang Ren,1 Ying Tian,1 Suxia Lin,4 Tongyu Lin1 1Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China; 2Department of Medical Oncology, Centro Hospitalar Conde De Sao Januario, Macau, People’s Republic of China; 3Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 4Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tongyu LinDepartment of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, People’s Republic of ChinaTel +86-20-87343363Fax +86-20-87343294Email tongyulin@hotmail.comPurpose: Programmed death ligand 1 (PD-L1) has been proposed as an important prognostic factor in many types of cancer. However, the role of predicting the prognosis of PD-L1 in extranodal natural killer/T-cell lymphoma (ENKTL) was controversial. Combining other biomarkers might enhance its predictive power. This study aims to evaluate the prognostic value of PD-L1 in conjunction with tumor-infiltrating FoxP3+Tregs for ENKTL after non-anthracycline-based chemotherapy.Patients and Methods: A total of 81 patients with ENKTL were included in this study. Clinicopathological characteristics were collected, and prognostic significance of PD-L1 in neoplastic cells (nPD-L1) and tumor-infiltrating FoxP3+Tregs were evaluated.Results: Patients with nPD-L1-positive had significantly inferior overall survival (OS) and progression-free survival (PFS) compared with nPD-L1-negative (3-year OS, 37.2% vs 67.3%, p = 0.014; 3-year PFS, 31.0% vs 61.8%, p =0.010, respectively). Patients who had low FoxP3+Tregs had significantly inferior OS and PFS compared with high FoxP3+Tregs (3-year OS, 36.4% vs 63.0%, p = 0.004; 3-year PFS, 31.7% vs 56.3%, p = 0.020, respectively). The results of multivariate analysis showed that nPD-L1 positivity (HR 6.629, 95% CI 1.966– 22.350, p=0.002) and low FoxP3+Tregs (HR 7.317, 95% CI 2.154– 24.855, p=0.001) were independent predictors of inferior OS. Using these 2 variables, we constructed a new prognostic model that singled out 3 groups with different risk profiles: group 1, no adverse factors; group 2, 1 adverse factor; and group 3, 2 adverse factors. The 3-year OS rates of group 1, group 2, and group 3 were 93.3%, 46.6% and 20.8%, respectively (p< 0.001), and the 3-year PFS rates were 86.7%, 40.8% and 15.0%, respectively (p=0.001).Conclusion: This study is the first to validate the prognostic value of nPD-L1 and tumor-infiltrating FoxP3+Tregs in ENKTL; the new immunological prognostic model might be used to stratify ENKTL patients in clinical trials for new therapeutic strategies.Keywords: extranodal natural killer/T-cell lymphoma, PD-L1, FoxP3+Tregs, prognosis

Abstract The cause of lung cancer is generally attributed to tobacco smoking. However lung cancer in never smokers accounts for 10 to 25% of all lung cancer cases. Arsenic, asbestos and radon are three prominent non-tobacco carcinogens strongly associated with lung cancer. Exposure to these agents can lead to genetic and epigenetic alterations in tumor genomes, impacting genes and pathways involved in lung cancer development. Moreover, these agents not only exhibit unique mechanisms in causing genomic alterations, but also exert deleterious effects through common mechanisms, such as oxidative stress, commonly associated with carcinogenesis. This article provides a comprehensive review of arsenic, asbestos, and radon induced molecular mechanisms responsible for the generation of genetic and epigenetic alterations in lung cancer. A better understanding of the mode of action of these carcinogens will facilitate the prevention and management of lung cancer related to such environmental hazards.

Abstract Background An important consideration when analyzing both microarray and quantitative PCR expression data is the selection of appropriate genes as endogenous controls or reference genes. This step is especially critical when identifying genes differentially expressed between datasets. Moreover, reference genes suitable in one context (e.g. lung cancer) may not be suitable in another (e.g. breast cancer). Currently, the main approach to identify reference genes involves the mining of expression microarray data for highly expressed and relatively constant transcripts across a sample set. A caveat here is the requirement for transcript normalization prior to analysis, and measurements obtained are relative, not absolute. Alternatively, as sequencing-based technologies provide digital quantitative output, absolute quantification ensues, and reference gene identification becomes more accurate. Methods Serial analysis of gene expression (SAGE) profiles of non-malignant and malignant lung samples were compared using a permutation test to identify the most stably expressed genes across all samples. Subsequently, the specificity of the reference genes was evaluated across multiple tissue types, their constancy of expression was assessed using quantitative RT-PCR (qPCR), and their impact on differential expression analysis of microarray data was evaluated. Results We show that (i) conventional references genes such as ACTB and GAPDH are highly variable between cancerous and non-cancerous samples, (ii) reference genes identified for lung cancer do not perform well for other cancer types (breast and brain), (iii) reference genes identified through SAGE show low variability using qPCR in a different cohort of samples, and (iv) normalization of a lung cancer gene expression microarray dataset with or without our reference genes, yields different results for differential gene expression and subsequent analyses. Specifically, key established pathways in lung cancer exhibit higher statistical significance using a dataset normalized with our reference genes relative to normalization without using our reference genes. Conclusions Our analyses found NDUFA1, RPL19, RAB5C, and RPS18 to occupy the top ranking positions among 15 suitable reference genes optimal for normalization of lung tissue expression data. Significantly, the approach used in this study can be applied to data generated using new generation sequencing platforms for the identification of reference genes optimal within diverse contexts.

Abstract Background Lung cancer is the most common cause of cancer-related deaths. Tobacco smoke exposure is the strongest aetiological factor associated with lung cancer. In this study, using serial analysis of gene expression (SAGE), we comprehensively examined the effect of active smoking by comparing the transcriptomes of clinical specimens obtained from current, former and never smokers, and identified genes showing both reversible and irreversible expression changes upon smoking cessation. Results Twenty-four SAGE profiles of the bronchial epithelium of eight current, twelve former and four never smokers were generated and analyzed. In total, 3,111,471 SAGE tags representing over 110 thousand potentially unique transcripts were generated, comprising the largest human SAGE study to date. We identified 1,733 constitutively expressed genes in current, former and never smoker transcriptomes. We have also identified both reversible and irreversible gene expression changes upon cessation of smoking; reversible changes were frequently associated with either xenobiotic metabolism, nucleotide metabolism or mucus secretion. Increased expression of TFF3, CABYR, and ENTPD8 were found to be reversible upon smoking cessation. Expression of GSK3B, which regulates COX2 expression, was irreversibly decreased. MUC5AC expression was only partially reversed. Validation of select genes was performed using quantitative RT-PCR on a secondary cohort of nine current smokers, seven former smokers and six never smokers. Conclusion Expression levels of some of the genes related to tobacco smoking return to levels similar to never smokers upon cessation of smoking, while expression of others appears to be permanently altered despite prolonged smoking cessation. These irreversible changes may account for the persistent lung cancer risk despite smoking cessation.

Abstract Background Reduced forced expiratory volume in one second (FEV1) has been linked to non small cell lung cancer (NSCLC). However, it is unclear whether all or only certain histological subtypes of NSCLC are associated with reduced FEV1. Moreover, there is little information on whether gender modifies this relationship. Using a large tissue registry, we sought to determine the relationship between FEV1 and subtypes of NSCLC and determine whether this relationship is modified by gender. Methods We used data from patients who underwent tumor resection for NSCLC at a teaching hospital in Vancouver and had various pre-operative clinical measurements including FEV1. We divided the cohort into quartiles of predicted FEV1 and using both logistic and linear regression modeling techniques determined whether FEV1 was related to the occurrence of adeno or squamous cell carcinoma in men and women. Results There were 610 patients in the study (36% females). On average, women were more likely to have adenocarcinoma than were men (72% of all cases of NSCLC in women versus 40% in men; p < 0.001). In women, there was no significant relationship between FEV1 and the risk of any histological subtypes of NSCLC. In men, however, there was an inverse relationship between the risk of adenocarcinoma and FEV1 such that the lowest quartile of FEV1 was 47% less likely to have adenocarcinoma compared with the highest FEV1 quartile (adjusted odds ratio, 0.52; 0.28 to 0.98; p for trend, 0.028). The reverse was observed for squamous cell carcinoma. Conclusion In individuals undergoing lung resection for NSCLC, the risk of adenocarcinoma and squamous cell carcinoma of the lung varies as a function of FEV1, independent of smoking intensity in men but not in women. Clinical Implications These data indicate that women are much more susceptible to adenocarcinoma than are men especially when they have normal or near normal lung function. It may thus be useful to conduct periodic surveillance chest radiographs in asymptomatic female smokers (or ex-smokers) to ascertain peripheral nodules or masses before distant metastases occur since adenocarcinomas tend to metastasize earlier in the disease course than squamous cell carcinomas.

Abstract Background The development of non-small cell lung carcinoma proceeds through a series of well-defined pathological steps before the appearance of invasive lung carcinoma. The molecular changes that correspond with pathology changes are not well defined and identification of the molecular events may provide clues on the progression of intraepithelial neoplasia in the lung, as well as suggest potential targets for chemoprevention. The acquisition of anti-apoptotic signals is critical for the survival of cancer cells but the pathways involved are incompletely characterized in developing intra-epithelial neoplasia (IEN). Methods We used immunohistochemistry to determine the presence, relative levels, and localization of proteins that mediate anti-apoptotic pathways in developing human bronchial neoplasia. Results Bronchial epithelial protein levels of the phosphorylated (active) form of AKT kinase and the caspase inhibitor cIAP-2 were increased in more advanced grades of bronchial IEN lesions than in normal bronchial epithelium. Additionally, the percentage of biopsies with nuclear localization of p65/RELA in epithelial cells increased with advancing pathology grade, suggesting that NF-κB transcriptional activity was induced more frequently in advanced IEN lesions. Conclusion Our results indicate that anti-apoptotic pathways are elevated in bronchial IEN lesions prior to the onset of invasive carcinoma and that targeting these pathways therapeutically may offer promise in prevention of non-small cell lung carcinoma.

Introduction: A previous meta-analysis indicated stable progress in cognitive functions in early psychosis, assessed through various tools. To avoid assessment-related heterogeneity, this study aims to examine the longitudinal cognitive function changes in early psychosis utilizing the MATRICS Consensus Cognitive Battery (MCCB)., Methods: Embase, PubMed, and Scopus were systematically searched from their inception to September 26th 2023. The inclusion criteria were longitudinal studies that presented follow-up MCCB data for individuals experiencing first-episode psychosis (FEP) and those with ultra-high risk for psychosis (UHR)., Results: Twelve studies with 791 participants (566 FEP patients and 225 healthy controls) were subjected to analysis. Suitable UHR studies were absent. Over time, both FEP patients and healthy controls showed significant improvements in MCCB total scores. Furthermore, FEP patients demonstrated improvements across all MCCB domains, while healthy controls only showed augmentations in specific domains such as speed of processing, attention, working memory, and reasoning and problem-solving. Visuospatial learning improvements were significantly greater in FEP patients compared to healthy controls. Subgroup analyses suggested that neither diagnostic type nor follow-up duration influenced the magnitude of cognitive improvement in FEP patients., Conclusion: The magnitude of cognitive improvement for MCCB domains was not significantly different between FEP and healthy controls other than visuospatial learning. This underscores visuospatial learning as a potentially sensitive cognitive marker for early pathologic state changes in psychotic disorders., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in the current study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Violent offending committed by people with schizophrenia has been a public concern. The present study aims to examine the incidence of violent offending among people with schizophrenia and its correlations with mental health resources and economic factors. In this study, an examination of violent offending by people with schizophrenia and those identified as not criminally responsible on account of mental disorder (NCRMD) between 2010 and 2019 in China's Hunan province was undertaken. Principal component analysis (PCA) and regression analyses were used to explore the association of violent offending in people with schizophrenia and those identified as NCRMD with violent offending in the general population, mental health medical resources, and provincial GDP. Between 2010 and 2019, a total of 2,093 people with schizophrenia committed violent offending in Hunan province, including 1,374 (65.6%) cases identified as NCRMD. Over the period, the incidence of violent offending in people with schizophrenia and those identified as NCRMD has been decreasing. The incidences were positively correlated with the incidence of violent offending in the general population and negatively associated with mental health resources and provincial GDP. These findings may be valuable in helping to develop strategies for violence prevention and risk management for people with schizophrenia., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

The kagome metal CsV[Formula: see text]Sb[Formula: see text] is an ideal platform to study the interplay between topology and electron correlation. To understand the fermiology of CsV[Formula: see text]Sb[Formula: see text], intensive quantum oscillation (QO) studies at ambient pressure have been conducted. However, due to the Fermi surface reconstruction by the complicated charge density wave (CDW) order, the QO spectrum is exceedingly complex, hindering a complete understanding of the fermiology. Here, we directly map the Fermi surface of the pristine CsV[Formula: see text]Sb[Formula: see text] by measuring Shubnikov-de Haas QOs up to 29 T under pressure, where the CDW order is completely suppressed. The QO spectrum of the pristine CsV[Formula: see text]Sb[Formula: see text] is significantly simpler than the one in the CDW phase, and the detected oscillation frequencies agree well with our density functional theory calculations. In particular, a frequency as large as 8,200 T is detected. Pressure-dependent QO studies further reveal a weak but noticeable enhancement of the quasiparticle effective masses on approaching the critical pressure where the CDW order disappears, hinting at the presence of quantum fluctuations. Our high-pressure QO results reveal the large, unreconstructed Fermi surface of CsV[Formula: see text]Sb[Formula: see text], paving the way to understanding the parent state of this intriguing metal in which the electrons can be organized into different ordered states., Competing Interests: Competing interests statement:The authors declare no competing interest.

This investigation explores the potential efficacy of machine learning algorithms (MLAs), particularly convolutional neural networks (CNNs), in distinguishing between benign and malignant breast cancer tissue through the analysis of 1000 breast cancer images gathered from Kaggle.com, a domain of publicly accessible data. The dataset was meticulously partitioned into training, validation, and testing sets to facilitate model development and evaluation. Our results reveal promising outcomes, with the developed model achieving notable precision (92%), recall (92%), accuracy (92%), sensitivity (89%), specificity (96%), an F1 score of 0.92, and an area under the curve (AUC) of 0.944. These metrics underscore the model's ability to accurately identify malignant breast cancer images. Because of limitations such as sample size and potential variations in image quality, further research, data collection, and integration of theoretical models in a real-world clinical setting are needed to expand the reliability and generalizability of these MLAs. Nonetheless, this study serves to highlight the potential use of artificial intelligence models as supporting tools for physicians to utilize in breast cancer detection., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Lam et al.)

The COVID-19 pandemic has strained health systems globally, with governments imposing strict distancing and movement restrictions. Little is known about the effects of the COVID-19 pandemic on sexual and reproductive health (SRH). This study examined perceived effects of COVID-19 on SRH service provision and use in the Asia-Pacific region. We conducted a qualitative study using semi-structured interviews with 28 purposively sampled SRH experts in 12 Asia-Pacific countries (e.g. United Nations, international and national non-governmental organisations, ministries of health, academia) between November 2020 and January 2021. We analysed data using the six-stage thematic analysis approach proposed by Braun and Clarke (2019). Interviewees reported that COVID-19 mitigation measures, such as transport restrictions and those that decreased the availability of personal protective equipment (PPE), reduced SRH service provision and use in most countries. SRH needs related to service barriers and gender-based violence increased. Systemic challenges included fragmented COVID-19 response plans and insufficient communication and collaboration, particularly between public and private sectors. SRH service-delivery challenges included COVID-19 response prioritisation, e.g. SRH staff task-shifting to COVID-19 screening and contact tracing, and lack of necessary supplies and equipment. Innovative SRH delivery responses included door-to-door antenatal care and family planning provision in the Philippines, online platforms for SRH education and outreach in Viet Nam, and increasing SRH service engagement through social media in Myanmar and Indonesia. To ensure continuation of SRH services during health emergencies, governments should earmark human and financial resources and prioritise frontline health-worker safety; work with communities and the private sector; and develop effective risk communications.

Introduction Platelet additive solutions (PASs) are nutrient media commonly used to replace and reduce the need for storage plasma. They are an alternative medium to maintain high-quality platelets lasting longer on the shelf for about seven days. Platelets with high titer of ABO antibody can pose a hemolytic transfusion reaction (HTR) risk if units are given across the ABO barrier. The risk of complication is greater when group O platelet is released to non-group O patients. The PAS has been known as a safe medium, where the titer of ABO antibodies is expected to be diluted. In this study, we compared the anti-A and anti-B antibody titers of apheresis platelets in PAS and non-PAS (plasma) as the suspending media. Methods A total of 20 apheresis platelet donors were selected, with seven from blood group A, eight from blood group B, and five from blood group O. The platelets were collected using an Amicus cell separator. They were suspended in PAS and plasma before being stored at a temperature range of 22-24 º  C. Anti-A (blood group B and O) and Anti-B (blood group A and O) antibody titers were measured and compared between the two suspending media. Wilcoxon signed-rank test is used for statistical analysis, and a p-value <0.05 is considered significant. Results The median titer of the anti-A antibody of apheresis platelets showed a significant difference between suspended in PAS (2.50) and plasma (4.00), p=0.002. Similar findings were also seen with the median titer of the anti-B antibody of apheresis platelet, in which it showed a significant difference between suspended in PAS (2.00) and plasma (4.00), p=0.004. It was observed that there was a significant reduction in both anti-A and anti-B antibody titers in the PAS as compared to the plasma group. Conclusion The decrease in ABO antibody titer in apheresis platelets stored with PAS can be beneficial for patients. This reduces the risk of HTRs if ABO-incompatible platelet units need to be issued. Thus, using PAS as a storage medium significantly improves platelet inventory management without compromising patient safety., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Adzahar et al.)

Introduction: Strengthening health systems in conflict-affected settings has become increasingly professionalised. However, evaluation remains challenging and often insufficiently documented in the literature. Many, particularly small-scale health system evaluations, are conducted by government bodies or non-governmental organisations (NGO) with limited capacity to publish their experiences. It is essential to identify the existing literature and main findings as a baseline for future efforts to evaluate the capacity and resilience of conflict-affected health systems. We thus aimed to synthesise the scope of methodological approaches and methods used in the peer-reviewed literature on health system evaluation in conflict-affected settings., Methods: We conducted a scoping review using Arksey and O'Malley's method and synthesised findings using the WHO health system 'building blocks' framework., Results: We included 58 eligible sources of 2,355 screened, which included examination of health systems or components in 26 conflict-affected countries, primarily South Sudan and Afghanistan (7 sources each), Democratic Republic of the Congo (6), and Palestine (5). Most sources (86%) were led by foreign academic institutes and international donors and focused on health services delivery (78%), with qualitative designs predominating (53%). Theoretical or conceptual grounding was extremely limited and study designs were not generally complex, as many sources (43%) were NGO project evaluations for international donors and relied on simple and lower-cost methods. Sources were also limited in terms of geography (e.g., limited coverage of the Americas region), by component (e.g., preferences for specific components such as service delivery), gendered (e.g., limited participation of women), and colonised (e.g., limited authorship and research leadership from affected countries)., Conclusion: The evaluation literature in conflict-affected settings remains limited in scope and content, favouring simplified study designs and methods, and including those components and projects implemented or funded internationally. Many identified challenges and limitations (e.g., limited innovation/contextualisation, poor engagement with local actors, gender and language biases) could be mitigated with more rigorous and systematic evaluation approaches., (© 2023. The Author(s).)

Background: Next-generation sequencing comprehensive genomic panels (NGS CGPs) have enabled the delivery of tailor-made therapeutic approaches to improve survival outcomes in patients with cancer. Within the China Greater Bay Area (GBA), territorial differences in clinical practices and health care systems and strengthening collaboration warrant a regional consensus to consolidate the development and integration of precision oncology (PO). Therefore, the Precision Oncology Working Group (POWG) formulated standardized principles for the clinical application of molecular profiling, interpretation of genomic alterations, and alignment of actionable mutations with sequence-directed therapy to deliver clinical services of excellence and evidence-based care to patients with cancer in the China GBA., Methods: Thirty experts used a modified Delphi method. The evidence extracted to support the statements was graded according to the GRADE system and reported according to the Revised Standards for Quality Improvement Reporting Excellence guidelines, version 2.0., Results: The POWG reached consensus in six key statements: harmonization of reporting and quality assurance of NGS; molecular tumor board and clinical decision support systems for PO; education and training; research and real-world data collection, patient engagement, regulations, and financial reimbursement of PO treatment strategies; and clinical recommendations and implementation of PO in clinical practice., Conclusion: POWG consensus statements standardize the clinical application of NGS CGPs, streamline the interpretation of clinically significant genomic alterations, and align actionable mutations with sequence-directed therapies. The POWG consensus statements may harmonize the utility and delivery of PO in China's GBA.

Background: The COVID-19 pandemic pushed governments worldwide to implement unprecedented mitigation measures, including safe-distancing, lockdowns, disruption of non-essential services, border closures and travel restrictions, with both potential to affect rural and urban service-users differently and unintended consequences including reductions in sexual and reproductive health (SRH) services. We aimed to explore rural-urban differences in progress and challenges in SRH services provision in Cambodia, particularly during initial months of the COVID-19 pandemic., Methods: We used a mixed-methods study design, including a household survey of 423 adolescents and women aged 18-49 and semi-structured interviews with 21 healthcare providers. We analysed survey data using multivariable logistic regression to identify associations between rural-urban setting and contraceptive perceptions or access. We analysed interview data thematically., Results: Rural-urban residence was significantly associated with reported perceptions about and access to contraceptives. Rural participants had higher odds of stating it was possible to change contraceptive methods early in the COVID-19 pandemic, compared with urban participants. Qualitative data showed that although SRH services continued, health-workers faced differential challenges in rural and urban areas, e.g. service-users not attending due to job losses in urban areas and not complying with safe-distancing and mask-wearing requests in rural areas., Conclusions: COVID-19 and inadequate mitigation responses differentially affected rural and urban SRH service providers and service-users, exacerbating existing socioeconomic stressors while adding new fears of infection, transport constraints, and reduced livelihoods. Added financial support could help mitigate challenges in both rural and urban areas., (© 2023. The Author(s).)

The kagome metal CsV 3 Sb 5 features an unusual competition between the charge-density-wave (CDW) order and superconductivity. Evidence for time reversal symmetry breaking (TRSB) inside the CDW phase has been accumulating. Hence, the superconductivity in CsV 3 Sb 5 emerges from a TRSB normal state, potentially resulting in an exotic superconducting state. To reveal the pairing symmetry, we first investigate the effect of nonmagnetic impurity. Our results show that the superconducting critical temperature is insensitive to disorder, pointing to conventional s -wave superconductivity. Moreover, our measurements of the self-field critical current ( I c , sf ), which is related to the London penetration depth, also confirm conventional s -wave superconductivity with strong coupling. Finally, we measure I c , sf where the CDW order is removed by pressure and superconductivity emerges from the pristine normal state. Our results show that s -wave gap symmetry is retained, providing strong evidence for the presence of conventional s -wave superconductivity in CsV 3 Sb 5 irrespective of the presence of the TRSB.

LiF-NaF-ZrF 4 multicomponent molten salts are promising candidate coolants for advanced clean energy systems owing to their desirable thermophysical and transport properties. However, the complex structures enabling these properties, and their dependence on composition, is scarcely quantified due to limitations in simulating and interpreting experimental spectra of highly disordered, intermediate-ranged structures. Specifically, size-limited ab initio simulations and accuracy-limited classical models used in the past are unable to capture a wide range of fluctuating motifs found in the extended heterogeneous structures of liquid salt. This greatly inhibits our ability to design tailored compositions and materials. Here, accurate, efficient, and transferable machine learning potentials are used to predict structures far beyond the first coordination shell in LiF-NaF-ZrF 4 . Neural networks trained at only eutectic compositions with 29% and 37% ZrF 4 are shown to accurately simulate a wide range of compositions (11-40% ZrF 4 ) with dramatically different coordination chemistries, while showing a remarkable agreement with theoretical and experimental Raman spectra. The theoretical Raman calculations further uncovered the previously unseen shift and flattening of bending band at ∼250 cm -1 which validated the simulated extended-range structures as observed in compositions with higher than 29% ZrF 4 content. In such cases, machine learning-based simulations capable of accessing larger time and length scales (beyond 17 Å) were critical for accurately predicting both structure and ionic diffusivities., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

We estimated the degree to which language used in the high-profile medical/public health/epidemiology literature implied causality using language linking exposures to outcomes and action recommendations; examined disconnects between language and recommendations; identified the most common linking phrases; and estimated how strongly linking phrases imply causality. We searched for and screened 1,170 articles from 18 high-profile journals (65 per journal) published from 2010-2019. Based on written framing and systematic guidance, 3 reviewers rated the degree of causality implied in abstracts and full text for exposure/outcome linking language and action recommendations. Reviewers rated the causal implication of exposure/outcome linking language as none (no causal implication) in 13.8%, weak in 34.2%, moderate in 33.2%, and strong in 18.7% of abstracts. The implied causality of action recommendations was higher than the implied causality of linking sentences for 44.5% or commensurate for 40.3% of articles. The most common linking word in abstracts was "associate" (45.7%). Reviewers' ratings of linking word roots were highly heterogeneous; over half of reviewers rated "association" as having at least some causal implication. This research undercuts the assumption that avoiding "causal" words leads to clarity of interpretation in medical research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown., Methods: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCV sig ) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs., Results: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCV sig . A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCV sig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCV sig in cell lines and organoids., Conclusions: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients., (© 2022. The Author(s).)

Background: Childhood vaccination is among the most effective public health interventions available for the prevention of communicable disease, but coverage in many humanitarian settings is sub-optimal. This systematic review critically evaluated peer-review and grey literature evidence on the effectiveness of system-level interventions for improving vaccination coverage in protracted crises, focusing on how they work, and for whom, to better inform preparedness and response for future crises., Methods: Realist-informed systematic review of peer-reviewed and grey literature. Keyword-structured searches were performed in MEDLINE, EMBASE and Global Health, CINAHL, the Cochrane Collaboration and WHOLIS, and grey literature searches performed through the websites of UNICEF, the Global Polio Eradication Initiative (GPEI) and Technical Network for Strengthening Immunization Services. Results were independently double-screened for inclusion on title and abstract, and full text. Data were extracted using a pre-developed template, capturing information on the operating contexts in which interventions were implemented, intervention mechanisms, and vaccination-related outcomes. Study quality was assessed using the MMAT tool. Findings were narratively synthesised., Results: 50 studies were included, most describing interventions applied in conflict or near-post conflict settings in sub-Saharan Africa, and complex humanitarian emergencies. Vaccination campaigns were the most commonly addressed adaptive mechanism (n = 17). Almost all campaigns operated using multi-modal approaches combining service delivery through multiple pathways (fixed and roving), health worker recruitment and training and community engagement to address both vaccination supply and demand. Creation of collaterals through service integration showed generally positive evidence of impact on routine vaccination uptake by bringing services closer to target populations and leveraging trust that had already been built with communities. Robust community engagement emerged as a key unifying mechanism for outcome improvement across almost all of the intervention classes, in building awareness and trust among crisis-affected populations. Some potentially transformative mechanisms for strengthening resilience in vaccination delivery were identified, but evidence for these remains limited., Conclusion: A number of interventions to support adaptations to routine immunisation delivery in the face of protracted crisis are identifiable, as are key unifying mechanisms (multi-level community engagement) apparently irrespective of context, but evidence remains piecemeal. Adapting these approaches for local system resilience-building remains a key challenge., (© 2022. The Author(s).)

Quantum materials exhibit intriguing properties with important scientific values and huge technological potential. Electrical transport measurements under hydrostatic pressure have been influential in unraveling the underlying physics of many quantum materials in bulk form. However, such measurements have not been applied widely to samples in the form of thin flakes, in which new phenomena can emerge, due to the difficulty in attaching fine wires to a thin sample suitable for high-pressure devices. Here, we utilize a home-built direct laser writing system to functionalize a diamond anvil to directly integrate the capability of conducting electrical transport measurements of thin flakes with a pressure cell. With our methodology, the culet of a diamond anvil is equipped with a set of custom-designed conducting tracks. We demonstrate the superiority of these tracks as electrodes for the studies of thin flakes by presenting the measurement of pressure-enhanced superconductivity and quantum oscillations in a flake of MoTe 2 .

With dual goals of efficient and accurate modeling of solvation thermodynamics in molten salt liquids, we employ ab initio molecular dynamics (AIMD) simulations, deep neural network interatomic potentials (NNIP), and quasichemical theory (QCT) to calculate the excess chemical potentials for the solute ions Na + and Cl - in the molten NaCl liquid. NNIP-based molecular dynamics simulations accelerate the calculations by 3 orders of magnitude and reduce the uncertainty to 1 kcal mol -1 . Using the Density Functional Theory (DFT) level of theory, the predicted excess chemical potential for the solute ion pair is -178.5 ± 1.1 kcal mol -1 . A quantum correction of 13.7 ± 1.9 kcal mol -1 is estimated via higher-level quantum chemistry calculations, leading to a final predicted ion pair excess chemical potential of -164.8 ± 2.2 kcal mol -1 . The result is in good agreement with a value of -163.5 kcal mol -1 obtained from thermo-chemical tables. This study validates the application of QCT and NNIP simulations to the molten salt liquids, allowing for significant insights into the solvation thermodynamics crucial for numerous molten salt applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Governmental awareness of the potential spread of infectious disease, exemplified by the current Covid-19 pandemic, ideally results in collective action, as countries coordinate a response that benefits all, contributing expertise, resources, knowledge and experience to achieve a common public good. However, operationalising regional cooperation is difficult, with barriers including lack of political will, regional heterogeneity, and existing geopolitical issues. We interviewed 23 people with regional expertise focusing on Asia, Africa, the Americas and Europe. All interviewees held senior positions in regional bodies or networks or had significant experience working with them. Operationalisation of a regional infectious disease body is complex but areas interviewees highlighted-organisational factors (e.g. integration and harmonisation; cross-border issues; funding, financing and sustainability; capacity-building; data sharing); governance and diplomacy (e.g. building collaborations and partnerships; communication; role of communities; diplomacy; leadership; ownership; sovereignty; political commitment); and stakeholders and multilateral agreements-will help promote successful operationalisation. The international infectious disease community has learned valuable lessons from the Covid-19 pandemic, not least the necessity of pooling human, financial and technological resources, constructing positive working relationships with neighbours, and sharing data. Without this kind of regional cooperation, infectious diseases will continue to threaten our future, and the next pandemic may have even more far-reaching effects., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Durrance-Bagale et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

An effective Monitoring and Evaluation (M&E) framework helps vaccination programme managers determine progress and effectiveness for agreed indicators against clear benchmarks and targets. We aimed to identify the literature on M&E frameworks and indicators used in national vaccination programmes and synthesise approaches and lessons to inform development of future frameworks. We conducted a scoping review using Arksey and O'Malley's six-stage framework to identify and synthesise sources on monitoring or evaluation of national vaccination implementation that described a framework or indicators. The findings were summarised thematically. We included 43 eligible sources of 4291 screened. Most (95%) were in English and discussed high-income (51%) or middle-income (30%) settings, with 13 in Europe (30%), 10 in Asia-Pacific (23%), nine in Africa (21%), and eight in the Americas (19%), respectively, while three crossed regions. Only five (12%) specified the use of an M&E framework. Most (32/43; 74%) explicitly or implicitly included vaccine coverage indicators, followed by 12 including operational (28%), five including clinical (12%), and two including cost indicators (5%). The use of M&E frameworks was seldom explicit or clearly defined in our sources, with indicators rarely fully defined or benchmarked against targets. Sources focused on ways to improve vaccination programmes without explicitly considering ways to improve assessment. Literature on M&E framework and indicator use in national vaccination programmes is limited and focused on routine childhood vaccination. Therefore, documentation of more experiences and lessons is needed to better inform vaccination M&E beyond childhood.

Since the early stages of the COVID-19 pandemic, there have been reports of increased violence against women globally. We aimed to explore factors associated with reported increases in gender-based violence (GBV) during the pandemic in the Asia-Pacific region. We conducted 47 semi-structured interviews with experts working in sexual and reproductive health in 12 countries in the region. We analysed data thematically, using the socio-ecological framework of violence. Risks associated with increased GBV included economic strain, alcohol use and school closures, together with reduced access to health and social services. We highlight the need to address heightened risk factors, the importance of proactively identifying instances of GBV and protecting women and girls through establishing open and innovative communication channels, along with addressing underlying issues of gender inequality and social norms. Violence is exacerbated during public health crises, such as the COVID-19 pandemic. Identifying and supporting women at risk, as well as preventing domestic violence during lockdowns and movement restrictions is an emerging challenge. Our findings can help inform the adoption of improved surveillance and research, as well as innovative interventions to prevent violence and detect and protect victims.

Background: During the COVID-19 pandemic, over 99% of adults in Hong Kong use face masks in public. With the limited supply of face masks in the market and the uncertainty about the future development of COVID-19, reusing face masks is a legitimate way to reduce usage. Although this practice is not recommended, reusing face masks is common in Hong Kong. This study aimed to examine the practice of reusing face masks among adults in Hong Kong during the COVID-19 pandemic and its association with their health beliefs toward this health crisis., Methods: A cross-sectional descriptive study was conducted. A quota sample of 1000 adults was recruited in Hong Kong in April 2020. Guided by the Health Belief Model, the subjects were invited to answer questions on their practice of reusing face masks and health beliefs toward COVID-19 through telephone interview. Their practice on reuse, storage, and decontamination of used face masks were summarized by descriptive statistics. The difference in health beliefs between the subjects who reused and did not reuse face masks was examined by conducting an independent t test. The association between health beliefs and reuse of face masks was determined by conducting a logistic regression analysis., Results: One-third (n = 345, 35.4%) of the subjects reused face masks in an average of 2.5 days. Among them, 207 subjects stored and 115 subjects decontaminated their used face masks by using various methods. The subjects who reused face masks significantly perceived having inadequate face masks (t = 3.905; p <  0.001). Having a higher level of perception of having inadequate face masks increased the likelihood of reusing face masks (OR = 0.784; CI 95%: 0.659-0.934; p = 0.006)., Conclusion: Despite having 90 face masks in stock, the adults who reused face masks significantly perceived that they had inadequate face masks. Concerted effort of health care professionals, community organizations, and the government will improve individuals' practice in use of face masks and alleviate their actual and perceived feeling of having inadequate face masks, which lead them to reuse.

Lithium-based molten salts have attracted significant attention due to their applications in energy storage, advanced fission reactors, and fusion devices. Lithium fluorides and particularly 66.6%LiF-33.3%BeF 2 (Flibe) are of considerable interest in nuclear systems, as they show an excellent combination of favorable heat transfer, neutron moderation, and transmutation characteristics. For nuclear salts, the range of possible local structures, compositions, and thermodynamic conditions presents significant challenges in atomistic modeling. In this work, we demonstrate that atom-centered neural network interatomic potentials (NNIPs) provide a fast method for performing molecular dynamics of molten salts that is as accurate as ab initio molecular dynamics. For LiF, these potentials are able to accurately reproduce ab initio interactions of dimers, crystalline solids under deformation, crystalline LiF near the melting point, and liquid LiF at high temperatures. For Flibe, NNIPs accurately predict the structures and dynamics at normal operating conditions, high-temperature-pressure conditions, and in the crystalline solid phase. Furthermore, we show that NNIP-based molecular dynamics of molten salts are scalable to reach long time scales (e.g., nanosecond) and large system sizes (e.g., 10 5 atoms) while maintaining ab initio density functional theory accuracy and providing more than 3 orders of magnitude of computational speedup for calculating structure and transport properties.

The urban forest is a green infrastructure system that delivers multiple environmental, economic, social and health services, and functions in cities. Environmental benefits of urban trees are well understood, but no review to date has examined how urban trees affect human health. This review provides a comprehensive summary of existing literature on the health impacts of urban trees that can inform future research, policy, and nature-based public health interventions. A systematic search used keywords representing human health, environmental health, and urban forestry. Following screening and appraisal of several thousand articles, 201 studies were conceptually sorted into a three-part framework. Reducing Harm, representing 41% of studies, includes topics such as air pollution, ultraviolet radiation, heat exposure, and pollen. Restoring Capacities, at 31%, includes attention restoration, mental health, stress reduction, and clinical outcomes. Building Capacities, at 28%, includes topics such as birth outcomes, active living, and weight status. The studies that were reviewed show substantial heterogeneity in purpose and method yet indicate important health outcomes associated with people's exposure to trees. This review will help inform future research and practice, and demonstrates why urban forest planning and management should strategically promote trees as a social determinant of public health.

Competing Interests: Author disclosures The authors report no actual or potential conflicts of interest with regard to this article.

The aim of this randomized phase II study was to investigate the optimal timing of the administration of thrombopoietin to prevent cytarabine-induced thrombocytopenia. Fifty-two patients who were scheduled for high-dose cytarabine treatment were randomly assigned to receive either the standard prophylactic mode (starting thrombopoietin, 15,000 units/day on days 2-11) or the pre-chemo mode (starting thrombopoietin, 15,000 units/day on days -4, -2, and 2-9) during the first cycle of chemotherapy with a switch to the other mode in the second cycle. The thrombocytopenia rate in the standard mode and the pre-chemo mode were PLT < 50 × 10 9 /L, 67.3% versus 46.2% (p = .001); and PLT < 25 × 10 9 /L, 48.1% versus 26.9% (p = .001). The platelet transfusion rate was reduced in pre-chemo mode, with 7 patients requiring 10 units of platelets, whereas 13 patients required 24 units in standard mode (p = .038). Grade III/IV thrombopoietin-related toxicity was not observed. The prophylactic use of thrombopoietin was effective and safe. Trial registration: ChiCTR-OPB-15007591.

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct subtype of peripheral T-cell lymphoma with unique clinical and pathological features. This study aim to design a prognostic model specifically for AITL, providing risk stratification in affected patients. A total of 115 newly diagnosed AITL patients were retrospectively analyzed. The estimated five-year overall survival (OS) rate for all patients was 45.4%. Multivariate analysis found prognostic factors for survival were bone marrow involvement, number of extranodal sites >1, and performance status >1. We categorized three risk groups: group 1, no adverse factor; group 2, one factor; and group 3, two or three factors. Five-year OS was 86.9% for Group 1, 46.3% for Group 2, and 16.2% for Group 3 (p < .0001). The novel prognostic model balanced the distribution of patients into different risk groups with better predictive discrimination as compared to the International Prognostic Index and Prognostic Index for PTCL, unless otherwise specified.

Purpose Traditional and complementary medicine (T&CM) strategies are commonly used in pediatric oncology. Patterns may vary based on country income. We systematically reviewed published studies describing T&CM use among pediatric oncology patients in low-income countries (LIC/LMIC), middle-income countries (UMIC), and high-income countries (HIC). Objectives included describing estimated prevalence of use, reasons for use, perceived effectiveness, modalities used, rates of disclosure, and reporting of delayed or abandoned treatment. Methods MEDLINE, EMBASE, Global Health, CINAHL, PsycINFO, Allied and Complementary Medicine Database, Cochrane Database of Systematic Reviews, and ProceedingsFirst were searched. Inclusion criteria were primary studies involving children younger than the age of 18 years, undergoing active treatment of cancer, and any T&CM use. Exclusion criteria included no pediatric oncology-specific outcomes and studies involving only children off active treatment. Data were extracted by two reviewers using a systematic data extraction form determined a priori. Results Sixty-five studies published between 1977 and 2015 were included, representing 61 unique data sets and 7,219 children from 34 countries. The prevalence of T&CM use ranged from 6% to 100%. Median rates of use were significantly different in LIC/LMIC (66.7% ± 19%), UMIC (60% ± 26%), and HIC (47.2% ± 20%; P = .02). Rates of disclosure differed significantly by country income, with higher median rates in HIC. Seven studies reported on treatment abandonment or delays. Conclusion The use of T&CM in pediatric oncology is common worldwide, with higher median prevalence of use reported in LIC/LMIC. Further research is warranted to examine the impact on treatment abandonment and delay.

Sotos syndrome (SS) represents an important human model system for the study of epigenetic regulation; it is an overgrowth/intellectual disability syndrome caused by mutations in a histone methyltransferase, NSD1. As layered epigenetic modifications are often interdependent, we propose that pathogenic NSD1 mutations have a genome-wide impact on the most stable epigenetic mark, DNA methylation (DNAm). By interrogating DNAm in SS patients, we identify a genome-wide, highly significant NSD1(+/-)-specific signature that differentiates pathogenic NSD1 mutations from controls, benign NSD1 variants and the clinically overlapping Weaver syndrome. Validation studies of independent cohorts of SS and controls assigned 100% of these samples correctly. This highly specific and sensitive NSD1(+/-) signature encompasses genes that function in cellular morphogenesis and neuronal differentiation, reflecting cardinal features of the SS phenotype. The identification of SS-specific genome-wide DNAm alterations will facilitate both the elucidation of the molecular pathophysiology of SS and the development of improved diagnostic testing.

Background: The Balance Evaluation Systems Test (BESTest) is a relatively new balance assessment tool. Recently, the Mini-BESTest and the Brief-BESTest, which are shortened versions of the BESTest, were developed., Objective: The purpose of this study was to estimate interrater and intrarater-interoccasion reliability, internal consistency, concurrent and convergent validity, and floor and ceiling effects of the 3 BESTests and other related measures, namely, the Berg Balance Scale (BBS), Functional Gait Assessment (FGA), and Activities-specific Balance Confidence (ABC) Scale, among patients with total knee arthroplasty (TKA)., Design: This was an observational measurement study., Methods: To establish interrater reliability, the 3 BESTests were administered by 3 independent raters to 25 participants with TKA. Intrarater-interoccasion reliability was evaluated in 46 participants with TKA (including the 25 individuals who participated in the interrater reliability experiments) by repeating the 3 BESTests, BBS, and FGA within 1 week by the same rater. Internal consistency of each test also was assessed with Cronbach alpha. Validity was assessed in another 46 patients with TKA by correlating the 3 BESTests with BBS, FGA, and ABC. The floor and ceiling effects also were examined., Results: The 3 BESTests demonstrated excellent interrater reliability (intraclass correlation coefficient [ICC] [2,1]=.96-.99), intrarater-interoccasion reliability (ICC [2,1]=.92-.96), and internal consistency (Cronbach alpha=.96-.98). These values were comparable to those for the BBS and FGA. The 3 BESTests also showed moderate-to-strong correlations with the BBS, FGA, and ABC (r=.35-.81), thus demonstrating good concurrent and convergent validity. No significant floor and ceiling effects were observed, except for the BBS., Limitations: The results are generalizable only to patients with TKA due to end-stage knee osteoarthritis., Conclusions: The 3 BESTests have good reliability and validity for evaluating balance in people with TKA. The Brief-BESTest is the least time-consuming and may be more useful clinically., (© 2015 American Physical Therapy Association.)

Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents., (©2015 American Association for Cancer Research.)

In the field of medicine, there is strong emphasis on the healing of others, but not as much on the healing of self. It is therefore not surprising that physicians may be ill-equipped to not only care for other physicians, but to be treated as patients. Multiple studies indicate that relatively few physicians have their own primary physicians and often rely on self-treatment, rather than obtaining comprehensive care from other physicians. Through the lens of a personal struggle with serious illness, the author develops a discussion about potential barriers physicians face in seeking care, the downstream effects of physicians' perceptions of health care, and ways to make changes to prevailing physician health attitudes. Potential changes at the undergraduate, graduate, and continuing medical education levels are considered, in order to help physicians both to embrace their roles as patients and also better serve their colleagues who are under their care.

Background: Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume., Methods and Results: Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis., Conclusions: This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Two experiments tested and confirmed the hypothesis that when the phenomenological characteristics of imagined events are more similar to those of related autobiographical memories, the imagined event is more likely to be considered to have occurred. At Time 1 and 2-weeks later, individuals rated the likelihood of occurrence for 20 life events. In Experiment 1, 1-week after Time 1, individuals imagined 3 childhood events from a first-person or third-person perspective. There was a no-imagination control. An increase in likelihood ratings from Time 1 to Time 2 resulted when imagination was from the third-person but not first-person perspective. In Experiment 2, childhood and recent events were imagined from a third- or first-person perspective. A significant interaction resulted. For childhood events, likelihood change scores were greater for third-person than first-person perspective; for recent adult events, likelihood change scores were greater for first-person than third-person perspective, although this latter trend was not significant., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Chromosomal microarray (CMA) is currently the first-tier genetic test for patients with idiopathic neuropsychiatric diseases in many countries. Its improved diagnostic yield over karyotyping and other molecular testing facilitates the identification of the underlying causes of neuropsychiatric diseases. In this study, we applied oligonucleotide array comparative genomic hybridization as the molecular genetic test in a Chinese cohort of children with DD/ID, autism or MCA., Results: CMA identified 7 clinically significant microduplications and 17 microdeletions in 19.0% (20/105) patients, with size of aberrant regions ranging from 11 kb to 10.7 Mb. Fourteen of the pathogenic copy number variant (CNV) detected corresponded to well known microdeletion or microduplication syndromes. Four overlapped with critical regions of recently identified genomic syndromes. We also identified a rare de novo 2.3 Mb deletion at 8p21.3-21.2 as a pathogenic submicroscopic CNV. We also identified two novel CNVs, one at Xq28 and the other at 12q21.31-q21.33, in two patients (1.9%) with unclear clinical significance. Overall, the detection rate of CMA is comparable to figures previously reported for accurately detect submicroscopic chromosomal imbalances and pathogenic CNVs except mosaicism, balanced translocation and inversion., Conclusions: This study provided further evidence of an increased diagnostic yield of CMA and supported its use as a first line diagnostic tool for Chinese individuals with DD/ID, ASD, and MCA.

22q11.2 deletion syndrome (22q11.2DS) is a multi-systemic disorder with high phenotypic variability. Under-diagnosis in adults is common and recognition of facial dysmorphic features can be affected by age and ethnicity. This study aims to determine the prevalence of undiagnosed 22q11.2DS in adult Chinese patients with conotruncal anomalies and to delineate their facial dysmorphisms and extra-cardiac manifestations. We recruited consecutively 156 patients with conotruncal anomalies in an adult congenital heart disease (CHD) clinic in Hong Kong and screened for 22q11.2DS using fluorescence-PCR and fluorescence in-situ hybridization. Assessment for dysmorphic features was performed by a cardiologist at initial screening and then by a clinical geneticist upon result disclosure. Clinical photographs were taken and childhood photographs collected. Eighteen patients (11.5%) were diagnosed with 22q11.2DS, translating into 1 previously unrecognized diagnosis of 22q11.2DS in every 10 adult patients with conotruncal anomalies. While dysmorphic features were detected by our clinical geneticist in all patients, only two-thirds were considered dysmorphic by our cardiologist upon first assessment. Evolution of facial dysmorphic features was noted with age. Extra-cardiac manifestations included velopharyngeal incompetence or cleft palate (44%), hypocalcemia (39%), neurodevelopmental anomalies (33%), thrombocytopenia (28%), psychiatric disorders (17%), epilepsy (17%) and hearing loss (17%). We conclude that under-diagnosis of 22q11.2DS in Chinese adults with conotruncal defects is common and facial dysmorphic features may not be reliably recognized in the setting of adult CHD clinic, referral for genetic evaluation and molecular testing for 22q11.2DS should be offered to patients with conotruncal defects., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacologic characterization of the pyridopyrimidinone derivative XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (α, β, γ, and δ) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP(3) in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects.

This retrospective study examined the levels of appreciation (applause) given by clients to Human Factors/Ergonomic (HFE) specialists after they have modified the systems of work. Thirteen non-academic projects were chosen because the HFE interventions involved changed the way workers work at their workplaces. Companies involved range from multi-national corporations and military organizations with thousands of employees to small trading companies with less than 10 employees. In 5 cases the HFE recommendations were fully adopted and well appreciated. In 4 they were largely ignored and not appreciated, with partial adoption and some appreciation in the other 4 cases. Three factors that predict appreciation were identified: (i) alignment between the benefits HFE can provide and the project's key performance indices; (ii) awareness of HFE among the client's senior management; and (iii) a team organization appropriate for applying HFE recommendations. Having an HFE specialist on the client's side can greatly increase levels of appreciation, but lack of such a specialist will not affect levels of appreciation. A clear contractual requirement for HFE intervention does not promote appreciation significantly, but its absence can greatly reduce levels of appreciation. These relationships are discussed using the Kano's model of quality. Means to generate greater appreciation of the benefits of HFE are discussed., (Copyright © 2013 Elsevier Ltd and The Ergonomics Society. All rights reserved.)

Despite the advances in the understanding of the molecular basis for oculopharyngeal muscular dystrophy in the last decade, it remains an underdiagnosed disease, especially among the Chinese. In the presence of a positive family history and late-onset ptosis, dysphagia, and proximal muscle weakness (its cardinal features), we suggest that PABPN1 gene analysis should be the first-line investigation to rule out this condition. Muscle biopsy can be reserved for atypical cases. Non-specific mitochondrial changes in the muscle specimens of these patients should be appreciated, so as to avoid diagnostic confusion. It is hoped that greater awareness among medical professionals and judicious use of PABPN1 gene analysis will lead to earlier diagnosis, better management, and avoidance of unnecessary invasive investigations of affected patients.