Pluripotent stem cells (PSCs) have the potential to revolutionise biomedical science; however, while it is simple to reproducibly obtain comparable, stable cell lines in mouse, those produced from human material typically show significant variability both within and between cell lines. This is likely due to differences in the cell identity of conventional mouse and human PSCs. It is hoped that recently identified conditions to reprogram human cells to a naïve-like state will produce better PSCs resulting in reproducible experimental outcomes and more consistent differentiation protocols. In this review we discuss the latest literature on the discovery of human naïve-like stem cells and examine how similar they are to both mouse naïve cells and the preimplantation human epiblast. Studies in mouse embryonic stem cells (mESCs) over many years have led to a detailed understanding of this cell state. While mouse cells are typically grown in a state of naïve pluripotency, equivalent to the naïve epiblast of the preimplantation blastocyst , human cin vitro they are analysed using criteria that are known to distinguish mouse naïve cells from primed cells. Such criteria include responses to extrinsic and intrinsic signalling pathways, the biophysical, biochemical and metabolic status of the cells, and the overall epigenetic and transcriptomic cell identity. However, recent advances in our understanding of the human embryo also allow direct comparisons to the naïve compartment in vivo. Recently, cells exhibiting human naïve epiblast molecular features have been described [There have been several attempts to generate human naïve pluripotent stem cells (nPSCs) over recent years. Most often when putative human naïve cells are generated escribed •,4••,5••in vitro in order to generate blastocyst-like embryos. Importantly, recent advances in RNA sequencing, particularly protocols for small cell numbers and even single cell sequencing, have made the analysis of these embryos possible.The transcriptional identity of a cell is often considered to be a readout of the cell’s state , part 1.et al. [et al. [et al. observed four distinct cell types by unsupervised clustering which appear to represent two trophectoderm populations as well as extra-embryonic endoderm and epiblast cells based on their expression of known marker genes, as expected in a mature blastocyst. However, both studies identified only a handful of epiblast cells, giving a fairly small sample size for further analysis.Using such techniques, Yan et al. , and mor [et al. , obtaineet al., the embryo derived human naïve ESCs (hnESCs) from Guo et al. [in vitro culture. Interestingly, established human primed lines are separated from primed epiblast outgrowths along this same axis.Comparing the human naïve induced pluripotent stem cells (hniPSCs) of Takashima o et al. , the embo et al. . This inet al. took a different approach to comparing their datasets to published human embryo data. They identified genes that are expressed in specific embryonic stages in the dataset of Yan et al. They then looked for the proportion of these genes that were differentially expressed between their hniPSCs and conventional primed hESCs. While genes specifically expressed in embryonic epiblast were enriched in the hniPSCs, so were genes specific to the morula and all other cell types of the late blastocyst [et al. [et al. [et al. [Theunissen astocyst . This is [et al.  indicate [et al. , this ma [et al.  suggestsESRRB nor KLF2 were upregulated in any of these naïve lines; however, this may be due to differences between primate and rodent and the redundant use of paralogue genes such as Klf4 [KLF2 alongside NANOG. Takashima elegantly demonstrated that the behaviour of the transcription factor network in his hniPSCs closely corresponded to that of mouse ESCs with a knockout and rescue strategy. Mouse ESCs can support the single loss of either Esrrb or Tfcp2l1 due to redundancies in the network [TFCP2L1 in hniPSCs resulted in greatly reduced colony formation, indicating that most cells had stopped self-renewing. Application of exogenous ESRRB during this knockdown was able to rescue self-renewal. Together this provides strong evidence that an interactive transcription network highly similar to that in mouse is active in these cells.At the core of the naïve cell identity in mouse ESCs is a highly interconnected transcription factor network which shows remarkable redundancy ,11 Figu, part 2. as Klf4 ,7. It is network ,16, but  network . AccordiA broad array of signalling pathways interact to maintain or destabilise the naïve state in mouse ESCs , part 3.et al. [et al. [Given the importance of LIF and downstream JAK/STAT signalling in reprogramming and maintenance of mouse naïve PSCs ,22 and iet al.  found hL [et al.  show tha [et al. , it is a [et al. ,27. Furtet al. identified increased differentiation on their double inhibition [In mouse, Fgf2 and Activin A are both used to support the undifferentiated growth of primed EpiSCs ,29, whilhibition . Notablyhibition . This aphibition ,34. The hibition ,36, but hibition ; in thiset al. [et al. reveals a decrease in N-Cadherin on transition to the naïve state; however, both N-cadherin and E-cadherin are expressed in primed human ESCs, and there is no further increase in E-cadherin in the naïve cells [Given the poor survival of hniPSCs Theunissen et al.  found itet al. , it was et al. ,5••. In et al. , which cet al. . The preet al. ,40. The et al. ,42. Examve cells . It coulve cells .in vivo [in vitro and shows links to developmental disorders and tumourogenisis [Another distinctive feature of most cell states, and particularly the naïve state, is the epigenetic landscape , part 5.in vivo –46. It hin vivo ,48. Howein vivo . In linein vivo ,5••,8•, in vivo . Beyond in vivo , which iogenisis .Another epigenetic property of mouse naïve ESCs is the absence of a silent X-chromosome in females resulting in the presence of two active X-chromosomes , part 6.The status of the X-chromosome in female primed cells has also been somewhat contentious –61. Primin vivo in very late human blastocysts [Recently, it was shown that in the reprogramming of human primed cells to a naïve-like state the silent X-chromosome reactivates ,63•. Desstocysts ,9•,63•. in vivo counterpart, and mouse ESCs.Together, these studies indicate that there are epigenetic differences between current human nPSCs, their By the majority of measures, the most up to date culture systems have produced human pluripotent cells with similarities to both mouse naïve ESCs and to the human preimplantation epiblast. Nonetheless, there are still significant discrepancies. The signalling pathways active in these cells and the transcription factor network they support, appear to be very similar to, yet far less stable than, their equivalents in mouse ESCs. It is currently not possible to say whether the reduced stability of the human naïve state is due to interspecies differences, suboptimal culture conditions, or the possibility that we have not yet isolated bona fide human nPSCs.Evidence from Takashima and from Guo show that their naïve cells have undergone metabolic reprogramming, showing a significant level of mitochondrial respiration , part 7 in vivo [Interestingly, recent papers have identified novel hPSCs with broader chimerism and differentiation potential than naïve or primed cells. These respectively demonstrate the ability to form interspecies chimaeras and the ability to differentiate into both embryonic and extraembryonic lineages in vivo ,68. The in vitro studies will require demonstrating superior differentiation potential and reliability compared to conventional human ES cultures, and methods to simplify the generation and culture of these cells. By identifying cell surface markers specific to hnPSCs, Collier et al. [The next major hurdles in establishing hnPSCs as the standard for r et al.  present in vitro developmental studies, and possibly advances in cell therapies.While the conditions for differentiation protocols may need to be optimised for these new cells, it will be important to learn whether the promises of more homogeneous, less cell-line dependent differentiation from a naïve starting population can be delivered. If so, then this cell state could take over to become the accepted standard starting point for drug discovery models,


Adaptive learning and emergence of integrative cognitive system that involve not only low-level but also high-level cognitive capabilities are crucially important in robotics . GP-HSMM can segment continuous motion trajectories without defining a parametric model for each primitive. That comprises Gaussian process, which is a regression method based on Bayesian non-parametric, and hidden semi-Markov model. This method enables a robot to find motion primitives from complex human motion in an imitation learning scenario. Manipulation using the left and right arms is an essential capability for a cognitive robot. Zhang et al. proposed a neural-dynamic based synchronous-optimization scheme manipulators. It was demonstrated that the method enables a robot to track complex paths.First, three papers focused on action and behavior learning. Imitation learning is an important topic related to the integration of high-level and low-level cognitive capability because it enables a robot to acquire behavioral primitives from social interaction including observation of human behaviors. Andries et al. proposes the formalism for defining and identifying affordance equivalence. The concept of affordance can be regarded as a relationship between an actor, an action performed by this actor, an object on which the action is performed, and the resulting effect. Learning affordance, i.e., inter-dependency between action and object concept, is an important topic in this field. Taniguchi et al. proposed a new active perception method based on multimodal hierarchical Dirichlet process, which is a hierarchical Bayesian model for multimodal object concept formation method. The important aspect of the approach is that the policy for active perception is derived based on the result of unsupervised learning without any manually designed label data and reward signals.Second, two papers focused on the relationship between action and object concept. Hagiwara et al. proposed hierarchical spatial concept formation method based on hierarchical multimodal latent Dirichlet allocation (hMLDA). They demonstrated that a robot could form concept for places having hierarchical structure, e.g., “around a table” is a part of “dining room,” using hMLDA, and became able to understand utterances indicating places in a domestic environment given by a human user. Yamada et al. described representation learning method that enables a robot to understand not only action-related words, but also logical words, e.g., “or,” “and” and “not.” They introduced an neural network having an encoder-decoder architecture, and obtained successful and suggestive results. Taniguchi et al. proposed a new multimodal cross-situational learning method for language acquisition. A robot became able to estimate of each word in relation with modality via which each word is grounded.Third, three papers are related to language acquisition and concept formation. Nakamura et al. proposed Symbol Emergence in Robotics tool KIT (SERKET) that can integrate many cognitive modules developed using hierarchical Bayesian models, i.e., probabilistic generative models, effectively without re-implementation of each module. Integration of low-level and high-level cognitive capability and developing an integrative cognitive system requires researchers and developers to construct very complex software modules, and this is expected to cause practical problems. Serket can be regarded as a practical solution for the problem, and expected to push the research field forward.The final paper presents a framework for cognitive architecture based on hierarchical Bayesian models. With the tremendous success of the past three Special issues of this Research Topic, we organized follow-up workshopsAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The 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.


With the advent of the new era of immune therapy, new aspects of inflammation as a process involved in therapy, in tumorigenesis, and in several other human pathologies have been highlighted . This spin vitro studies, PAR4 can have a tumor suppressor role and can be used as a future therapeutic target. In endometrial cancer, S. Gu et al. show that tumor-associated macrophages are predominantly type 2 (M2) that contribute to the progression of this type of cancer and that the anti-CD27 therapy could have an antitumoral effect. Similarly, tumor-associated macrophages are reviewed by H. Degroote et al. in another type of cancer, hepatocellular carcinoma. The preclinical evolution and hitherto clinical trials for TAM-targeted therapy in HCC have been highlighted.It is possible to trait two distinct sections discussing inflammation aspects; a series of papers focusing on oncology and a series of papers focusing on other inflammation-related pathologies. From the first series of papers, M. Tampa et al. review the inflammatory markers of oral squamous cell carcinoma highlighting the main markers of inflammation that could improve early diagnosis. In esophageal squamous cell carcinoma cells, M. Wang et al. show that in A syndrome associated with cancer progression is cachexia, reviewed by E. Manole et al. The paper is describing several myokines produced and released by myocytes that can become potential biomarkers and future therapeutic targets.As already mentioned, immune therapy would be probably one of the major breakthroughs in oncology. C. Vajaitu et al. review checkpoint inhibitor new treatments and the role of inflammation in these therapies presenting biomarkers that could predict efficacy and immune therapy resistance.A. Calinescu et al. reviewed an inflammatory-related protein, carcinoembryonic antigen-related cell adhesion molecule 1, and its involvement in malignancies. The paper shows its importance as a prognostic factor in oncology and a future target specific cancer therapy.The second section of the special issue consists of reviews and original papers evaluating inflammation in various nononcological diseases. A. Pedrinolla et al. evaluate proinflammatory markers of age-related obesity. M. Bucur et al. highlight in their original paper that there are clear profibrotic and antifibrotic factors expression differences in oral mucosa and skin scars.M. Dobre et al. show that differences found in various transcript levels of inflammatory molecules could aid the differential diagnosis between ulcerative colitis and Crohn's disease. Chronic kidney disease could benefit from current proteomic approaches, as S. Mihai et al. are describing the inflammasomes and gut microbiota dysbiosis involvement in this disease and moreover in the renal malignancy.An in vivo animal model is shown by E. Codrici et al. where a caveolin-1-knockout mouse is thoroughly characterized and presented as a good inflammatory disease model. Another original paper by V.M. Anghelescu et al. shows the inflammatory pattern evaluation in animal models associated with various bone implants. Last, but not least, S.R. Georgescu et al. revise the traits of chronic inflammation in HPV infection that can lead to tumorigenesis.We are very satisfied that our subject resulted in so many valuable papers, and we would like to thank all the authors who submitted their work for consideration to this special issue. Without their effort, this special issue would have not taken place. Editors would like to thank the reviewers who thoroughly revised the papers and provided important suggestions that significantly improved the papers.


Given that “patience” is a recommended means to attain academic, social, and economic success (Mischel et al., Across disciplines (e.g., Mischel et al., Here, we argue that patience, which we define as the “ability to tolerate delay” (Barragan-Jason et al., Watts et al. suggest that “unobserved factors underlying children's delay ability may have driven long-run correlations” (in Watts et al., per se, that is key to explaining why patient children become more successful adults but, rather, a greater capacity to internalize behaviors as social norms during childhood. Specifically, successful adults may better internalize patience and other important abilities (e.g., cooperation: Gavrilets and Richerson, Consequently, our second argument is that it is not higher levels of patience, In conclusion, Watts et al.'s  study unGB-J and CA drafted the manuscript. AH, JS, and MC provided critical revisions. All the authors approved the final version of the manuscript for submission.The 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.


Saccharomyces cerevisiae. We further present the first cell-wide spatial proteome map of S. cerevisiae, generated using hyperLOPIT, a mass spectrometry-based protein correlation profiling technique. We compare protein subcellular localisation assignments from this map, with two published fluorescence microscopy studies and show that confidence in localisation assignment is attained using multiple orthogonal methods that provide complementary data.Subcellular protein localisation is essential for the mechanisms that govern cellular homeostasis. The ability to understand processes leading to this phenomenon will therefore enhance our understanding of cellular function. Here we review recent developments in this field with regard to mass spectrometry, fluorescence microscopy and computational prediction methods. We highlight relative strengths and limitations of current methodologies focussing particularly on studies in the yeast  Current Opinion in Chemical Biology 2019, 48:86–95OmicsThis review comes from a themed issue on Ileana M Cristea and Kathryn S LilleyEdited by Issue and the EditorialFor a complete overview see the Available online 29th November 2018https://doi.org/10.1016/j.cbpa.2018.10.026http://creativecommons.org/licenses/by/4.0/).1367-5931/© 2018 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license  . Importantly this method is able to determine proteins residing in multiple compartments and large protein complexes.A more rigorous and holistic approach has been afforded by hyperplexed Localisation of Organelle Proteins by Isotope Tagging (hyperLOPIT) ••,71, a S. cerevisiae [Fluorescent protein tagging has emerged as a powerful tool to visualise the localisations of individual proteins by microscopy on a cell-wide scale in revisiae . Variantrevisiae ,31,74,75revisiae  in whichrevisiae . Of 5330S. cerevisiae which facilitates the manipulation and generation of systematic organism libraries in a much more routine manner [A recent study has described the use of a new strategy (SWAp-Tag) in e manner •. This me manner •,27•. Ine manner . It is wet al. [et al. [et al. captured time-lapse films of protein localisation during culture and carried out localisation analysis in an automated fashion, whereas Tkach et al. captured localisation at a single time point and carried out localisation analysis manually. Using their method, Dénervaud et al. found 81 more re-localisation events in response to the same stress than were observed in Ref. [et al. [et al. [et al. further compared their data with the work of Tkach et al. who used one of the same stresses, to benchmark their protein re-localisation analysis method, finding that approximately half of their protein re-localisation predictions were in agreement with the Tkach study.Interrogation of published data for yeast protein subcellular localisation datasets highlights two issues. Firstly, many studies ,68••,69•et al.  of resul [et al.  interrog in Ref.  . We performed the experiment as described in Ref. [et al. [et al. [No comprehensive comparison of data acquired using a truly orthogonal method of capturing cell wide protein localisation with data arising from high throughput microscopy exists to date. Unlike other organisms, there is no data resulting from correlation profiling methods for  in Ref.  using th [et al.  that wer [et al. . We carr [et al.  to obtai [et al. ••,71  and can be interactively explored using the pRolocGUI [https://bioconductor.org/packages/pRolocGUI) or using the standalone online interactive app (https://proteome.shinyapps.io/yeast2018).All protein-level datasets are available in the R  BioconduRolocGUI  package • of special interest•• of outstanding interestPapers of particular interest, published within the period of review, have been highlighted as:


This study aims to assess the treatment adherence rate among People Living With HIV/AIDS (PLWHA) receiving treatment in a Nigerian tertiary Hospital.This was a cross-sectional study that assessed self-reported treatment adherence among adults aged 18 years and above who were accessing drugs for the treatment of HIV. Systematic random sampling method was used to select 550 participants and data were collected by structured interviewer administered questionnaire.The mean age of respondents was 39.9±10 years. Adherence rate for HIV patients was 92.6%. Factors affecting adherence include lack of money for transportation to the hospital (75%), traveling (68.8%), forgetting (66.7%), avoiding side effects (66.7%), and avoiding being seen (63.6%).The adherence rate was less than optimal despite advancements in treatment programmes. Adherence monitoring plans such as home visit and care should be sustained. Adherenive care . Rates oive care , 6, 7. Hive care . Adherenive care , 9-11. Iive care . The disive care , 14. Howive care . In Nigeive care  and Fedeive care . This reive care , 19. ParStigmatization has been documented as one of many factors related to varying ART adherence . BetweenThis study was conducted at the HIV clinic of University of Ilorin Teaching Hospital (UITH), Kwara State, a tertiary health care centre in middle-belt, Nigeria in 2012. It was a descriptive survey with analysis of the observed variables in PLWHA aged 18 years and above who are accessing treatment at the clinic. Self-reported treatment adherence rate was assessed among the respondents over the preceding 7 days to minimize recall bias. Respondents were asked to indicate how many pills they missed during each of the previous 7 days. The mean percent adherence was calculated based on the total number of pills taken divided by the total number of pills respondents reported being expected to take or prescribed by the doctor. In this study treatment adherence was defined as at least 95% of the prescribed dose of cART taken by the patient [2 is the abscissa of the normal curve that cuts off an area α at the tails ; p is the estimated proportion of an attribute that is present in the population  . Data weA total number of 550 HIV patients who met the criteria for the study were surveyed. The age distribution of the respondents ranged from 18 to 65 years with the mean age of 39.9 years±10.0 . A high et al [et al.[et al. [et al. [This study found out that 89.8% of the patients did not miss their drugs. Of those who missed their drugs only 27.3% of the prescribed antiretroviral drugs were taken by them. The mean adherence rate of all the respondents was 92.6%. Although this was below the optimal level of greater than 95% , 8, 9-11et al  in the set al . This stl [et al. in which.[et al.  and Ches [et al.  in whichet al. [et al. [et al. [et al. [et al. [et al [et al. [This study found that support from friend and family could improve treatment adherence. Higher proportion (27%) of patients that missed their drugs did not have support from friends and family. Support from friends and families could reduce psychological stress and financial burden especially in our environment where extended family system is practiced. Lack of money for transportation was also identified as a significant factor affecting treatment adherence. Seventy five percent of the patients who did not have money for transportation to keep hospital appointment missed their drugs. Lack of money for transportation has been reported in a similar study at Enugu, Nigeria by Uzochukwu et al.  and in M [et al. . Possibl [et al.  in a ter [et al.  Forgetfu [et al.  at the A. [et al  among HI [et al.  in BotswIn conclusion, we were able to demonstrate a mean adherence rate of 92.6% among all the respondents which was below the optimal level of greater than 95% but higher than the treatment adherence level of 70.8% reported  in the sOptimal management of PLWHA can be ensured if clients with indicators of poor adherence can be identified and closely monitored;ART treatment adherence rates of between 54% and 62.6% have been documented in Northern Nigeria;Stigmatization has been identified as one of several factors related to varying ART adherence.This study also found that factors affecting adherence include lack of money for transportation, feeling sick and depressed, running out of drugs at home, wanting to avoid side effects of drugs and no access to drugs due to unscheduled public holidays;Support from friends and family was found to be significantly associated with treatment adherence.The authors declare competing interests.


To describe the occurrence of psychiatric diagnoses in a specialist care setting in older people with intellectual disability (ID) in relation to those found in the same age group in the general population.n = 7936), aged 55 years or more in 2012, was identified, as was an age and sex-matched cohort from the general population (n = 7936). Information regarding psychiatric diagnoses during 2002–2012 was collected from the National Patient Register, which contains records from all inpatient care episodes and outpatient specialist visits in Sweden. The mean age at the start of data collection  was 53 years (range 44–85 years).A cohort of people with ID (n = 1382) of the people in the ID cohort had at least one psychiatric diagnosis recorded during the study period. The corresponding number in the general population cohort was 10% (n = 817), which translates to an odds ratio (OR) of 1.84. The diagnoses recorded for the largest number of people in the ID cohort were ‘other’ (i.e. not included in any of the diagnostic groups) psychiatric diagnoses (10% of the cohort had at least one such diagnosis recorded) and affective disorders (7%). In the general population cohort, the most common diagnoses were affective disorders (4%) and alcohol/substance-abuse-related disorders (4%). An increased odds of having at least one diagnosis was found for all investigated diagnoses except for alcohol/substance-abuse-related disorders (OR = 0.56). The highest odds for the ID cohort was found for diagnosis of psychotic disorder (OR = 10.4) followed by attention deficit/hyperactive disorder (OR = 3.81), dementia (OR = 2.71), personality disorder (OR = 2.67), affective disorder (OR = 1.74) and anxiety disorder (OR = 1.36). People with ID also had an increased odds of psychiatric diagnoses not included in any of these groups (OR = 8.02). The percentage of people with ID who had at least one diagnosis recorded during the study period decreased from more than 30% among those aged 55–59 years in 2012 (i.e. born 1953–1957) to approximately 20% among those aged 75+ years in 2012 (i.e. born in or before 1937).Seventeen per cent (Older people with ID seem to be more likely to have psychiatric diagnoses in inpatient or outpatient specialist care than their peers in the general population. If this is an effect of different disorder prevalence, diagnostic difficulties or differences in health care availability remains unknown. More research is needed to understand the diagnostic and treatment challenges of psychiatric disorders in this vulnerable group. In addition, they had to be alive at the end of that year. A one-to-one sex and age-matched control cohort from the general population (gPop cohort) was established by Statistics Sweden using the Swedish population register. People included in the ID cohort could not be included in the gPop cohort also. However, people with ID but without LSS support were not excluded from the gPop cohort.Swedish National Patient Register (NPR) is also managed by the Swedish National Board of Health and Welfare. It contains information about all in- and outpatient specialist care in Sweden. However, it does not contain information about visits to primary health care. For inpatient care, registration in the NPR is made at the date of discharge, and for outpatient care it is made at the date of the visit. For each registration, one primary and up to 21 secondary diagnoses are listed, coded according to the 10th revision of the International Classification of Disease (ICD-10).The Information on psychiatric diagnoses during the study period was obtained from the NPR for 2002–2012. The mean age at the start of data collection (i.e. 1 January 2002) was 53 years (range 44–85 years). These were categorised as attention deficit/hyperactivity disorder (ADHD) and equivalents, psychotic disorders, affective disorders, anxiety disorders, personality disorders, alcohol/substance-abuse-related disorders, dementia or other psychiatric disorders . Each peTo compare the number of people with at least one of each respective category of psychiatric diagnoses in the ID cohort to the corresponding number in the gPop cohort, we estimated odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. In order to illustrate possible age-effects, we performed age stratified analyses, using the 5-year age categories. Moreover, we investigated age effects within the ID cohort by comparing each age group to the youngest one. Statistical interaction was evaluated by introducing an interaction term (e.g. cohort*age group) to the logistic regression model, and trends were assessed by treating the category variable as a continuous factor.In order to evaluate using the LSS register as a proxy for ID, we performed sensitivity analyses on sub-cohorts of people with known diagnosis of either ID or ASD. Through diagnoses available from the NPR, we were able to identify 1145 men and 1002 women who had at least one diagnosis of ID (F7 in ICD-10) during 2002–2012. Moreover, we identified 242 men and 156 women who had at least one diagnosis of ASD . The overlap was 209 individuals. Analyses were made comparing psychiatric diagnoses among those with ASD only to those with ID only or ASD in combination with ID. Also, as people with ID may be difficult to diagnose with respect to psychiatric disorders, we performed sensitivity analyses including only diagnoses recorded at psychiatric clinics, i.e. by psychiatric specialists.p-value of 0.05 was considered statistically significant. All analyses were performed in IBM SPSS Statistics 23.Analyses were only performed if each of the two compared group comprised at least five observations. A two-tailed n = 2559 in each cohort), 44% among those aged 60–64 years (n = 2097), 46% among those aged 65–69 years (n = 1636), 48% among those aged 70–74 years (n = 839) and 53% among those aged 75+ years (n = 805).Each cohort comprised 7936 people, whereof 45% were women. The percentage of women increased over the age categories, with 43% among those aged 55–59 years  or the Diagnostic Criteria for psychiatric disorders for use with adults with Learning Disabilities/mental retardation (DC-LD). These are not identical with respect to diagnostic criteria, and so diagnoses may differ between them. Differences between diagnostic criteria have been found both in the general population .Over the 11-year study period, people with ID had three times higher odds than those in the general population to have .et al. b found a .psychotic disorders. This is well in line with previous studies investigating people with and without ID, where a considerable increase in overall psychotic disorders and schizophrenia specifically has been found for people with ID, regardless of which diagnostic system was used (Deb et al.et al.et al.et al.et al.The largest OR for people with ID compared with those in the general population in the present study was found for diagnoses of affective disorders among people with ID in the present study is similar to what has been found in other community-based populations (Deb et al.et al.et al. (The 74% increased odds for diagnoses of .et al.  found ananxiety disorders to be more common among people with ID than in the general population, which is in line with some (Gentile et al.et al.et al.et al.et al.et al.et al.et al. (et al. (et al. (We found diagnoses of .et al.  and Howl (et al. , as the  (et al.  had, howpersonality disorders among criminal offenders with ID, not much research has been published on this dual diagnosis in a more general ID population. The limited evidence available suggests that people with ID are at a greater risk for diagnoses of personality disorders (Pridding & Procter, et al.Although several studies have investigated substance-abuse-related disorder (McGillicuddy & Blane, et al.et al.et al.dementia diagnosis associated with having ID. Cooper et al. (et al. (et al. (People with ID seem to be more sensitive than the general population to developing a r et al.  and Care (et al.  both use (et al.  who let ADHD was the least frequent psychiatric diagnosis among people with ID, with less than one percent of the cohort getting a diagnosis during the study period. As people in this age group are unlikely to ‘lose’ their ADHD diagnosis, this number may be used as a prevalence estimate. Compared with other studies, it is a low one (Fox & Wade, et al.In the present study, The co-existence of ID and psychiatric disorders does not only have a negative impact on the individual, but also places a burden on the health care system and family members. Therefore, further research into the understanding of diagnosis and treatment of such disorders in this vulnerable group of people is vital.


Microbial production of chemical compounds often requires highly engineered microbial cell factories. During the last years, CRISPR-Cas nucleases have been repurposed as powerful tools for genome editing. Here, we briefly review the most frequently used CRISPR-Cas tools and describe some of their applications. We describe the progress made with respect to CRISPR-based multiplex genome editing of industrial bacteria and eukaryotic microorganisms. We also review the state of the art in terms of gene expression regulation using CRISPRi and CRISPRa. Finally, we summarize the pillars for efficient multiplexed genome editing and present our view on future developments and applications of CRISPR-Cas tools for multiplex genome editing. Current status of multiplex genome editing in bacteria and eukaryotic microorganisms using CRISPR-Cas tools. Industrial microbiology plays a key role in the transition towards a more sustainable industry to produce food and feed ingredients, bio-based materials, biofuels and direct synthesis of cosmetic and pharmaceutical compounds  are bacterial and archaeal adaptive immune defence systems, which can be repurposed as versatile genetic editing or regulation tools in a broad range of organisms. The effector endonucleases of these systems are guided by short RNA molecules encoded by CRISPR arrays. Native CRISPR arrays consist of a succession of spacers originating from invader organisms separated by direct repeats  and Cas12a (type V) in industrial microorganisms. Both bacterial and eukaryotic examples are described, although more attention is given to yeast and filamentous fungi, since the diversity of strategies using Cas endonucleases for genome editing applications is more extensive in this group of organisms.et al. et al. Streptococcus pyogenes (SpCas9) has become the most widely used RNA-guided endonuclease for genome editing and transcription regulation purposes  and a trans-activating CRISPR RNA (tracrRNA). To simplify gRNA expression, a synthetic chimeric construct named single guide RNA (sgRNA) can be synthesized by fusing the tracrRNA and the crRNA  (type V) can cleave dsDNA directed by a crRNA, hence without the requirement of a tracrRNA , non-homologous end joining repair (NHEJ) or alternative non-homologous end joining systems such as microhomology-mediated end joining (MMEJ)  have been designed by substituting one or more of the catalytic amino acids in the nuclease domains  are routinely used for gRNA expression  have also been demonstrated to yield multiple functional gRNAs in eukaryotes  as well  repeated usage of equal sets of promoters and terminators for gRNA expression, (ii) requirement for multiple selection markers, and more importantly, (iii) labor-intensive expression cassettes and plasmid construction. By expressing multiple gRNAs under the control of a single promoter, polycistronic expression cassettes overcome these hurdles. To date, two polycistronic cassette-based approaches have been shown that enable multiplex genome editing Fig. .et al. SpCas9 has been accomplished in S. cerevisiae    (Ryan and Cate S. cerevisiae or ∼50–100 bp for E. coli), to longer, PCR-based HFs for many bacteria, non-conventional yeasts and fungi (200–1000 bp) , either as single-stranded  of the dDNA. Commonly used dDNA sequences may vary from short-sized HFs  the presence of NHEJ or alternative-NHEJ repair systems, (ii) the presence of inefficient HDR systems, or (iii) an unfavorable balance between NHEJ and HDR repair mechanisms.et al. E. coli, Lactobacillus  relies on the stochastic allocation of dDNAs into the nucleus. In et al. Y. lipolytica , the frequency of targeted integration is significantly increased in multiple fungi  or the PCP and Com proteins (tested only in S. cerevisiae). By fusing the transcriptional activation domain SoxS (in E. coli) or VP64 (in S. cerevisiae) to these RNA binding proteins, expression of a gene downstream a target promoter can be enhanced, and pathway fluxes sequentially directed  obtained either through software prediction based on generalized well defined guide-design principles, preferential PAM domains and secondary structure prediction  for the specific host organism to be edited is required. Additionally, dDNA might be stabilized by chemical modifications , including techniques to incorporate repetitive DNA elements such as the repeat sequences of CRISPR arrays (Cress et al. et al. S. cerevisiae for the obtainment of up to 6 simultaneous deletions using SpCas9 with a efficiency of 23.3%. The strategy combined multiple successful strategies presented in this manuscript. Three transcripts (each of them containing two gRNAs flanked by tRNAgly sequences were expressed from a single plasmid encoding for SpCas9. The assembly of the plasmid via Golden Gate reaction was performed in the yeast (Zhang et al. Organism-specific CRISPR tools: smart choice of the CRISPR-Cas expression approach depending on final application of the production strain or the target organism of choice. For instance, CRISPR-Cas tools can be combined with the introduction of dDNA containing selective markers, which makes screening and selection of positive clones more efficient. This approach can be used in proof of principle studies, whereas in other cases, marker-free strains are important. In a similar way, guides and Cas nucleases can be co-expressed from plasmid-borne expression cassettes or expressed sequentially in strains pre-expressing the Cas nuclease from a second plasmid or from a genome integrated copy.Editing conditions: optimization of organism-specific CRISPR-Cas delivery systems and recovery protocols. Cell synchronization protocols in combination with CRISPR-Cas systems have been used in human cells to enhance HDR versus NHEJ repair (Lin et al. et al. et al. Novel or improved endonucleases: these endonucleases should have alternative or less-stringent PAM recognition selection. In addition, nucleases are preferred that are smaller, more specific and more active, as reviewed by Kleinstiver et al. (et al. et al. et al. et al. et al. et al. et al. et al. et al. (r et al. . Cas9 va. et al. , as well. et al. .In recent years, remarkable progress has been achieved in the field of multiplexed genome editing. Besides broadening the spectrum of microorganisms that can be engineered using CRISPR-Cas endonucleases, novel approaches have recently been implemented in terms of gRNA and dDNA delivery for increasing multiplexing efficiency. Below, a summary is provided of the major challenges related to the development of efficient multiplexing CRISPR-Cas systems in microorganisms.et al. et al. et al. et al. In multiplexed genome editing experiments, a negative correlation is experienced between the number of targets and the amount of obtained colonies after transformation in most microorganisms. The introduction of DSBs dramatically reduces the cell survival rate, and this causes limited numbers of simultaneous modifications as a delicate balance between DNA cleavage and repair needs to be established. Alternatively, multiplexed single-base editing does not depend on DSB generation nor dDNA supply and can be used to introduce nucleic acid base changes at a targeted window of DNA (Eid, Alshareef and Mahfouz Advances in multiplexed genome editing of microorganisms can significantly accelerate future strain construction programs of cell factories with unprecedented efficiencies. Therefore, the CRISPR revolution continues: new tools and workflows are being developed to broaden the range of functionalities of currently used CRISPR-Cas systems as well as knowledge about the mechanism of these systems. As identified in this review, dedicated optimization of each of the elements involved in CRISPR-Cas genome editing is crucial for efficient multiplex genome editing and for stretching the number of simultaneous editing events.


We read with interest the recent report by Reimann et al. , in whicn = 736) where diagnoses were assigned by a panel of dermatopathologists from a variety of different institutions [The scarcity of melanocytic neoplasms with known outcomes often necessitates use of histopathology-based reference standards, but such standards are limited by the inherent inter-observer variability and diagnostic discordance that occurs even among experts –6. The ditutions . When suitutions .either category—positive or negative—would have substantially improved concordance. In fact, in every circumstance, the classification strategy selected by Reimann et al. [The authors’ conclusions are also influenced by their decision to re-classify all cases with indeterminate myPath results as ‘benign’ in their calculations of sensitivity and specificity. The authors claim this was done to 'avoid exclusion of indeterminate results in statistical analysis,' yet their own indeterminate results are, in fact, excluded from statistical analyses. Cases that they declared ‘diagnostically ambiguous’ are eliminated from some calculations , and len et al.  is the on et al. , 13.Re-analysis of the data generated by Reimann et al.  using thThe accuracy of the myPath melanoma test has been evaluated in three separate peer-reviewed clinical validation studies , 11, 14


Humanitarian emergencies can impact people's psychosocial well-being and mental health. Providing mental health and psychosocial support (MHPSS) is an essential component of humanitarian aid responses. However, factors influencing the delivery MHPSS programmes have yet to be synthesised. We undertook a systematic review on the barriers to, and facilitators of, implementing and receiving MHPSS programmes delivered to populations affected by humanitarian emergencies in low- and middle-income countries.A comprehensive search of 12 bibliographic databases, 25 websites and citation checking was undertaken. Studies published in English from 1980 onwards were included if they contained evidence on the perspectives of adults or children who had engaged in or programmes providers involved in delivering, MHPSS programmes in humanitarian settings. Thirteen studies were critically appraised and analysed thematically.Community engagement was a key mechanism to support the successful implementation and uptake of MHPSS programmes. Establishing good relationships with parents may also be important when there is a need to communicate the value of children and young people's participation in programmes. Sufficient numbers of trained providers were essential in ensuring a range of MHPSS programmes were delivered as planned but could be challenging in resource-limited settings. Programmes need to be socially and culturally meaningful to ensure they remain appealing. Recipients also valued engagement with peers in group-based programmes and trusting and supportive relationships with providers.The synthesis identified important factors that could improve MHPSS programme reach and appeal. Taking these factors into consideration could support future MHPSS programmes achieve their intended aims. Populatet al.et al.et al.et al.et al.et al.et al.Notwithstanding the recommendations on MHPSS by the Inter-Agency Standing Committee, which advocates taking a wide range of possible responses to humanitarian emergencies, many empirically evaluated MHPSS programmes continue to draw from Western-based approaches to the treatment of trauma and trauma-related symptoms  definition of MHPSS and included any programme seeking ‘to protect or promote psychosocial well-being and/or prevent or treat mental disorder’ IASC, , p. 11.We conducted a comprehensive search of 12 electronic databases covering health and social science disciplines including Medline, PsycINFO and ASSIA, 13 specialist databases and grey literature portals, in addition to 25 topic-specific websites, consultation with experts and citation checking of includes. (See further details in the web appendix). Key index and free text search terms were determined by the review questions and the inclusion criteria. For example, the type of humanitarian emergency (e.g. war or typhoon or genocide), combined with the type of mental health and psychosocial intervention  and study design .et al.Search results were imported into EPPI-Reviewer 4: systematic review software . Piloting and refinement of tools took place before the commencement of full coding. The reliability and usefulness of studies were assessed using EPPI-Centre tools for qualitative studies using the following dimensions: sampling, data collection, data analysis, the extent to which the study findings were grounded in the data (criteria 1–4) and; the extent to which the study privileged the perspectives of participants, and breadth and depth of findings (criteria 5–6). An overall judgement of study quality was made according to two key dimensions. First, a weight of high, medium or low was assigned according to the reliability of the study using criteria 1–4. Second, a weight of high, medium or low was assigned according to the usefulness of the findings in answering the review question on contexts and barriers to implementation and receipt of MHPSS programmes using criteria 5–6. To be judged as ‘high’ quality on methodological reliability, studies needed to have taken steps to ensure rigour in at least three of the first four criteria. Studies were judged as ‘medium’ when scoring on only 2–3 criteria and ‘low’ when scoring on only one or none. To achieve a rating of high on usefulness in answering the review questions, studies needed to achieve depth and breadth in their findings and use methods that enabled participants to express their views on implementing or engaging in programmes. Studies rated as a medium on usefulness only met either one of these criteria and studies rated low were judged to have met neither criterion. Low-quality studies were not excluded from the review. Instead, quality judgements were used to inform the synthesis with none of the themes solely generated by studies judged as low on both dimensions  and immediately after an earthquake (n = 1), tier-three ‘focused, non-specialised supports’ programmes addressing the psychological and social impact of the Rwandan genocide (n = 3); while tier-two ‘community and family supports’ programmes primarily targeted children (n = 5) rather than adults (N = 1). Only one study addressed the basic services and security needs of affected populations. Overall, study quality was a combination of high or medium reliability and usefulness (n = 10). Of the four studies judged as being of low reliability, three contributed findings of medium usefulness  reference group responsible for the greater co-ordination of MHPSS in emergency settings IASC, . We founness see .Table 2et al.et al.et al.et al.A key theme across nine studies  they could ‘facilitate district health workers to establish and run mental health clinics’ (tier-four) in post-conflict Northern Uganda; however, their efforts were hindered by ‘an attrition of government health workers trained by the project’ (p. 298). Issues with staff retention meant a loss of knowledge and skills in being able to ‘recognise, assess, and manage mental illness’ (p. 298). Chauvin et al.  or tier-three MHPSS programmes (n = 1). The high-quality study by Song et al. (et al. (Even when services were more adequately staffed, there were concerns about the extent to which providers felt sufficiently skilled to deliver and address the mental health needs of the local population in tier-four (g et al.  reports g et al.  found thg et al.  found th (et al.  found th (et al. . report et al.et al.et al.Recipients across five studies evaluating tier-two MHPSS programmes (Boothby et al.et al.The extent to which engagement in MHPSS programmes was more enjoyable or meaningful to recipients when they included a range of activities, including creative or other forms of play was identified across three studies. Two studies were judged as highly reliable and providing medium useful findings (Nastasi et al. (et al.Sahin's et al.  evaluati. et al., p. 527.. et al., found t. et al. found thet al. (A further sub-theme, identified in two highly useful and medium reliable studies was the importance of culturally relevant activities to support engagement and increase programme impact. Interviews with FCSs in the study by Boothby et al.  found thet al.  reportedet al.et al.The benefits of group-based MHPSS programmes were cited in five studies (Nastasi et al.et al.et al.et al.et al.’s (A sub-theme in four studies was the importance of the group as a resource and a source of support. Two studies were judged as highly reliable and provided high (Christensen & Edward, et al.’s  evaluatiet al.’s  also fouet al. (Two studies, evaluating tier-three programmes for women in post-genocide Rwanda, provided highly useful evidence of medium reliability on the challenging but rewarding experience of sharing their personal stories with others. In the Healing of Life Wounds programme, King  found thet al.  reportedet al.A key theme across four studies (Boothby The importance of building trusting and supporting relationships was a sub-theme emerging from two studies judged to be of medium reliability and providing highly useful findings. In the post-earthquake city of Bam, Kunz  evaluatiet al. (In addition to the importance of building trusting and supportive relationships, programme recipients in three studies, providing highly useful findings of medium quality, also reflected on the individual qualities and attributes of programme providers, citing them as key factors in supporting them to participate and benefit from MHPSS programmes. For example, in the evaluation of a tier-three programme by King  adult suet al.  reportedet al. , p. 1153et al.et al.et al.et al.et al.et al.et al.A number of themes emerged from our synthesis. Community engagement was identified as a key mechanism to support the successful delivery and uptake of MHPSS programmes in humanitarian settings. In particular, mental health sensitisation and mobilisation strategies, and the need to develop effective partnerships with governments and local communities were seen as pivotal to increasing overall programme accessibility and reach. These findings resonate with a growing body of literature on contextual factors influencing effective implementation of MHPSS programmes in humanitarian settings (Kruk et al.et al.et al.et al.Another key mechanism contributing to the successful implementation of MHPSS programmes is ensuring they are delivered by sufficient numbers of trained providers. However, the recruitment and retention of practitioners sufficiently skilled to deliver MHPSS programmes continues to be an ongoing challenge, especially in resource-limited settings where there may be a lack of incentives to work in the mental health sector (Eisenbruch et al.et al.et al.et al.Another key theme was the importance of designing programmes that are socially and culturally meaningful to local populations to ensure they are appealing and achieve their intended aims. The importance of attending to cultural and ethical issues when supporting the mental health and psychosocial well-being of different groups is well documented (Chu A final theme in our synthesis concerned the importance of building trusting and supporting relationships between programme providers and recipients to maximise engagement and increase programme impact. We found that providers who could relate by bridging differences and show nurturing qualities, and who could act as role models, were highly valued. The wider research literature also attests to the value of establishing a robust and attuned therapeutic relationship to improve recipient outcomes (Norcross & Wampold, We have taken a systematic and transparent approach to synthesising qualitative evidence on the implementation and receipt of MHPSS programmes delivered to populations affected by humanitarian emergencies in LMICs; filling a notable gap in the evidence base. Although our search was successful in locating qualitative studies, their methodological reliability and usefulness varied. Some studies lacked analytical depth, and thus important themes may have been missed. The relatively smaller number of studies on the impact of natural disasters and the predominance of findings from post-conflict settings may also have obscured findings specifically relevant to those settings. Despite conducting a comprehensive and sensitive search, we cannot be certain that we found all relevant studies; in particular, we may not have identified grey literature or unpublished reports, which are more likely to include qualitative evidence on the process of implementing programmes. Limiting the review to English language studies also means key insights from other languages have not been included. However, despite these limitations, we developed a contextually rich synthesis exploring contextual factors that can be taken into consideration to facilitate greater programme feasibility, fidelity, acceptability and reach.This review has synthesised qualitative evidence from process evaluations on the implementation and receipt of MHPSS programmes delivered to people affected by humanitarian emergencies. Our findings suggest that future MHPSS programmes and services would benefit from continuing to invest in community engagement and outreach efforts to promote the value and improve the co-ordination of MHPSS services at local and national levels; explore models of best practice to support the training needs of providers, deliver culturally sensitive and socially appropriate MHPSS programmes for individuals and their families and build high quality therapeutic relationships to improve recipient engagement and outcomes. Further research should build on these findings and current practice recommendations, alongside evaluations of programme effectiveness. This could support better theorisation on the links between programme aims, choice of programme components, delivery mechanisms and how programmes intend to improve outcomes for affected populations.


BMC Medical Genomics.During June 10–12, 2018, the International Conference on Intelligent Biology and Medicine (ICIBM 2018) was held in Los Angeles, California, USA. The conference included 11 scientific sessions, four tutorials, one poster session, four keynote talks and four eminent scholar talks that covered a wide range of topics ranging from 3D genome structure analysis and visualization, next generation sequencing analysis, computational drug discovery, medical informatics, cancer genomics to systems biology. While medical genomics has always been a main theme in ICIBM, this year we for the first time organized the BMC Medical Genomics Supplement for ICIBM. Here, we describe 15 ICIBM papers selected for publishing in  For the past 6 years, the International Conference on Intelligent Biology and Medicine (ICIBM) meeting has been covering extensive cutting edge research topics in genome and medicine –5. At 20Predicting cellular responses to drugs has been a major challenge for personalized drug therapy regimen. In the first paper by Wang et al. , the autThe next paper by Zhang et al.  aimed toThe next paper from Fan et al.  proposedIn the next paper by Djotsa et al. , the autRELN and one exon in NOS1 more skipped in AD patients compared to cognitively normal elderly individuals, but also splicing-affecting SNPs associated with amyloid-β deposition in the brain. Their integrative analysis with multiple omics and neuroimaging data confers possible mechanisms for understanding AD pathophysiology through exon skipping. This result may provide a useful resource of a novel therapeutic development.The next study by Han et al.  was aimeIn the next paper by Menor et al. , a novelAlthough many methods have been developed for predicting the single nucleotide variant effects, only a few have been specifically designed for identifying deleterious sSNVs (synonymous single nucleotide variants). In the next work by Shi et al. , the autThe objective of Cheng et al.  was to uHaplotype phasing is important in cancer genomics, as it facilitates a comprehensive understanding of clonal architecture and further provides potentially valuable reference in clinical diagnosis and treatment. In the next paper of this supplement, Wang et al.  proposedThe paper by Li et al.  represenThe next paper by Chen and Xu  integratThe paper by Chiu et al.  presentsXia et al.  present During the past 11 years, genome-wide association studies have reported many thousands of association signals between genetic variants and a specific phenotype. Phenome-Wide Association Studies (PheWAS) take advantage of large patients-based cohorts with a panel of wide range of phenotypes and are well suited to facilitate new marker SNPs as well as SNPs with pleiotropy. The paper by Zhao et al.  presentsRNA-sequencing has now become a routine technique in genomic studies and data continue to accumulate with increasing rate in the public domain. This enables repurposing of existing data for new applications. In the final paper of this Supplement, Zeng et al.  presente


They also studied its pressure sensitivity and showed its application in smart cushions for monitoring human sitting positions. Lee et al. [2 nanoparticles in PDMS to improve the TENG performance. They also demonstrated the output enhancement using a windmill-integrated TENG system.Triboelectric Nanogenerators (TENG). Lee et al.  providede et al.  proposede et al.  investige et al.  proposede et al.  investig(2)Thermoelectric Nanogenerators. Culebras et al.  provided(3)7 cycles of tension and compression. The tension experiments showed stable polarization, while the compression experiments showed a 7% decrease in polarization. However, no notable decrease in output voltage was observed.Piezoelectric Nanogenerators. Shin et al.  investig(4)Metamaterial Nanogenerators. Lee et al.  investigNanogenerator-based technologies have found outstanding accomplishments in energy harvesting applications over the past two decades. These new power production systems include thermoelectric, piezoelectric, and triboelectric nanogenerators, which have great advantages such as eco-friendly low-cost materials, simple fabrication methods, and operability with various input sources. Since their introduction, many novel designs and applications of nanogenerators as power suppliers and physical sensors have been demonstrated based on their unique advantages. This Special Issue in Micromachines, titled “Nanogenerators in Korea”, compiles some of the recent research accomplishments in the field of nanogenerators for energy harvesting. It consists of 12 papers, which cover both the fundamentals and applications of nanogenerators, including two review papers. These papers can be categorized into four groups as follows:We would like to thank all the authors for their papers submitted to this Special Issue. We would also like to acknowledge all the reviewers for their careful and timely reviews to help improve the quality of this Special Issue.


I have read with interest the recent review paper by Southward and colleagues . While aReliability refers to the reproducibility of values of a given test . In sporWe have reported that caffeine ingestion in the dose of 6 mg/kg enhanced lower-body one-repetition maximum (1RM) strength and upper-body ballistic performance . A scrutJenkins et al.  tested tAstorino et al.  tested tAs discussed herein, the estimate by Southward et al.  that the


Antenatal common mental disorders (CMDs) including anxiety, depressive, adjustment, and somatoform disorders are prevalent worldwide. There is emerging evidence that experiencing a natural disaster might increase the risk of antenatal CMDs. This study aimed to synthesise the evidence about the prevalence and determinants of clinically-significant symptoms of antenatal CMDs among women who had recently experienced an earthquake.This systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The search included both electronic and manual components. Five major databases were searched. A data extraction table was used to summarise study characteristics and findings. Two authors examined the quality of studies independently using a quality assessment tool. A narrative synthesis of the findings reported.In total seven articles met inclusion criteria. Quality scores ranged from six to seven out of ten. All the studies were cross-sectional surveys and were conducted in high and middle-income countries. Sample sizes varied among studies. The prevalence of clinically-significant symptoms of antenatal CMD ranged from 4.6%  experiencing ‘psychological stress’ in Japan to 40.8%  ‘depression’ in China. While all studies were conducted in an earthquake context, only four examined some aspect of earthquake experiences as a risk factor for antenatal CMDs. In multivariable analyses, higher marital conflict, poor social support, multiparity, stresses of pregnancy and the personality characteristic of a negative coping style were identified as risks and a positive coping style as protective against antenatal CMDs.This systematic review found that women who have recently experienced an earthquake are at heightened risk of antenatal mental health problems. It indicates that in addition to the establishment of services for safe birth which is recognised in post-disaster management strategies, pregnancy mental health should be a priority. The review also revealed that there is no evidence available from the world’s low-income nations where natural disasters might have more profound impacts because local infrastructure is more fragile and where it is already established that women experience a higher burden of antenatal CMDs.CRD42017056501.PROSPERO- Antenatal common mental disorders (CMDs) which include anxiety, depressive, adjustment, and somatoform disorders  are prevSome determinants of antenatal CMDs in general circumstances have been established. Lancaster et al.’s  systematThere is limited empirical research about the links between experiences of a disaster and prevalence of antenatal CMDs. Harville et al.  conducteThese two systematic reviews included some papers reporting experiences of earthquakes, other natural disaster and antenatal CMDs and indicated that earthquake might increase the risk of antenatal CMDs , 7. HoweThe aim of this study was to identify and synthesise the evidence available about the prevalence and determinants of clinically-significant symptoms of antenatal CMDs among women who have recently experienced an earthquake.We used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines . The proThe search incorporated both electronic and manual components. The electronic databases: Psychi Info, Cochrane Library, PubMed, Scopus, Medline, Web of Science, CINAHL, ProQuest were searched. We used keywords, boolean operators and truncation to search for the relevant articles. The search terms were:  AND  AND (disaster* or earthquake*). These search terms revised according to the specificities of each database.The reference lists of articles that met inclusion criteria were searched manually to identify any further publications which had not been identified in the electronic searches.Eligibility criteria were that papers had to report studies from any country that: 1) were about women who had experienced an earthquake in the prior five years, 2) ascertained and reported the prevalence of symptoms of antenatal CMDs using a standard method, 3) had been published in the English in the peer-reviewed literature to October 31st 2017.A data extraction table was used to summarise study characteristics and findings. We summarised the prevalence of clinically-significant symptoms of CMDs and extracted or derived confidence interval, odds ratio, relative risk, coefficients, and significance of determinants of CMDs.Two authors (GKK and TDT) examined the quality of studies independently using a quality assessment tool designed by Greenhalgh  and modiThe steps to select eligible papers based on the eligibility criteria are reported in Fig. All the studies were conducted in Japan, Taiwan, or China. All were cross-sectional surveys. In total, data were contributed by 2209 women who had experienced an earthquake and 7381 women in comparison conditions who had not. Sample sizes varied among studies. The smallest was Hibino et al.’s investigation of 99  women anSix studies , 15–19 rAlthough all studies were conducted in an earthquake context, the magnitude of earthquakes, the distance between the study site and the epicentre, and timing of experience of the earthquakes varied among studies Table . The magThree studies , 17, 19 Three studies , 16, 17 All studies used a standardised screening tool to measure CMD. Five studies –17, 19 uThe prevalence of clinically-significant symptoms of antenatal CMD ranged from 4.6%  experiencing ‘psychological stress’ in Japan  to 40.8%Of four studies in China, two reported the prevalence of depressive symptoms among women who had experienced the earthquake during pregnancy: 7.1%   and 35.2Among the studies in Japan, Hibino et al.  found thWhile all studies examined some determinants, none included all potential risk and protective factors for pregnancy mental health problems , 5 Tabl. One stup = 0.002). Qu et al. [p < 0.001). However, there was no significant association between earthquake experiences and depressive symptoms [While all studies were conducted in an earthquake context, only four , 18, 19 u et al.  used a ssymptoms .r = − 0.372; p = 0.01), objective support  and support use  and EPDS total score. Subjective support remained significant  in multivariable analysis but the other two dimensions of social support were not significant [p < 0.05) [Ren et al.  used a snificant . Lau et nificant  found a  < 0.05) .p < 0.001) and depressive symptoms  compared to older women (≥30 years). Lau et al. [p < 0.05); but the association was not significant in multivariable analysis. Other studies [Three studies found a significant association of antenatal CMDs with at least one socio-demographic factor. Qu et al.  found inu et al.  also fou studies , 18, 19 p < 0.001), but they did not find an association with depressive symptoms in bivariate analysis. The significance for PTSD also disappeared in multivariate analysis. Lau et al. [p < 0.01) but the association was not significant in multivariable analysis. Dong et al. [Qu et al.  found thu et al.  found thg et al. , and Reng et al.  did not p = 0.001). In Lau et al. [p < 0.05); the association disappeared in multivariable analysis. Qu et al. [p < 0.001), but the association did not remain significant in a multivariable analysis. They also did not find a significant association between family income with depressive symptoms. In a similar case, Lau et al. [p < 0.01); the association was not significant in a multivariable analysis.Ren et al.  found thu et al. ‘s study,u et al.  found thu et al.  found thr = − 0.30, p < 0.01), ‘thoughts and feelings regarding the marriage and one’s spouse’ , and ‘agreement on relationship matter’  were significantly negatively correlated with EPDS scale score. However, the association did not remain significant in multivariable analysis. Lau et al. [p < 0.01). Qu et al. [r = − 0.18, p < 0.01) but the association was not significant with PTSD. They did not find any significant association with depressive symptoms or PTSD in multivariable analyses.While the quality of intimate partner relationship is consistently related to the mental health of pregnant women , only thu et al.  found thu et al.  found thp < 0.05) [p < 0.05) [p = 0.025) [p = 0.033) [Five studies –17, 19 e < 0.05) ; (ɳ = 0.= 0.025) ; (p = 0.p < 0.05) [p < 0.001) [p < 0.001) but not in multivariable analyses.Two studies found that multiparous women were more likely experiencing depressive symptoms than nulliparous women  . On the < 0.001)  did not p = 0.001) and depressive symptoms  [p < 0.001) [Qu et al.  and Dong< 0.001) ;  .p = 0.006). On the other hand, they found that a higher level of negative coping was a risk factor for depressive symptoms .Ren et al.  examinedp < 0.01). However, they did not find a significant association in multivariable analysis.Dong et al.  measuredIn summary, these studies reported that wounded relatives, poor social support, younger age, new residence of the study area, higher marital conflict, medium support from husbands, multiparity, the perceived stress of pregnancy, and negative coping were risks, and positive coping was protective against antenatal CMDs in multivariable analyses. It was also found that a higher composite score of earthquake experiences, younger age, and perceived stress of pregnancy were a risk factor for PTSD during pregnancy in multivariable analyses.To our knowledge, this is the first systematic review of the evidence available about clinically-significant symptoms of antenatal CMDs among women who had recently experienced an earthquake. It provides a narrative synthesis of the existing evidence, but we acknowledge that because of the heterogeneity of these studies, we could not conduct a meta-analysis and provide meaningful estimates of the prevalence of pregnancy mental health problems among women who have experienced an earthquake. We also acknowledge that as the review was limited to the English-language literature, it is possible that articles published in languages other than English have been missed. Nevertheless, this review provides a comprehensive summary and evaluation of the available evidence in the field.Only seven studies, all from high and middle-income countries met inclusion criteria for this review. They reported a wide range of prevalence of clinically-significant symptoms of antenatal CMDs. The differences in prevalence estimates might be attributable to study methods, but, as has been found in other post-disaster research, can reflect the local circumstances and post-disaster responses .. The studies had varied sample size—small to relatively large—and none justified the sample size or representative adequacy of the samples. This could bring varied results of prevalence of antenatal CMDs. In addition, different measures of psychological symptoms were used, which reduces comparability and might account in part for the wide variation in prevalence estimates. Most importantly, only two studies [Standard study methods include the use of an adequately powered sample size, following standard sample recruitment strategies, and the use of valid and reliable outcome measures studies , 16 usedThere were differences in earthquake characteristics and settings which might also have influenced the outcomes. It is likely that women who were near the epicentres had more severe earthquake experiences compared to those up to 90 km away and they were more likely to experience a higher prevalence of antenatal CMDs. For instance, Lau et al.  reportedThe wide prevalence estimates of pregnancy mental health problems might also be attributable to local circumstances and post-disaster response. Compared to the prevalence reported from China, the prevalence in Japan was consistently lower. Japan is a well-resourced country with experience of earthquakes and well-developed post-disaster practices. These may assist more rapid recovery of post-adversities and explain why Japanese women appear to have a less negative psychological impact from experiencing an earthquake. In general circumstances too, Japanese have less prevalence of mental health problems compared to other high-income countries . On the Dong et al.’s study  conducteWhile these studies contribute to enhancing understanding of the field, they do not show clearly whether and how much earthquake experiences determine the mental health of pregnant women. Without a robust examination of potential factors together with earthquake experiences, it is not possible to conclude whether and how much earthquake experiences contributed to increasing mental health problems during pregnancy. However, this evidence is crucial for making public health decisions about whether to address post-earthquake antenatal mental health problems with universal or targeted strategies.This systematic review found that women with recent direct experience of an earthquake appear to be at higher risk of clinically-significant antenatal CMD symptoms. These findings have implications for disaster responses. At present, the recommendation in this situation is that provisions for a safe birth and neonatal care  should bIt also identifies knowledge gaps, in particular, that there is no evidence about the mental health of women who are pregnant and living in low-income nations at the time of an earthquake.It is clearly a priority, that, despite the difficulties of conducting ethical, sensitive, comprehensive, culturally-competent research in such situations, it is needed in order to provide the evidence to inform effective interventions. At a minimum, this research should include standardised measures of earthquake experiences and examine all potential risk and protective factors in order to delineate the nature, prevalence and duration of antenatal mental health problems among women.


The annual prevalence of ADHD drug use was defined as the number of prevalent users per 1000 inhabitants.et al.et al.et al.et al.Next, we identified the subgroup focusing on the incident and persistent users of ADHD drugs. First, we defined the index date as the date on which the ADHD drug was first prescribed to the patient during the fiscal year of 2014. We included the patients who had been enrolled in the database at least 180 days before and after the index date, as in previous studies . All estimates were calculated with 95% confidence intervals (CI). All analyses were conducted using R version 3.4.1.v. 43%).There were 86 756 prevalent and 30 449 incident users of ADHD drugs in the database . The annet al.et al.et al.et al.et al.et al.et al.This is the first study to establish the representative prescribing practices of ADHD drugs in Japan. The prevalence of ADHD drug use in children and adolescents in Japan (0.4%) is much lower than that in the USA (5.3%)  than in the UK (94%)  than that in the USA (10–29% at 150 days) (Lawson The main limitation of this study is that the entire population was not accounted for in the database, which comprised 1–2% of all inhabitants. Nevertheless, our study provides representative evidence on the treatment pattern of ADHD drug use in children and adolescents in Japan.


Wireless microdevices are getting smaller and smaller, and in this special issue seven papers address a few miniaturization challenges in the biomedical field, which are common across different applications. Kargaran et al.  proposes


Understanding the long-term health impacts of the early-life exposome requires the characterization and assimilation of multi ‘omics’ data to ultimately link molecular changes to exposures. In this way, markers associated with negative health outcomes, such as increased disease risk, can be ascertained. However, determining the extent and direction of metabolic perturbations relies on comparisons to existing metabolomic reference profiles. While such resources are increasingly available for adult populations, analogous tools for children are decidedly lacking. Lau et al. have compiled robust, translatable quantitative metabolomics data on urine and serum samples for European children across six study locations. Metabolites were associated with body mass index, diet and demographics, and correlated within and between biofluids. As a result, a novel association between urinary 4-deoxyerythronic acid and body mass index was uncovered. This work serves as a crucial reference for future studies in exposomics, and – more broadly – represents a significant step forward for metabolomics by creating the foundation for a comprehensive reference metabolome for children.https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1190-8Please see related article:  BMC Medicine article, Lau et al. [In their recent u et al.  characteu et al. . The expu et al. . As statu et al. . Studiesu et al. .Metabolic syndrome is a collection of features, including obesity, hyperglycemia, and hypertension, which increase the risk of developing cardiovascular disease and type 2 diabetes (T2D) , 7. ObesTo define a set of metabolic markers that reflects the exposome first requires a high quality reference metabolome to be established. This was the primary objective of Lau et al. . Such a IDQ p180 kit, along with appropriately stringent inclusion criteria, generated reproducible quantitative information for 177 serum metabolites. While this is by no means a comprehensive characterization of the either metabolome , data from the Biocrates kit are highly precise, reproducible, and – importantly – translatable between laboratories and instruments [Recent work confirming diagnoses of various inborn errors of metabolism highlights the importance of a quantitative reference metabolome – not only for determining pathological elevations in target analytes, but also for untargeted approaches that aim to discover additional or improved metabolic markers . The useGenerating robust, high-quality quantitative data for both the urine and serum metabolomes was a prudent choice for Lau et al.; many differentiating metabolites from biomarker discovery studies remain unidentified. They cannot be quantified for use in a targeted clinical assay, or be linked to metabolic pathways, genomic or proteomic data , and thuThis study by Lau et al.  represen


Other external causes may be dietary. Such microbes are capable of shedding small, but functionally significant amounts of highly inflammagenic molecules such as lipopolysaccharide and lipoteichoic acid. Sequelae include significant coagulopathies, not least the recently discovered amyloidogenic clotting of blood, leading to cell death and the release of further inflammagens. The extensive evidence discussed here implies, as was found with ulcers, that almost all chronic, infectious diseases do in fact harbour a microbial component. What differs is simply the microbes and the anatomical location from and at which they exert damage. This analysis offers novel avenues for diagnosis and treatment.Since the successful conquest of many acute, communicable (infectious) diseases through the use of vaccines and antibiotics, the currently most prevalent diseases are chronic and progressive in nature, and are all accompanied by inflammation. These diseases include neurodegenerative , vascular  and autoimmune (e.g. rheumatoid arthritis and multiple sclerosis) diseases that may appear to have little in common. In fact they all share significant features, in particular chronic inflammation and its attendant inflammatory cytokines. Such effects do not happen without underlying and initially ‘external’ causes, and it is of interest to seek these causes. Taking a systems approach, we argue that these causes include ( The great enemy of truth is very often not the lie – deliberate, contrived and dishonest – but the myth – persistent, persuasive and unrealistic. Too often we hold fast to the clichés of our forebears. We subject all facts to a prefabricated set of interpretations. We enjoy the comfort of opinion without the discomfort of thought’. John F. Kennedy, Commencement Address, Yale University, June 11 1962‘These germs ‐ these bacilli ‐ are transparent bodies. Like glass. Like water. To make them visible you must stain them. Well, my dear Paddy, do what you will, some of them won't stain; they won't take cochineal, they won't take any methylene blue, they won't take gentian violet, they won't take any colouring matter. Consequently, though we know as scientific men that they exist, we cannot see them’. Sir Ralph Bloomfield‐Bonington. The Doctor's Dilemma. George Bernard Shaw, 1906.‘I.et al.,et al.,et al.,et al., A very large number of chronic, degenerative diseases are accompanied by inflammation. Many of these diseases are extremely common in the modern ‘developed’ world, and include vascular , autoimmune , and neurodegenerative  diseases. On the face of it these diseases are quite different from each other, but in fact they share a great many hallmarks  among o3; 25(OH)D3] and is indeed widely observed in inflammation 3 to 1,25‐dihydroxyvitamin D3 2D3); 1,25(OH)2D3 suppresses elements of the adaptive immune system while stimulating elements of the innate immune system D3, explaining how inflammation can simultaneously cause high 1,25(OH)2D3 and low 25(OH)D3 levels  and the cytochrome P450 enzyme CYP27B1 that converts 25(OH)Dm Bikle, . In addim Bikle,  1,25(OH)et al. 2D3 and low 25(OH)D3 levels et al., et al., 3 levels and Alzheimer's disease 2D3, and any effects of chronic conditions on the CYP enzymes that produce them. Biomarkers [such as taurinuria  et al., et al., et al., et al. 2D but assessed by serum 25‐hydroxyvitamin D (25(OH)D)) are inversely associated with hepcidin concentrations and are positively associated with levels of haemoglobin and iron'  and LL‐37 antimicrobial peptide, which lead to a reduction in plasma iron levels  the production of hydroxyl radicals, catalysed by ‘free’ iron that can itself lead to cell death (step 1); and (ii) the iron‐based reactivation of dormant microbes (step 2). In this section we concentrate on the first mechanism. Many reviews of general iron metabolism are available elsewhere  that affect its reactivity in two linked reactions involving peroxide and superoxide . The amount of ‘free’ iron varies, but Fe(III) salts are virtually insoluble at neutral pH ; the typical cytoplasmic levels of ‘free’ iron are in the range 1–10 µM .Both hydrogen peroxide and superoxide are common products of the partial reduction of oxygen by mitochondria, among other sources Kell, . HydrogeThe ferric iron can then react with superoxide in the Haber–Weiss reaction Kehrer,  generativia the products of such reactions, including 8‐hydroxy‐guanine  the reducing agent ascorbic acid (vitamin C) actually becomes a pro‐oxidant when poorly liganded, e.g. with ligands such as ethylene diamine tetraacetate (EDTA)  ferritin is an intracellular marker, so that the serum ferritin level (widely but erroneously used as a measure of iron status) is simply a sign of cell death  Kell, ; and  is known as eryptosis  et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., The inflammagenic potency of LPS is so great that it is commonly  even used as a model to induce symptoms more or less similar to many of the inflammatory diseases of interest. Typically this involves injecting LPS at the site of interest for such diseases. Examples of the use of endotoxin in this way include pre‐eclampsia et al., et al., et al., et al., et al., et al., et al., et al., et al., Gram‐positive bacteria have a cell wall structure that differs from that of Gram‐negatives both in its number of barriers and in the fact that the cell wall component equivalent to LPS is lipoteichoic acid (LTA). LTA is equivalently capable of producing an inflammatory response. In contrast to LPS, which mainly interacts with toll‐like receptor 4 (TLR4) . This opens up a considerable new biology et al., et al., et al., et al., There is considerable evidence that fibrin(ogen) can interact with other amyloid structures /ERK signalling pathways in macrophages and TLR4SAA seems to be a ligand for the receptor for advanced glycation end products (RAGE)  is also an important and potent amyloid. SAA belongs to a family of apolipoproteins associated with high‐density lipoprotein (HDL) in plasma and is an acute‐phase protein synthesised predominantly by the liver  is associated with a variety of diseases and coagulopathies  and of amyloids generally  between inflammation, cytokine production, amyloid formation and disease see Fig. . A varieXV.It is hard to disentangle diseases caused or exacerbated directly by inflammation from those where the mediating agent is explicitly a cytokine. Figure XVI.Induction of cell death will normally cause disease; for example, if the cells in the substantia nigra pars compacta die the patient will develop Parkinson's, and so on. A great many amyloids have been shown to be cytotoxic, and this is why they are considered in detail herein. What is less clear Uversky, , althouget al., et al., et al., et al., et al., et al., et al., et al.  fibrin amyloid, which is considerably larger in fibre diameter than those involved in classical amyloid diseases , with differences only apparent at a finer scale . The conditions considered herein are all chronic inflammatory diseases, often with quite slow kinetics, and are all in effect diseases of ageing  A systems biology strategy was used to show that chronic, inflammatory diseases have many features in common besides simple inflammation.(2) The physiological state of most microbes in nature is neither ‘alive’ (immediately culturable on media known to support their growth) nor ‘dead’ (incapable of such replication), but dormant.i) inoculation by microbes that become and remain dormant, largely because they lack the free iron necessary to replicate, and (ii) traumas that induce cell death and the consequent liberation of free iron; these together are sufficient to initiate replication of the microbes.(3) The inflammatory features of chronic diseases must have external causes, and we suggest that the chief external causes are ((4) This replication is accompanied by the production and shedding of potent inflammagens such as lipopolysaccharide or lipoteichoic acid, and this continuing release explains the presence of chronic, low‐grade inflammation.(5) Recent findings show that tiny amounts of these inflammagens can cause blood to clot into an amyloid form; such amyloid forms are also capable of inducing cell death and thereby exacerbating the release of iron.et al., (6) Additional to the formal literature that we have reviewed here, it seems to be commonly known that infection is in fact the proximal cause of death in Alzheimer's, Parkinson's, rheumatoid arthritis, multiple sclerosis, etc. It may, for instance, be brought on by the trauma experienced following a fall. Such infections leading to death in chronically ill patients may involve the re‐awakening of dormant bacteria rather than novel exogenous infection. This implies that therapies involving the careful use of anti‐infectives active against dormant microbes could be effective  The role of microbes in stomach ulcers is now well established (Marshall,