bluuebunny/crossref_metadata_2025 huggingface dataset:
p53, Pirh2, and L1CAM as Promising Prognostic Biomarkers of Endometrial Carcinoma: An Immunohistochemical and Genetic Study
Authors: Abdelrahman Aziza E. , Salem Amira , Al Attar Ahmed Z. , Elsebai Eman , Samy Walaa , Ibrahim Mohamed A. , Ibrahim Hanaa M.
Published: October 2022

Endometrial cancer (EC) is the most common gynecologic cancer and the current methods for the prediction of its prognosis and treatment response are unfortunately suboptimal. In this study, we evaluated the prognostic value of p53, Pirh2, and L1CAM in 60 cases of EC using immunohistochemistry (IHC) and polymerase chain reaction. TP53 missense mutations result in nuclear accumulation of p53 protein that can be detected as overexpression by IHC. This is in the form of diffuse strong nuclear positivity involving at least at least >50% of the tumor cells as a whole or if >50% of the tumor cells of a discrete geographical areas. Abnormal p53 IHC expression was expressed in 33.3% of the cases and significantly associated with the tumor grade, myometrial invasion (MI), lymphovascular invasion (LVSI), nodal metastasis, and FIGO stage, and the advanced European Society for Medical Oncology (ESMO) risk groups (P<0.001 for each). High IHC Pirh2 expression was noted in 58.3% of the cases, and significantly associated with MI, LVSI, nodal metastasis, FIGO stage, and high-risk group (P<0.001, P=0.011, P=0.010, P=0.024, P=0.005, respectively). There was a significant upregulation of Pirh2 mRNA expression in EC specimens as compared with the control adjacent tissues (P=0.001). Upregulated Pirh2 mRNA expression had a significant association with Pirh2 immunostaining, tumor grade, tumor stage, MI, lymph node involvement, LVSI, and relapse (P<0.001 for each). Positive L1CAM immunoexpression was noted in 26.7% and was significantly associated with grade, MI, LVSI, nodal metastasis, FIGO stage, and high-risk group (P=0.003, P=0.023, P=0.003, P<0.001, P<0.001, P=0.002, respectively). Analysis of follow-up period revealed that EC with abnormal p53 IHC expression, high pirh2 and positive L1CAM expression exhibited a potent relation with tumor relapse, shorter overall survival and disease-specific survival (P<0.001 for each). Mutant p53, high Pirh2, and L1CAM-positive EC are highly aggressive tumors with a shortened survival rate, dismal outcome, and high risk of relapse after the standard protocol of therapy.
Commentary on High-Flow Nasal Cannula and Continuous Positive Airway Pressure Practices After the First-Line Support for Assistance in Breathing in Children Trials
Authors: Shein Steven L. , Kneyber Martin C. J. , Rotta Alexandre T.
Published: October 2022

Continuous positive airway pressure (CPAP) and heated humidified high-flow nasal cannula (HFNC) are commonly used to treat children admitted to the PICU who require more respiratory support than simple oxygen therapy. Much has been published on these two treatment modalities over the past decade, both in Pediatric Critical Care Medicine (PCCM) and elsewhere. The majority of these studies are observational analyses of clinical, administrative, or quality improvement datasets and, therefore, are only able to establish associations between exposure to treatment and outcomes, not causation. None of the initial randomized clinical trials comparing HFNC and CPAP were definitive due to their relatively small sample sizes with insufficient power for meaningful clinical outcomes (e.g., escalation to bilevel noninvasive ventilation or intubation, duration of PICU-level respiratory support, mortality) and often yielded ambiguous findings or conflicting results. The recent publication of the First-Line Support for Assistance in Breathing in Children (FIRST-ABC) trials represented a major step toward understanding the role of CPAP and HFNC use in critically ill children. These large, pragmatic, randomized clinical trials examined the efficacy of CPAP and HFNC either for “step up” (i.e., escalation in respiratory support) during acute respiratory deterioration or for “step down” (i.e., postextubation need for respiratory support) management. This narrative review examines the body of evidence on HFNC published in PCCM, contextualizes the findings of randomized clinical trials of CPAP and HFNC up to and including the FIRST-ABC trials, provides guidance to PICU clinicians on how to implement the literature in current practice, and discusses remaining knowledge gaps and future research priorities.
Integration and Implementation of Patient-Reported Outcomes (PRO): A Prospective, Observational Clinical Quality Improvement Study
Authors: Rios-Diaz Arturo J. , Nathan Shelby L. , Cunning Jessica R. , Kozak Geoffrey M. , Messa Charles A. , Whitely Cutler B. , Davis Harrison D. , Thrippleton Sheri , Broach Robyn B. , Fischer John P.
Published: October 2022

Background:

Implementation of patient-reported outcomes (iPROs) represents a critical barrier to their widespread use and poses challenges to workflow and patient satisfaction. We sought to implement PRO surveys into surgical practice while identifying principles for successful/broader implementation.

Methods:

Outpatient surgical encounters (2016-2019) related to hernia, breast surgery, and post-bariatric body-contouring were assessed for the use of Abdominal-Hernia-Q (AHQ), BREAST-Q™, and BODY-Q™ surveys (implemented in that order). Outcomes were implementation rates/quarter and time to optimal implementation (≥80%). Successful implementation principles were identified during the first implemented PRO instrument and applied to subsequent ones. Logistic regression models were used to estimate increase in rate of implementation/quarter by instrument controlling for clinic volume. Risk-adjusted generalized linear models determined predicted mean differences in total clinic time and patient satisfaction.

Results:

1,206 encounters were identified. Overall survey implementation rate increased from 15% (first-quarter) to 90% (last-quarter; p<0.01). AHQ optimal implementation was reached by 15 months. Principles for successful iPROs were workflow optimization, appropriate patient selection, staff engagement, and electronic survey integration. Consistent application of these principles optimized time to optimal implementation for BREAST-Q™ (9 months; 18.1% increase in implementation/quarter [95% CI 1.5-37.5%]; p<0.01) and BODY-Q™ (3 months; 56.3% increase in implementation/quarter [95% CI 26.8-92.6%]; p=0.03). Neither patient clinic time (p=0.16) nor patient satisfaction differed during the iPRO process (p=0.98).

Conclusions:

Prospective iPROs can be achieved in surgical practice without an adverse effect on patient satisfaction or workflow. The proposed principles of implementation may be used to optimize efficiency for iPROs.
Minimally invasive, nerve and muscle sparing surgical decompression for occipital neuralgia
Authors: Pietramaggiori Giorgio , Scherer Saja
Published: October 2022

Background:

Occipital Neuralgia (ON) is a well-defined type of headache, whose treatment algorithm is still debated across medical specialties. From the analysis of the literature, it appears that surgical decompression of the occipital nerves is the most effective invasive approach to improve the quality of life of patients suffering from ON refractory to medications. We describe here a minimally invasive nerve and muscle sparing technique to decompress the occipital nerves.

Methods:

The results in terms of reduction of migraine days / month, use of medications, pain evaluation, and decrease in migraine headache index (MHI) were analyzed via a retrospective chart review of 87 patients who underwent nerve and muscle sparing surgical decompression of the greater and lesser occipital nerves mono- or bi-lateral in our institution and were followed up for at least 12 months. The surgical technique is described in detail.

Results:

Surgical decompression significantly reduced ON burden (at least 50% improvement) in 91% of patients, with 45% reporting a complete remission of occipital pain. Days with pain per month decreased by 80%, chronic background pain intensity decreased by 81% and pain intensity during crisis decreased by 76%. Accordingly, drug usage dropped by about 70%. Only minor complications were reported in 4 patients.

Conclusion:

The described technique could contribute to further attest surgical decompression as the first option among the invasive approaches to treat ON. Results corroborates previous findings adding a less invasive, nerve and muscle sparing approach.
Prevalence and Patterns of Renal Involvement Among Patients With Systemic Lupus Erythematous at a Tertiary Center
Authors: Hasan Manal Ahmed , Alali Lina , Alsadah Fatimah , Alobud Sarah , Alsaif Janat , Alali Zainab
Published: October 2022

Background

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by widespread inflammation and damage to multiple organ systems. One of the most common and severe manifestations of SLE is lupus nephritis (LN).

Objectives

To determine the prevalence of LN among subjects with SLE and to identify the demographic, clinical, and laboratory parameters of SLE in subjects diagnosed with LN.

Methods

This is a descriptive study conducted at a tertiary hospital. Medical records were reviewed from outpatients who visited between January 2015 and October 2019 and who has fulfilled the classification criteria for diagnosis of SLE and had LN.

Results

Among 365 patients with SLE, 36% had LN. The most prevalent World Health Organization class of LN was IV, which significantly correlated with both abnormal creatinine levels and nephrotic range proteinuria. Elevated serum creatinine correlated with the presence of hypertension and thrombocytopenia. Cutaneous manifestations were noted to be present in 100% of LN patients, followed by arthritis and/or arthralgia (82.9%), anemia (94.6%), and lymphopenia (87.6%).

Conclusion

This study aids in the recognition of the demographic, clinical, laboratory features, and the histological patterns of LN patients in Saudi Arabia, that probably has a role in the development and disease progression. A significant correlation was found between abnormal kidney function and hypertension, thrombocytopenia and nephrotic range proteinuria. The presence of World Health Organization class IV LN correlated with both impaired kidney function and nephrotic range proteinuria.
Unusual Cause of Iatrogenic Calcifications
Authors: Thoma Anna
Published: October 2022

We report a case of extended and painful subcutaneous calcifications due to local injections with pethidine.
Psychometric Evaluation of the Perceived Research Burden Assessment (PeRBA) in Longitudinal Studies of Alzheimer Disease Using Rasch Analysis
Authors: Keleman Audrey A. , Chang Chih-Hung , Bollinger Rebecca M. , Lingler Jennifer H. , Gabel Matthew , Stark Susan L.
Published: October 2022

Introduction:

The Perceived Research Burden Assessment (PeRBA) was developed to measure participant perceptions of burden in research studies. This study aimed to examine the psychometric properties of this assessment using Rasch analysis in participants in the longitudinal studies of the Alzheimer disease (AD) and their family members.

Methods:

PeRBA was administered to 443 participants in studies of AD and 212 family members across 4 Alzheimer Disease Research Centers. We used Rasch analysis to examine PeRBA’s psychometric properties, and data-model fit both at item and scale levels.

Results:

PeRBA demonstrated good reliability and item and person fit for participants and family members. A few items did not fit the model for participants or family members. Areas of content redundancy were found in items assessing similar amounts of perceived research burden. Areas of content gaps were also found, with no items assessing certain levels of perceived research burden.

Conclusion:

Analysis results support the good overall psychometric properties of PeRBA among research participants in studies of AD and their family members. Recommendations have been provided to improve the assessment, including rewording items and adding items that could account for a broader range of perceived research burden.
Journey of the mouse primitive endoderm: from specification to maturation
Authors: Chowdhary Sayali , Hadjantonakis Anna-Katerina
Published: October 2022

The blastocyst is a conserved stage and distinct milestone in the development of the mammalian embryo. Blastocyst stage embryos comprise three cell lineages which arise through two sequential binary cell fate specification steps. In the first, extra-embryonic trophectoderm (TE) cells segregate from inner cell mass (ICM) cells. Subsequently, ICM cells acquire a pluripotent epiblast (Epi) or extra-embryonic primitive endoderm (PrE, also referred to as hypoblast) identity. In the mouse, nascent Epi and PrE cells emerge in a salt-and-pepper distribution in the early blastocyst and are subsequently sorted into adjacent tissue layers by the late blastocyst stage. Epi cells cluster at the interior of the ICM, while PrE cells are positioned on its surface interfacing the blastocyst cavity, where they display apicobasal polarity. As the embryo implants into the maternal uterus, cells at the periphery of the PrE epithelium, at the intersection with the TE, break away and migrate along the TE as they mature into parietal endoderm (ParE). PrE cells remaining in association with the Epi mature into visceral endoderm. In this review, we discuss our current understanding of the PrE from its specification to its maturation.

This article is part of the theme issue ‘Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom’.
Embryonic and extraembryonic tissues during mammalian development: shifting boundaries in time and space
Authors: Thowfeequ Shifaan , Srinivas Shankar
Published: October 2022

The first few days of embryonic development in eutherian mammals are dedicated to the specification and elaboration of the extraembryonic tissues. However, where the fetus ends and its adnexa begins is not always as self-evident during the early stages of development, when the definitive body axes are still being laid down, the germ layers being specified and a discrete form or bodyplan is yet to emerge. Function, anatomy, histomorphology and molecular identities have been used through the history of embryology, to make this distinction. In this review, we explore them individually by using specific examples from the early embryo. While highlighting the challenges of drawing discrete boundaries between embryonic and extraembryonic tissues and the limitations of a binary categorization, we discuss how basing such identity on fate is the most universal and conceptually consistent.

This article is part of the theme issue ‘Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom’.
The extended analogy of extraembryonic development in insects and amniotes
Authors: Panfilio Kristen A. , Chuva de Sousa Lopes Susana M.
Published: October 2022

It is fascinating that the amnion and serosa/chorion, two extraembryonic (EE) tissues that are characteristic of the amniote vertebrates (mammals, birds and reptiles), have also independently evolved in insects. In this review, we offer the first detailed, macroevolutionary comparison of EE development and tissue biology across these animal groups. Some commonalities represent independent solutions to shared challenges for protecting the embryo (environmental assaults, risk of pathogens) and supporting its development, including clear links between cellular properties (e.g. polyploidy) and physiological function. Further parallels encompass developmental features such as the early segregation of the serosa/chorion compared to later, progressive differentiation of the amnion and formation of the amniotic cavity from serosal–amniotic folds as a widespread morphogenetic mode across species. We also discuss common developmental roles for orthologous transcription factors and BMP signalling in EE tissues of amniotes and insects, and between EE and cardiac tissues, supported by our exploration of new resources for global and tissue-specific gene expression. This highlights the degree to which general developmental principles and protective tissue features can be deduced from each of these animal groups, emphasizing the value of broad comparative studies to reveal subtle developmental strategies and answer questions that are common across species.

This article is part of the theme issue ‘Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom’.
Extraembryonic tissue in chelicerates: a review and outlook
Authors: Prpic Nikola-Michael , Pechmann Matthias
Published: October 2022

The formation of extraembryonic membranes (EEMs) contributes to the proper development of many animals. In arthropods, the formation and function of EEMs have been studied best in insects. Regarding the development of extraembryonic tissue in chelicerates (spiders and relatives), most information is available for spiders (Araneae). Especially two populations of cells have been considered to represent EEMs in spiders. The first of these potential EEMs develops shortly after egg deposition, opposite to a radially symmetrical germ disc that forms in one hemisphere of the egg and encloses the yolk. The second tissue, which has been described as being extraembryonic is the so-called dorsal field, which is required to cover the dorsal part of the developing spider germ rudiment before proper dorsal closure. In this review, we summarize the current knowledge regarding the formation of potential extraembryonic structures in the Chelicerata. We describe the early embryogenesis of spiders and other chelicerates, with a special focus on the formation of the potential extraembryonic tissues.

This article is part of the theme issue ‘Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom’.
Why are GWASs limp about the X chromosome?
Authors: Amos Christopher I. , Gorlov Ivan P.
Published: October 2022

The X-chromosome is among the largest human chromosomes. It differs from autosomes by a number of important features including hemizygosity in males, an almost complete inactivation of one copy in females, and unique patterns of recombination. We used data from the Catalog of Published Genome Wide Association Studies to compare densities of the GWAS-detected SNPs on the X-chromosome and autosomes. The density of GWAS-detected SNPs on the X-chromosome is 6-fold lower compared to the density of the GWAS-detected SNPs on autosomes. Differences between the X-chromosome and autosomes cannot be explained by differences in the overall SNP density, lower X-chromosome coverage by genotyping platforms or low call rate of X-chromosomal SNPs. Similar differences in the density of GWAS-detected SNPs were found in female-only GWASs (e.g. ovarian cancer GWASs). We hypothesized that the lower density of GWAS-detected SNPs on the X-chromosome compared to autosomes is not a result of a methodological bias, e.g. differences in coverage or call rates, but has a real underlying biological reason – alower density of functional SNPs on the X-chromosome versus autosomes. This hypothesis is supported by the observation that (i) the overall SNP density of X-chromosome is lower compared to the SNP density on autosomes and that (ii) the density of genic SNPs on the X-chromosome is lower compared to autosomes while densities of intergenic SNPs are similar.

Author summary

One of the most striking observations from the Genome Wide Association Studies (GWAS) is that the density of GWAS hits is much lower on X-chromosome compared to autosomes. This was initially explained by technical/analytical reasons such as lower coverage and lack of adequate methods to analyze X-chromosomal SNPs. Since then, a better coverage and better analytical methods to analyze X-chromosomal SNPs were developed. We recently revisited the issue and found that the density of GWAS hits on X-chromosome is at least 5-fold lower compared to autosomes. We demonstrated that the difference cannot be explained by technical or analytical reasons. We proposed a hypothesis of a real biological phenomenon underlying X versus autosomal differences in the density of GWAS-detected SNPs, namely that X-chromosome has a lower density of functional polymorphisms compared to autosomes because of a stronger selection against X-chromosomal mutations since X-chromosomal variants are more exposed to natural selection due to hemizygosity in males and X-chromosome inactivation in females. The hypothesis is supported by the analysis of the densities of intergenic, intronic and exonic SNPs on human chromosomes.
Thymic mesenchymal niche cells drive T cell immune regeneration
Authors: Gustafsson Karin , Isaev Sergey , Kooshesh Kameron A. , Baryawno Ninib , Kokkaliaris Konstantinos D. , Severe Nicolas , Zhao Ting , Scadden Elizabeth W. , Spencer Joel A. , Burns Christian , Akilan Kumaran , Barkas Nikolaos , Gessessew Hayalneh , Lin Charles P. , Kharchenko Peter V. , Scadden David T.
Published: October 2022

Thymic atrophy and the progressive immune decline that accompanies it is a major health problem, chronically with age and acutely with immune injury. No solution has been defined. Here we demonstrate that one of the three mesenchymal cell subsets identified by single-cell analysis of human and mouse thymic stroma is a critical niche component for T lymphopoiesis. The Postn+ subset is located perivascularly in the cortical-medullary junction, medulla and subcapsular regions. Cell depletion demonstrated that it recruits T competent cells to the thymus and initiates T lymphopoiesisin vivo. This subset distinctively expresses the chemokineCcl19necessary for niche functions. It markedly declines with age and in the acute setting of hematopoietic stem cell transplant conditioning. When isolated and adoptively transferred, these cells durably engrafted the atrophic thymus, recruited early T progenitors, increased T cell neogenesis, expanded TCR complexity and enhanced T cell response to vaccination. These data define a thymus lymphopoietic niche cell type that may be manipulated therapeutically to regenerate T lymphopoiesis.
Direct Brain Recordings Suggest a Causal Subsequent-Memory Effect
Authors: Rubinstein Daniel Y. , Weidemann Christoph T. , Sperling Michael R. , Kahana Michael J.
Published: October 2022

Endogenous variation in brain state and stimulus-specific evoked activity can both contribute to successful encoding. Previous studies, however, have not clearly distinguished among these components. We address this question by analyzing intracranial EEG recorded from epilepsy patients as they studied and subsequently recalled lists of words. We first trained classifiers to predict recall of either single items or entire lists and found that both classifiers exhibited similar performance. We found that list-level classifier output—a biomarker of successful encoding—tracked item presentation and recall events, despite having no information about the trial structure. Across widespread brain regions, decreased low- and increased high-frequency activity (HFA) marked successful encoding of both items and lists. We found regional differences in the hippocampus and prefrontal cortex, where in the hippocampus HFA correlated more strongly with item recall, whereas in the prefrontal cortex HFA correlated more strongly with list performance. Despite subtle differences in item- and list-level features, the similarity in overall classification performance, spectral signatures of successful recall, and fluctuations of spectral activity across the encoding period argue for a shared endogenous process that causally impacts the brain’s ability to learn new information.
Rapid and Efficient Ambient Temperature X-ray Crystal Structure Determination at Turkish Light Source
Authors: Gul Mehmet , Ayan Esra , Destan Ebru , Johnson J Austin , Shafiei Alaleh , Kepceoğlu Abdullah , Yilmaz Merve , Ertem Fatma Betül , Yapici İlkin , Tosun Bilge , Baldir Nilüfer , Tokay Nurettin , Nergiz Zeliş , Karakadioğlu Gözde , Paydos Seyide Seda , Kulakman Cahine , Ferah Cengiz Kaan , Güven Ömür , Atalay Necati , Akcan Enver Kamil , Cetinok Haluk , Arslan Nazlı Eylül , Şabanoğlu Kardelen , Aşci Bengisu , Tavli Serra , Gümüsboğa Helin , Altuntaş Sevde , Otsuka Masami , Fujita Mikako , Tekin Şaban , Çiftçi Halilibrahim , Durdaği Serdar , Karaca Ezgi , Kaplan Türköz Burcu , Kabasakal Burak Veli , Kati Ahmet , DeMirci Hasan
Published: October 2022

High-resolution biomacromolecular structure determination is essential to better understand protein function and dynamics. Serial crystallography is an emerging structural biology technique which has fundamental limitations due to either sample volume requirements or immediate access to the competitive X-ray beamtime. Obtaining a high volume of well-diffracting, sufficient-size crystals while mitigating radiation damage remains a critical bottleneck of serial crystallography. As an alternative, we introduce the plate-reader module adapted for using a 72-well Terasaki plate for biomacromolecule structure determination at a convenience of a home X-ray source. We also present the first ambient temperature lysozyme structure determined at the Turkish Light Source (Turkish DeLight). The complete dataset was collected in 18.5 mins with resolution extending to 2.39 Å and 100% completeness. Combined with our previous cryogenic structure (PDB ID: 7Y6A), the ambient temperature structure provides invaluable information about the structural dynamics of the lysozyme.Turkish DeLightprovides robust and rapid ambient temperature biomacromolecular structure determination with limited radiation damage.
Cross-sex cecal microbiota transfer alters depressive-like behaviours in mice
Authors: Hinks Meagan , Martin Yellow , Burke Francine , Bambico Francis R. , Swift-Gallant Ashlyn
Published: October 2022

Major depressive disorder (MDD) is a leading cause of non-fatal global disease burden, with females being two-fold more likely than males to be diagnosed with the disorder. Despite this distinct sex-linked disparity of diagnosis, it is unclear what underlies the sex bias of MDD prevalence. Recent findings suggest a role for the gut in mediating affective disorders through the gut-brain-axis (GBA). However, few studies have included sex as a biological variable. For this study, cross-sex transfer of cecal microbiota was performed between male and female C57Bl/6 mice to elucidate the effects of sex and the gut microbiome on a standard battery of tests measuring depressive-like behaviours. Specifically, regardless of sex, recipients of male cecal content had a greater sucrose preference than controls and recipients of female cecum. Conversely, in the splash test, recipients of female cecum displayed a decrease in grooming behaviour compared to both controls and recipients of male cecum, suggestive of an increase in depressive-like behaviour. These results support a role for female-specific gut microbes in contributing to female vulnerability to depression, while male-specific gut microbes may protect in part against an anhedonia-like phenotype
The science of child and adolescent mental health in Greece: a nationwide systematic review of the literature
Authors: Koumoula Anastasia , Marchionatti Lauro Estivalete , Caye Arthur , Karagiorga Vasiliki Eirini , Balikou Panagiota , Lontou Katerina , Arkoulaki Vicky , Simioni André , Serdari Aspasia , Kotsis Konstantinos , Basta Maria , Kapsimali Efi , Mitropoulou Andromachi , Klavdianou Nikanthi , Zeleni Domna , Mitroulaki Sotiria , Botzaki Anna , Gerostergios Giorgos , Samiotakis Giorgos , Moschos Giorgos , Giannopoulou Ioanna , Papanikolaou Katerina , Aggeli Katerina , Scarmeas Nikolaos , Koulouvaris Panagiotis , Emanuele Jill , Schuster Kenneth , Karyotaki Eirini , Kalikow Lily , Pronoiti Katerina , Gosmann Natan Pereira , Schafer Julia Luiza , Merikangas Kathleen R. , Szatmari Peter , Cuijpers Pim , Georgiades Katholiki , Milham Michael P. , Corcoran Mimi , Burke Sarah , Koplewicz Harold , Salum Giovanni Abrahão
Published: October 2022

Background

Evidence-based information is essential to delivering effective mental health care, yet the extent and accessibility of the scientific literature are critical barriers for professionals and policymakers. To map the necessities and make validated resources accessible, we undertook a comprehensive analysis of scientific evidence on child and adolescent mental health in Greece.

Methods

This systematic review encompasses three research topics related to the mental health of children and adolescents in Greece: prevalence estimates, assessment instruments, and interventions. We searched Pubmed, Web of Science, PsycINFO, Google Scholar, and IATPOTEK from inception to December 16th, 2021. We included studies assessing the prevalence of conditions, reporting data on assessment tools, and experimental interventions. For each area, manuals informed data extraction and the methodological quality was ascertained using validated tools. This review was registered in protocols.io [68583].

Outcomes

We included 104 studies reporting 533 prevalence estimates, 223 studies informing data on 261 assessment instruments, and 34 intervention studies. We report the prevalence of conditions according to regions within the country. A repository of locally validated instruments and their psychometrics were compiled. An overview of interventions provided data on their effectiveness. The outcomes are made available in an interactive resource on-line [https://camhi.gr/en/systematic-review-tables/].

Interpretation

Scientific evidence on child and adolescent mental health in Greece has been cataloged and appraised. This timely and accessible compendium of up-to-date evidence offers valuable resources for clinical practice and policy making in Greece and may encourage similar assessments in other countries.

Funding

The Stavros Niarchos Foundation.
Metastability as a neuromechanistic biomarker of schizophrenia pathology
Authors: Hancock Fran , Rosas Fernando E. , McCutcheon Robert A. , Cabral Joana , Dipasquale Ottavia , Turkheimer Federico E.
Published: October 2022

The disconnection hypothesis of schizophrenia proposes that symptoms of the disorder arise as a result of aberrant functional integration between segregated areas of the brain. The concept of metastability characterizes the coexistence of competing tendencies for functional integration and functional segregation in the brain and is therefore well suited for the study of schizophrenia. In this study we investigate metastability as a neuromechanistic biomarker of schizophrenia pathology, including a demonstration of reliability and face validity.

Group-level discrimination, individual-level classification, and pathophysiological relevance were assessed using two independent case-control studies of schizophrenia, the Human Connectome Project Early Psychosis (HCPEP) study (controlsn=82, non-affective psychosisn=53) and the Cobre study (controlsn=71, casesn=59). In this work we introduce a new framework that uses Leading Eigenvector Dynamic Analysis (LEiDA) to capture specific features of dynamic functional connectivity and then implements a novel approach to estimate metastability. We used non-parametric testing to evaluate group-level differences and a naïve Bayes classifier to discriminate cases from controls.

Our results show that our new approach is capable of discriminating cases from controls with elevated effect sizes relative to published literature, reflected in an up to 76% area under the curve (AUC) in out-of-sample classification analyses. Furthermore, our analyses demonstrated that patients with early psychosis exhibit intermittent disconnectivity of subcortical regions with frontal cortex and cerebellar regions, introducing new insights about the mechanistic bases of these conditions.

Overall, these findings demonstrate reliability and face validity of metastability as a neuromechanistic biomarker of schizophrenia pathology.
Diabetes and Cognitive Health in India: A Nationally Representative Survey of Adults Aged 45 Years and Older
Authors: Flood David , Green Hunter , Gross Alden L. , Kobayashi Lindsay C. , Levine Deborah A. , Lee Jinkook , Wixom Caroline R. , Langa Kenneth M.
Published: October 2022

Background

Few studies have assessed the relationship between diabetes and cognitive health outside of high-income countries. We described this relationship in India, a middle-income country of 1.4 billion people.

Methods

Data were analyzed from 58,027 adults aged ≥45 years in the baseline wave of the nationally representative Longitudinal Aging Study in India, from 2017 to 2019. Outcomes were scaled cognitive scores (mean of 0 and standard deviation [SD] of 1) and cognitive impairment, defined as a cognitive score 1.5 standard deviations or below the age- and education-matched mean. Diabetes was defined as a self-report of a prior diabetes diagnosis made by a health professional or having a measured hemoglobin A1c ≥6.5% at the time of the LASI survey. To describe the cross-sectional relationship between cognitive health and diabetes, we constructed survey-weighted multivariable linear and logistic regression models controlling for prespecified covariates, including age, sex, sociodemographic characteristics, and rural versus urban residence.

Results

In age- and sex-adjusted models, people with diabetes had cognitive scores that were 0.25 SD higher (95% CI: 0.23 to 0.27) and had a 1.3% (95% CI: 0.7 to 1.8) lower prevalence of cognitive impairment than people without diabetes. Differences persisted even when adjusting for demographic, socioeconomic, and geographic characteristics. Rural versus urban residence modified the relationships of diabetes with cognitive score (P = 0.001) and cognitive impairment (P = 0.004). In fully adjusted models, rural respondents with diabetes had 0.05 SD (95% CI: 0.03 to 0.07) greater cognitive scores and 1.7% (95% CI: 0.9 to 2.5) lower prevalence of cognitive impairment than those without diabetes. In urban areas, respondents with and without diabetes had similar cognitive scores and prevalence of cognitive impairment.

Conclusion

Urban-rural health differences, the nutrition transition, and social conditions likely influence the observed cross-sectional relationship between diabetes and cognitive dysfunction in India, leading to different associations than previously reported in many high-income countries.

Funding

National Institutes of Health, USA and the Ministry and of Health and Family Welfare, Government of India
Multi-omic profiling of the developing human cerebral cortex at the single cell level
Authors: Zhu Kaiyi , Bendl Jaroslav , Rahman Samir , Vicari James M. , Coleman Claire , Clarence Tereza , Latouche Ovaun , Tsankova Nadejda M. , Li Aiqun , Brennand Kristen J. , Lee Donghoon , Yuan Guo-Cheng , Fullard John F. , Roussos Panos
Published: October 2022

The cellular complexity of the human brain is established via dynamic changes in gene expression throughout development that is mediated, in part, by the spatiotemporal activity of cis-regulatory elements. We simultaneously profiled gene expression and chromatin accessibility in 45,549 cortical nuclei across 6 broad developmental time-points from fetus to adult. We identified cell-type specific domains in which chromatin accessibility is highly correlated with gene expression. Differentiation pseudotime trajectory analysis indicates that chromatin accessibility at cis-regulatory elements precedes transcription and that dynamic changes in chromatin structure play a critical role in neuronal lineage commitment. In addition, we mapped cell-type and temporally specific genetic loci implicated in neuropsychiatric traits, including schizophrenia and bipolar disorder. Together, our results describe the complex regulation of cell composition at critical stages in lineage determination, serve as a developmental blueprint of the human brain and shed light on the impact of spatiotemporal alterations in gene expression on neuropsychiatric disease.

One-Sentence Summary

Simultaneous profiling of gene expression and chromatin accessibility in single nuclei from 6 developmental time-points sheds light on cell fate determination in the human cerebral cortex and on the molecular basis of neuropsychiatric disease.
Cortical gradients during naturalistic processing are hierarchical and modality-specific
Authors: Samara Ahmad , Eilbott Jeffrey , Margulies Daniel S. , Xu Ting , Vanderwal Tamara
Published: October 2022

Understanding cortical topographic organization and how it supports complex perceptual and cognitive processes is a fundamental question in neuroscience. Previous work has characterized functional gradients that demonstrate large-scale principles of cortical organization. How these gradients are modulated by rich ecological stimuli remains unknown. Here, we utilize naturalistic stimuli via movie-fMRI to assess macroscale functional organization. We identify principal movie gradients that delineate separate hierarchies anchored in sensorimotor, visual, and auditory/language areas. At the opposite/heteromodal end of these perception-to-cognition axes, we find a more central role for the frontoparietal network along with the default network. Even across different movie stimuli, movie gradients demonstrated good reliability, suggesting that these hierarchies reflect a brain state common across different naturalistic conditions. The relative position of brain areas within movie gradients showed stronger and more numerous correlations with cognitive behavioral scores compared to resting state gradients. Together, these findings provide an ecologically valid representation of the principles underlying cortical organization while the brain is active and engaged in multimodal, dynamic perceptual and cognitive processing.

Highlights

Movie-fMRI reveals novel, more granular principles of hierarchical cortical organization

Top movie gradients delineate three separate perception-to-cognition hierarchies

A distinctive third gradient in movie-watching is anchored by auditory/language regions

Gradient scores demonstrate good reliability even across different movie stimuli

Movie gradients yield stronger correlations with behavior relative to resting state gradients
Decolonizing WASH Research: Results of a qualitative study and consensus-building process to develop principles for increasing equity in WASH Research
Authors: Lue J’Anna-Mare , Bah Salamata , Grant Kaelah , Lee Justine , Nzekele Leila , Tidwell James B
Published: October 2022

There have long been critiques of colonial legacies influencing global health. In recent years with growing public awareness of unjust systems, a new wave of calls for anti-racist initiatives and decolonization of the sector has emerged. This study examined research inequities in the water, sanitation, and hygiene (WASH) sector, centering the perspectives of researchers from low- and middle-income countries (LMICs), to catalyze collective action in a sub-sector of global health.

Nineteen semi-structured interviews were conducted with researchers of different backgrounds regarding nationality, gender, and research experience. Researchers from eight countries were asked about their experiences and direct observations of discrimination across various stages of the research process. Five interviews were conducted with key WASH research funders to assess perceptions of obstacles faced by LMIC researchers, successes achieved, and challenges faced by these organizations when working towards more equitable research processes within the WASH sector.

The results were analyzed using an emergent framework that categorized experiences based on power differentials and abuse of power; structural barriers due to organizational policies; institutional and individual indifference; othering speech, action, and practices; and context-specific discrimination. The Socio-Ecological Model was also combined with this framework to identify the types of actors and level of coordination needed to address these issues. Respondents were often reluctant to describe actions as discriminatory unless there was clear intent. Researchers who worked in both LMICs and HICs at different career stages were particularly aware of discrimination.

Ensuring pro-equity authorship and funding practices were identified as two significant actions to catalyze change within the sector. Sector-wide efforts must center LMIC voices when identifying research questions, conducting research, and dissemination. Individuals, organizations, and the entire WASH sector must examine how they participate in upholding inequitable systems of power to begin to dismantle the system through the intentional yielding of power and resources.
The death toll of armed conflict and food insecurity in north-east Nigeria, 2016-2019: a statistical study
Authors: Checchi Francesco , Gimma Amy , Jarvis Christopher I , van Zandvoort Kevin , Warsame Abdihamid
Published: October 2022

Background

Armed conflict, compounded by displacement and food insecurity, has affected Adamawa, Borno and Yobe states of northeast Nigeria (population ≈ 12 million) since 2009. The crisis escalated in 2013-2014 and featured a delayed humanitarian response. We wished to estimate the death rate and toll attributable to the crisis. Data availability constraints restricted estimation to the period 2016 to 2019.

Methods

We did a small-area estimation statistical analysis of previously collected data, stratified by local government area and month. We fitted a mixed effects model to household mortality data collected as part of 70 ground surveys implemented by humanitarian actors within the study area and period. Model predictors, selected from a wider candidate list, included livelihood typology, the price of staple cereal, vaccination geo-coverage and the presence of humanitarian actors. To project accurate death tolls, we adjusted population denominators based on internal and refugee displacements. We used the model and population estimates to project mortality under observed conditions and under different assumptions of counterfactual conditions, had there been no crisis, with the difference between observed and counterfactual providing excess mortality.

Results

Crude and under 5 years death rates were highly elevated across most ground surveys, with net negative household migration. Between April 2016 and December 2019, we projected that 490,000 deaths (230,000 children under 5y) died in excess of the counterfactual non-crisis level; this death toll ranged from medians of 90,000 to 550,000 depending on the counterfactual assumptions chosen, specifically whether to consider a Nigeria-wide price inflation phase as inherently part of the crisis in the north-east. Crude and under 5 years death rates were two to three times higher than counterfactual levels, and highest in 2016-2017.

Discussion

This may be the first crisis-wide estimate of mortality attributable to the crisis in north-east Nigeria. Our findings do not reflect acute emergency periods before 2016 and the situation in neighbouring countries affected by the conflict. Sensitivity analysis suggests that results for Borno state, where conflict has been most intense, are subject to under-estimation due to data not representing hard-to-access areas. Further studies to document mortality in this and other crises are needed to guide decision-making and memorialise their human toll.
Improvedin situsequencing for high-resolution targeted spatial transcriptomic analysis in tissue sections
Authors: Tang Xinbin , Chen Jiayu , Zhang Xinya , Liu Xuzhu , Xie Zhaoxiang , Wei Kaipeng , Qiu Jianlong , Ma Weiyan , Lin Chen , Ke Rongqin
Published: October 2022

Spatial transcriptomics enables the study of localization-indexed gene expression activity in tissues, providing the transcriptional landscape that in turn indicates the potential regulatory networks of gene expression.In situsequencing (ISS) is a targeted spatial transcriptomic technique, which is based on padlock probe and rolling circle amplification combined with next-generation sequencing chemistry, for highly multiplexedin situgene expression profiling. Here, we present improvedin situsequencing (IISS) that exploits a new probing and barcoding approach, combined with advanced image analysis pipeline for high-resolution targeted spatial gene expression profiling. We developed an improved combinatorial probe anchor ligation chemistry using a 2-base encoding strategy for barcode interrogation. The new encoding strategy resulted in higher signal intensity as well as improved specificity forin situsequencing, while maintaining a streamlined analysis pipeline for targeted spatial transcriptomics. We showed that IISS can be applied to both fresh frozen tissue and formalin-fixed paraffin embedded tissue sections for single cell level spatial gene expression analysis, based on which the developmental trajectory and cell-cell communication networks can also be constructed. In conclusion, our method is a versatile molecular tool for targeted spatial transcriptomic analysis.
Legionellapara-effectors target chromatin and promote bacterial replication
Authors: Schator Daniel , Mondino Sonia , Berthelet Jérémy , Di Silvestre Cristina , Ben Assaya Mathilde , Rusniok Christophe , Rodrigues-Lima Fernando , Wehenkel Annemarie , Buchrieser Carmen , Rolando Monica
Published: October 2022

Legionella pneumophilareplicates intracellularly by secreting effectorsviaa type IV secretion system. One of these effectors is a eukaryotic methyltransferase (RomA) that methylates K14 of histone H3 (H3K14me3) to counteract host immune responses. However, it is not known howL. pneumophilainfection catalyses H3K14 methylation as this residue is usually acetylated. Here we show thatL. pneumophilasecretes a eukaryotic-like histone deacetylase (LphD) that specifically targets H3K14ac and works in synergy with RomA. Both effectors target host chromatin and bind the HBO1 histone acetyltransferase complex that acetylates H3K14. Full activity of RomA is dependent on the presence of LphD as H3K14 methylation levels are significantly decreased in a ΔlphDmutant. The dependency of these two chromatin-modifying effectors on each other is further substantiated by mutational and virulence assays revealing that the presence of only one of these two effectors impairs intracellular replication, while a double knockout (ΔlphDΔromA) can restore intracellular replication. Uniquely, we present evidence for “para-effectors”, an effector pair, that actively and coordinately modify host histones to hijack the host response. The identification of epigenetic marks modulated by pathogens opens new vistas for the development of innovative therapeutic strategies to counteract bacterial infection and strengthening host defences.