Systematic analysis of intrinsic enhancer-promoter compatibility in the mouse genome.

Gene expression is in part controlled by cis-regulatory elements (CREs) such as enhancers and repressive elements. Anecdotal evidence has indicated that a CRE and a promoter need to be biochemically compatible for promoter regulation to occur, but this compatibility has remained poorly characterized in mammalian cells. We used high-throughput combinatorial reporter assays to test thousands of CRE-promoter pairs from three Mb-sized genomic regions in mouse cells. This revealed that CREs vary substantially in their promoter compatibility, ranging from striking specificity to broad promiscuity. More than half of the tested CREs exhibit significant promoter selectivity. Housekeeping promoters tend to have similar CRE preferences, but other promoters exhibit a wide diversity of compatibilities. Higher-order transcription factors (TF) motif combinations may account for compatibility. CRE-promoter selectivity does not correlate with looping interactions in the native genomic context, suggesting that chromatin folding and compatibility are two orthogonal mechanisms that confer specificity to gene regulation.

The landscape of the methodology in drug repurposing using human genomic data: a systematic review.

The process of drug development is expensive and time-consuming. In contrast, drug repurposing can be introduced to clinical practice more quickly and at a reduced cost. Over the last decade, there has been a significant expansion of large biobanks that link genomic data to electronic health record data, public availability of various databases containing biological and clinical information and rapid development of novel methodologies and algorithms in integrating different sources of data. This review aims to provide a thorough summary of different strategies that utilize genomic data to seek drug-repositioning opportunities. We searched MEDLINE and EMBASE databases to identify eligible studies up until 1 May 2023, with a total of 102 studies finally included after two-step parallel screening. We summarized commonly used strategies for drug repurposing, including Mendelian randomization, multi-omic-based and network-based studies and illustrated each strategy with examples, as well as the data sources implemented. By leveraging existing knowledge and infrastructure to expedite the drug discovery process and reduce costs, drug repurposing potentially identifies new therapeutic uses for approved drugs in a more efficient and targeted manner. However, technical challenges when integrating different types of data and biased or incomplete understanding of drug interactions are important hindrances that cannot be disregarded in the pursuit of identifying novel therapeutic applications. This review offers an overview of drug repurposing methodologies, providing valuable insights and guiding future directions for advancing drug repurposing studies.

Tools to facilitate communication during physician-patient consultations in cancer care: An overview of systematic reviews.

Tools have been developed to facilitate communication and support information exchange between people diagnosed with cancer and their physicians. Patient-reported outcome measures, question prompt lists, patient-held records, tape recordings of consultations, decision aids, and survivorship care plans have all been promoted as potential tools, and there is extensive literature exploring their impact on patient outcomes. Eleven systematic reviews of studies evaluating tools to facilitate patient-physician communication were reviewed and summarized in this overview of systematic reviews. Across the systematic reviews, 87 publications reported on 84 primary studies involving 15,381 participants. Routine use of patient-reported outcome measures and feedback of results to clinicians can improve pain management, physician-patient communication, and symptom detection and control; increase utilization of supportive care; and increase patient involvement in care. Question prompt lists can increase the number of questions asked by patients without increasing consultation length and may encourage them to reflect and plan questions before the consultation. There is limited benefit in audio recording consultations or using patient-held records during consultations. Physicians should be supported by adequately resourced health services to respond effectively to the range of clinical and broader patient needs identified through the routine use of tools to facilitate communication.

Improving the accuracy of bulk fitness assays by correcting barcode processing biases.

Measuring the fitnesses of genetic variants is a fundamental objective in evolutionary biology. A standard approach for measuring microbial fitnesses in bulk involves labeling a library of genetic variants with unique sequence barcodes, competing the labeled strains in batch culture, and using deep sequencing to track changes in the barcode abundances over time. However, idiosyncratic properties of barcodes can induce non-uniform amplification or uneven sequencing coverage that causes some barcodes to be over- or under-represented in samples. This systematic bias can result in erroneous read count trajectories and misestimates of fitness. Here we develop a computational method, REBAR, for inferring the effects of barcode processing bias by leveraging the structure of systematic deviations in the data. We illustrate this approach by applying it to two independent data sets, and demonstrate that this method estimates and corrects for bias more accurately than standard proxies, such as GC-based corrections. REBAR mitigates bias and improves fitness estimates in high-throughput assays without introducing additional complexity to the experimental protocols, with potential applications in a range of experimental evolution and mutation screening contexts.

Sodium-glucose cotransporter-2 inhibitors and their potential role in dementia onset and cognitive function in patients with diabetes mellitus: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to determine the association between the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and dementia onset as well as cognitive function in patients with diabetes mellitus. We comprehensively searched the MEDLINE, Embase, and CENTRAL databases to select relevant studies published up to August 2023. The use of SGLT-2 inhibitors significantly lowers dementia risk compared to SGLT-2i non-users (Hazard ratio: 0.68, 95 % CI: 0.50-0.92). Furthermore, our findings indicated a positive effect of SGLT-2 inhibitor use on cognitive function score improvement, as demonstrated by the standardized mean difference of 0.88 (95 % CI: 0.32-1.44), particularly among populations with mild cognitive impairment or dementia. This systematic review and meta-analysis indicate a potential role of SGLT-2 inhibitors in reducing the risk of dementia in patients with diabetes mellitus. These findings underscore the need for well-controlled large clinical trials and future research in this field.

Symptoms of mental disorders and oral contraception use: A systematic review and meta-analysis.

Worldwide, over 150 million adolescent and adult women use oral contraceptives (OC). An association between OC-use and the emergence of symptoms of mental disorders has been suggested. This systematic review and meta-analysis provide an overview of published research regarding symptoms of mental disorders in association with OC-use, factoring the influence of OC types, age of first-use, duration of OC-intake, and previous diagnoses of mental disorders. A systematic literature search was conducted between June-July 2022. 22 studies were included. While most found no significant OC-use effects on mental symptoms, some hinted at OCs as a potential risk. The existing evidence regarding the potential link between progestin-only OC-use and an elevated risk of mental symptoms in comparison to combined OC-use remains inconclusive. However, due to emerging indications suggesting that the formulation of OC might play a role in mental health outcomes, this topic warrants further investigation. Moreover, indications of an increased risk for depressive symptoms in adolescent OC-users should be noted. Hence, while general population effects seem unlikely, they cannot be completely disregarded. The decision on OC-use should depend on the patient's medical history and should be re-evaluated regularly.

Neurodevelopmental copy-number variants: A roadmap to improving outcomes by uniting patient advocates, researchers, and clinicians for collective impact.

Copy-number variants and structural variants (CNVs/SVs) drive many neurodevelopmental-related disorders. While many neurodevelopmental-related CNVs/SVs give rise to complex phenotypes, the overlap in phenotypic presentation between independent CNVs can be extensive and provides a motivation for shared approaches. This confluence at the level of clinical phenotype implies convergence in at least some aspects of the underlying genomic mechanisms. With this perspective, our Commission on Novel Technologies for Neurodevelopmental CNVs asserts that the time has arrived to approach neurodevelopmental-related CNVs/SVs as a class of disorders that can be identified, investigated, and treated on the basis of shared mechanisms and/or pathways (e.g., molecular, neurological, or developmental). To identify common etiologic mechanisms among uncommon neurodevelopmental-related disorders and to potentially identify common therapies, it is paramount for teams of scientists, clinicians, and patients to unite their efforts. We bring forward novel, collaborative, and integrative strategies to translational CNV/SV research that engages diverse stakeholders to help expedite therapeutic outcomes. We articulate a clear vision for piloted roadmap strategies to reduce patient/caregiver burden and redundancies, increase efficiency, avoid siloed data, and accelerate translational discovery across CNV/SV-based syndromes.

Validation of transcriptome signature reversion for drug repurposing in oncology.

Transcriptome signature reversion (TSR) has been extensively proposed and used to discover new indications for existing drugs (i.e. drug repositioning, drug repurposing) for various cancer types. TSR relies on the assumption that a drug that can revert gene expression changes induced by a disease back to original, i.e. healthy, levels is likely to be therapeutically active in treating the disease. Here, we aimed to validate the concept of TSR using the PRISM repurposing data set, which is-as of writing-the largest pharmacogenomic data set. The predictive utility of the TSR approach as it has currently been used appears to be much lower than previously reported and is completely nullified after the drug gene expression signatures are adjusted for the general anti-proliferative downstream effects of drug-induced decreased cell viability. Therefore, TSR mainly relies on generic anti-proliferative drug effects rather than on targeting cancer pathways specifically upregulated in tumor types.

Application of deep learning in cancer epigenetics through DNA methylation analysis.

DNA methylation is a fundamental epigenetic modification involved in various biological processes and diseases. Analysis of DNA methylation data at a genome-wide and high-throughput level can provide insights into diseases influenced by epigenetics, such as cancer. Recent technological advances have led to the development of high-throughput approaches, such as genome-scale profiling, that allow for computational analysis of epigenetics. Deep learning (DL) methods are essential in facilitating computational studies in epigenetics for DNA methylation analysis. In this systematic review, we assessed the various applications of DL applied to DNA methylation data or multi-omics data to discover cancer biomarkers, perform classification, imputation and survival analysis. The review first introduces state-of-the-art DL architectures and highlights their usefulness in addressing challenges related to cancer epigenetics. Finally, the review discusses potential limitations and future research directions in this field.

Recent application of artificial intelligence on histopathologic image-based prediction of gene mutation in solid cancers.

PURPOSE: Evaluation of genetic mutations in cancers is important because distinct mutational profiles help determine individualized drug therapy. However, molecular analyses are not routinely performed in all cancers because they are expensive, time-consuming and not universally available. Artificial intelligence (AI) has shown the potential to determine a wide range of genetic mutations on histologic image analysis. Here, we assessed the status of mutation prediction AI models on histologic images by a systematic review. METHODS: A literature search using the MEDLINE, Embase and Cochrane databases was conducted in August 2021. The articles were shortlisted by titles and abstracts. After a full-text review, publication trends, study characteristic analysis and comparison of performance metrics were performed. RESULTS: Twenty-four studies were found mostly from developed countries, and their number is increasing. The major targets were gastrointestinal, genitourinary, gynecological, lung and head and neck cancers. Most studies used the Cancer Genome Atlas, with a few using an in-house dataset. The area under the curve of some of the cancer driver gene mutations in particular organs was satisfactory, such as 0.92 of BRAF in thyroid cancers and 0.79 of EGFR in lung cancers, whereas the average of all gene mutations was 0.64, which is still suboptimal. CONCLUSION: AI has the potential to predict gene mutations on histologic images with appropriate caution. Further validation with larger datasets is still required before AI models can be used in clinical practice to predict gene mutations.

Explainable artificial intelligence for omics data: a systematic mapping study.

Researchers increasingly turn to explainable artificial intelligence (XAI) to analyze omics data and gain insights into the underlying biological processes. Yet, given the interdisciplinary nature of the field, many findings have only been shared in their respective research community. An overview of XAI for omics data is needed to highlight promising approaches and help detect common issues. Toward this end, we conducted a systematic mapping study. To identify relevant literature, we queried Scopus, PubMed, Web of Science, BioRxiv, MedRxiv and arXiv. Based on keywording, we developed a coding scheme with 10 facets regarding the studies' AI methods, explainability methods and omics data. Our mapping study resulted in 405 included papers published between 2010 and 2023. The inspected papers analyze DNA-based (mostly genomic), transcriptomic, proteomic or metabolomic data by means of neural networks, tree-based methods, statistical methods and further AI methods. The preferred post-hoc explainability methods are feature relevance (n = 166) and visual explanation (n = 52), while papers using interpretable approaches often resort to the use of transparent models (n = 83) or architecture modifications (n = 72). With many research gaps still apparent for XAI for omics data, we deduced eight research directions and discuss their potential for the field. We also provide exemplary research questions for each direction. Many problems with the adoption of XAI for omics data in clinical practice are yet to be resolved. This systematic mapping study outlines extant research on the topic and provides research directions for researchers and practitioners.

Clinical manifestations of dengue, Zika and chikungunya in the Pacific Islands: A systematic review and meta-analysis.

Dengue, Zika and chikungunya outbreaks pose a significant public health risk to Pacific Island communities. Differential diagnosis is challenging due to overlapping clinical features and limited availability of laboratory diagnostic facilities. There is also insufficient information regarding the complications of these arboviruses, particularly for Zika and chikungunya. We conducted a systematic review and meta-analysis to calculate pooled prevalence estimates with 95% confidence intervals (CI) for the clinical manifestations of dengue, Zika and chikungunya in the Pacific Islands. Based on pooled prevalence estimates, clinical features that may help to differentiate between the arboviruses include headache, haemorrhage and hepatomegaly in dengue; rash, conjunctivitis and peripheral oedema in Zika; and the combination of fever and arthralgia in chikungunya infections. We estimated that the hospitalisation and mortality rates in dengue were 9.90% (95% CI 7.67-12.37) and 0.23% (95% CI 0.16-0.31), respectively. Severe forms of dengue occurred in 1.92% (95% CI 0.72-3.63) of reported cases and 23.23% (95% CI 13.58-34.53) of hospitalised patients. Complications associated with Zika virus included Guillain-Barré syndrome (GBS), estimated to occur in 14.08 (95% CI 11.71-16.66) per 10,000 reported cases, and congenital brain malformations such as microcephaly, particularly with first trimester maternal infection. For chikungunya, the hospitalisation rate was 2.57% (95% CI 1.30-4.25) and the risk of GBS was estimated at 1.70 (95% CI 1.06-2.48) per 10,000 reported cases. Whilst ongoing research is required, this systematic review enhances existing knowledge on the clinical manifestations of dengue, Zika and chikungunya infections and will assist Pacific Island clinicians during future arbovirus outbreaks.

Risk of kidney and liver diseases after COVID-19 infection: A systematic review and meta-analysis.

COVID-19 is not only associated with substantial acute liver and kidney injuries, but also with an elevated risk of post-acute sequelae involving the kidney and liver system. We aimed to investigate whether COVID-19 exposure increases the long-term risk of kidney and liver disease, and what are the magnitudes of these associations. We searched PubMed, Embase, Web of Science, ClinicalTrials.gov, and the Living Overview of the Evidence COVID-19 Repository for cohort studies estimating the association between COVID-19 and kidney and liver outcomes. Random-effects meta-analyses were performed to combine the results of the included studies. We assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Fifteen cohort studies with more than 32 million participants were included in the systematic review COVID-19 was associated with a 35% greater risk of kidney diseases (10 more per 1000 persons; low certainty evidence) and 54% greater risk of liver disease (3 more per 1000 persons; low certainty evidence). The absolute increases due to COVID-19 for acute kidney injury, chronic kidney disease, and liver test abnormality were 3, 8, and 3 per 1000 persons, respectively. Subgroup analyses found no differences between different type of kidney and liver diseases. The findings provide further evidence for the association between COVID-19 and incident kidney and liver conditions. The absolute magnitude of the effect of COVID-19 on kidney and liver outcomes was, however, relatively small.

Global seroprevalence and prevalence of infection of influenza in dogs (Canis familiaris): A systematic review and meta-analysis.

Influenza in dogs holds considerable public health significance due to their close companionship with humans, yet several facets of this phenomenon remain largely unexplored. This study undertook a systematic review and meta-analysis of observational studies to gauge the global seroprevalence of influenza in dogs. We also assessed whether pet dogs exhibited a higher seroprevalence of influenza compared to non-pet dogs, explored seasonal variations in seroprevalence, scrutinised the design and reporting standards of existing studies, and elucidated the geographical distribution of canine influenza virus (cIV). A comprehensive analysis of 97 studies spanning 27 countries revealed that seroprevalence of various influenza strains in dogs consistently registered below 10% and exhibited relative stability over the past decade. Significantly, we noted that seroprevalence of human influenza virus was notably higher in pet dogs compared to their non-pet counterparts, whereas seroprevalence of other influenza strains remained relatively uniform among both categories of dogs. Seasonal variations in seroprevalence of cIV were not observed. In summary, our findings indicated the global circulation of cIV strains H3N2 and H3N8, with other strains primarily confined to China. Given the lack of reported cases of the transmission of cIV from dogs to humans, our findings suggest a higher risk of reverse zoonosis than zoonosis. Finally, we strongly advocate for standardised reporting guidelines to underpin future canine influenza research endeavours.

An overview of SARS-CoV2 natural infections in companion animals: A systematic review of the current evidence.

This systematic review provides a comprehensive overview of natural SARS-CoV-2 infections in companion animals. The findings show that these infections are relatively rare. Among the examined dogs, only 1.32% tested positive for SARS-CoV-2, while for cats, the rate was 1.55%. Infections in rabbits and ferrets were even less common, at less than 1%. These results support previous research indicating the infrequency of natural infections in companion animals. The review also includes updated studies that involved various pets, such as cats, dogs, ferrets, and rabbits. The majority of the studies analyzed were primarily concerned with screening pets that visited veterinary clinics, regardless of whether they showed any specific signs of SARS-CoV-2 infection. Only a limited number of studies investigated infections in animals suspected of being in contact with owners or other animals that had COVID-19 or were exhibiting symptoms. The most common variant identified among the SARS-CoV-2 variants in the reviewed studies was B.1.1.7 (alpha), followed by B.1.617.2 (delta), B.1.526 (Iota), and others. The emergence of these variants raises concerns about their potential for increased transmissibility and virulence, highlighting the importance of ongoing monitoring of SARS-CoV-2 infections in both humans and animals. Furthermore, most of the reviewed studies indicated that infected pets either showed no symptoms or experienced mild symptoms. This aligns with previous reports suggesting that animals infected with SARS-CoV-2 generally have less severe illness compared to humans. However, it is essential to recognize the possibility of severe illness or death in animals, particularly those with underlying health conditions. Continuous surveillance of SARS-CoV-2 infections in companion animals is crucial for better understanding the virus's epidemiology in animals and developing effective strategies to protect both animal and human health.

Prevalence and factors associated with viral non-suppression in people living with HIV receiving antiretroviral therapy in sub-Saharan Africa: A systematic review and meta-analysis.

Despite advances in HIV treatment, the burden of viral non-suppression (VNS) remains a treatment success concern, particularly in Sub-Saharan African (SSA) countries. We determined the prevalence and factors associated with VNS for people living with HIV (PLHIV) receiving antiretroviral therapy (ART). This review, registered with PROSPERO (CRD42023470234), conducted an extensive search for evidence, focusing on PLHIV living in SSA on ART from the year 2000 to 19th October 2023, across databases including PubMed/MEDLINE, Embase, Web of Science, and Scopus. A total of 2357 articles were screened, from which 32 studies met the criteria for the final analysis, involving 756,620 PLHIV of all ages. The pooled prevalance for VNS was found to be 20.0% (95% CI: 15.43%-25.52%, I2 = 100%, p-value <0.01) Children and adolescents demonstrated the highest prevalence of VNS (viral load ≥1000 copies/mL) at 27.98% (95% CI: 21.91%-34.97%, I2 = 94%, p-value <0.01). The study revealed various factors associated with increased odds (risk) of VNS, p-value <0.05. These factors encompassed socio-demographics such as sex, age, education level, and marital status. Additionally, aspects related to HIV care, such as the facility attended, HIV status disclosure and adherence exhibited higher odds of VNS. Suboptimal ART adherence, longer duration on ART, socio-economic factors, lack of family and social support, presence of co-morbidities, advanced WHO HIV clinical stage, ART regimens, lower CD4+ count, abnormal body mass index, history of treatment interruptions, and progression of HIV illness were associated with VNS. Furthermore, behavioural/psychological factors including depression, substance use, negative perceptions towards ART, experiences of abuse, alcohol use, stigma, and certain patterns of sexual behaviour were also identified as factors for VNS. The occurrence of two VNS to every ten PLHIV on ART poses a threat to the progress made towards reaching the third 95% UNAIDS target in SSA. Additionally, these findings highlight the intricate interplay of various factors, encompassing patient characteristics, behavioural patterns, sociocultural influences, and pharmacological factors, all impacting VNS among PLHIV. Recognising its multifaceted nature, we recommend designing and implementing high impact interventions to effectively address VNS in SSA.

A methodological framework for rigorous systematic reviews: Tailoring comprehensive analyses to clinicians and healthcare professionals.

Systematic reviews represent a fundamental study design, providing the highest level of evidence across diverse research inquiries, encompassing both public health and clinical research and practice. However, for healthcare professionals, the process of selecting, synthesizing, and interpreting evidence can be challenging, and requires specialized skills. Therefore, it is imperative to explore innovative solutions aimed at simplifying and making the traditional systematic review process more accessible while ensuring the validity and reliability of results. In this perspective, our research objective is to develop a systematic review framework that, while maintaining a rigorous methodological approach, streamlines the process for healthcare professionals. This study describes such approach in every phase, from the collection of evidence to the writing of the text, creating a guide for the healthcare professional who approaches this type of research. The qualitative and organizational analysis tools are also described, providing useful information for the use of non-paid programs. This systematic review aims to develop a framework with a rigorous methodological approach that allows simplify the process for clinicians and healthcare professionals. The implementation of this methodology in clinical practice offers new perspectives to ensure a thoughtful consideration and application of scientific evidence and opens the way to innovative and easily accessible solutions to facilitate the conduct of systematic reviews in the clinical care setting.

International treaties have mostly failed to produce their intended effects.

There are over 250,000 international treaties that aim to foster global cooperation. But are treaties actually helpful for addressing global challenges? This systematic field-wide evidence synthesis of 224 primary studies and meta-analysis of the higher-quality 82 studies finds treaties have mostly failed to produce their intended effects. The only exceptions are treaties governing international trade and finance, which consistently produced intended effects. We also found evidence that impactful treaties achieve their effects through socialization and normative processes rather than longer-term legal processes and that enforcement mechanisms are the only modifiable treaty design choice with the potential to improve the effectiveness of treaties governing environmental, human rights, humanitarian, maritime, and security policy domains. This evidence synthesis raises doubts about the value of international treaties that neither regulate trade or finance nor contain enforcement mechanisms.

Cardiovascular disease risk communication and prevention: a meta-analysis.

BACKGROUND AND AIMS: Knowledge of quantifiable cardiovascular disease (CVD) risk may improve health outcomes and trigger behavioural change in patients or clinicians. This review aimed to investigate the impact of CVD risk communication on patient-perceived CVD risk and changes in CVD risk factors. METHODS: PubMed, Embase, and PsycINFO databases were searched from inception to 6 June 2023, supplemented by citation analysis. Randomized trials that compared any CVD risk communication strategy versus usual care were included. Paired reviewers independently screened the identified records and extracted the data; disagreements were resolved by a third author. The primary outcome was the accuracy of risk perception. Secondary outcomes were clinician-reported changes in CVD risk, psychological responses, intention to modify lifestyle, and self-reported changes in risk factors and clinician prescribing of preventive medicines. RESULTS: Sixty-two trials were included. Accuracy of risk perception was higher among intervention participants (odds ratio = 2.31, 95% confidence interval = 1.63 to 3.27). A statistically significant improvement in overall CVD risk scores was found at 6-12 months (mean difference = -0.27, 95% confidence interval = -0.45 to -0.09). For primary prevention, risk communication significantly increased self-reported dietary modification (odds ratio = 1.50, 95% confidence interval = 1.21 to 1.86) with no increase in intention or actual changes in smoking cessation or physical activity. A significant impact on patients' intention to start preventive medication was found for primary and secondary prevention, with changes at follow-up for the primary prevention group. CONCLUSIONS: In this systematic review and meta-analysis, communicating CVD risk information, regardless of the method, reduced the overall risk factors and enhanced patients' self-perceived risk. Communication of CVD risk to patients should be considered in routine consultations.