As skin physiology, immunology and wound healing is markedly different in animals and since keloids are exclusive to humans, there is a need for relevant human in vitro models. Of these, the direct co-culture systems that generate full thickness keloid equivalents appear the most promising and will be key to further advance keloid research on its pathogenesis and thereby ultimately advance keloid treatment. Finally, the recent change in keloid nomenclature will be discussed, which has moved away from identifying keloids solely as abnormal scars with a purely cosmetic association toward understanding keloids for the fibroproliferative disorder that they are.Keloids constitute an abnormal fibroproliferative wound healing response in which raised scar tissue grows excessively and invasively beyond the original wound borders. This review provides a comprehensive overview of several important themes in keloid research: namely keloid histopathology, heterogeneity, pathogenesis, and model systems. Although keloidal collagen versus nodules and α-SMA-immunoreactivity have been considered pathognomonic for keloids versus hypertrophic scars, conflicting results have been reported which will be discussed together with other histopathological keloid characteristics. Importantly, histopathological keloid abnormalities are also present in the keloid epidermis. Heterogeneity between and within keloids exists which is often not considered when interpreting results and may explain discrepancies between studies. At least two distinct keloid phenotypes exist, the superficial-spreading/flat keloids and the bulging/raised keloids. Within keloids, the periphery is often seen as the actively growing margin compared to the more quiescent center, although the opposite has also been reported. Interestingly, the normal skin directly surrounding keloids also shows partial keloid characteristics. Keloids are most likely to occur after an inciting stimulus such as (minor and disproportionate) dermal injury or an inflammatory process  at a keloid-prone anatomical site  in a genetically predisposed individual (patient-related factors). The specific cellular abnormalities these various patient, topological and environmental factors generate to ultimately result in keloid scar formation are discussed. Existing keloid models can largely be divided into  Additionally, we would argue that it is worth including the surrounding normal skin in any keloid research study when possible.in vitro keloid scar model resembling in vivo keloid tissue would not only benefit drug development and testing, it would also greatly aid research into the underlying mechanisms leading to keloid scarring. The fact that keloid pathogenesis remains so poorly understood  associated with keloids  at a keloid-prone anatomical site  in a genetically predisposed individual (patient-related factor). The specific cellular abnormalities this generates to ultimately result in keloid scar formation, are discussed next .Although the keloid fibroblast is still considered the main culprit responsible for keloid scar formation, recent studies have shifted the focus to recognize the potential role of the epidermal compartment and the immune system in keloidogenesis. This section will address the trends in reported cellular abnormalities across the entire spectrum of cells present in skin and/or involved in wound healing see .Often overlooked or even designated as ‘normal appearing’ , the kelHOXA7), minichromosome maintenance 8 (MCM8), proteasome subunit α type 4 (PSMA4) and proteasome subunit β type 2 (PSMB2) as key differentially expressed genes. In another gene expression study, in vitro even in fibroblasts of normal skin origin  in keloid scarring, a phenomenon by which epithelial cells undergo phenotypic changes and acquire more mesenchymal characteristics . EMT hasLittle has been published on the role of melanocytes in keloid pathogenesis see , S3A, deThe increased melanin in keloid-prone patients may also contribute to keloid scar formation by inhibiting the senescence-inducing and anti-inflammatory effects of UVB radiation  and vitaBy their very nature, hypertrophic and keloid scars are defined by the presence of raised, protruding scar tissue. The focus of most studies has therefore understandably been on the dermal component and more specifically on the extracellular matrix (ECM) and the ECM-producing fibroblasts. Both keloid and hypertrophic scars showed increased cellularity and were in excess of all three primary ECM components of water, collagen and proteoglycans. Notably, in keloids these processes were significantly upregulated compared with normal skin and hypertrophic scars .A summary of the reported keloid dermal abnormalities has been listed in in vitro monoculture findings will be summarized in the following paragraphs.An overwhelming number of studies have been devoted to the keloid-derived fibroblast. However, the sheer multitude of papers published on keloid fibroblasts have made it impossible to discuss them all in this review and is outside our scope. For this reason, the focus of this review was limited to fibroblast abnormalities as they pertain to the main themes listed by in vitro monolayer studies support keloid fibroblast hyperproliferation , presence or absence of serum in culture medium, and 3D vs. monolayer culturing, are all potential culturing artifacts which have differed across studies and may influence outcome parameters significantly. It is important to consider the potential confounding effects of these culturing differences while interpreting different results. As a final consideration, it should be noted that keloid fibroblasts are usually compared with fibroblasts derived from healthy non-lesional skin, while in fact normotrophic scars represent the true standard against which keloids should be compared. This holds true for all the tissue and cellular components studied in keloid research, and is not limited to the comparison of keloid fibroblasts to normotrophic scar-derived fibroblasts. In conclusion, keloid fibroblast monocultures have generated a multitude of interesting findings, but it is important to remember the inherent limitations associated with monoculture model systems and consider the influence of differences in cell isolation and culture methods.Although highly informative, findings from fibroblast monolayer cultures are not without their limitations. Serial culturing, methods of fibroblast cell isolation  in Japan were significantly more likely to have hypertension than patients with mild keloids (<2 or <10 cm2). Furthermore, in patients with keloids, those with more severe hypertension were significantly more likely to have multiple and/or larger keloids than patients with normotension or less severe hypertension  onto an upper porous transwell insert and fibroblasts cultured in a monolayer on the underlying bottom well see . These iin vivo-like in vitro culture model and include either mixed monolayer cultures or full thickness skin equivalents comprised of keloid-derived cells  represents the international standard for reporting diseases and health conditions and in the most recently released clinically as non-metastatic malignancies, although histologically they are benign.” Similarly, in vitro treatment despite overall reduced levels of apoptosis. The term refers to the manner in which keloids show some, but not all the changes associated with tumourigenesis. The absence of metastasis despite their invasive growth and the aforementioned cancer-like characteristics, separates keloids from true malignant tumors and lends further support to the ‘incomplete malignancy’ term coined by By their very definition of continued, invasive horizontal growth , keloidsThe change in nomenclature reflected in the newest edition of the ICD may seem like an exercise in semantics, but it should be noted that the cosmetic association with the word ‘keloid scar’ significantly complicates both insurance coverage for treatment as well as funding for research. This is not to say this nomenclature change must result in an altogether ban on the association of the word ‘scar’ with keloids, merely that we shift the focus away from a purely cosmetic association, toward broadening our perspective of keloids for the fibroproliferative disorders that they are and in this way recognize the severity of this fibrotic disorder.Keloid research remains plagued by significant controversy and contradictory findings, which has been highlighted throughout this manuscript where possible. Much of this could be resolved by the standardization of study designs and general research approach. Important considerations for future research include (i) inclusion of a description of the keloid phenotype (based on growth pattern), (ii) clarification of the location within the keloid from which samples were taken , (iii) inclusion of scars of similar maturation stage (at least 1 year old). Lastly, the inclusion of both hypertrophic and normotrophic scars would be a valuable addition to keloid research, as this provides a more comprehensive view of the entire scarring spectrum.GL, SG, and FN conceived the manuscript outline. GL performed the literature study and wrote the manuscript with input from all the authors. SG, FN, and RS supervised, helped shape the manuscript, and offered final critical revision.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.


We describe a case of spontaneous partial segmental thrombosis of the corpus cavernosum (PSTCC).PSTCC is a rare condition in which thrombus formation occurs in the corpus cavernosum. This condition is managed in conjunction with a urologist, and management typically includes anticoagulation and pain control. A 39-year-old man presented to the emergency department for two days of worsening pain and swelling to the base of his penis. The patient denied trauma or a history of coagulopathy, had a non-contributory sexual history, and no recent use of erectile dysfunction medications. Examination demonstrated mild swelling to the penile base without evidence of hernia, infection, or shaft injury.Computed tomography (CT) revealed penile asymmetry . UltrasoPSTCC is a rare condition that manifests as penile or perineal pain and swelling. Thrombus formation likely arises secondary to microtrauma, thrombophilia, hemoglobinopathies and, rarely, medication side effect.3What do we already know about this clinical entity?Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare condition classically diagnosed with ultrasound or magnetic resonance imaging.What is the major impact of the image(s)?Although computed tomography (CT) has not been previously recommended for identifying this pathology, our case demonstrates that PSTCC can be clearly identified with CT.How might this improve emergency medicine practice?This example of a rare pathology that may go unrecognized by emergency providers demonstrates the use of CT to aid in diagnosis.


Lung cancer is one of the leading causes of cancer-related death worldwide, with nearly 1.8 million-diagnosis and 1.59 million deaths. Surgery, radiotherapy, and chemotherapy in individual or combination are commonly used to treat lung cancers. Photodynamic therapy (PDT) is a highly selective method for the destruction of cancer cells by exerting cytotoxic activity on malignant cells. PDT has been the subject of numerous clinical studies and has proven to be an effective strategy for cancer therapy. Clinical studies revealed that PDT could prolong survival in patients with inoperable cancers and significantly improve quality of life. For inoperable lung cancer cases, PDT could be an effective therapy. Despite the clinical success reported, PDT is still currently underutilized to treat lung cancer and other tumors. PTD is still a new treatment approach for lung cancer mainly due to the lack of enough clinical research evaluating its' effectiveness and side effects. In this review, we discuss the current prospects and future potentials of PDT in lung cancer treatment. Lung cancer is the most prevalent cancer in the world, with nearly 2.1 million diagnoses and 1.8 million deaths in 2018 The history of PDT has been well described in previous literature . The choice of optimal combinations of photosensitizers, light sources, and treatment parameters are crucial for effective PDT The basic concept and mechanism of PDT are well described in the previous review papers The alone or simultaneous combined effect of apoptosis, autophagy, mitoptosis, or necrosis alone events is the main pathway leading to PTD-induced cancer cell death The mechanism of PDT-mediated antitumor activity has been examined for the past several decades. Most of the photosensitizers used in cancer therapy are based on a tetrapyrrole structure, similar to that of the protoporphyrin in hemoglobin. Combinations of various therapeutic modalities with non-overlapping toxicities are among the commonly used strategies to improve the therapeutic index of treatments in modern oncology. Sensitization of tumor cells to PDT and interference with cytoprotective molecular responses triggered by PDT in surviving tumor cells increase the antitumor effectiveness. More than 25 years ago, PDT was clinically approved for the treatment of selected tumors PDT for non-small cell lung cancer (NSCLC) was first used in 1982 to achieve tumor necrosis and airway reopening. PDT is considered to be more specific and lesion-oriented compared with other available treatment modalities and produces less collateral damage with fewer complications. PDT was also tried in patients with early central lung cancer when patients were unable to undergo surgery to improve their general life quality. PDT was deemed well-tolerated and effective as part of a multi-modal treatment for non-small cell lung cancer (NSCLC) in a small retrospective study PDT frequently provokes a strong acute inflammatory reaction that can lead to the development of systemic immune response observed as localized edema at the targeted site. The relative contribution of PDT depends to a large extent on the type, and a dose of photosensitizer used, the time between photosensitizer administration and light exposure, total light dose and its fluence rate, tumor oxygen concentration, and perhaps other still poorly recognized variables. The acute inflammatory response is a major protective effect. The inflammation elicited by PDT is a tumor antigen nonspecific process orchestrated by the innate immune system. The onset of PDT-induced inflammation is marked by dramatic changes in the tumor vasculature Over conventional lung cancer treatment approaches, PDT has several advantages such as less invasive procedure compared to surgical resection, more target-specific, minimum adverse effect on surrounding healthy tissues, negligible systemic adverse effects, and cost-effectiveness. PDT is convenient to administer, can be applied in outpatient setup, and possible to apply multiple times on the desired location without leaving scars after healing. Both the photosensitizer and visible light source are not as toxic as the chemotherapies or radiotherapies. PDT can be used in combination with other cancer therapies, including radiotherapy, chemotherapy, and photothermal therapy.Similar to other therapies for lung cancer, PDT also holds limitations. Low tissue penetration properties of visible light used in PDT causes difficulties to treat deep-seated tumors in lung tissue. Similarly, a limited amount of oxygen in tumor tissues surrounded by dense necrotic tissue and tumor masses can reduce the effectiveness of PDT. Commonly available photosensitizers for lung cancer treatment are non-specific to cancer cells. PDT is mainly for localized cancer and generally cannot be used to treat metastasized cancer Development of efficient photosensitizers that can more specifically target cancer cells, and approaches to deliver light that can penetrate large or deep tumor tissue should be developed. Photosensitizers conjugated with specific nanoparticle platform could be developed for better penetration. Moreover, nanoplatforms functionalized with specific receptor-based detectors such as antibody constructs, monoclonal antibodies, or small molecules inhibitors could improve lung cancer cell-specific delivery of photosensitizers As a stand-alone treatment, PDT proved an alternative for palliative chemotherapy or radiotherapy in unresectable lung cancer as it achieved an overall response of nearly 87% and improved patient quality of life. PDT is still considered to be a new and promising antitumor strategy. The advantages of PDT compared with surgery, chemotherapy, or radiotherapy are reduced long-term morbidity and the fact that PDT does not compromise future treatment options for patients with recurrent disease. Thus, the application of PDT for lung cancer treatment needs to be further evaluated in extensive clinical trials.


Tuberculosis remains a leading cause of death worldwide. Transmission is the dominant mechanism sustaining the multidrug-resistant tuberculosis epidemic. Tuberculosis infection prevention and control (TBIPC) guidelines for healthcare facilities are poorly implemented. This systematic review aimed to explore the barriers and facilitators of implementation of TBIPC guidelines in low- and middle-income countries from the perspective of healthcare workers. Two separate reviewers carried out an electronic database search to select qualitative and quantitative studies exploring healthcare workers attitudes towards TBIPC. Eligible studies underwent thematic synthesis. Derived themes were further organised into a macro-, meso- and micro-level framework, which allows us to analyse barriers at different levels of the healthcare system. We found that most studies focused on assessing implementation within facilities in accordance with the hierarchy of TBIPC measures—administrative, environmental and respiratory protection controls. TBIPC implementation was over-estimated by self-report compared with what researchers observed within facilities, indicating a knowledge-action gap. Macro-level barriers included the lack of coordination of integrated HIV/tuberculosis care, in the context of an expanding antiretroviral therapy programme and hence increasing opportunity for nosocomial acquisition of tuberculosis; a lack of funding; and ineffective occupational health policies, such as poor systems for screening for tuberculosis amongst healthcare workers. Meso-level barriers included little staff training to implement programmes, and managers not understanding policy sufficiently to translate it into an IPC programme. Most studies reported micro-level barriers including the impact of stigma, work culture, lack of perception of risk, poor supply and use of respirators and difficulty sensitising patients to the need for IPC. Existing literature on healthcare workers’ attitudes to TBIPC focusses on collecting data about poor implementation at facility level. In order to bridge the knowledge-action gap, we need to understand how best to implement policy, taking account of the context. Tuberculosis (TB) remains one of the top 10 causes of death in the world, causing an estimated 1.45 million deaths in 2018, of which 250,000 were among HIV-positive people , 4.Nosocomial transmission of TB and DRTB remains an important mode of transmission. The 2005 outbreak of extensively drug-resistant TB at the Church of Scotland Hospital in KwaZulu-Natal, Tugela Ferry, highlights the risk of nosocomial infection towards patients , 7, who Despite the presence of TBIPC guidelines in most facilities and at a national level, implementation is usually limited. We undertook a systematic literature review with the aim of identifying barriers to and facilitators of TBIPC implementation in low and middle-income countries (LMIC) from the perspective of healthcare workers.The authors received no specific funding for this work.We Included only studies published in English, with no restriction on the earliest date of publication up to 12 May 2020, which explored barriers or facilitators of TBIPC implementation by healthcare workers. We restricted the review to studies conducted in LMIC, because the prevalence of TB is higher, thus healthcare workers in LMIC have an increased risk of nosocomial transmission . We inclStudies which merely surveyed TBIPC implementation rates without investigating explanatory factors were excluded. Unpublished studies, opinion pieces and letters were also excluded.The search strategy, which was developed with the help of a librarian, was refined in EMBASE using the OVID interface  and repeFocused search on the MeSH heading “tuberculosis”Exploded MeSH headings “infection control” and “communicable disease control” were combined using Boolean operator “OR”Exploded MeSH heading “health care personnel” was combined using the Boolean operator “OR” with free texts “ adj (worker or personnel or staff)”.Two reviewers  conducted the search independently, reviewing the titles and discarding papers with clearly irrelevant titles, and going through the abstracts of papers with possibly relevant titles. We then compared the relevant articles we each found in the three databases and resolved any disagreements by revisiting the aim to determine if the paper could contribute to answering the question. The reference lists of all relevant papers were manually scanned for further additional articles that met our criteria.Data extraction was guided by the Cochrane Data Extraction Template. Extracted information included that of study designs and methods, type of healthcare facility, type of healthcare worker, objectives and aims of study, information relating to factors which influence TBIPC practice, suggested measures to improve TBIPC implementation, and themes generated by both quantitative and qualitative studies. Data extraction was carried out independently by two separate reviewers and summarized in We assessed quality using the Consolidated Criteria for Reporting Qualitative Research (COREQ)  for qualThematic synthesis was used for data analysis. The reviewers familiarized themselves with the extracted data on the barriers and facilitators of TBIPC. The data was organised using the macro-, meso- and micro-framework, as suggested by reviewer AG. This is a variation of Goffman’s frame analysis, which was used to allow the identification of barriers within and between the different stages of the transformation of policy to practice. This framework has been used in bridging the gap from translating research-based policy into application at a facility level within a healthcare system . The macWithin each level of the framework, two reviewers (CT) then identified broad themes. The reviewers then revisited the extracted data to generate key themes from the broader themes within each level . The theThe search yielded 248 papers from EMBASE, 252 from Medline, 299 from Global Health and 92 papers from Google Scholar. This totaled 891 studies . After rThe twenty-four eligible studies were published between 2011 and 2020, originating from twelve countries, including South Africa (eleven studies), Ethiopia (two studies) and the Dominican Republic (two studies). Discussion sections of quantitative studies identified barriers that were similar to themes in qualitative studies.Focus group discussions (FGDs) were the most common method used (nine studies). Four qualitative studies used in-depth individual interviews, two intervention studies conducted a follow-up group feedback session with participants and collected data informally via these sessions, and five studies included the observation of the participants’ TBIPC practice (not as the main method), carried out to validate self-reported data obtained from questionnaires. Five of the eight quantitative studies were knowledge, attitude and practice studies.Only three of the studies assessed interventions. One conducted in South Africa, involving healthcare worker trainees, was a knowledge, attitude and practice questionnaire done before and after an TBIPC education programme based on the health belief model . The secFound Poor adherence was also found to be passed from a senior to junior level in a different study of healthcare worker students in Uganda . 66% of A South African Study reported a sense of powerless to change the way things are done .“This is such longstanding problems in the primary healthcare that even if you tell me it will change [by] December I will think it’s a big joke!’In South Africa, feeling undervalued and unsupported were attributed to reasons such not receiving danger pay when working with DR-TB, being unable to claim compensation despite acquiring TB nosocomially , managemDifficulty in educating and sensitizing patients. healthcare workers in Zambia and Botswana brought up patient cooperation as a barrier to implementing TBIPC  was considered discriminatory, he or she is a patient like any other patient and then we started to mix them with the others”Another study in Uganda found that the reason healthcare workers did not screen for TB symptoms in the waiting area was because they felt that the questions were too sensitive and should be asked in private during the consultation. In patients where a diagnosis was suspected but not confirmed, healthcare workers were uncomfortable informing the patient .In attempt to build a closer patient-healthcare provider relationship, healthcare workers in Mozambique were found to forego the use of respirators . StudiesThe stigma surrounding TB and HIV also impacted the decisions healthcare workers made regarding their own health. Two studies from South Africa found that healthcare workers were uncomfortable with attending occupational health screening for TB or HIV for fear of their colleagues breaching confidentiality , 26, andHealthcare workers perceived risks towards others. healthcare workers in Russia and Mozambique were motivated to adhere to TBIPC measures to avoid putting their family members at risk of acquiring TB [iring TB , 34, whiiring TB , 27 and The two studies from the Dominican Republic found that a strong sense of duty of care felt by healthcare workers towards their patients manifested itself in two contrasting schools of thought. While some felt a moral obligation to adhere to TBIPC measures to protect their patients, whom they felt were powerless to protect themselves , others Healthcare workers perceived risks towards themselves. A desensitization to the risks of acquiring nosocomial TB was common. The study from Russia found that healthcare workers perception of their risk seemed to diminish with time [ith time , while tith time , 31. Othith time  or, in tith time  and expoith time , 31.The study conducted in Mozambique cited that healthcare workers felt empowered by knowledge. They argued that knowledge allowed them to manage the risks by taking precautionary measures with TBIPC . SimilarA study conducted in Georgia  based onAcross the included studies, the most consistent concern reported by healthcare workers was the lack of funding and resources for effective TBIPC. Given the higher rate of hospital-acquired TB among healthcare workers in LMICs compared with high-income countries , it mighTraining was another widely-covered theme. In line with a review on the role of education in IPC , we founMany of the micro-level barriers identified are resonant with social cognitive models, which have been used to explain the knowledge-action gap. For example, the Health Belief Model  suggestsWhatever the role of individual-level factors, however, we should recognize that gaps in translating knowledge into action usually reflect systems-related and structural issues and not solely provider behaviour . A revieWe found that both the quality and the scope of studies meeting our inclusion criteria was limited. Most studies focused on documenting poor practice at the different TBIPC levels, namely administrative control measures, environmental control measures, and respiratory protection. Although three of the five knowledge, attitude and practice studies concluded that poor adherence was due to insufficient knowledge, these results were derived from questionnaires about self-reported behaviour, which may be influenced by social desirability bias. The focus on healthcare workers’ practice assumes that poor TBIPC implementation is due to nonadherence by healthcare workers, which as discussed earlier, apportions blame to healthcare workers without considering system deficiencies. Knowledge, attitude and practice surveys also have the disadvantage of being restricted to questions and responses preset by the researcher. Qualitative studies are needed to uncover themes beyond those already known to the researcher. Most qualitative studies reviewed could have included more consideration of reflexivity.Existing research under-represents the experience of IPC implementation in primary health care facilities. Primary health care facilities are usually smaller and less well resourced, and would face a different set of challenges to tertiary facilities, but are very important with respect to TB IPC because of the large numbers of patients who attend, particularly the increasing numbers of HIV-positive people who are more susceptible to developing tuberculosis.There was also a lack of studies at the meso- and macro-levels, with only three of the twenty-four studies having been conducted at a national level  and one study from South Africa focusing on macro barriers to implementation . This eiThe small number of available studies exploring the research question indicates that work is needed to achieve a more nuanced understanding of why implementation of TBIPC remains limited in many settings. The focus of existing literature is on documenting poor practice at the various levels of TBIPC and framing the problem as one of poor adherence to guidelines by healthcare workers. Future research should take more account of the broader context in which policy is implemented, both within individual healthcare facilities and the communities which they serve, in order to find effective solutions to protect healthcare workers and their patients from nosocomial transmission.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file.


This is followed by an array of cell physiology assays and signaling studies that can examine cell proliferation, migration, adhesion, cytoskeletal organization, responses to specific agonists or metabolic perturbations, among others. Frequently, the data generated are not sufficient to have a clear idea about molecular pathways involved and potential physiological impacts. Therefore, these studies are then followed by in vivo evaluations using organisms such as mice and zebrafish. The process of creating genetically engineered animals with altered gene expression followed by phenotype evaluation is both time- and resource-consuming and functional alterations may be hard to pinpoint. Thus, there is a strong need for an alternative strategy that would predict functional outcomes based on in silico gene expression profiling.One of the challenges of modern-day biology is a rapid and cost-effective functional evaluation of novel (or poorly understood) genes. Typically, a priori biological knowledge. This strategy affords the derivation of highly informative putative causal dependency structures within gene interaction networks based on conditional probabilities of gene expression states. The goal is to discern hierarchical relationships driving changes in gene expression between two or more different states. In its simplest form it can be used to unveil genetic relationship networks following exposure of a cell population to a signal. For example, to predict the role of gene X in a particular cell type, this computing framework strategy can be used to analyze changes in gene expression before and after gene X knockout or overexpression in order to arrive at a functional role played by this gene.The advent of inexpensive sequencing techniques, including bulk DNA, bulk RNA and single cell RNA sequencing makes such an approach feasible. Yet there remains a challenge of interpreting these large-scale omics data and making functional predictions. An important step forward in this regard has been the development of an ensemble artificial intelligence strategy that combines integrated deep learning and probabilistic programming. This causal statistical computing framework is designed to generate working hypotheses from high-dimensional datasets without the use of in silico analyses, while 4 were then used for functional predictions [This statistical computing framework was tested in the context of extracellular response kinase (ERK) signaling in endothelial cells. ERKs are a part of a ubiquitous and extensive family of mitogen-activated kinases (MAPK) that are involved in numerous biological processes and orchestrate a complex series of biological events ,2. WhileAfter initial data processing and feature learning to reduce dimensionality of the analysis, a deep artificial neural network (DANN) was trained and tested to predict experimental and control endothelial cell conditions based on gene expression profiles. The most informative genes identified by the DANN model were then used to build as Bayesian belief network (BBN). The BBN produced a putative causal gene dependency structure, which provided biological context for all downstream analyses . For exaThese predictions were tested in mice with an endothelial-specific disruption of ERK signaling. Phenotypic and functional evaluation revealed that following deletion of ERK1/2 genes in adult endothelial cells, mice developed hypertension due to a decrease in NO production (driven by reduced NOS3 expression) that was followed, at a later time point, by increased endothelin-1 expression . Along win silico phenotype projection is a highly efficient AI-driven approach capable of predicting complex phenotypes by teasing out the causal molecular underpinnings of disease. While requiring further validation, these results point to the significant potential for AI-driven analysis of omics data.This study thus provides the first biologically validated evidence that intelligently engineered machine learning strategies can glean meaningful insights into highly complex disease etiologies by robustly inferring informative gene network dependencies, reflective of the signal transduction cascades that drive cellular behavior and dictate phenotype. Analogous to established experimental methods of reverse genetics, this Our findings suggest that asymmetric divisions are the predominant mode of stem cell division in the adult hippocampus. This calls for reevaluating widely held assumptions on the distribution, maintenance, and divisions of neural stem cells, on the possibility of switching modes of division in response to cognitive or emotional stimuli, environment, and disease, and on the prospects of rejuvenation of the ailing nervous system. These findings also emphasize the need for finding new agents and targets for controlling the modes of stem cell division: if neural stem cells are not dividing symmetrically on their own, then we may need to induce that mode of replication to repair the aging or damaged brain.


The purpose of this review is to critically evaluate current sarcoidosis models and assess their potential to progress the field toward the goal of improved therapies in this disease. We conclude with the potential integrated use of preclinical models to accelerate progress toward identifying and testing new drugs and drug combinations that can be rapidly brought to clinical trials.The inability to effectively model sarcoidosis in the laboratory or in animals continues to hinder the discovery and translation of new, targeted treatments. The granuloma is the signature pathological hallmark of sarcoidosis, yet there are significant knowledge gaps that exist with regard to how granulomas form. Significant progress toward improved therapeutic and prognostic strategies in sarcoidosis hinges on tractable experimental models that recapitulate the process of granuloma formation in sarcoidosis and allow for mechanistic insights into the molecular events involved. Through its inherent representation of the complex genetics underpinning immune cell dysregulation in sarcoidosis, a recently developed  Significant progress toward improved therapeutic and prognostic strategies in sarcoidosis hinges on tractable experimental models that recapitulate the process of granuloma formation in sarcoidosis and allow for mechanistic insights into the molecular events involved. The purpose of this review is to critically evaluate current sarcoidosis models and assess their potential to progress the field toward these goals. Selected sarcoidosis models described in the following sections have been summarized in Sarcoidosis is a complex immune disease with genetic susceptibility and environmental factors playing important roles. The disease occurs in about 15–40 per 100,000 people in the United States . Severe Studies of diseased patient biopsy tissue are the foundation of sarcoidosis research. The original description of sarcoidosis in 1877 was based on the characteristic appearance of biopsied skin lesions and histological features that discriminated sarcoidosis from tuberculosis (TB) and other infectious granulomatous disorders . DespiteSarcoidosis granuloma formation is considered to be environmental antigen-mediated , and thePropionibacterium acnes are consistent with hypersensitivity pneumonitis in that, unlike sarcoidosis granulomas, they are poorly formed, transient, and surrounded by prominent lymphocytic pneumonitis , which normally represses the activity of mammalian target of rapamycin complex 1 (mTORc1)  . The Tsctivation . HoweverA major barrier to developing a viable sarcoidosis model is the inability to identify a specific sarcoidosis disease-causing antigen. However, pulmonary sarcoidosis is clinically and histologically very similar to berylliosis, a human disease linked to genetic variability of T cell receptors for divalent beryllium molecules . Given t+ T cells derived from sarcoidosis BAL samples induced fibroblasts to produce increased amounts of collagen in a STAT3-IL17A dependent manner, thus clarifying signaling events upstream of fibrotic tissue changes  naïve sarcoidosis patients and healthy controls. No difference in PBMC gene expression profiles was observed between M.tb naïve sarcoidosis patients and healthy controls at baseline  as reflected by >1,000 differentially expressed (DE) genes  genes . While tanulomas  and prodanulomas . These ranulomas .in vitro granuloma model holds promise in providing detailed mechanistic insight into sarcoidosis–specific disease regulating pathways at play during early stages of granuloma formation. This was demonstrated through the common stimulation of PBMCs derived from M.tb naïve sarcoidosis patients and individuals with latent TB infection (LTBI) with M.tb-derived antigens. Both groups produced granuloma-like structures following stimulation, albeit the structures derived from LTBI individuals had a denser lymphocytic cuff. However, gene expression differences were vast between the groups revealing divergent mechanisms of granuloma formation that once again were dependent on antigen stimulation (+-ATPase (V-ATPase), a multisubunit proton pump that actively acidifies lysosomal compartments. In addition to this role, V-ATPase forms a signaling complex with mTORc1 that promotes its activation when phagolysosomes are acidified  inhibition  into human trials to effectively inhibit the cycle of pathological granuloma formation (As cell-based laboratory models continue to advance, the use of mathematical models will act in concert with them to accelerate the pace of discovery , 56. A cver time . We enviormation .in vitro human granuloma models as complementary platforms for testing new therapies and evaluating pharmacokinetic and toxicity aspects ahead of human trials (As we look toward the future of therapeutic development in sarcoidosis, the role of animal models is currently unclear. Undoubtedly animal models have proven valuable for defining new aspects of disease pathogenesis and pre-clinical testing of new therapeutics. Relevant to sarcoidosis, novel imaging techniques can be performed in mice to enable powerful visual insights into the interplay of immune cells and tissue stroma . The futn trials .in vitro human granuloma model could be leveraged to screen novel therapies and determine the contribution of specific genes to granuloma formation using siRNA or CRISPR technology (in vitro human granuloma model is that it can be used to better understand the dynamic, multicellular mechanisms underpinning distinct granulomatous immune responses that occur in humans and is not restricted to sarcoidosis (In addition to the providing greater insights into granuloma formation in sarcoidosis, the chnology . Becausechnology , the modcoidosis . For exain vitro cell culture models to address. For example, the in vitro human granuloma model is likely not capturing the entire spectrum of disease due to the absence of a tissue-mimicking environment. Recent advances in organ-on-a-chip technology are beginning to provide new opportunities in in vitro cell culture models such as the modeling of more complex cell interactions involving extracellular matrix components and stromal cells, although to date most of these models lack immune cells (There are some caveats of current ne cells . Enablinne cells . Organ-oin vitro granuloma model allows for the interrogation of antigen-immune cell interplay and related cell-cell interactions driving the various stages of granuloma formation in sarcoidosis and underpinned by the complex and, as yet, undefined genetic features of this disease. The in vitro human granuloma model provides a powerful approach to addressing critical knowledge gaps in sarcoidosis, and we envision its complementary use with other pre-clinical models will likely accelerate progress toward identifying and testing new drugs and drug combinations that can be rapidly brought to clinical trials.The failure to effectively model sarcoidosis in the laboratory or in animals continues to hinder the discovery and translation of new, targeted treatments. Preclinical models that are capable of clarifying the significant knowledge gap surrounding the triggers and mechanisms driving granuloma formation and self-perpetuation in sarcoidosis will be key to this cause. Compared to modeling approaches that study only a single cell type, the patient-derived PBMC-based EC, LS, and LL wrote the article. EC and LL contributed to designing the figures and table for the article. All authors contributed to the article and approved the submitted version.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.


Dear Editor,Dementia is a pandemic condition in aging societies, affecting about 50 million people.People with dementia may not be able to follow health recommendations such as keeping social distancing, covering their mouth and nose when coughing, and hand hygiene,Taking care of dementia patients is more probable to get a poor outcome.,During this pandemic, individuals with dementia showed higher mortality rate compared to patients without dementia which makes severe dementia independent risk factors for death due to COVID-19.According to statistics from the World Health Organization (WHO), 60–70% of dementia cases are in the form of Alzheimer disease (AD).The long-term effects of SARS-CoV2 infection on neurodegeneration are still unknown.,The direct neuroinvasive capacity of coronavirus to infect the central nervous system is not well known, but there are multiple possible mechanisms suggested for indirectly mediated inflammation.These findings may lead to an even higher rate of dementia in the long run after the COVID-19 pandemic.Disruption in routine medical visits, diagnosis, and follow-up results in a rapid increase of severe cases of dementia in the future. We are not sure when the world society condition will become stable again; but we are sure that the mental and physical health of patients with dementia should not be neglected during this pandemic and COVID-19 should not overshadow dementia treatment.


Scars are generated in mature skin as a result of the normal repair process, but the replacement of normal tissue with scar tissue can lead to biomechanical and functional deficiencies in the skin as well as psychological and social issues for patients that negatively affect quality of life. Abnormal scars, such as hypertrophic scars and keloids, and cutaneous fibrosis that develops in diseases such as systemic sclerosis and graft-versus-host disease can be even more challenging for patients. There is a large body of literature suggesting that inflammation promotes the deposition of scar tissue by fibroblasts. Mast cells represent one inflammatory cell type in particular that has been implicated in skin scarring and fibrosis. Most published studies in this area support a pro-fibrotic role for mast cells in the skin, as many mast cell-derived mediators stimulate fibroblast activity and studies generally indicate higher numbers of mast cells and/or mast cell activation in scars and fibrotic skin. However, some studies in mast cell-deficient mice have suggested that these cells may not play a critical role in cutaneous scarring/fibrosis. Here, we will review the data for and against mast cells as key regulators of skin fibrosis and discuss scientific gaps in the field. When the skin is injured, the body initiates a wound-healing response. Depending on the tissue type and the severity of the injury, one of three general outcomes can result: regeneration of normal tissue without scarring, repair of the tissue with a scar, or fibrosis with excessive scar tissue production. Although regeneration is the ideal response to skin injury, this type of healing rarely occurs except in developing fetal skin. The normal response to tissue damage in the skin is repair. This well-characterized process begins with an inflammatory response during which resident inflammatory cells  become activated and circulating inflammatory cells  are recruited. This is followed by a period of marked cellular proliferation and eventually the production/remodeling of collagen by fibroblasts to form a scar ,2,3.Scars are a significant clinical concern, and they pose many problems. Scar tissue has altered biomechanical properties, causing it to be weaker and more rigid than normal skin ,5. Scar An imbalanced or persistent inflammatory response is believed to contribute to scar formation and fibrosis . One infThe diversity of activities described above that have been attributed to mast cells is likely due to the ability of these cells to produce a wide range of mediators  Figure . Many maAlthough most types of injury in mature skin lead to the formation of a scar, there is a period during fetal development during which regenerative, scarless healing is known to occur. Fetal skin is capable of healing scarlessly prior to the third trimester of development, whereas more mature skin beyond this stage of development heals with the formation of a fibrotic scar ,23,24. TW/W-v mice healed with smaller scars compared to wild-type mice that contain normal dermal mast cell numbers [Interestingly, the density of dermal mast cells is known to increase as fetal skin becomes more developed and loses its ability to heal scarlessly. This has been shown by several groups in rat  and mous numbers . TogetheThe normal cutaneous wound repair process leads to the formation of a scar. Several studies have quantified mast cells in normal human scar tissue and found that mast cells are more abundant in scars compared to normal skin. In excisional wounds, mast cells were shown to significantly increase after injury, and the number of mast cells in 4-week and 6-week scars was approximately double the number found in uninjured skin . SeveralIn addition to the human studies discussed above, animal models have been used to carry out functional studies testing the importance of mast cells in the normal scar formation process. These types of studies have generally used mast cell stabilizers to block mast cell degranulation or mouse strains deficient in mast cells. Disodium cromoglycate, also known as cromolyn, is a mast cell stabilizer that has been used in several animal studies. Direct injection of this drug into rat wounds has been shown to reduce collagen content . In anotW/W-v mice are naturally occurring mutant mice that lack mast cells as a result of mutations in the gene encoding the tyrosine kinase receptor Kit. This receptor mediates signaling in response to stem cell factor, which is required for mast cell development. In a scald wound model, KitW/W-v mice were reported to heal with less wound edge fibrosis [W/W-v mice as well as mice lacking the mast cell enzymes murine mast cell protease (mMCP)-4 (chymase) or mMCP-5 (elastase) healed with hair regrowth and less scarring [W/W-v mice [W/W-v mice were shown to produce less granulation tissue and collagen in response to negative pressure, which causes microdeformation and enhances granulation tissue formation and collagen deposition in normal wild-type mice [Aside from mast cell stabilizers, several different mast cell-deficient mouse strains have also been used to examine the role of mast cells in normal scar formation. Kitfibrosis . In anotscarring . In largW-v mice . In anotype mice .W/W-v, KitW-sh/W-sh, or Cpa3-Cre/Mcl-1fl/fl mice [W/W-v and KitW-sh/W-sh strains have mutations in the Kit receptor, whereas Cpa3-Cre/Mcl-1fl/fl mice lack mast cells due to cre recombinase-mediated ablation of the anti-apoptotic factor Mcl-1 (myeloid leukemia cell differentiation protein-1) in carboxypeptidase A (Cpa3)-expressing mast cells [Cre/+ mice [Other studies in various mast cell-deficient strains have suggested that mast cells do not play a strong role in scar formation. In splinted excisional wounds, no differences were found in scar size or collagen density in mast cell-deficient Kit/fl mice . KitW/W-st cells . Anothere/+ mice , which ae/+ mice . Finallye/+ mice , which ae/+ mice . The reae/+ mice . Although the production of scar tissue even at normal levels can be problematic, excessive or abnormal scarring poses even more of a concern from aesthetic, functional, and clinical points of view. Hypertrophic scars (HTS) and keloids are two types of abnormal scars that can develop after injury. HTS are raised red scars that fall within the borders of the original injury, whereas keloids are abnormal raised scars that spread beyond the margins of the original wound. A number of studies have assessed the potential role of mast cells in abnormal scars.Several published studies have examined mast cells in human HTS. Early studies showed an increase in histamine in HTS compared to normal skin, suggesting the presence of active mast cells in HTS . An incrMast cells have also been examined in animal models of HTS. The red Duroc pig is often used as a model of HTS and mimics several important features of human HTS. In this model, HTS tissue was shown to have more mast cells compared to normal skin . AnotherSince there is no standardized, widely accepted animal model for keloids, studies on mast cells in keloid disease have primarily been limited to descriptive studies and ex vivo evaluation of human samples. Many of the studies published to date have suggested a potential role for mast cells in keloid scarring. Elevated histamine levels  and highOverall, the majority of studies on HTS and keloids seem to indicate that the presence of mast cells may promote abnormal scarring, but the studies reporting results contrary to this idea raise questions about whether mast cell numbers are truly associated with scar formation. Although the exact reasons for the conflicting results are not known, there are a few items that should be considered when weighing the data. First, many of the studies use different histological or immunostaining methods to identify mast cells. These methods may stain mast cell granules (toluidine blue), mast cell proteases (tryptase or chymase), or membrane receptors on mast cells (CD117/Kit), which may yield different results. Of particular importance is the fact that mast cells can degranulate and may also release proteases upon activation, making it more difficult to accurately count the number of mast cells in settings with pronounced mast cell activation in toluidine blue- or protease-stained sections. In addition, the number of samples, type of samples, and the specific area(s) within the samples being analyzed could also impact the results. For example, mast cell numbers can vary depending on the age of the scar ,63 and c+/chymase−) cells compared to MCTC (tryptase+/chymase+) cells has been described in SSc skin lesions [Systemic sclerosis (SSc) is a disease characterized by fibrosis in the skin and other internal organs, and it is associated with vascular damage and immune dysfunction . Many st lesions , and oth lesions  or inter lesions .In skin from SSc patients, there appears to be a close association between mast cells and fibroblasts, and mast cell degranulation seems to be closely tied to fibrosis , with deW/W-v mice showed that in early phases (1 week), sclerosis did not develop in mast cell-deficient mice, but there were no significant differences compared to control mice at later stages (2–4 weeks), suggesting that mast cells may accelerate the formation of sclerotic lesions at early stages [Several animal models are used to study scleroderma , and mosy stages . In a moy stages ; howeverTsk1+/− mice has been shown to be a result of a mutation in the fibrillin 1 gene [Tsk1+/− mice [Tsk1+/− mice is at least partially due to enhanced local production of cytokines such as TGF-β1, SCF, and IL-15 [Tsk1+/− mice [Tsk1+/− mice and treatment with a chymase inhibitor can reduce fibrosis [Tsk1+/− mice into irradiated normal mice caused the development of skin fibrosis; however, this was not associated with an increase in mast cell numbers or degranulation [Tsk1+/− mice. However, studies in which Tsk1+/− and KitW/W-v mice were crossed to generate mast cell-deficient Tsk1+/− mice suggested that while there was no change in the onset of fibrosis in the absence of mast cells, there was a reduction in the degree of fibrosis that developed in mice lacking mast cells [Tight skin (Tsk) mutant mice are also commonly used as a model of skin fibrosis . Fibrosin 1 gene . An incr+/− mice ,109,110.+/− mice ,112. Stufibrosis . In adopnulation . These rst cells .More recent studies have suggested a role for mast cells in fibrosis using another model that has been reported to mimic several features of scleroderma. In this model, skin fibrosis develops in transgenic mice that overexpress the transcription factor Snail in epidermal keratinocytes . Skin fiW-sh/W-sh mice with GVHD compared to control mice with GVHD [Skin fibrosis is a recognized complication of graft-versus-host disease (GVHD), and the fibrotic process associated with GVHD shares several key features with progressive SSc . An incrith GVHD .A number of mechanisms have been described by which mast cells can stimulate the activity of dermal fibroblasts and presumably promote scar formation and fibrosis. These include the secretion of paracrine mediators by mast cells and direct mast cell–fibroblast interactions .Activated mast cells are known to influence the activity of fibroblasts ,129,130.Tryptase and chymase are two mast cell proteases for which a wide range of effects on dermal fibroblasts have been reported. Tryptase has been shown to enhance fibroblast proliferation ,132,133,Histamine is a vasoactive amine produced primarily by mast cells. Although the primary target of mast cell-derived histamine may be vascular endothelial cells, histamine also affects dermal fibroblasts. Studies have shown that histamine can increase the expression of collagen ,140 and Several other mast cell-derived mediators can affect the activity of dermal fibroblasts. Studies have shown that the ability of activated mast cells to increase collagen expression/secretion  and prolMast cells and fibroblasts are known to be closely associated in fibrotic tissues, and studies have shown that they directly adhere to and communicate with one another via heterocellular gap junctions in vitro (The review of the literature presented above highlights the broad scope of published studies that have examined mast cells in cutaneous scarring and fibrosis. There is a distinct period of mast cell degranulation in response to various types of skin injury that leads to the release of mediators, many of which have been shown to stimulate dermal fibroblasts. Furthermore, based on the bulk of results from both animal studies and human samples, it seems clear that most scars and fibrotic diseases in the skin contain elevated numbers of mast cells, and these conditions are also often associated with prominent mast cell activation. Despite these key pieces of information, questions still remain about whether mast cells are actually critical for the development of scar tissue and fibrosis, primarily due to conflicting data on the functional role of dermal mast cells.Factors that may be contributing to lingering questions about the importance of mast cells in fibrosis include limitations in the currently existing experimental approaches used to study mast cells in vivo. Mast cell stabilizers, such as ketotifen and disodium cromoglycate, have been used to prevent the release of mast cell mediators via degranulation. However, no drugs have been described that can specifically target mast cells  and the W/W-v and KitW-sh/W-sh mice. The Kit mutations lead to mast cell deficiency, but they also cause additional abnormalities such as macrocytic anemia and neutrophil defects that can confound the results when directly comparing Kit mutant and wild-type mice [In addition to mast cell stabilizers, a variety of different mast cell-deficient mouse strains have been used to study mast cell function in scar formation and cutaneous fibrosis, but the results have been variable. Many of these studies have used mice with mutations in the Kit receptor, such as Kitype mice . One metype mice . Howeverype mice , but theype mice . For exaThe concept of mast cell heterogeneity and the possible existence of different functional mast cell subpopulations in the skin is not new, but detailed studies in this area are lacking. Published reports ,37 and oAlthough there are data correlating high mast cell numbers with scarring and skin fibrosis in human skin, the relative importance of mast cells in these processes is not known. It is difficult to carry out cell-specific functional analyses in clinical studies, which is one reason animal models are commonly used to study in vivo mast cell function. Although murine models can be useful for understanding basic mechanisms of scar/fibrosis development in vivo and genetic alterations can be used to deplete mast cells or mast cell mediators, anatomical differences between mouse and human make it difficult to know how relevant results from murine studies are to human clinical disease. Further studies will have to be done to clarify the role of mast cells in cutaneous scarring and fibrosis in humans and to determine whether targeting mast cells could be a viable approach to prevent or limit scar tissue formation in human skin.A comprehensive review of the published literature indicates a strong link between mast cells and cutaneous scarring/fibrosis, as well as strong evidence that mast cell-derived mediators influence fibroblast behavior. However, questions still remain about how critical mast cells are for the development of scar tissue. It is possible that mast cell activity is not absolutely required for scar formation but that mast cells promote this process. In order to better understand the role of mast cells in scar formation, more research needs to be done to characterize in detail the different mast cell subpopulations in the skin and how they change over time. More precise methods of depleting mast cells in animal models and more specific drugs to target mast cells are needed to advance the current knowledge about mast cell function in vivo. Overall, more work will be needed in order to gain a full understanding of dermal mast cells and how they contribute to the production of scar tissue during wound repair and the development of fibrosis in the skin.


Invasive species represent a serious ecological threat for many ecosystems worldwide and provide a unique opportunity to investigate rapid adaptation and evolution. Genetic variation allows populations of organisms to be both robust and adaptable to different environmental conditions over evolutionary timeframes. In contrast, invasive animals can rapidly adapt to new environments, with minimal genetic diversity. Thus, the extent to which environmental effects can trigger epigenetic responses is particularly interesting for understanding the role of epigenetics in rapid adaptation. In this review, we provide a brief overview of the different epigenetic mechanisms that control gene expression, and emphasize the importance of epigenetics for environmental adaptation. We also discuss recent publications that provide important examples for the role of epigenetic mechanisms in environmental adaptation. Furthermore, we present an overview of the current knowledge about epigenetic modulation as an adaptive strategy for invasive species. A particularly interesting example is provided by the marbled crayfish, a novel, monoclonal freshwater crayfish species that has colonized diverse habitats within a few years. Finally, we address important limitations of current approaches and highlight the potential importance of less well-known mechanisms for non-genetic organismal adaptation. It is commonly accepted that differences in the deoxyribonucleic acid (DNA) sequence  provide organisms with the ability to adapt to different environmental conditions. Natural selection acting on genetic variants explains how organisms can colonize ecological niches over evolutionary timeframes. However, several examples of rapid adaptation and invasion are difficult to explain solely by the selection of genetic variants. As such, epigenetic mechanisms have been increasingly used to explain these phenomena. We delimit epigenetic plasticity from transgenerational epigenetic inheritance, which is controversially discussed and would allow the inheritance of acquired epigenetic traits . In contOur article focuses on epigenetic adaptation in animals, as several reviews are already available for plants . We begiMulticellular organisms are genetically homogeneous, but different cell types and functions arise from the differential expression of genes. It has been shown that differentiating mammalian cells undergo dynamic epigenetic changes, resulting in the establishment of cell-type-specific programs . TranscrTranscription in eukaryotes takes place in the context of chromatin. In general, nucleosomes impede DNA transcription, either by physically obstructing or by compartmentalizing the binding of transcription factors to DNA. An important feature of histones, and particularly of their N-terminal tails, is their ability to carry post-translational modifications, which can affect chromatin structure in different ways. Many of these modifications are dynamically regulated by families of enzymes that write or erase the modifications . BesidesRNA-based mechanisms have also been involved in epigenetic regulation, but are less well understood in animals. Key molecules are noncoding RNAs that belong to several classes. Small interfering RNAs (siRNAs) and microRNAs are derived from longer precursor RNAs by the action of RNAse III-family enzymes, such as Drosha and Dicer, and can inhibit translation or direct mRNA degradation . AdditioDNA methylation represents the most well-studied epigenetic mechanism, and characterizing the biological relevance of this modification and its impact on gene expression has driven research in the field for a long time . The dynMechanistically, the effects of DNA methylation are often explained by their complex association between DNA methylation and transcription factor binding . An addiFrom an ecological perspective, epigenetic mechanisms could promote phenotypic plasticity and adaptation to different environments . Thus, tWith the emergence of epigenetics and the development of methods for the detection of epigenetic modifications, many studies have attempted to link adaptive changes to epigenetic changes . More reAnolis sagrei), suggesting a relationship between epigenetic variation and rapid responses to environmental changes , this process is not accompanied by known genetic mutations in eye developmental genes. Instead, it was shown that promoter hypermethylation could repress eye-specific genes and thus results in defective eye development  and proposed as a rapid response mechanism to environmental challenges (Xenostrobus secures), global DNA hypomethylation was detected in a recently evolved population and interpreted as a mechanism to promote phenotypic plasticity and thereby facilitate the expansion of invasive populations (Bemisia tabaci), DNA methyltransferase 1 (DNMT1) knockdown caused reduced thermotolerance, but DNA methylation patterns were not investigated  represents a novel freshwater crayfish species that emerged from the German aquarium trade about 25 years ago  from Florida , many genes showed reduced levels of gene body methylation and increased levels of gene expression variability (The combination of obligatory apomictic parthenogenesis with an extremely young species age (25–30 years) in marbled crayfish creates unique opportunities for elucidating the role of epigenetic mechanisms in invasiveness. Indeed, the genome of the marbled crayfish encodes a conserved and active DNA methylation toolkit . A detaiiability . This miOf note, marbled crayfish possess key prerequisites for a laboratory model, such as suitable size, resistance against handling stress, high fertility, and a relatively short generation time . In addiElucidating the role of epigenetic mechanisms in phenotypic plasticity and adaptation will remain an important research topic for many years to come. It will be important to avoid known issues in the design and interpretation of epigenome mapping studies that have plagued the field in the past . In thisIt will also be critically important to analyze the functional role of epigenetic mechanisms in rapid adaptation and invasiveness. This can be achieved by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-mediated editing  and inacFinally, it is also likely, that additional epigenetic mechanisms will emerge in the context of rapid adaptation and invasiveness. A prominent example is provided by small RNAs that can be loaded into oocytes and sperm and can thus be transmitted from parents to offspring . If thes


A growing body of research indicates that mindfulness training can have beneficial effects on critical aspects of psychological well-being, cognitive function, and brain health. Although these benefits have been generalized to the population level, individual variability in observed effects of mindfulness training has not been systematically investigated. Research on other similar forms of psychological intervention demonstrates that individual differences are prominent in terms of intervention responsiveness and outcomes. Furthermore, individual characteristics such as personality traits have been shown to play a crucial role in influencing the effects of intervention. In light of these lines of evidence, we review representative work on individual differences in mindfulness training and advocate for an individual difference perspective in mindfulness training research. We discuss relevant empirical evidence of individual differences potentially influencing behavioral outcomes of mindfulness training, focusing on both cognitive function and psychological well-being. Finally, theoretical considerations and potentially fruitful research strategies and directions for studying individual differences in mindfulness training are discussed, including those involving cognitive neuroscience methods. Mindfulness training (or mindfulness-based intervention) has garnered popularity both within the scientific community, and among the lay public, as an effective intervention that promotes health and well-being. Adapting practices and techniques from Eastern Buddhist traditions, mindfulness training was first introduced to Western culture in the 1970s as a set of secular and contemplative practices that alleviate stress and psychological distress . SubsequNonetheless, this widespread application of mindfulness training deserves careful scrutiny. Most of the extant literature on mindfulness training has generalized its benefits to the population level, assuming homogeneous effects of training for every individual based on group-averaged results. However, this one-size-fits-all model is in tension with existing theoretical frameworks and empirical evidence that have been amassed with regard to individual variability in response to psychological interventions . FurtherIndeed, the Precision Medicine Initiative announced by the U.S. government directly highlights the importance of tailoring prevention and intervention programs based on individual characteristics, in order to achieve better outcomes . ConsequNonetheless, encouraging and emerging efforts have been made to advance our understanding of individual differences in domains such as personality traits , psychola priori hypotheses regarding putative variables associated with differential intervention effects  with major depressive disorder, higher neuroticism was associated with more improvement in depressive severity post-treatment, if PHT was administered, but not if CBT was used , which focuses on problem solving exercises – rather than treatment as usual (TAU) devoted largely to group therapy, in which general strategies of crisis resolution and symptom reduction are discussed . AccordiFor mindfulness-based intervention, such as the most popular variants of mindfulness training , group discussion and activities are involved in almost every class session . It is pOpenness to experience represents a sense of curiosity, acceptance and open-mindedness to diverse experiences. This is highly relevant for mindfulness training, since individuals high in openness to experience may be more likely to seek out and practice complementary and alternative medicine (CAM) techniques, such as yoga and mindfulness-based practices in daily life . As evidBased on these findings, openness to experience seems to have a special relevance to mindfulness training, as this trait is likely to determine how much individuals would engage in the actual practices that may lead to observable improvement in any training-related outcomes. This is not surprising since previous evidence suggests that individuals high in openness tend to benefit more from approaches focusing on self-exploration and discovery  and theyN = 47), high conscientiousness was positively associated with overall improved working memory performance at post-training in conjunction with high training enjoyment reported by participants  showed that the positive relationship between trait mindfulness and executive attention performance is mediated by the brain P300 event-related potential component, as assessed via electroencephalography (EEG), suggesting a neuropsychological basis for such relationship  of an 8-week of mindfulness intervention further confirms the notion that mindfulness training not only elicits cognitive reappraisal during training, but also increases self-reported positive reappraisal at post-training  for mindfulness training effects on psychological well-being: (1) cognitive reappraisers would show more improvement since they can easily acquire and practice mindfulness techniques involving reappraisal for emotion regulation, thereby leading to better psychological outcomes and cognitive function; or (2) expressive suppressors would exhibit more enhancement in psychological health and cognition, especially in positive affect, since they could gradually shift away from the previous mentally taxing strategy, to a more beneficial and effective way of emotion regulation through recurrent mindfulness practices. Although there has not been empirical research specifically examining these two hypotheses, the abovementioned inter-relationships among emotion regulation, psychological well-being, and mindfulness training suggest that the tendency for either reappraisal or suppression should theoretically be relevant for influencing the extent of mindfulness training effects on psychological health and cognitive function.Taken together, individual differences in styles of emotion regulation could potentially interact with intervention processes, by influencing the state of learning and acquisition of relevant techniques to induce differential effects at the individual level. It should be noted that the putative emotional regulatory strategies mentioned above are by no means exhaustive, but they do serve as useful examples to illustrate the importance of examining pre-existing individual differences in emotion regulation tendencies in relation to mindfulness training effectiveness and outcomes.A rapidly growing body of empirical studies has shown three broad domains of cognitive function are often enhanced following mindfulness training: attention, memory, and executive functions . Among tIndeed, individual variability in cognitive function partly appears to be the result of genetic contributions mediated through core neural circuits. Extensive behavioral genetic analyses have found moderate heritability (0.25–0.55) in individual tasks, but this rises to high heritability (0.75) at the level of latent variables, where shared variance across multiple tasks can be extracted to reflect an underlying global process or ability that influences overall performance . SimilarAttentional control is one fundamental component of mindfulness training, since cultivating mindfulness requires the ability to control attention in detecting when the mind is wandering, being able to reorient cognitive focus back to the target of concentration, and in sustaining concentration throughout the practice . RelatedFollowing this line of logic, a number of theoretical accounts of mindfulness training mechanisms have strongly argued for the role of attentional control in subserving training-related cognitive improvements in working memory and inhibitory control . This thN = 48) demonstrated that improved working memory capacity following 2 weeks of mindfulness training was mediated by attentional control ability at baseline, such that participants who were initially prone to distraction  exhibited greater benefits in working memory capacity  running multiple training groups in parallel with multiple instructors (one per group); and (2) having more teaching assistants with one instructor to guide a larger training group. The former option is an ideal solution when there are adequate financial and instructional resources to support such large-scale study. The latter option would likely reduce the financial burden more than the former, but it is currently an unstudied question as to whether or not having trained teaching assistants would introduce unknown effects to training quality.A related issue is that of participant attrition. This factor, which is common in intervention research, also makes collecting large sample size data challenging, especially for the types of longitudinal designs becoming more common in mindfulness training research, which require a significant time commitment and persistence from participants throughout the study period. This challenge may be potentially addressed by offering greater incentives for study completion or by providing easily accessible training programs to participants via online platforms. Indeed, web-based mindfulness programs have increasingly been developed and distributed in recent years, but the standardization and effectiveness of such programs warrants further investigation. In particular, a recent review suggests some support for the efficacy of web-based mindfulness training programs on improving psychological well-being, with most studies showing large effect sizes . Yet metThe second issue to consider is the reliability and validity of measurement tools used for examining mindfulness training effects. Reliability refers to the overall consistency of a measure to produce similar results when administered multiple times in the same individual when all other factors are held constant, whereas validity is the extent to which an assessment measures what it is supposed to measure. While both concepts are fundamental to psychometric theory and are valued highly in psychology and cognitive neuroscience research, they are especially worth underscoring for studies adopting an individual differences approach. Validity is generally less of a concern if the construct of interest is clearly defined and operationalized by the measurement tools, based on established theories, and more importantly, if the measurement tools have previously been examined in empirical studies for validity. However, Reliability plays an even more pivotal role in individual differences research, by directly influencing the extent to which individual differences effects can be observed in studies, as well as the stability of such effects, if any. Intuitively, low measurement reliability could lead to fluctuating results, since the assessment would yield fairly different scores each time it is administered to the same individual. For example, low reliability can lead to unstable correlational relationships between the measured variables, resulting in inconsistent conclusions about individual differences in these variables. Another notable, perhaps more serious consequence arises from the reliability paradox, which has recently been shown to be especially pernicious with regard to robust cognitive paradigms. Here, well-established experimental effects are consistently replicated at the group level, simply because these tasks are less sensitive to between-subject variability .The reliability paradox is problematic because most studies of individual differences employ a correlational approach for data analysis; yet if seemingly well-validated tasks that nevertheless have low between-subject variability are employed, it can greatly undermine the correlational relationships observed between theoretically important variables, resulting in misleading conclusions. As a concrete example, the cognitive tasks that are frequently utilized to assess mindfulness training effects on attentional control and related constructs , are precisely the ones demonstrated by Although the abovementioned issues are troublesome for individual differences research in mindfulness training, two straightforward solutions could potentially remedy some of the negative impacts. The first solution is to compute and report reliability coefficients for each assessment , and for each new sample, by following guidelines from the psychometric literature . This quFurthermore, it is worth mentioning that for individual differences research, it is imperative to select measurement tools that not only have good reliability but also are sensitive to inter-individual variability. As described above, it is not logically entailed that a paradigm yielding consistent experimental effects at the group-level will also capture unique variance between individuals. Fortunately, there has been new progress in the development of cognitive task batteries sensitive to both group and individual level effects , and somN = 247) also established the presence of individual preferences for specific meditation techniques, but not all techniques, taught within a training program, suggesting that people may not find every training technique to be helpful and may only engage in techniques they find most effective (N = 117) who practice mindfulness and such preferences also underwent change over the course of mindfulness training in some individuals , acquired during both task-evoked and resting states , with thBrain functional connectivity profiles provide a particularly clear example. In particular, connectivity profiles in task and resting states can act as a “fingerprint” that reliably distinguishes individuals from rest of the group . LikewisNeuroimaging studies of individual differences are strongly benefited by a longitudinal design with multiple sessions of scanning data per participant, to most accurately identify features unique to the individuals . FortunaRelatedly, recent advances in neuroimaging analytic approaches also hold promise for interrogating individual differences within the context of mindfulness training. Some of these approaches include but not limited to: (1) structural equation modeling, which can directly model between-subject variability and is sensitive to the complexities of brain-behavior relationships, as well as the psychometric properties of data critical for individual differences-type analysis  indicating individual preferences for certain delivery formats  of mindfulness training (Finally, the personalized medicine and patient-centered care movements suggest a completely new direction of research that affords tremendous opportunities and progress for bridging psychology and health science. In particular, mindfulness research has yet to investigate the feasibility of modifying and tailoring existing established prevention and treatment programs to individual’s characteristics and needs. Although standardized programs enable a widespread implementation of intervention protocols in an easily controlled and accessible manner, customizing these multifaceted packages could potentially be illuminating at the individual level. For instance, prior work (training , which cAs this review has highlighted, evidence is accumulating that individual differences in dispositional traits, psychological well-being, and cognitive function could play a critical role in contributing to the heterogeneity in mindfulness training effects across individuals. Consequently, moving toward an individual difference perspective is imperative for accurately evaluating mindfulness training effects and outcomes to inform subsequent application in real-world settings. In this review, we discussed putative traits and characteristics relevant to mindfulness training effectiveness, as well as theoretical considerations and useful examples for future investigations on this topic. It is our hope that researchers will not only be made aware of these critical issues associated with individual differences research within the context of psychological intervention, but will also be encouraged to explore various ideas and approaches to tackle this emerging question in mindfulness training research.RT contributed to the conception, writing, and critical revision of the manuscript, and final approval of the version to be published. TB contributed to the writing and critical revision of the manuscript, and final approval of the version to be published.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.


Operational and scientific inefficiencies in clinical trials represent roadblocks that need to be identified and circumvented to advance drug development in oncology. The collaboration of key stakeholders to advance this agenda is crucial to accelerate clinical research and ultimately benefit patient care through the optimal allocation of time and resources. These tangible and intangible costs rise as clinical trials become increasingly more complex and arduous, underscoring an urgent need to examine the ways in which their efficiency can be optimised.Clinical trials represent one of the most important mechanisms to translate scientific discoveries into clinical knowledge, evaluate new diagnostic or therapeutic regimens, and advance practice beyond the standard of care. The financial cost for conducting pivotal clinical trials of novel oncology therapeutic drugs that formed the basis for the United States Food and Drug Administration approval in 2015–2017 was estimated at 31.7 million .2 demonstrated that, based on 13 Phase 3 studies conducted under the auspices of a cooperative group, it took >370 distinct processes and a median duration of 784 days (range 537–1130 days) to activate a trial from the initial concept. In 2008, the United States National Cancer Institute (NCI) established an Operational Efficiency Working Group (OEWG) to identify the strategies to expedite trial activation, including setting target timelines for each step, promoting developmental processes to occur in parallel, and streamlining the contract and financial review procedures.3 The NCI invested in transformative measures such as centralised infrastructure and biomarker support to enhance drug development processes.4 For instance, a Central Institutional Review Board Initiative enabled a coordinated approach to human subject protection for national multicentre cancer treatment trials. Currently, the OEWG clock starts from the actual initial concept evaluation and stops at trial opening to enrolment, with absolute deadlines of 400–450 days for Phase 1 or 2 concepts and 540 days for Phase 3 concepts. The start-up timelines for industry-sponsored trials are less transparent to the public, but are closely scrutinised internally within pharmaceutical companies due to financial pressures such as those arising from the competitive environment and concerns regarding patent expiry. The urgency to speed up clinical trial processes has led to the launch of TransCelerate Biopharma in 2012, a non-profit organisation that aims to address critical challenges and establish harmonisation and sharing of the data, with prime examples being a shared investigator database and a common investigator curriculum vitae template that is accepted by all of its biopharmaceutical members.In 2006, Dilts et al.5 Recruitment of under-represented patient populations into clinical trials represents an important strategy to accelerate study completion, but outreach efforts to fulfil this mandate must be prioritised and sustained. In the contemporary artificial intelligence era, tools that can match potentially eligible subjects to clinical trials are emerging as a reality.6 Some adaptations made during the coronavirus disease 2019 (COVID-19) pandemic may become permanent considerations to increase the clinical trial efficiency, while maintaining the principles of good clinical practice and pharmacovigilance. Processes and procedures amenable to modifications include the application of validated electronic signatures to replace wet-ink signatures, administration of parenteral trial treatments associated with low adverse event risks in local medical centres, and remote study monitoring.Multiple factors can lead to slow and inefficient enrolment of research subjects into clinical trials, such as unnecessarily strict eligibility criteria, burdensome trial requirement for visits and investigations beyond what would be appropriate for safety monitoring and endpoint evaluation, and the inflexibility of trial stipulations.Perhaps the least attention has been paid to increasing the clinical trial efficiency at the stage when enrolment has been completed. Typically, after the recruitment activity has ceased, study participants are followed for a specific period of time for their vital status, and ultimately the final database lock and trial closure ensue. In a retrospective review of the early-phase clinical trials conducted by our Princess Margaret Cancer Centre Phase 1 Trials Programme from 2013 to 2019, 44 trials had patients in active survival follow-up. Of these, 30 (68%) trials mandated prolonged surveillance till death. Of the 552 patients enrolled in these 44 trials, 116 (21%) were in active survival follow-up with a median duration of 6.5 (range 1–48) months and had a median of 4 follow-up encounters (range 0–65). These data demonstrate that clinical trial protocols often remain open for prolonged periods of time despite all patients having completed the study treatment, thus substantially increasing the administrative burden at the trial sites. One approach to enable appropriate tracking is to transfer all patients to a single institution-based follow-up protocol, thus minimising the need to keep numerous study files active and repeatedly renewed. Some pharmaceutical partners have adopted such a practice to establish “roll-over” protocols to consolidate the follow-up requirements of multiple studies that shared the same sponsor. Lastly, the storage of clinical trial documents to fulfil regulatory requirements should be replaced by digitally scanned electronic formats. This conversion from paper into bytes would not only save time whenever access to archived files is needed in the future but also constitute an environmentally friendly solution.In addition to the abovementioned ways to improve the operational efficiency of clinical trials, scientific strategies must be in place to maximise their chances of success while utilising the least patient resources and infrastructure. Only the most promising drug candidates should be selected for clinical testing, duplicative efforts without a strong justification  should be discouraged, and a high bar must be set for go-no-go decisions to launch large randomised registrational studies. Innovative clinical trial designs such as adaptive studies have pre-specified allowances to alter their enrolment criteria, and thus offer unique advantages by adjusting dynamically to changes in the existent therapeutic landscape. Biomarkers, especially those of sensitivity or resistance, are critical in accelerating clinical research by selecting patients who are most or least likely to benefit; yet, the current pace of biomarker discovery and validation is slow. To a large extent, the scientific inefficiency in clinical trials is attributable to the lack of data sharing of pre-competitive and post-competitive information, such as early nonclinical evaluations and individual patient-level clinical and biomarker results in published clinical trials, respectively.The optimisation of operational and scientific efficiency in clinical trials requires concerted efforts from investigators and study teams, sponsors, regulatory agencies, and other key stakeholders. The elimination of bottlenecks is critical to conserve resources and time, and, importantly, to accelerate progress in cancer research.