Silicon Valley Meets Biomedical Research in the Chan Zuckerberg Initiative.

The Chan Zuckerberg Initiative, the philanthropy launched by Facebook CEO Mark Zuckerberg and his wife Priscilla Chan, drew attention with its stated goal of helping to "cure, manage, or treat all diseases" by the end of the century. They intend to do it through funding basic research and addressing gaps in biomedical technology.

Translating Microbiome Research From and To the Clinic.

Extensive research has elucidated the influence of the gut microbiota on human health and disease susceptibility and resistance. We review recent clinical and laboratory-based experimental studies associating the gut microbiota with certain human diseases. We also highlight ongoing translational advances that manipulate the gut microbiota to treat human diseases and discuss opportunities and challenges in translating microbiome research from and to the bedside.

TheMarker: a comprehensive database of therapeutic biomarkers.

Distinct from the traditional diagnostic/prognostic biomarker (adopted as the indicator of disease state/process), the therapeutic biomarker (ThMAR) has emerged to be very crucial in the clinical development and clinical practice of all therapies. There are five types of ThMAR that have been found to play indispensable roles in various stages of drug discovery, such as: Pharmacodynamic Biomarker essential for guaranteeing the pharmacological effects of a therapy, Safety Biomarker critical for assessing the extent or likelihood of therapy-induced toxicity, Monitoring Biomarker indispensable for guiding clinical management by serially measuring patients' status, Predictive Biomarker crucial for maximizing the clinical outcome of a therapy for specific individuals, and Surrogate Endpoint fundamental for accelerating the approval of a therapy. However, these data of ThMARs has not been comprehensively described by any of the existing databases. Herein, a database, named 'TheMarker', was therefore constructed to (a) systematically offer all five types of ThMAR used at different stages of drug development, (b) comprehensively describe ThMAR information for the largest number of drugs among available databases, (c) extensively cover the widest disease classes by not just focusing on anticancer therapies. These data in TheMarker are expected to have great implication and significant impact on drug discovery and clinical practice, and it is freely accessible without any login requirement at: https://idrblab.org/themarker.

Molecular mechanisms of aging and anti-aging strategies.

Aging is a complex and multifaceted process involving a variety of interrelated molecular mechanisms and cellular systems. Phenotypically, the biological aging process is accompanied by a gradual loss of cellular function and the systemic deterioration of multiple tissues, resulting in susceptibility to aging-related diseases. Emerging evidence suggests that aging is closely associated with telomere attrition, DNA damage, mitochondrial dysfunction, loss of nicotinamide adenine dinucleotide levels, impaired macro-autophagy, stem cell exhaustion, inflammation, loss of protein balance, deregulated nutrient sensing, altered intercellular communication, and dysbiosis. These age-related changes may be alleviated by intervention strategies, such as calorie restriction, improved sleep quality, enhanced physical activity, and targeted longevity genes. In this review, we summarise the key historical progress in the exploration of important causes of aging and anti-aging strategies in recent decades, which provides a basis for further understanding of the reversibility of aging phenotypes, the application prospect of synthetic biotechnology in anti-aging therapy is also prospected.

RNA and disease.

Cellular functions depend on numerous protein-coding and noncoding RNAs and the RNA-binding proteins associated with them, which form ribonucleoprotein complexes (RNPs). Mutations that disrupt either the RNA or protein components of RNPs or the factors required for their assembly can be deleterious. Alternative splicing provides cells with an exquisite capacity to fine-tune their transcriptome and proteome in response to cues. Splicing depends on a complex code, numerous RNA-binding proteins, and an enormously intricate network of interactions among them, increasing the opportunity for exposure to mutations and misregulation that cause disease. The discovery of disease-causing mutations in RNAs is yielding a wealth of new therapeutic targets, and the growing understanding of RNA biology and chemistry is providing new RNA-based tools for developing therapeutics.

Estimating tree-based dynamic treatment regimes using observational data with restricted treatment sequences.

A dynamic treatment regime (DTR) is a sequence of decision rules that provide guidance on how to treat individuals based on their static and time-varying status. Existing observational data are often used to generate hypotheses about effective DTRs. A common challenge with observational data, however, is the need for analysts to consider "restrictions" on the treatment sequences. Such restrictions may be necessary for settings where (1) one or more treatment sequences that were offered to individuals when the data were collected are no longer considered viable in practice, (2) specific treatment sequences are no longer available, or (3) the scientific focus of the analysis concerns a specific type of treatment sequences (eg, "stepped-up" treatments). To address this challenge, we propose a restricted tree-based reinforcement learning (RT-RL) method that searches for an interpretable DTR with the maximum expected outcome, given a (set of) user-specified restriction(s), which specifies treatment options (at each stage) that ought not to be considered as part of the estimated tree-based DTR. In simulations, we evaluate the performance of RT-RL versus the standard approach of ignoring the partial data for individuals not following the (set of) restriction(s). The method is illustrated using an observational data set to estimate a two-stage stepped-up DTR for guiding the level of care placement for adolescents with substance use disorder.

The New Mythology of the Body and the Transformation of the Therapeutic Space.

BACKGROUND: The history of medicine has flowed in the wake of knowledge and social perceptions about the body and corporeality. There is no idea of health without reference to the notion of body (although "health" can have other meanings, figuratively). Considering the same history, the body was the subject of numerous segregations and categorizations due to which it was and is a "social object" and a "political object." In turn, the spatial and cultural framework was the environment and determinant of the medicine development which is not only a science but also an inter-human interactive practice. AREAS OF UNCERTAINTY: In this article, we will analyze the current social (re)construction of the notions of body and space by referring to the technological and structural changes that are manifested in medicine and society and their ethical implications. DATA SOURCES: A review of the specialized literature was performed in June-July 2023, using keywords like human enhancement, therapeutic enhancement, transhumanist medicine, ethics from PubMed, Scopus, Web of Science, and Google Scholar, and official documents issued at the international level (World Health Organization, European Commission). ETHICS AND THERAPEUTIC ADVANCES: This literature review suggests that few practical solutions to human enhancement, both curative and preventive, whether cognitive or physical, have been approached entirely from an ethical point of view. The historical evolution of the concept of human enhancement has led to debates between "transhumanists" and "bioconservatives" depending on how they relate to the improvement of the human condition without or with reticence interventions to improve human capabilities being related to various interventions, from pharmacological, surgical ones to those in the field of genetics, nanomedicine, or cybernetics. In addition to the technical aspects, which are often the major concern of researchers and those applying new technologies, there are also ethical and legislative aspects, to better understand the impact that the dynamics and diffusion of these processes have on the evolution of the human species. CONCLUSIONS: In interference with these technologies, the body is exposed to possibilities of change and evolution with colossal (expected) social impact that can change norms and values that have been stable for centuries. Social space and place are also proving to be "processes in the making'" for which we need to detect what developments are possible or have already imposed themselves as a trend in the social and medical world.

Development and evaluation of a customized checklist to assess the quality control of disease registry systems of Tehran, the capital of Iran in 2021.

BACKGROUND: Clinical registries facilitate medical research by providing 'real data'. In the past decade, an increasing number of disease registry systems (DRS) have been initiated in Iran. Here, we assessed the quality control (QC) of the data recorded in the DRS established by Shahid Beheshti University of Medical Sciences in Tehran, the capital city of Iran, in 2021. METHODS: The present study was conducted in two consecutive qualitative and quantitative phases and employed a mixed-method design. A checklist containing 23 questions was developed based on a consensus reached following several panel group discussions, whose face content and construct validities were confirmed. Cronbach's alpha was calculated to verify the tool's internal consistency. Overall, the QC of 49 DRS was assessed in six dimensions, including completeness, timeliness, accessibility, validity, comparability, and interpretability. The seventy percent of the mean score was considered a cut-point for desirable domains. RESULTS: The total content validity index (CVI) was obtained as 0.79, which is a reasonable level. Cronbach's alpha coefficients obtained showed acceptable internal consistency for all of the six QC domains. The data recorded in the registries included different aspects of diagnosis/treatment (81.6%) and treatment quality requirements outcomes (12.2%). According to the acceptable quality cut-point, out of 49 evaluated registries, 48(98%), 46(94%), 41(84%), and 38(77.5%), fulfilled desirable quality scores in terms of interpretability, accessibility, completeness, and comparability, however, 36(73.5%) and 32(65.3%) of registries obtained the quality requirement for timeliness and validity, respectively. CONCLUSION: The checklist developed here, containing customized questions to assess six QC domains of DRSs, provided a valid and reliable tool that could be considered as a proof-of-concept for future investigations. The clinical data available in the studied DRSs fulfilled desirable levels in terms of interpretability, accessibility, comparability, and completeness; however, timeliness and validity of these registries needed to be improved.

Mapping Factors That Affect the Uptake of Digital Therapeutics Within Health Systems: Scoping Review.

BACKGROUND: Digital therapeutics are patient-facing digital health interventions that can significantly alter the health care landscape. Despite digital therapeutics being used to successfully treat a range of conditions, their uptake in health systems remains limited. Understanding the full spectrum of uptake factors is essential to identify ways in which policy makers and providers can facilitate the adoption of effective digital therapeutics within a health system, as well as the steps developers can take to assist in the deployment of products. OBJECTIVE: In this review, we aimed to map the most frequently discussed factors that determine the integration of digital therapeutics into health systems and practical use of digital therapeutics by patients and professionals. METHODS: A scoping review was conducted in MEDLINE, Web of Science, Cochrane Database of Systematic Reviews, and Google Scholar. Relevant data were extracted and synthesized using a thematic analysis. RESULTS: We identified 35,541 academic and 221 gray literature reports, with 244 (0.69%) included in the review, covering 35 countries. Overall, 85 factors that can impact the uptake of digital therapeutics were extracted and pooled into 5 categories: policy and system, patient characteristics, properties of digital therapeutics, characteristics of health professionals, and outcomes. The need for a regulatory framework for digital therapeutics was the most stated factor at the policy level. Demographic characteristics formed the most iterated patient-related factor, whereas digital literacy was considered the most important factor for health professionals. Among the properties of digital therapeutics, their interoperability across the broader health system was most emphasized. Finally, the ability to expand access to health care was the most frequently stated outcome measure. CONCLUSIONS: The map of factors developed in this review offers a multistakeholder approach to recognizing the uptake factors of digital therapeutics in the health care pathway and provides an analytical tool for policy makers to assess their health system's readiness for digital therapeutics.

Reparative inflammation takes charge of tissue regeneration.

Inflammation underlies many chronic and degenerative diseases, but it also mitigates infections, clears damaged cells and initiates tissue repair. Many of the mechanisms that link inflammation to damage repair and regeneration in mammals are conserved in lower organisms, indicating that it is an evolutionarily important process. Recent insights have shed light on the cellular and molecular processes through which conventional inflammatory cytokines and Wnt factors control mammalian tissue repair and regeneration. This is particularly important for regeneration in the gastrointestinal system, especially for intestine and liver tissues in which aberrant and deregulated repair results in severe pathologies.

Is It Possible to Achieve Favorable Accelerated Dental Changes with No Periodontal Complications When Retracting Upper Anterior Teeth Assisted by Flapless Corticotomy Compared to Traditional Corticotomy? A Two-Arm Randomized Controlled Trial.

Objectives: The objective of this trial was to evaluate the dental changes, periodontal health, and tooth vitality in mini-screw-supported en-masse retraction with two corticotomy-based acceleration techniques. Study Design. The sample included 38 adult patients presenting with class II division 1 malocclusion (three males, 35 females; age range between 18 and 30 years), needing the extraction of upper first premolars followed by en-masse retraction. The sample was divided randomly and equally into two groups. Randomization was carried out by random numbers generated by the computer with a 1 : 1 allocation ratio. The allocation concealment was carried out by sequentially numbered, opaque, sealed envelopes. The interventions were traditional corticotomy (TC) versus flapless corticotomy (FC). Mini-screws were inserted between the upper second premolar and first molar, bilaterally. The primary outcome was evaluating dental changes. Secondary outcomes were the periodontal health and pulp vitality of the maxillary teeth. Mann-Whitney U test and two-sample t-test with Bonferroni correction were used to analyze the data. Results: The en-masse retraction rate in the first three months was higher in the TC group than the FC group (1.82, 1.66, and 1.39 mm/month vs 1.60, 1.42, and 1.22 mm/month, respectively) with statistically significant differences (P < 0.001, P < 0.001, P=0.001, respectively). The en-masse retraction amount was greater in the TC group than the FC group (6.84 mm vs 6.18 mm, respectively) with statistically significant differences (P=0.002). There was an increase in the inter-canine and inter-molar widths with a minor distal movement of the upper first molar in the two groups, with no significant differences between them (P > 0.008). The values of gingival, papillary bleeding and plaque indices in the TC group were significantly greater than those in the FC group after performing the corticotomy (P < 0.001, P < 0.003, P=0.002, respectively). No gingival recession was found on any of the examined teeth in both groups. All teeth maintained their vitality at all measurement times in both groups. No severe harms were noticed in any group. Conclusions: Both traditional and flapless corticotomy techniques resulted in clinically similar rates of the en-masse retraction of upper anterior teeth, with similar dental changes and no significant periodontal complications or tooth vitality loss. The minimally invasive flapless corticotomy appeared to be a good alternative to the more invasive traditional corticotomy. This trial is registered with https://www.clinicaltrials.gov (Identification code: NCT04847492), retrospectively registered.

Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

Importance: Among patients younger than 21 years of age, the optimal duration of anticoagulant therapy for venous thromboembolism is unknown. Objective: To test the hypothesis that a 6-week duration of anticoagulant therapy for provoked venous thromboembolism is noninferior to a conventional 3-month therapy duration in patients younger than 21 years of age. Design, Setting, and Participants: Randomized clinical trial involving 417 patients younger than 21 years of age with acute, provoked venous thromboembolism enrolled at 42 centers in 5 countries from 2008-2021. The main exclusions were severe anticoagulant deficiencies or prior venous thromboembolism. Patients without persistent antiphospholipid antibodies and whose thrombi were resolved or not completely occlusive upon repeat imaging at 6 weeks after diagnosis underwent randomization. The final visit for the primary end points occurred in January 2021. Interventions: Total duration for anticoagulant therapy of 6 weeks (n = 207) vs 3 months (n = 210) for provoked venous thromboembolism. Main Outcomes and Measures: The primary efficacy and safety end points were centrally adjudicated symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 year blinded to treatment group. The primary analysis was noninferiority in the per-protocol population. The noninferiority boundary incorporated a bivariate trade-off that included an absolute increase of 0% in symptomatic recurrent venous thromboembolism with an absolute risk reduction of 4% in clinically relevant bleeding events (1 of 3 points on the bivariate noninferiority boundary curve). Results: Among 417 randomized patients, 297 (median age, 8.3 [range, 0.04-20.9] years; 49% female) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of the primary efficacy outcome was 0.66% (95% CI, 0%-1.95%) in the 6-week anticoagulant therapy group and 0.70% (95% CI, 0%-2.07%) in the 3-month anticoagulant therapy group, and for the primary safety outcome, the incidence was 0.65% (95% CI, 0%-1.91%) and 0.70% (95% CI, 0%-2.06%). Based on absolute risk differences in recurrent venous thromboembolism and clinically relevant bleeding events between groups, noninferiority was demonstrated. Adverse events occurred in 26% of patients in the 6-week anticoagulant therapy group and in 32% of patients in the 3-month anticoagulant therapy group; the most common adverse event was fever (1.9% and 3.4%, respectively). Conclusions and Relevance: Among patients younger than 21 years of age with provoked venous thromboembolism, anticoagulant therapy for 6 weeks compared with 3 months met noninferiority criteria based on the trade-off between recurrent venous thromboembolism risk and bleeding risk. Trial Registration: ClinicalTrials.gov Identifier: NCT00687882.

Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients.

The medical and scientific literature is dominated by highly cited historical theories and findings [...].

Modulating host gene expression via gut microbiome-microRNA interplay to treat human diseases.

The human gastrointestinal (GI) tract hosts trillions of microbial inhabitants involved in maintaining intestinal homeostasis, dysbiosis of which provokes a motley of pathogenic and autoimmune disorders. While the mechanisms by which the microbiota modulates human health are manifold, their liberated metabolites from ingested dietary supplements play a crucial role by bidirectionally regulating the expression of micro-ribonucleic acids (miRNAs). miRNAs are small endogenous non-coding RNAs (ncRNAs) that have been confirmed to be involved in an interplay with microbiota to regulate host gene expression. This comprehensive review focuses on key principles of miRNAs, their regulation, and crosstalk with gut microbiota to influence host gene expression in various human disorders, by bringing together important recent findings centric around miRNA-microbiota interactions in diseases along various axis of the gut with other organs. We also attempt to lay emphasis on exploiting the avenues of gut-directed miRNA therapeutics using rudimentary dietary supplements to regulate abnormal host gene expression in diseases, opening doors to an accessible and economical therapeutic strategy.

The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.

Primary cutaneous lymphomas are a heterogeneous group of T- and B-cell lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. The 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) consensus classification has served as a golden standard for the diagnosis and classification of these conditions. In September 2018, an updated version of the WHO-EORTC was published in the fourth edition of the WHO Classification of Skin Tumours Blue Book. In this classification, primary cutaneous acral CD8+ T-cell lymphoma and Epstein-Barr virus positive (EBV+) mucocutaneous ulcer are included as new provisional entities, and a new section on cutaneous forms of chronic active EBV disease has been added. The term "primary cutaneous CD4+ small/medium T-cell lymphoma" was modified to "primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder" because of its indolent clinical behavior and uncertain malignant potential. Modifications have also been made in the sections on lymphomatoid papulosis, increasing the spectrum of histologic and genetic types, and primary cutaneous marginal zone lymphomas recognizing 2 different subtypes. Herein, the characteristic features of these new and modified entities as well as the results of recent molecular studies with diagnostic, prognostic, and/or therapeutic significance for the different types of primary cutaneous lymphomas are reviewed. An update of the frequency and survival of the different types of primary cutaneous lymphomas is provided.

Serum levels of TARC, MDC, IL-10, and soluble CD163 in Hodgkin lymphoma: a SWOG S0816 correlative study.

Serum soluble chemokines/cytokines produced by Hodgkin cells and the tumor microenvironment might be of value as biomarkers in classic Hodgkin lymphoma (cHL). We assessed serum thymus and activation-related chemokine (TARC), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), and soluble CD163 (sCD163) levels at baseline, time of interim fluorodeoxyglucose positron emission tomography (PET), and after therapy in cHL patients treated on S0816, an intergroup phase 2 response-adapted study evaluating escalated therapy for interim PET (PET2)-positive patients (www.clinicaltrials.gov #NCT00822120). Epstein-Barr virus (EBV) status was assessed, and 559 serum samples were evaluated for TARC, MDC, IL-10, and sCD163 by immunoassay. EBV positivity correlated with higher sCD163 and IL-10 levels but lower TARC levels. While baseline biomarker levels were not associated with outcome, sCD163 levels at the time of PET2 were associated with favorable progression-free survival (PFS), adjusting for PET2 status. After therapy TARC, MDC, and IL-10 correlated with PFS and overall survival (OS) on univariable analysis, which remained significant adjusting for international prognostic score. When also adjusting for end-of-therapy PET results, TARC and IL-10 remained significantly associated with shorter PFS and OS. Exploratory analysis in PET2-negative patients showed that elevated posttherapy TARC and IL-10 levels were associated with PFS. Serum cytokine levels correlate with outcome in cHL and should be investigated further in risk-adapted cHL trials.

Disease managing capacities and mechanisms of host effects of lactic acid bacteria.

Consumption of lactic acid bacteria (LAB) has been suggested to confer health-promoting effects on the host. However, effects of LABs have been reported to be species- and strain-specific and the mechanisms involved are subjects of discussion. Here, the possible mechanisms by which LABs induce antipathogenic, gut barrier enhancing and immune modulating effects in consumers are reviewed. Specific strains for which it has been proven that health is improved by these mechanisms are discussed. However, most strains probably act via several or combinations of mechanisms depending on which effector molecules they express. Current insight is that these effector molecules are either present on the cell wall of LAB or are excreted. These molecules are reviewed as well as the ligand binding receptors in the host. Also postbiotics are discussed. Finally, we provide an overview of the efficacy of LABs in combating infections caused by Helicobacter pylori, Salmonella, Escherichia coli, Streptococcus pneumoniae, and influenza virus, in controlling gut inflammatory diseases, in managing allergic disorders, and in alleviating cancer.

Fifty Years of Acute Ischemic Stroke Treatment: A Personal History.

BACKGROUND: It has been 50 years since the first explorations of the physiology of cerebral ischemia by measuring cerebral blood flow (CBF), and 25 years since the approval of tissue plasminogen activator for treating acute ischemic stroke. My personal career began and matured during those eras. Here, I provide my perspective on the evolution of acute stroke research and treatment from 1971 to the present, with some in-depth discussion of the National Institutes of Neurologic Disease and Stroke (NINDS) tissue-type plasminogen activator (tPA) stroke trial and development of mobile stroke units. SUMMARY: Studies of CBF and metabolism in acute stroke patients revealed graded tissue injury that was dependent on the duration of ischemia. Subsequent animal research unraveled the biochemical cascade of events occurring at the cellular level after cerebral ischemia. After a decade of failed translation, the development of a relatively safe thrombolytic allowed us to achieve reperfusion and apply the lessons from earlier research to achieve positive clinical results. The successful conduct of the NINDS tPA stroke study coupled with positive outcomes from companion tPA studies around the world created the specialty of vascular neurology. This was followed by an avalanche of research in imaging, a focus on enhancing reperfusion through thrombectomy, and improving delivery of faster treatment culminating in mobile stroke units. Key Messages: The last half century has seen the birth and evolution of successful acute stroke treatment. More research is needed in developing new drugs and catheters to build on the advances we have already made with reperfusion and also in evolving our systems of care to get more patients treated more quickly in the prehospital setting. The history of stroke treatment over the last 50 years exemplifies that medical "science" is an evolving discipline worth an entire career's dedication. What was impossible 50 years ago is today's standard of care, what we claim as dogma today will be laughed at a decade from now, and what appears currently impossible will be tomorrow's realities.

The potential role of mesenchymal stem cells in modulating antiageing process.

Ageing and age-related diseases share some basic origin that largely converges on inflammation. Precisely, it boils down to a common pathway characterised by the appearance of a fair amount of proinflammatory cytokines known as inflammageing. Among the proposed treatment for antiageing, MSCs gained attention in recent years. Since mesenchymal stem cells (MSCs) can differentiate itself into a myriad of terminal cells, previously it was believed that these cells migrate to the site of injury and perform their therapeutic effect. However, with the more recent discovery of huge amounts of paracrine factors secreted by MSCs, it is now widely accepted that these cells do not engraft upon transplantation but rather unveil their benefits through excretion of bioactive molecules namely those involved in inflammatory and immunomodulatory activities. Conversely, the true function of these paracrine changes has not been thoroughly investigated all these years. Hence, this review will describe in detail on ways MSCs may capitalize its paracrine properties in modulating antiageing process. Through a comprehensive literature search various elements in the antiageing process, we aim to provide a novel treatment perspective of MSCs in antiageing related clinical conditions.