Basic Scientists Research Articles

TRANSLATIONAL RESEARCH ETHICS

The purpose of translational research is to test novel therapeutic strategies and drugs throughout basic and clinical research. The basic concept of translational research is ‘Bench to Bedside’, defining the collaboration between clinicians and basic scientists. That means translational research involves synergistic partnerships between industry, foundations, and public health services. The collaboration between partners provides a network structure that uses multiple methods and technologies to harmonize parameters such as complexity, expertise, safety, and efficiency with national regulations, institutional policies, and best practices that govern cell, animal, and human research. One might think that the ethics of translational research is simple because there are extensive rules regarding basic and clinical research ethics. Nevertheless, translational research brings new tools to the scene such as employing biomarkers based on omics technology and genomics. On the other hand, data science using real-world data, big data, data mining, and artificial intelligence is another huge leverage for translational research bringing new ethical and legal issues, especially concerning data protection. Therefore, new ethical issues arise that have not been addressed before. As the name reflects, translational research ethics should be considered as the means of a literal translation as well. Ethics should serve to translate the language used by different disciplines and moreover by all stakeholders including social areas from the public to the governmental bodies etc. to translate these different languages and attitudes to each other and make the science more transparent and reliable.

Progress report on new antiepileptic drugs: A summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): I. Drugs in preclinical and early clinical development.

The Eilat Conferences have provided a forum for discussion of novel treatments of epilepsy among basic and clinical scientists, clinicians, and representatives from regulatory agencies as well as from the pharmaceutical industry for 3 decades. Initially with a focus on pharmacological treatments, the Eilat Conferences now also include sessions dedicated to devices for treatment and monitoring. The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain, on May 22-25, 2022 and was attended by 157 delegates from 26 countries. As in previous Eilat Conferences, the core of EILAT XVI consisted of a sequence of sessions where compounds under development were presented and discussed. This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO-3-02, GRT-X, NBI-921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes.

To Infinity and Beyond: Expanding the Scope of Basic Sciences in Meeting Accreditation Standards.

Interprofessional training, social sciences curricula, service-learning, pre-clerkship integration, and self-directed learning are all cornerstones of medical education and closely align with accreditation elements for most accreditation bodies within health professions education. As a sequel to the Winter 2022 series, the Spring 2022 Webcast Audio Seminar (WAS) of the International Association of Medical Science Educators (IAMSE) continued to examine the evolving roles of basic science educators. From March 3 to March 31, 2022, the five-part webinar series was broadcast live to audiences at academic institutions worldwide; recordings are available on the IAMSE website. This series built a framework through which basic scientists can leverage their content to meet various accreditation standards.

The Link between Obstructive Sleep Apnea and Neurocognitive Impairment: An Official American Thoracic Society Workshop Report.

There is emerging evidence that obstructive sleep apnea (OSA) is a risk factor for preclinical Alzheimer’s disease (AD). An American Thoracic Society workshop was convened that included clinicians, basic scientists, and epidemiologists with expertise in OSA, cognition, and dementia, with the overall objectives of summarizing the state of knowledge in the field, identifying important research gaps, and identifying potential directions for future research. Although currently available cognitive screening tests may allow for identification of cognitive impairment in patients with OSA, they should be interpreted with caution. Neuroimaging in OSA can provide surrogate measures of disease chronicity, but it has methodological limitations. Most data on the impact of OSA treatment on cognition are for continuous positive airway pressure (CPAP), with limited data for other treatments. The cognitive domains improving with CPAP show considerable heterogeneity across studies. OSA can negatively influence risk, manifestations, and possibly progression of AD and other forms of dementia. Sleep-dependent memory tasks need greater incorporation into OSA testing, with better delineation of sleep fragmentation versus intermittent hypoxia effects. Plasma biomarkers may prove to be sensitive, feasible, and scalable biomarkers for use in clinical trials. There is strong biological plausibility, but insufficient data, to prove bidirectional causality of the associations between OSA and aging pathology. Engaging, recruiting, and retaining diverse populations in health care and research may help to decrease racial and ethnic disparities in OSA and AD. Key recommendations from the workshop include research aimed at underlying mechanisms; longer-term longitudinal studies with objective assessment of OSA, sensitive cognitive markers, and sleep-dependent cognitive tasks; and pragmatic study designs for interventional studies that control for other factors that may impact cognitive outcomes and use novel biomarkers.

Research and academic output evaluation for career initiation or progression: Critical issues for Health Professionals

In current times, much stress is being laid on the evaluation of research productivity of researchers or faculty in addition to the academic qualifications and experience for the purposes of recruitment, promotion, and research grant funding. Over the years, several quantitative indices have been devised for this purpose. Some of these indices such as h-index, impact factor and e-index are being extensively used by research organizations, universities, accreditation bodies and funding agencies for basic scientists as well as health professionals. In the absence of any formal training, these parameters or their advantages and shortcomings may not be well understood by the health professionals, especially in the early stages of their careers and sometimes, even by the evaluators. A big unanswered question is the validity of the same criteria for health professionals as are applicable for the basic science researchers. Since health professional undertaking research assignments are neither adequately trained in basic research nor can they comprehend these indices well, the same yardstick to evaluate these two widely different groups of researchers often places the health professionals at a disadvantage. This paper aims to highlight certain vital issues related to the application of research productivity indicators for recruitment and career progression of health care professionals.

Comparison of freshly cultured versus cryopreserved mesenchymal stem cells in animal models of inflammation: A pre-clinical systematic review.

Mesenchymal stem cells (MSCs) are multipotent cells that demonstrate therapeutic potential for the treatment of acute and chronic inflammatory-mediated conditions. Although controversial, some studies suggest that MSCs may lose their functionality with cryopreservation which could render them non-efficacious. Hence, we conducted a systematic review of comparative pre-clinical models of inflammation to determine if there are differences in in vivo measures of pre-clinical efficacy (primary outcomes) and in vitro potency (secondary outcomes) between freshly cultured and cryopreserved MSCs. A systematic search on OvidMEDLINE, EMBASE, BIOSIS, and Web of Science (until January 13, 2022) was conducted. The primary outcome included measures of in vivo pre-clinical efficacy; secondary outcomes included measures of in vitro MSC potency. Risk of bias was assessed by the SYRCLE 'Risk of Bias' assessment tool for pre-clinical studies. Eighteen studies were included. A total of 257 in vivo pre-clinical efficacy experiments represented 101 distinct outcome measures. Of these outcomes, 2.3% (6/257) were significantly different at the 0.05 level or less; 2 favoured freshly cultured and 4 favoured cryopreserved MSCs. A total of 68 in vitro experiments represented 32 different potency measures; 13% (9/68) of the experiments were significantly different at the 0.05 level or less, with seven experiments favouring freshly cultured MSC and two favouring cryopreserved MSCs. The majority of preclinical primary in vivo efficacy and secondary in vitro potency outcomes were not significantly different (p<0.05) between freshly cultured and cryopreserved MSCs. Our systematic summary of the current evidence base may provide MSC basic and clinical research scientists additional rationale for considering a cryopreserved MSC product in their pre-clinical studies and clinical trials as well as help identify research gaps and guide future related research. Ontario Institute for Regenerative Medicine.

Cell-Free Treatments: A New Generation of Targeted Therapies for Treatment of Ischemic Heart Disease.

Although recent progress in medicine has substantially reduced cardiovascular diseases (CVDs)-related mortalities, current therapeutics have failed miserably to be beneficial for all patients with CVDs. A wide array of evidence suggests that newly-introduced cell-free treatments (CFTs) have more reliable results in the improvement of cardiac function. The main regeneration activity of CFTs protocols is based on bypassing cells and using paracrine factors. In this article, we aim to compare various stem cell secretomes, a part of a CFTs strategy, to generalize their effective clinical outcomes for patients with CVDs. Data for this review article were collected from 70 published articles (original, review, randomized clinical trials (RCTs), and case reports/series studies done on human and animals) obtained from Cochrane, Science Direct, PubMed, Scopus, Elsevier, and Google Scholar) from 2015 to April 2020 using six keywords. Full-text/full-length articles, abstract, section of book, chapter, and conference papers in English language were included. Studies with irrelevant/insufficient/data, or undefined practical methods were excluded. CFTs approaches involved in growth factors (GFs); gene-based therapies; microRNAs (miRNAs); extracellular vesicles (EVs) [exosomes (EXs) and microvesicles (MVs)]; and conditioned media (CM). EXs and CM have shown more remarkable results than stem cell therapy (SCT). GF-based therapies have useful results as well as side effects like pathologic angiogenesis. Cell source, cell′s aging and CM affect secretomes. Genetic manipulation of stem cells can change the secretome’s components. Growing progression to end stage heart failure (HF), propounds CFTs as an advantageous method with practical and clinical values for replacement of injured myocardium, and induction of neovascularization. To elucidate the secrets behind amplifying the expansion rate of cells, increasing life-expectancy, and improving quality of life (QOL) for patients with ischemic heart diseases (IHDs), collaboration among cell biologist, basic medical scientists, and cardiologists is highly recommended.

The 6th international cell senescence association conference.

The 6th conference of the international cell senescence association (ICSA) on the theme of "A New Era of Senescence Research: The Challenge of Controlling Aging and Cancer" was held on December 12-15, 2021 in Osaka, Japan as a Hybrid Meeting. The conference brought together basic and translational scientists to discuss recent developments in the field of cellular senescence research. In recent years, the study of cellular senescence has become a very hot field of research. It is clear that the ICSA, founded in 2015, has played an important role in this process. The 6th ICSA conference has provided another opportunity for exchanges and new connections between basic and translational scientists. The scientific program consisted of keynote lectures, invited talks, short talks selected from abstracts, a poster session, and luncheon seminars sponsored by the Japanese Society of Anti-Aging Medicine. In the Meet the Editor session, Dr Christoph Schmitt, Editor-in-Chief of Nature Metabolism, gave a short presentation about the journal and answered questions from the audience. Being a hybrid meeting, there was only so much that could be done, but we hope that the meeting was fruitful.

Abstract 5967: ROSA: An ambassador program facilitating bidirectional partnerships between communities and basic scientists

Abstract Background: Community Outreach and Engagement (COE) is integral in NCI-designated Cancer Centers. COEs work with community stakeholders identifying community needs, communicating research, and catalyzing significant activities to Cancer Center’s catchment areas. To facilitate this, the University of Arizona Cancer Center (UACC) Office of COE established the Research Outreach for Southern Arizona (ROSA) program, supporting bidirectional partnerships between basic scientists and underrepresented communities in catchment areas. Objective: To describe a community and student ambassador program developed as ROSA, bridging gaps between basic science programs and community needs in UACC catchment areas. Methods: The UACC catchment areas include five southern Arizona counties where 40% of residents are Hispanic, compared to 18.3% in the US. Moreover, ambassadors were bilingual/bicultural Hispanic undergraduate students (n=4) and Hispanic community members (n=4). The ambassador program held weekly cancer educational discussions, research methods, monthly Meet the Scientist events, and presentations on experiences. Evaluations for ROSA were completed by all affiliates. Results: Overall, ROSA ambassadors reported increased knowledge of research and increased confidence sharing cancer information. Facilitators of ROSA community members included a bilingual/bicultural team, outreach collaborations, and participant compensation. Barriers included payments for undocumented members, lack of Spanish-speaking scientists, and reduced in-person activities. As a result of ROSA partnerships, scientists, healthcare professionals, and stakeholders is developing Scientific Cafes where scientists present research proposals for community feedback. The workgroup will select a community-driven project to implement in the future. Discussion: Based on positive ambassador evaluations and working group collaborations, ROSA is successful in growing authentic partnerships between scientists and communities. Recently, a community-based survey was developed by members to examine perceptions of cancer and willingness of clinical research participation. This survey will inform how basic scientists align research within community needs. ROSA will continue to be valuable in providing bidirectional engagement from basic scientists and community members in cancer research. Citation Format: Gabriela Ruiz, MEd., Amanda Lee. ROSA: An ambassador program facilitating bidirectional partnerships between communities and basic scientists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5967.

EPCT-08. Disease-specific working groups within the Pacific Pediatric Neuro-Oncology Consortium (PNOC) and Children’s Brain Tumor Network (CBTN) facilitate multi-disciplinary collaboration and translation of innovative strategies in pediatric neuro-oncology

Abstract BACKGROUND: In Summer 2019, PNOC leadership developed working groups to align basic scientists, clinical researchers, and foundations for rapid translation of novel therapies for children and young adults with central nervous system tumors. Soon after, PNOC partnered with the Children’s Brain Tumor Network (CBTN) to grow collaborations and augment preclinical resources. Since their inception, working groups have advanced translation of new therapies and biomarkers, developed pipelines for preclinical and clinical research, and expanded global collaborations. DESIGN: Each working group is led by 2 to 3 experts in a disease, such as medulloblastoma, diffuse midline glioma, or craniopharyngioma, or subject matter, like imaging, nursing, or diversity, equity, and inclusion. A project manager coordinates regular multidisciplinary meetings to share new findings from research laboratories, provide updates on clinical trial development (with real-time feedback and incorporation of trial endpoints and biomarkers), and invite speakers to share advancements in the disease or subject of interest. RESULTS: Eleven working groups have been created with over 200 members across the United States, Europe, Australia. More than 20 foundations, led predominantly by families, provide support and insight to guide working group efforts. Working groups have developed 4 clinical trials (n=2, diffuse midline glioma; n=1, craniopharyngioma; n=1, medulloblastoma) and completed 3 international surveys, investigating experiences of patients/families affected by craniopharyngioma, evaluating diversity and inclusion throughout the consortia, and assessing nursing and advanced practice provider needs. Additional accomplishments include a registry for atypical teratoid rhabdoid tumors, a population dataset evaluating diversity in clinical research participation across consortia, incorporation of nursing members for review and refinement of clinical trial protocols, and updated imaging case report forms for application across clinical trials. CONCLUSION: Multidisciplinary working groups within international consortia facilitate efficient translation of multi-pronged strategies to improve the care of children and young adults with central nervous system tumors.

Chasing LDL cholesterol to the bottom — PCSK9 in perspective

Low-density lipoprotein (LDL) indubitably contributes causally to atherosclerosis, a leading challenge to health worldwide. Interventions that lower LDL cholesterol (LDL-C) have made remarkable inroads against this global scourge. Recent therapeutic advances have achieved ever lower levels of LDL-C. Improved cardiovascular outcomes continue to accrue from these interventions. In particular, the discovery of the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) as the causal gene in autosomal-dominant hypercholesterolemia has led with remarkable speed to the development of novel agents to lower LDL-C concentrations beyond prior measures, and to alleviate further cardiovascular risk. We review how this story, and its position in the broader landscape of therapy to prevent atherosclerotic events, represents a notable victory of contemporary cardiovascular medicine and reflects successful partnerships between basic scientists, the pharmaceutical and biotechnology sectors, and clinical investigators. Continued cooperation in this manner promises to yield further progress in combating cardiovascular diseases beyond interventions on LDL-C. Libby and Tokgözoğlu discuss the management of atherogenic lipoproteins, notably low-density lipoprotein, with an emphasis on the role of strategies that target PCSK9.

Basic science research opportunities in thrombosis and hemostasis: Communication from the SSC of the ISTH

Bleeding and thrombosis are major clinical problems with high morbidity and mortality. Treatment modalities for these diseases have improved in recent years, but there are many clinical questions remaining and a need to advance diagnosis, management, and therapeutic options. Basic research plays a fundamental role in understanding normal and disease processes, yet this sector has observed a steady decline in funding prospects thereby hindering support for studies of mechanisms of disease and therapeutic development opportunities. With the financial constraints faced by basic scientists, the ISTH organized a basic science task force (BSTF), comprising Scientific and Standardization Committee subcommittee chairs and co‐chairs, to identify research opportunities for basic science in hemostasis and thrombosis. The goal of the BSTF was to develop a set of recommended priorities to build support in the thrombosis and hemostasis community and to inform ISTH basic science programs and policy making. The BSTF identified three principal opportunity areas that were of significant overarching relevance: mechanisms causing bleeding, innate immunity and thrombosis, and venous thrombosis. Within these, five fundamental research areas were highlighted: blood rheology, platelet biogenesis, cellular contributions to thrombosis and hemostasis, structure–function protein analyses, and visualization of hemostasis. This position paper discusses the importance and relevance of these opportunities and research areas, and the rationale for their inclusion. These findings have implications for the future of fundamental research in thrombosis and hemostasis to make transformative scientific discoveries and tackle key clinical questions. This will permit better understanding, prevention, diagnosis, and treatment of hemostatic and thrombotic conditions.

Applying cognitive integration to oncology: A novel asynchronous foundational science curriculum for medical students during clerkships.

11028 Background: Cognitive integration (CI) connects foundational science (FS) to medical practice and improves clinical reasoning. While evidence supports CI in medical training, the clinical relevance of FS is often obscure to medical students, particularly in oncology, and few learning materials exist to support CI during clerkships. Providing effective and engaging tools to promote CI may enhance understanding of FS relevance to clinical medicine. We therefore aimed to create an online module to integrate FS into clerkships. Methods: Previous student feedback at our institution advocated for clinically relevant FS content. Applying Cognitive Theory of Multimedia Learning principles, we (an oncologist, a biochemist, and an instructional designer) created a cancer module grounded in the hallmarks of cancer (HoC), a key FS principle. To emphasize clinical relevance, we recorded patient interviews incorporating FS. The module, composed in Qualtrics, includes an introduction and four cases, each starting with a brief patient interview, followed by clinical text, images, questions, and explanations. Content co-created by the oncologist and biochemist combined clinical and FS perspectives and referenced the HoC throughout. We piloted a draft with a focus group of four students. The evaluation plan includes written learner feedback, a case-based pre/post-test, and review of clerkship assessments for evidence of CI. Results: We produced an FS oncology module with an estimated engagement time of two hours, which students may complete over multiple sittings. The development team met monthly over the course of one year. Filming and editing cost $100/hour. Overall, the project required approximately 60 faculty person-hours and 12 instructional designer person-hours. The patients interviewed for the module expressed gratitude for sharing their stories with students. The student focus group yielded unanimously positive feedback about the content, the multimedia format, the level of FS covered, and the use of authentic patient videos to enhance clinical relevance. Students strongly preferred this module compared to prior online learning activities. Conclusions: This novel interactive module can serve as a model for development of clerkship curricula promoting CI. Module creation based on real patients resulted in authentic story-telling and enhanced FS relevance. Content development involving a clinician and a basic scientist aligned with CI goals. Limitations include the need for funding and instructional design assistance. A randomized controlled trial comparing a series of novel FS modules to older recorded lectures may demonstrate improved outcomes. Involving learners in curriculum development may decrease faculty burden and increase student interest in FS.

A mathematical model for the corneal transparency problem

AbstractUnderstanding the physical basis of corneal transparency has been a subject of interest amongst physicists, basic scientists and ophthalmologists. Impairment of corneal clarity is a significant cause of visual morbidity worldwide. Thus, it is essential to understand the mechanisms behind corneal transparency and how the alterations due to corneal pathologies affect vision. We use Maxwell’s equations to model light propagation in ocular tissues and a nodal discontinuous Galerkin method combined with an explicit Runge-Kutta method to simulate light propagation in normal and pathological corneas. Our simulation results illustrate that an increase in the diameter of some fibres causes an increase in backscattering. Thus, these may represent some of the physical changes in the cornea that might result in loss of transparency and visual morbidity.

Physiological Effects of Binary Mixtures of Common Bath Salt Constituents: Studies with MDPV, Methylone, and Caffeine in Rats

It is becoming increasingly clear among treatment providers, policy makers, and basic scientists alike, that polysubstance abuse is the norm rather than the exception. This is supported by the increased incidence of drug mixtures in drug overdoses, both fatal and nonfatal. In particular, toxicity produced via use of multiple substances has been highlighted by “bath salts” mixtures, often comprising at least one synthetic cathinone (e.g. 3,4‐methylenedioxypyrovalerone [MDPV] or 3,4‐methylenedioxy‐N‐methylcathinone [methylone]), in addition to other stimulants such as caffeine. Use of these drug mixtures has garnered much attention in the popular press due to frequent reports of bizarre behaviors, and adverse psychiatric (paranoia, hallucinations, aggression) and physiological (tachycardia, hypertension, hyperthermia) events leading to large numbers of emergency room visits and/or death. Although synergistic interactions between the reinforcing effects of common “bath salts” constituents have been observed (e.g., greater than predicted breakpoints under a progressive ratio schedule of reinforcement and greater economic demand), much less is known regarding interactions between the physiological effects of these drugs. The goal of the current study was to characterize the behavioral, cardiovascular, and thermoregulatory effects of MDPV, methylone, and caffeine, and subsequently, to determine the nature of the interactions between binary mixtures of these drugs. Male Sprague Dawley rats were implanted with an intravenous catheter and a radio‐telemetric probe capable of recording core body temperature, heart rate, blood pressure, and locomotor activity. Rats were habituated to the test chamber for one hour before receiving an intravenous infusion of either MDPV (0.032‐3.2 mg/kg), methylone (0.1‐10 mg/kg), caffeine (0.32‐32 mg/kg), or a binary mixture (3:1, 1:1, or 1:3) of methylone+MDPV, methylone+caffeine, or MDPV+caffeine. Recordings continued for six hours following drug administration. MDPV, methylone, and caffeine produced dose‐dependent increases in core body temperature (caffeine &gt; MDPV &gt; methylone), blood pressure (MDPV &gt; caffeine &gt; methylone), heart rate (methylone &gt; MDPV &gt; caffeine), and locomotor activity (MDPV &gt; caffeine = methylone) relative to baseline measurements. MDPV was more potent than methylone, which was more potent than caffeine. Binary mixtures of methylone+MDPV, methylone+caffeine, and MDPV+caffeine resulted in largely additive interactions across all endpoints, with possible departures from additivity observed at the largest dose‐pairs evaluated. These data demonstrate that intravenous administration of either MDPV, methylone, or caffeine alters temperature, heart rate, blood pressure, and locomotor activity in a dose‐dependent manner, consistent with what has been reported in “bath salts” users in emergency room settings. To more deeply characterize the interactions between these constituents, future studies will determine the degree to which the reinforcing and physiological effects of these drug mixtures could be mediated by pharmacokinetic interactions between individual constituents.

Electronic posters: Future of learning.

Objective: To explore student’s perception regarding use of E-posters as a learning strategy after its use in the learning of public health concepts in the Gastro Intestinal Tract module. Study Design: Interventional study. Setting: Shifa College of Medicine, Islamabad. Period: August 2019 to August 2020. Material &amp; Methods: Year 3 undergraduate medical students of a private college of Pakistan were given a task to present an e-poster in the module of Gastro-Intestinal Tract, focusing on the public health aspect. Students were divided into 7 groups comprising of 13 students each. Each group was provided with one individual study theme. They were provided with a template to cover all aspects of public health. All the basic scientists involving 30 faculty members were invited to judge the e-poster through a checklist. The mean score was calculated. A certificate was awarded to the group that scored the highest. A focused group interview involving one voluntary participant from each group was carried out. Thematic analysis was done manually. Results: Themes generated in focus group discussion are Opportunities for Self-Directed Learning, Opportunities for Self-reflection, Good formative assessment, Peer to Peer Interaction and Collaboration, Opportunities for developing Self-Regulation, Innovative learning strategy, Working in teams and Confidence Building, Use of IT Related Skills, Need of More Facilities. Conclusion: Students welcomed the use of innovative learning through electronic media when carried out in a relaxed environment.

Understanding the Pathobiology of Pulmonary Hypertension Due to Left Heart Disease.

The development of pulmonary hypertension (PH) is common and has adverse prognostic implications in patients with heart failure due to left heart disease (LHD), and thus far, there are no known treatments specifically for PH-LHD, also known as group 2 PH. Diagnostic thresholds for PH-LHD, and clinical classification of PH-LHD phenotypes, continue to evolve and, therefore, present a challenge for basic and translational scientists actively investigating PH-LHD in the preclinical setting. Furthermore, the pathobiology of PH-LHD is not well understood, although pulmonary vascular remodeling is thought to result from (1) increased wall stress due to increased left atrial pressures; (2) hemodynamic congestion-induced decreased shear stress in the pulmonary vascular bed; (3) comorbidity-induced endothelial dysfunction with direct injury to the pulmonary microvasculature; and (4) superimposed pulmonary arterial hypertension risk factors. To ultimately be able to modify disease, either by prevention or treatment, a better understanding of the various drivers of PH-LHD, including endothelial dysfunction, abnormalities in vascular tone, platelet aggregation, inflammation, adipocytokines, and systemic complications (including splanchnic congestion and lymphatic dysfunction) must be further investigated. Here, we review the diagnostic criteria and various hemodynamic phenotypes of PH-LHD, the potential biological mechanisms underlying this disorder, and pressing questions yet to be answered about the pathobiology of PH-LHD.

Organ-on-a-chip: current gaps and future directions.

As an emerging hot topic of the last decade, Organ on Chip (OoC) is a new technology that is attracting interest from both basic and translational scientists. The Biochemical Society, with its mission of supporting the advancement of science, with addressing grand challenges that have societal impact, has included OoC into their agenda to review the current state of the art, bottlenecks and future directions. This conference brought together representatives of the main stakeholders in the OoC field including academics, end-users, regulators and technology developers to discuss and identify requirements for this new technology to deliver on par with the expectations and the key challenges and gaps that still need to be addressed to achieve robust human-relevant tools, able to positively impact decision making in the pharmaceutical industry and reduce overreliance on poorly predictive animal models.

The human enteric nervous system. Historical and modern advances. Collaboration between science and surgery.

There are considerable advantages and opportunities for surgeons and trainee surgeons in conducting a period of research allied with basic scientists. Such clinicians are well placed to define relevant clinical questions, provide human material (tissue, biopsy and blood) and translate the techniques derived in experimental animals to human subjects. This small review explores research conducted on the nervous system of the intestines, with an emphasis on the translation of findings from animal to human. This work shows that new techniques of immunohistochemistry and retrograde tracing, developed in animal tissue, have greatly expanded our knowledge of the structure of the human enteric nervous system. Such findings have sparked therapeutic trials for the treatment of gastrointestinal disorders in patients.

Future of Perioperative Precision Medicine: Integration of Molecular Science, Dynamic Health Care Informatics, and Implementation of Predictive Pathways in Real Time.

Conceptually, precision medicine is a deep dive to discover disease origin at the molecular or genetic level, thus providing insights that allow clinicians to design corresponding individualized patient therapies. We know that a disease state is created by not only certain molecular derangements but also a biologic milieu promoting the expression of such derangements. These factors together lead to manifested symptoms. At the level of molecular definition, every average, "similar" individual stands to be "dissimilar." Hence, there is the need for customized therapy, moving away from therapy based on aggregate statistics. The perioperative state is a mix of several, simultaneously active molecular mechanisms, surgical insult, drugs, severe inflammatory response, and the body's continuous adaptation to maintain a state of homeostasis. Postoperative outcomes are a net result of several of those rapid genetic and molecular transformations that do or do not ensue. With the advent and advances of artificial intelligence, the translation from identifying these intricate mechanisms to implementing them in clinical practice has made a huge leap. Precision medicine is gaining ground with the help of personalized health recorders and personal devices that identify disease mechanics, patient-reported outcomes, adverse drug reactions, and drug-drug interaction at the individual level in a closed-loop feedback system. This phenomenon is especially true given increasing surgeries in older adults, many of whom are on multiple medications and varyingly frail. In this era of precision medicine, to provide a comprehensive remedy, the perioperative surgical home must expand, incorporating not only clinicians but also basic science experts and data scientists.