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Cases of the respiratory syncytial virus (RSV), monkeypox virus (MPXV), and avian influenza A Virus (IAV) have increased during our current prolonged Corona Virus Disease 2019 (CoViD-19) pandemic. The rise of these viral infectious diseases may be associated or even inter-dependent with acute, latent or recurrent infection with Systemic Acute Respiratory Syndrome Corona virus-2 (SARS-CoV2). The nonsensical neologism 'tripledemic' was tentatively introduced to describe the confluent nature of these trends (epidemic comes from two Greek words: epi=on, about, demos=people; pandemic is also derived from Ancient Greek: pan=all, demos=people; but 'tripledemic' would derive from Latin triplus=three, Greek demos=people, and would at best signify 'three countries, three peoples', but certainly not the current threat of confluence of three, or perhaps more pandemics). Emerging evidence suggests that monkey pox and CoViD-19, among several other viral diseases, produce significant observable manifestations in the oral cavity. From a clinical standpoint, dentists and dental personnel may be among the first health professionals to encounter and diagnose clinical signs of converging infections. From the immune surveillance viewpoint, viral recombination and viral interference among these infectious diseases must be examined to determine the potential threat of these colliding pandemics.

There have been over five million cases of infection with the second Corona virus to induce SARS (SARS-CoV2) and close to half a million deaths worldwide since the first report of Corona Virus Disease in late December 2019 (CoViD-19). Over two million CoViD-19 patients have recovered. The factors and variables that lead certain CoViD-19 patients to survive this otherwise aggressive and lethal viral infection are intensely researched, as is the development of productive anti-virals and of safe and effective vaccines. Several hypotheses invoke putative mutations of the ss-positive RNA SARS-CoV2 virus to states of stronger or weaker virulence and lethality. Other hypotheses propose that the patient's status of immunity, vitamin D level, Zinc deficiency or other physiological parameters determine how any given patient will effectively weather the viremia and the consequential multi-symptomatic CoViD-19. The initial cause - causa prima - underlying all the symptoms of CoViD-19 is infection of the host human cell by SARS-CoV2. The virus spike (S) protein finds its binding site, ACE2, widely distributed in all cells and tissues that potentially proffer CoViD-19 pathology. S consists of two subunits, S1 and S2, which are cleaved by the widely expressed transmembrane protease serine 2 (TMPRSS2) before the virus fuses to the plasma membrane and infects the cell. Current trends show that variant alleles resulting from single nucleotide polymorphisms (SNPs) of ACE2, and genetic variants of TMPRSS2, with putative distinct affinities for S clip, may determine a complex multi-factorial spectrum of SARS-CoV2 virulence across patients, and predict CoViD-19 susceptibility.

CoViD-19 is the current pandemic caused by the Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2). Infection by SARS-CoV-2 occurs via the binding of its S protein to the angiotensin-converting enzyme-2 receptor (ACE2-R). S binding to ACE2-R leads to a drop in ACE2, a homolog of angiotensin converting enzyme (ACE). In the central nervous system (CNS), ACE mediates neuroinflammation, neurodegeneration and neurotoxicity responsible for several CNS disorders. ACE2 counteracts the damaging effects of ACE on CNS neurons. SARS-CoV-2 can directly access the CNS via the circulation or via cranial nerve I and the olfactory bulb. Inactivation of ACE2 following binding of SARS-CoV-2 S protein to ACE2-R in situ might blunt ACE2-moderating effects upon ACE CNS neurotoxicity and neurodegeneration. Here, we propose a neurobiological mechanism directly involving SARS-CoV-2 binding to ACE2-R in the etiology of putative Neuro-CoViD-19.

The first report of the unusual manifestation of pneumonia-like symptoms in Wuhan City, China was made on 31 December 2019. Within one week, the Chinese authorities reported that they had identified the causative agent as a new member of the Coronavirus family, the same family of that was responsible for MERS and SARS not so many years ago. The new virus was called Novel Coronavirus 2019 (2019-nCoV). Three weeks later, the World Health Organization declared that 2019-nCoV was capable of direct human-to-human transmission, the virus had spread across several countries in three continents, and had infected close to two thousand people, of whom at least 1 in 5 quite severely. The number of fatalities was fast rising. Yet, the World Health Organization officially announced that there is still at present no recommended anti-nCoV vaccine for subject at-risk, nor treatment for patients with suspected or confirmed nCoV, let alone 2019-nCov. It is therefore timely and critical to propose new possible and practical approaches for preventive interventions for subjects at-risk, and for treatment of patients afflicted with 2019-nCov-induced disease (Corona Virus Disease 2019; COVID-19) before the present situation explodes into a worldwide pandemic. One such potential clinical protocol is proposed as a hypothesis.

Our planet has experienced several drastic changes in climate during its history. Nonetheless, human activity in the last two hundred years of industrialization has brought about a significant rise in greenhouse gases, which have led to inexorable global warming and climate change, a direct threat to our ecosystem. Global warming is precipitating the thawing of peri-glacial permafrost, which then releases additional greenhouse gasses, which can be toxic to our health, and alter fresh water supplies and crops. Melting permafrost also releases ancient and novel pathogens potentially harmful to human health. This paper outlines certain nature-based solutions that could bring about carbon-neutral energy generation, as well as immune protective interventions.

Chiappelli argues that the article by Dai and colleagues is an informative piece of writing on the main protease (Mpro, i e , 3C-like protease, 3-CLpro;E C 3 4 22 69) of SARS-CoV2, the virus responsible for CoViD-19 Mpro is a cysteine protease enzyme key for the replication and transcription of SARS Corona viral genome The X-ray structures of the unliganded protease and its complex with an a-ketoamide inhibitor, were the basis for design of a-ketoamide inhibitors for a treatment of SARS-CoV infection a decade ago He said that it is an experimental study, with a small Phase 0 trial component on a laboratory-manufactured compound that blocks the replication of SARS-CoV2, the virus responsible for the CoViD-19 pandemic The study is important because it is foundational for the development of specific anti-SARS-CoV2 drugs It has limited immediate value due to lack thereof, on human cells in vitro

Background In 1999, the American Dental Association proffered a definition of the term evidence-based dentistry, which is still very much used to this day. It stated that “… evidence-based dentistry is an approach to oral health care that requires the judicious integration of systematic assessments of clinically relevant scientific evidence, relating to the patient's oral and medical condition and history, with the dentist's clinical expertise and the patient's treatment needs and preferences.” Concerted research during the past 2 decades have defined and characterized the protocols that obtain the qualitative and quantitative consensus of the best evidence base. This component of evidence-based dentistry, which is referred to as evidence-based dental research, is brought about as comparative effectiveness research with the research synthesis design. The best evidence base is judiciously used to generate evidence-based clinical practice guidelines, which in turn inform evidence-based dental practice. Discussion At this juncture, the complexity of the construct of evidence-based dentistry dictates several avenues of current and future inquiry and development. The most urgent and important of these is undoubtedly to craft and validate novel didactic and practical methodologies to teach evidence-based dentistry—both research and practice—to the next generation of dental researchers and clinical dentists and to optimize the integration of evidence-based dentistry in the dental curriculum. Secondarily, but certainly not of lesser importance, is the need to open and expand new research opportunities in subdomains critical to successful evidence-based dental practice, such as stakeholder engagement, teledentistry, patient-centered care, individual patient data analysis, and health literacy of the patients and caregivers. Conclusions The course that has led evidence-based dentistry from its infancy in 1999 to a state of relative recognition, if not acceptance across academic and private clinical dentistry in the United States and abroad that the field enjoys today, has been arduous. The concerted efforts by researchers and clinicians were aided considerably by the political environment, which, during the years, proffered funding to the Agency for Healthcare Research and Quality and the Patient-Centered Outcome Research Institute. These have been significant catalysts of the field of comparative effectiveness research and evidence-based research in medicine and dentistry and have fostered and defended the pursuit of evidence-based endeavors in translational health care. The road ahead does not promise to be easier in next 2 decades. In fact, it has become all the murkier and more complicated now as phrases such as science based and evidence based have presently been banned and declared politically incorrect.

This article informs dental professionals of timely and critical recommendations to keep the practice of dentistry safe for the patients, the staff, the hygienists and the dentists. Teaching of these recommendations are being integrated in the clinical curriculum of pre-DDS and pre-DMD professionals, as well as in dental hygiene and dental assisting schools. The paper provides an essential and clearly-written overview of new mandatory procedures and protocols for the practice of dentistry, which will spread world-wide in the near future.

New evidence on the T-cell immuno-pathology in patient's with Corona Virus Disease 2019 (CoViD-19) was reported by Diao et al. in MedRxiv (doi: 10.1101/2020.02.18.20024364) [1]. It reports observations on 522 patients with confirmed CoViD-19 symptomatology, compared to 40 control subjects. In brief, notable T cytopoenia was recorded by flow cytometry in the CD4+ and the CD8+ populations, which were significantly yet inversely correlated with remarkably increased serum levels of the pro-inflammatory cytokines IL-6, IL-10 and TNF-a. Flow cytometry established a progressive increase in the expression of programmed cell death marker-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) as patients (n=14) deteriorated from prodromal to symptomatic CoViD-19 requiring intensive care. Here, we interpret these observations of Diao et al from our current understanding of T cell immunophysiology and immunopathology following an immune challenge in the form of sustained viral infection, as is the case in CoViD-19, with emphasis on exhausted T cells (Tex). Recent clinical trials to rescue Tex show promising outcomes. The relevance of these interventions for the prevention and treatment of CoViD-19 is discussed. Taken together, the data of Diao et al could proffer the first glimpse of immunopathology and possible immunotherapy for patients with CoViD-19.

Background The temporomandibular joint (TMJ) is well innervated by braches of the trigeminal nerve. The temporomandibular joint disorders (TMD) can cause neural-inflammation in the peripheral nervous system (PNS) at the site of injury, or compression, and may have systemic effects on the central nervous system (CNS). Neural-inflammation causes elevations in cytokine expression and microglia activation. When the site of injury, or compression is treated, or relieved, neural inflammation is reduced. These changes can be seen and measured with fMRI brain activities. Methods For this study, patients with comorbid TMD and systemic/neurologic conditions were compared using clinical diagnostic markers, inflammatory, pain, tissue destruction enzymatic biomarkers, and functional magnetic resonance imaging (fMRI) activity of the brain, with and without a custom-made dental orthotic. Results Our results showed a correlation between the clinical diagnosis of the pathological TMJ, biomarkers and the fMRI study. There was a marked elevation of biomarkers in samples taken from TMJ of patients who were clinically diagnosed with TMD. The fMRI study of TMD patients showed an abnormal hyper-connected salience network and a diminished blood flow to the anterior frontal lobes when they did not wear their customized dental orthotics. Conclusions Our findings highlight the importance of TMJ-CNS connections and use of fMRI as an investigative tool for understanding TMD and its related neurological pathologies.

Novel developments in bioinformation, bioinformatics and biostatistics, including artificial intelligence (AI), play a timely and critical role in translational care. Case in point, the extent to which viral immune surveillance is regulated by immune cells and soluble factors, and by non-immune factors informs the administration of health care. The events by which health is regained following viral infection is an allostatic process, which can be modeled using Hilbert's and Volterra's mathematical biology criteria, and biostatistical methodologies such as linear multiple regression. Health regained following viral infection can be given as Y being the sum-total of the positive factors and events (∏) that inherently push allostasis forward (i.e., the orderly process of immune activation and maturation) and the negative (N) factors and events that, allostatically speaking, interfere with regaining health. Any gaps in knowledge are filled by AI-aided immune tweening. Proof of concept can be tested with the fast-gaining infection using tick-borne Bunyavirus that cause severe fever with thrombocytopenia syndrome (SFTS).

Translational science conceptualizes healthcare as a concerted set of processes that integrate research findings from the bench to the bedside. This model of healthcare is effectiveness-focused, patient-centered, and evidence-based, and yields evidence-based revisions of practice-based guidelines, which emerge from research synthesis protocols in comparative effectiveness research that are disseminated in systematic reviews. Systematic reviews produce qualitative and quantitative consensi of the best available evidence. The quantitative consensus is derived from meta-analysis protocols that are often achieved by probabilistic approach Bayesian statistical models.

Lubricin is a synovial glycoprotein that contributes to joint lubrication. We propose the hypothesis that lubricin is a key modulator of the psychoneuroendocrine-osteoimmune interactome, with important clinical relevance for osteoarthritic pathologies. We consider a variety of neuroendocrine-immune factors, including inflammatory cytokines and chemokines that may contribute to the modulation of lubricin in rheumatic complications. Based on our preliminary immunocytochemistry and fractal analysis data, and in the context of translational research of modern healthcare, we propose that molecular lubricin gene expression modification by means of the novel CRISPR/Cas system be considered for osteoarthritic therapies.

Cholera remains a feared, aggressive, infectious and lethal disease today, despite several decades of intense research, concerted public health modalities designed to prevent, and to control outbreaks, availability of efficacious vaccines aimed at containing its contagious spread, and effective patient-centered medical interventions for reducing morbidity and mortality. Despite these advances, cholera still strikes communities around the world, especially in countries and regions of the globe where medical and nursing care cannot be as effectively proffered to the population at risk as in First World economies. Case in point, the number of suspected cholera cases that currently afflicts Yemen escalates at an "unprecedented rate", according to the World Health Organization. Here, following a brief introduction of the history of the medical knowledge about cholera, we discuss current trends of our understanding of clinical immune surveillance against the bacillus that causes cholera, vibrio Cholera (vCh). We cite the current state of best available evidence about anticholera vaccines, and outline certain directions for future study to characterize the clinical immunology of cholera.

Prakṛti (innate human constitution) is one of the most fundamental and versatile components of ayurvedic principles and has wide implications for preventive and curative healthcare. Its characteristics were conceived of empirically but have recently been explored in terms of genomics and molecular biology. If proven convincingly, an ayurvedic prakṛti analysis may be of immense value in personalized healthcare from both a curative and a preventive point of view. Despite their extensive application in practice, ayurvedic prakṛti examination methods have unfortunately not yet been standardized, and for this reason the inferences made on the basis of conventional methods are often questionable. Following a pilot test observation of a Prototype Prakṛti Analysis Tool (ppat), a subsequent Modified Prakṛti Analysis Tool (mpat) was developed in order to eliminate the limitations observed in the first test. The mpat was again tested for its interrater reliability for a prakṛti analysis among healthy volunteers. Forty-two healthy volunteers in the age group of young adults participated in the study and completed the prakṛti examination conducted by three independent observers who were institutionally qualified ayurvedic physicians. The result is a statistically significant correlation between independent observations and the scores obtained for vāta, pitta, and kapha (the three doṣas responsible for a prakṛti determination) variables.

Health care is optimized when the best evidence base (BEB) is translated into policies whose effectiveness can be verified. Bioinformation disseminates BEB and is critical to translational health care. The survival of all prokaryotes and eukaryotes, including mammals, and ultimately our species, depends upon their ability to adapt to changes in their micro-environmental milieu and to the challenges of their surrounding macro-environment. Disturbances in the organism's macro-environment, such as the stressful stimuli derived from environmental changes akin to the current climate crisis, alter its physiological, cytological, biological, epigenetic and molecular microenvironment, and trigger concerted allostatic responses to regain homeostasis. Individual patient data analysis advocates the allostasiome as the specific pattern of biological events and pathways each individual organism undergoes to regain a balanced state of homeostasis following macro-environmental insults. Translational Environmental Restoration (TER) is the translation of BEB in climate change research into effective and efficacious policies for restorative renewal of our macro-environment. Patient-centered translational health care in the current climate crisis depends upon defining and characterizing the allostasiome as a complex systemic process intertwined with TER. Bioinformation is timely and critical to climate crisis research in general and to TER specifically, because it informs and disseminates the best available evidence for each subject's allostasiome. Concerted research must define and characterize BEB of the multi-dimensional medical emergency produced by the current climate crisis. Novel lines of investigation, including allostasione research, increasingly depend on bioinformation for dissemination, and are foundational for TER, one plausible solution to this complex health care crisis.

Metascience refers to the systematic process that uncovers, builds, evaluates, organizes and disseminates scientific advances. It is the principal tool at the disposal of the society to combat the debilitating effects of "false information" on health related data and its constituents.

Immune surveillance to viruses and other foreign pathogens involves a specific process, which is well-characterized in terms of the immune and non-immune cells and factors involved, and their specific timeline. For example, first exposure to a viral antigen involves major histocompatibility complex type I molecules to present the ‘self’ and ‘nonself’ antigen to CD3 + CD8 + CD45RA+ T cells. This presentation initiates the event of T cell activation, which results in the production of T cell growth factor (interleukin 2, IL-2), interferon-gamma (IFN-g) and other immune soluble products, which together act to promote the clonal proliferative expansion of the responding cell population. Soluble immune factors produced during this initial phase of the immune response also initiate the maturation of the responding T cells into CD3 + CD8 + CD45R0+ memory cells against that specific viral antigen, and of related cell populations that act to control and dampen cellular immune reactivity. Contemporaneously, these soluble immune factors trigger non-immune cells to release of non-immune soluble factors, including pituitary and adrenocortical hormones (e.g., glucocorticoids), which finely modulate immune cell responses. Together, immune and non-immune cells and soluble factors act in concert to engender and sustain a finely tuned immune surveillance process, whose ultimate end (Y) is to regain homeostatic balance of the organism – a healthy state, that is eradication of the immune-pathological signs and symptoms that derived from the viral infection, referring here to homeostatic balance Y.

Our awareness of the climate crisis/catastrophe is a convoluted story, which began in chemistry laboratories several decades ago. In that context, scientists first described the greenhouse effect: the potential CO2 accumulation allows solar heat to penetrate the atmosphere, but prevents radiated warmth to escape from it. A theoretical proposition at first, scientists first described the greenhouse effect as the potential accumulation of CO2, allowing solar heat to penetrate the atmosphere while simultaneously preventing the radiated warmth from escaping it. This increase in atmospheric CO2 would hypothetically then raise the planet’s temperature, and if left unchecked, this phenomenon could lead to a multitude of issues including the melting of polar ice caps, rising of oceanic waters, alterations in the acidity and temperature of global water reservoirs (i.e., rivers, lakes, and seas), and changes in the patterns and strength of the gulf streams and consequently the jet stream.

Over one third of the patients sero-positive for the human immunodeficiency virus (HIV) with signs of the acquired immune deficiency syndrome (AIDS), and under treatment with anti-retroviral therapy (ART), develop the immune reconstitution inflammatory syndrome (IRIS). It is not clear what variables are that determine whether a patient with HIV/AIDS will develop ART-related IRIS, but the best evidence base thus far indicates that HIV/AIDS patients with low CD4 cell count, and HIV/AIDS patients whose CD4 count recovery shows a sharp slope, suggesting a particularly fast "immune reconstitution", are at greater risk of developing IRIS. Here, we propose the hypothesis that one important variable that can contribute to low CD4 cell count number and function in ART-treated HIV/AIDS patients is altered hypothalamic-pituitary-adrenal (HPA) cell-mediated immune (CMI) regulation. We discuss HPA-CMI deregulation in IRIS as the new frontier in comparative effectiveness research (CRE) for obtaining and utilizing the best evidence base for treatment of patients with HIV/AIDS in specific clinical settings. We propose that our hypothesis about altered HPA-CMI may extend to the pathologies observed in related viral infection, including Zika.

Translational Ayurveda, in tune to the translational science, calls for an urgent assembly of translational research and translational effectiveness research to extend the benefits of its accumulated knowledge and research to its ultimate users. On the basis of end points desired to be delivered, such translational research may be of diverse nature looking at diverse needs of the society. Such translation therefore can be from the perspectives of physicians asking help in disease diagnosis, of patients asking solutions to their individual set of problems, of industry looking at realistic solutions of producing bulk quantity of formulations to meet the demands without compromising the quality standards, of environmentalists for preserving the nature yet fulfilling the human needs essentially being catered from nature, etc.

The human temporomandibular joint (TMJ) is a bilateral articulation between the mandible and the temporal bone of the skull. Temporomandibular disorders (TMD) are a group of pathologies affecting the TMJ, the muscles of mastication, and the related ligaments causing the joint dysfunction. TMD is most often manifested as internal derangements and is considered to be among the most complex and yet common conditions involving orofacial pain. Pain is a common symptom, due to the sensory innervations of the joint and related muscles/ligaments, followed by inflammation as a result of damage and stress upon the surrounding neurons and tissues.Neuroinflammation, mediated in part by chemokine activity and release of inflammatory cytokines, contributes to increased permeability of the blood-brain barrier (BBB), the potential for continued pathogen and immune cell invasion into the brain. Inflammatory response of the CNS is involved in recruitment of peripheral cells to the brain, which may promote glial cell hyper-activation and neuronal damage.

Human chondroitin sulfate proteoglycan 4, also known as lubricin, plays a vital role in joint lubrication and synovial homeostasis. Our findings from our immunocytochemistry experiments discuss and hypothesize that lubricin is a key modulator in the psychoneuroendocrine-osteoimmune interactome. Synovial lubricin has clinically relevant implications for future treatments of osteoarthritic pathologies. Based on our preliminary studies and quantification of lubricin expression by fractal analysis, we propose interactome-based interventions to be considered for novel osteoarthritic therapy treatments. At the forefront of translational research and healthcare, we recommend the CRISPR/Cas system, which targets genome modification, to be implemented in the clinical treatments for patients who suffer from osteoarthritic pathologies.

In the previous chapter, we discussed the basic principles of inferential statistics and emphasized the difference between descriptive and inferential statistics. The latter allows the researcher to make inferences about the population based on the observations collected. Through analytical tools, inferential statistics help researchers decide whether the difference between groups is statistically significant enough to support our hypothesis that the difference exists in the population.

This chapter discusses the fundamental principles of the research synthesis process in the context of treatment for TMD. It briefly introduces the ongoing controversy in the etiological factors that lead to TMD, which could be broadly divided into two schools of thought: (1) the muscular cause of TMD (disorders of the joint that occur as a result of excessive or dysregulated activities such as clenching and bruxism of the masticatory muscles) or (2) the articular cause of TMD (the disorders of the joint that are consequential to dysfunctional positioning of the mandible onto the maxillary bone, which itself may result from trauma to the facial skeletal structure, malocclusion particularly with respect to molar contact and support). The chapter discusses perspectives of the arthrokinetic reflex in TMD. The chapter defines the best available evidence and discusses the process leading to EBDM for treating TMD, including the generation and dissemination of evidence-based revisions of clinical practice guidelines (EBrCPGs).