Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases. Its leading features include chronic synovial inflammation and degeneration of the bones and joints. In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs). Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease. Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA. Its dysregulation in various associated cell types contributes to the development of RA. In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA.

New Materials in Dentistry

The use of an appropriate implant biomaterial significantly determines the success of implants. The biologic environment where implants are placed does not necessarily accept any material. Therefore, biologic performance can be optimized by selecting implants that reduce negative biologic response while at the same time functioning adequately. Besides, clinicians should be knowledgeable of different biomaterials used for purposes of dental implants. The purpose of this paper is to provide an overview on the issue of dental implants. Some of the implants discussed in the paper include titanium and zirconia implants. Furthermore, the paper discusses how physical properties of the materials influence the treatment outcome.

Machine Learning Predictive Outcomes Modeling in Inflammatory Bowel Diseases

There is a rising interest in use of big data approaches to personalize treatment of inflammatory bowel diseases (IBDs) and to predict and prevent outcomes such as disease flares and therapeutic nonresponse. Machine learning (ML) provides an avenue to identify and quantify features across vast quantities of data to produce novel insights in disease management. In this review, we cover current approaches in ML-driven predictive outcomes modeling for IBD and relate how advances in other fields of medicine may be applied to improve future IBD predictive models. Numerous studies have incorporated clinical, laboratory, or omics data to predict significant outcomes in IBD, including hospitalizations, outpatient corticosteroid use, biologic response, and refractory disease after colectomy, among others, with considerable health care dollars saved as a result. Encouraging results in other fields of medicine support efforts to use ML image analysis—including analysis of histopathology, endoscopy, and radiology—to further advance outcome predictions in IBD. Though obstacles to clinical implementation include technical barriers, bias within data sets, and incongruence between limited data sets preventing model validation in larger cohorts, ML-predictive analytics have the potential to transform the clinical management of IBD. Future directions include the development of models that synthesize all aforementioned approaches to produce more robust predictive metrics.

Anti-Lethal Therapy of COVID-19 for Home Health Outpatient Therapy

The article presents the rationale for a new therapeutic strategy for treatment of patients with COVID-19, based on the combined use of biologic response modifiers and drugs targeting etiology and pathophysiology of the novel coronavirus infection, excluding disadvantages of polypharmacy, and providing a high clinical effect. This approach has been predominantly used in home health outpatient treatment of 324 patients with COVID-19 of variable severity using the biologic response modifiers “double drug cocktail” made of recombinant human interleukin-2 and recombinant human interferon alpha-2b in combination with alimemazine, nimesulide, rivaroxaban and antibiotic therapy (co-amoxiclav, or ceftriaxone) if secondary bacterial pneumonia was diagnosed. The results obtained indicate a dramatic improvement in the condition of patients, even with a severe COVID-19, which made possible to avoid artificial ventilation and prevent deaths.

A pharmacist-managed virtual consult service to improve tuberculosis screening

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose To describe a pharmacist-managed virtual consult service practice model to improve medication safety in a population of rheumatology patients and evaluate its initial impact on guideline compliance. Summary Optimal pharmacologic care of patients with rheumatologic conditions often revolves around the use of specialty medications such as self-injectable biologics and infused therapies, including biologic response modifiers (BRMs), nearly all of which carry risks of serious adverse events due to their immune-suppressive properties. Possible adverse events include serious infections such as reactivation of tuberculosis (TB) and viral hepatitis B (HBV). This articles describes a pharmacist-managed virtual consult service introduced by a large university-affiliated health system in 2018 to integrate clinical, specialty pharmacy, and therapeutic infusion services for proactive medication and safety management for patients with rheumatologic conditions requiring specialty or infused medications. During a 4-month evaluation period, 157 referrals were sent to the consult service; of 137 consults included in the analysis, 42% were for self-injectable biologic medications, 28% were for intra-articular injections, 26% were for infusions, and 4% were for oral specialty medications. Forty-one percent of the pharmacy benefit consult orders required an intervention prior to submission of prior authorization requests. Most interventions (61%) were clinical in nature and involved the pharmacists ensuring that necessary laboratory work, clinical disease activity scoring, or radiographic imaging were completed prior to submission of the consult results for insurer approval. Conclusion National rates of HBV screening and TB screening for patients prescribed BRMs continue to be suboptimal. The pharmacist-managed virtual consult service is a novel practice model to increase the screening rate to 100% to ensure the safety and appropriate monitoring of patients who are starting or continued on these complex medications.

Atto 465 derivative is a nuclear stain with unique excitation and emission spectra for multiplex immunofluorescence histochemistry

The architecture of a biologic response is inextricably linked with the tissue architecture of the target site. Multiplex immunofluorescence (mIF) is an effective technique for the maximal visualization of multiple target proteins in situ. This powerful tool is limited by the spectral overlap separation of the currently available synthetic fluorescent dyes. The fluorescence excitation wavelengths ranging between 405nm and 488nm are rarely used in mIF imaging and serve as a logical additional slot for a fluorescent probe. In the present study, we demonstrate that Atto 465-pentafluoroaniline (Atto 465-p), a derivative of the fluorescent dye Atto 465, can serve as a nuclear stain in the violet-blue region of the visible spectrum. This opens the 405nm channel, traditionally used for nuclear stain, for detection of another experimental target. This increases the flexibility of the mIF panel and, with appropriate staining and microscopy, enables the quantitative analysis of at least six targets in one tissue section.

Biomarkers in Hereditary Angioedema

A biomarker is a defined characteristic measured as an indicator of normal, biologic, pathogenic processes, or biological responses to an exposure or intervention. Diagnostic biomarkers are used to detect a disease or a subtype of a disease; monitoring biomarkers are measured serially to assess a medical condition; response biomarkers are used to check biologic response following a medical intervention; predictive biomarkers are used to identify patients who are more likely to respond to a medical intervention; and prognostic biomarkers are used to assess the future likelihood of a clinical event. Although biomarkers have been extensively investigated and validated in many diseases and pathologies, very few are currently useful for the diagnosis, evaluation of disease activity, and treatment of hereditary angioedema (HAE). Pathophysiologic pathways involved in HAE reveal a plethora of molecules from the complement, coagulation, and fibrinolysis systems or from the vascular endothelium, which may serve as biomarkers. The most promising candidates, together with their laboratory readout systems, should be evaluated with regard to their analytical and clinical validity and utility. To be highly specific, such biomarkers should be linked to the pathomechanisms of HAE, particularly the bradykinin-generating cascade. Additionally, major advances in high-throughput omics-based technologies may facilitate the discovery of new candidate biomarkers in the future. This review will cover the existing as well as future potential biomarkers that will support the diagnosis, monitor disease activity, and can be used to assess the efficacy of new avenues of therapy of HAE and other forms of angioedema.

Is Rotavirus Immunization Safe in Infants Born to Mothers Treated with Immunosuppressive Drugs for Inflammatory Bowel Disease During Pregnancy?

The licensed rotavirus vaccines are live attenuated and are a component of the routine U.S. childhood immunization schedule. Live vaccines administered to infants of mothers who received biologic response modifiers (BRM) during pregnancy can potentially cause serious vaccine-associated disease. The Advisory Committee on Immunization Practices (ACIP) recommends infants born to women who received BRM during pregnancy avoid live viral vaccines during the first year of life. There is a paucity of information regarding adverse events following inadvertent administration of live viral vaccines in these infants. We report three infants, born to mothers receiving infliximab during pregnancy, who tolerated multiple doses of rotavirus vaccine. Live viral vaccines may be safe in infants who were exposed to BRM in utero. Further studies are needed to support this observation, as this could affect current ACIP recommendations.