Checking the Pulse: A Global Survey on the Evolving Roles of the Insurance Medical Director.

BACKGROUND AND OBJECTIVE: -The traditional role of the insurance medical director is evolving. RGA surveyed insurance medical directors to provide an overview of their roles, skill sets, future trends, and their increasing and changing contributions to the insurance industry in recent years and throughout the current pandemic. METHOD: -RGA conducted a first-of-a-kind global survey of medical directors in the insurance industry. The online survey took place from April to June 2021 and had seven key sections: medical experience and qualifications, roles and responsibilities, underwriting and claims capabilities, adapting to change, disease and product trends in insurance, challenges, and future opportunities. Globally, 124 insurance medical directors from 84 companies participated in the survey. RESULTS: -Respondents are an experienced group of medical directors, with 88% active in the medical profession for 10 years or more. Eighty-seven respondents (70%) dedicate the majority of their time to providing technical medical expertise. Forty-eight percent of medical directors were involved in medical issue briefings prior to the pandemic, and that number increased to 63% during the pandemic. Three of every five respondents (60%) reported a shift in underwriting to an emphasis on more competitive decisions, e-underwriting, and data analytics, while for claims practices, 35% reported a shift to more decisions being challenged and increasing complexity of claims and products. In addition, 31% of insurance medical directors are involved in product development on a regular basis. Only 50% of respondents reported a high or moderate level of investment from employers for training and development with their companies. Forty-three percent of survey respondents are interested in a change of role, especially those with less than 15 years of experience in the insurance industry. Medical directors see data and analytics (50%) as the largest area of development for future growth. Eighty-eight percent of participants surveyed believe that the future role of the medical director in the life and health insurance industry is promising. CONCLUSION: -The future of the medical director role will require more strategic responsibilities, greater product development expertise, and stronger data and analytics skills to support insurer needs. It will be important for insurance medical directors to engage in conversations with their employers to discuss their current and emerging roles.

Exploring family medicine preceptor and resident perceptions of medical assistance in dying and desires for education.

OBJECTIVE: To examine the perspectives of family medicine preceptors and residents, including their interest and intent to participate in and their knowledge and willingness to teach or learn about medical assistance in dying (MAID). DESIGN: Two anonymous surveys were distributed via e-mail using a Dillman approach to residents and preceptors. Responses were collected between August 23 and November 29, 2016. Data were analyzed using descriptive and inferential statistics. SETTING: The large, 4-site Queen's University family medicine residency program in southeastern Ontario. PARTICIPANTS: A total of 71 preceptors and 62 residents. MAIN OUTCOME MEASURES: Physician and resident knowledge of and experience, comfort, and confidence with MAID; willingness to participate in MAID; perspectives on the effect of MAID on team relationships; and the importance, desired content, and delivery of MAID education. RESULTS: Overall, 45.2% of preceptors and 33.3% of residents responded. A low proportion of both preceptors and residents felt competent or comfortable discussing and exploring MAID with a patient, with preceptors feeling significantly more competent and comfortable than residents (P < .001 and P < .01, respectively). Paradoxically, significantly more residents than preceptors were willing to be part of a clinical team providing MAID through oral or intravenous routes (P < .001). In spite of this willingness to be involved, significantly fewer residents felt safe discussing personal perspectives on MAID in various clinical environments (P < .001). Most participants from both groups believed it was important to include MAID in the core family medicine residency curriculum and identified specific curriculum content and delivery strategies. CONCLUSION: Family medicine preceptors and residents are willing and want to learn about MAID. Our research demonstrates a need to integrate MAID into the family medicine residency curriculum, with faculty development and continuing professional development for preceptors.

HIV: A Chronic Condition.

By virtue of the success of anti-retroviral therapy (ART), human immunodeficiency virus (HIV) infection has evolved into a chronic disease in which the typical complications of acquired immune deficiency syndrome (AIDS) are no longer the dominant problem. Rather than dealing with acute and potentially life-threatening complications, clinicians are now confronted with managing a chronic disease that, in the absence of a cure, will persist for many decades. (1) This review will focus on the longer term sequelae and consequences of chronic HIV infection.

Apical hypertrophic cardiomyopathy--a benign condition?

Apical hypertrophic cardiomyopathy (ApHCM) is a less common type of hypertrophic cardiomyopathy (HCM) and is often characterized as benign. However, more recent publications indicate that there is significant heterogeneity among individuals with ApHCM and that for many the condition is less than benign. This review will discuss the most recent understanding of ApHCM in the context of a case presentation and will provide a basic framework for risk stratification.

Current status of immunological therapies for rheumatoid arthritis with a focus on antigen-specific therapeutic vaccines.

Rheumatoid arthritis (RA) is recognized as an autoimmune joint disease driven by T cell responses to self (or modified self or microbial mimic) antigens that trigger and aggravate the inflammatory condition. Newer treatments of RA employ monoclonal antibodies or recombinant receptors against cytokines or immune cell receptors as well as small-molecule Janus kinase (JAK) inhibitors to systemically ablate the cytokine or cellular responses that fuel inflammation. Unlike these treatments, a therapeutic vaccine, such as CEL-4000, helps balance adaptive immune homeostasis by promoting antigen-specific regulatory rather than inflammatory responses, and hence modulates the immunopathological course of RA. In this review, we discuss the current and proposed therapeutic products for RA, with an emphasis on antigen-specific therapeutic vaccine approaches to the treatment of the disease. As an example, we describe published results of the beneficial effects of CEL-4000 vaccine on animal models of RA. We also make a recommendation for the design of appropriate clinical studies for these newest therapeutic approaches, using the CEL-4000 vaccine as an example. Unlike vaccines that create or boost a new immune response, the clinical success of an immunomodulatory therapeutic vaccine for RA lies in its ability to redirect autoreactive pro-inflammatory memory T cells towards rebalancing the "runaway" immune/inflammatory responses that characterize the disease. Human trials of such a therapy will require alternative approaches in clinical trial design and implementation for determining safety, toxicity, and efficacy. These approaches include adaptive design (such as the Bayesian optimal design (BOIN), currently employed in oncological clinical studies), and the use of disease-related biomarkers as indicators of treatment success.

Infant mortality: an insured population perspective.

Many insurers offer life coverage to individuals during the first year of life. The policies tend to have small face values, but frequently contain premium waiver or additional purchase options. General population mortality is significantly higher at this age relative to older children and even middle-aged adults. This article presents the mortality experience of an insured cohort in which death occurred under 1 year of age. In summary, the insured population's mortality rate was significantly lower and the leading causes of death were different than the general population.

Vaccination by Two DerG LEAPS Conjugates Incorporating Distinct Proteoglycan (PG, Aggrecan) Epitopes Provides Therapy by Different Immune Mechanisms in a Mouse Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic epitopes including those in cartilage proteoglycan (PG, aggrecan) and type II collagen. RA is driven by T helper 1 (Th1) or Th17 pro-inflammatory T cell responses. LEAPS (Ligand Epitope Antigen Presentation System) DerG peptide conjugate vaccines were prepared using epitopes from PG that elicit immune responses in RA patients: epitope PG70 (DerG-PG70, also designated CEL-4000) and the citrullinated form of another epitope (PG275Cit). The LEAPS peptides were administered alone or together in Seppic ISA51vg adjuvant to mice with PG G1 domain-induced arthritis (GIA), a mouse model of RA. Each of these LEAPS peptides and the combination modulated the inflammatory response and stopped the progression of arthritis in the GIA mouse model. Despite having a therapeutic effect, the DerG-PG275Cit vaccine did not elicit significant antibody responses, whereas DerG-PG70 (alone or with DerG-PG275Cit) induced both therapy and antibodies. Spleen T cells from GIA mice, vaccinated with the DerG LEAPS peptides, preferentially produced anti-inflammatory (IL-4 and IL-10) rather than pro-inflammatory (IFN-γ or IL-17) cytokines in culture. Similarly, cytokines secreted by CD4+ cells of unvaccinated GIA mice, differentiated in vitro to Th2 cells and treated with either or both DerG vaccine peptides, exhibited an anti-inflammatory (IL-4, IL-10) profile. These results suggest that the two peptides elicit different therapeutic immune responses by the immunomodulation of disease-promoting pro-inflammatory responses and that the combination of the two LEAPS conjugates may provide broader epitope coverage and, in some cases, greater efficacy than either conjugate alone.

Restoring the Balance between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights from Animal Models.

Rheumatoid arthritis (RA) and other autoimmune inflammatory diseases are examples of imbalances within the immune system (disrupted homeostasis) that arise from the effects of an accumulation of environmental and habitual insults over a lifetime, combined with genetic predispositions. This review compares current immunotherapies-(1) disease-modifying anti-rheumatic drugs (DMARDs) and (2) Janus kinase (JAK) inhibitors (jakinibs)-to a newer approach-(3) therapeutic vaccines (using the LEAPS vaccine approach). The Ligand Epitope Antigen Presentation System (LEAPS) therapies are capable of inhibiting ongoing disease progression in animal models. Whereas DMARDs ablate or inhibit specific proinflammatory cytokines or cells and jakinibs inhibit the receptor activation cascade for expression of proinflammatory cytokines, the LEAPS therapeutic vaccines specifically modulate the ongoing antigen-specific, disease-driving, proinflammatory T memory cell responses. This decreases disease presentation and changes the cytokine conversation to decrease the expression of inflammatory cytokines (IL-17, IL-1(α or ß), IL-6, IFN-γ, TNF-α) while increasing the expression of regulatory cytokines (IL-4, IL-10, TGF-ß). This review refocuses the purpose of therapy for RA towards rebalancing the immune system rather than compromising specific components to stop disease. This review is intended to be thought provoking and look forward towards new therapeutic modalities rather than present a final definitive report.

Maturation of dendritic cell precursors into IL12-producing DCs by J-LEAPS immunogens.

LEAPS (ligand epitope antigen presentation system) vaccines consist of a peptide containing a major histocompatibility antigen binding peptide conjugated to an immune cell binding ligand (ICBL) such as the 'J' peptide from beta-2-microglobulin. Treatment of monocytes, monocytes plus GMCSF, or monocytes plus GMCSF and IL4 with JgD (containing a peptide from gD of herpes simplex virus type 1) or JH (with a peptide from HIV p17 gag protein) was sufficient to promote their maturation into Interleukin 12 producing dendritic cells. JgD-dendritic cells supported allotypic activation of T cells to produce Th1-related cytokines.

Offensive language in the general hospital.

BACKGROUND: Offensive language (spoken by medical staff and by patients and their families) is often heard in the general hospital, but its manifestations and clinical implications have not been previously examined. OBJECTIVE: The authors sought to facilitate an understanding of the effects and treatment of offensive utterances and their downstream consequences. METHOD: The authors present a sampling of clinical vignettes that illustrate a variety of examples of hospital-based events in which offensive language was used and discuss differential diagnoses and management strategies. RESULTS: Swearing can also be used as a psychological tool in the service of helping. Swearing may provide a channel of catharsis for aggressive drives and affects that have been building in either the doctor or the patient. DISCUSSION: Placing offensive behaviors, for example, use of profane language, in a biopsychosocial context can facilitate an understanding of the causes, effects, and treatment of these events.

Why Don't We Have a Vaccine Against Autoimmune Diseases? - A Review.

This review examines some of the reasons why we don't have a vaccine against autoimmune diseases and highlights the progress that has been made. Many autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS) and type 1 diabetes (T1D), are driven by autoimmune T cell responses. Unlike vaccines for most infectious diseases, which elicit antibody responses, are intended for immuno-naive individuals and considered preventative, a vaccine for an autoimmune disease must be therapeutic and resolve or control the on-going autoimmune response and condition in the diseased host. Despite these differences, many of the same considerations for infectious disease vaccines must also be addressed to develop a therapeutic vaccine for autoimmune diseases. The disease initiator/triggers, antigens and autoantigens, nature of the immunopathogenic and protective/therapeutic immune response will be compared for infectious and autoimmune diseases as will approaches for developing vaccines including formulations, animal models and indicators of success. The rationale for a therapeutic vaccine for RA will be discussed in greater detail with a relatively limited discussion of T1D, MS and other autoimmune diseases.

Lessons from next generation influenza vaccines for inflammatory disease therapies.

Lessons can be learned for treating inflammatory diseases such as rheumatoid arthritis (RA) from next generation approaches for development of universal influenza vaccines. Immunomodulation of inflammatory diseases, rather than ablation of cytokine or cellular responses, can address the root cause of the disease and provide potential cure. Like influenza, there are different antigenic 'strains' and inflammatory T cell responses, Th1 or Th17, that drive each person's disease. As such, next generation vaccine-like antigen specific therapies for inflammatory diseases can be developed but will need to be customized to the patient depending upon the antigen and T cell response that is driving the disease.

L.E.A.P.S. heteroconjugate is able to prevent and treat experimental autoimmune myocarditis by altering trafficking of autoaggressive cells to the heart.

We evaluated the efficacy of the Ligand Epitope Antigen Presentation System (L.E.A.P.S.trade mark) in preventing or treating experimental autoimmune myocarditis (EAM) in A/J mice. L.E.A.P.S. (here, J-My-1) is a conjugate of the myocarditogenic peptide of cardiac myosin MyHCalpha(334-352) (My-1) and J peptide, derived from the sequence of human beta-2 microglobulin. Remarkably, early prophylactic (J-My-1 injected on days -14 and -7 before EAM induction), late prophylactic (J-My-1 injected on days 0, 7, 14, and 21), and therapeutic (J-My-1 injected on days 7, 14, and 21 or 10, 17 and 24) administration of J-My-1 significantly decreased the incidence and severity of EAM. However, extended therapeutic treatment was associated with anaphylaxis and death, corresponding with global immune activation associated with J-My-1 treatment. In J-My1-treated animals, we observed expanded numbers of activated CD69+ and CD44+ CD4+ and CD8+ T cells in the spleens. J-My-1 treatment also increased the proportion of CD11c+ dendritic cells in spleens and induced strong production of anti-J-My-1 specific antibodies. J-My-1 injections resulted in decreased levels of chemokines MIP-1alpha and IP-10 in hearts. We propose that J-My-1 treatment interferes with trafficking of autoaggressive immune cells to the heart.

Pediatric overweight: a weighty mortality concern.

Overweight children add a new dimension to pediatric underwriting due to their increasing numbers and unprecedented consideration in the risk stratification process. The lay and medical literature is rife with publications addressing the etiology, prevention, morbidity, and treatment of pediatric obesity. Less attention has been paid to long-term outcomes and mortality associated with pediatric overweight, although recent publications indicate that situation is changing. This review focuses specifically on mortality associated with pediatric overweight and its effect on the current and future insurability of children.

LEAPS Vaccine Incorporating HER-2/neu Epitope Elicits Protection That Prevents and Limits Tumor Growth and Spread of Breast Cancer in a Mouse Model.

The prototype J-LEAPS T cell vaccine for HER-2/neu breast cancer (J-HER) consists of the murine HER-2/neu66-74 H-2d CD8 T cell epitope covalently attached through a triglycine linker to the J-immune cell binding ligand (ICBL) (human ß2 microglobulin38-50 peptide). The J-ICBL was chosen for its potential to promote Th1/Tc1 responses. In this proof-of-concept study, the ability of J-HER to prevent or treat cancer was tested in the TUBO cell-challenged BALB/c mouse model for HER-2/neu-expressing tumors. The J-HER vaccine was administered as an emulsion in Montanide ISA-51 without the need for a more potent adjuvant. When administered as a prophylactic vaccination before tumor challenge, J-HER protected against tumor development for at least 48 days. Despite eliciting protection, antibody production in J-HER-immunized, TUBO-challenged mice was less than that in unimmunized mice. More importantly, therapeutic administration of J-HER one week after challenge with TUBO breast cancer cells limited the spread of the tumors and the morbidity and the mortality in the challenged mice. The ability to elicit responses that prevent spread of the TUBO tumor by J-HER suggests its utility as a neoimmunoadjuvant therapy to surgery. Individual or mixtures of J-LEAPS vaccines can be readily prepared to include different CD8 T cell epitopes to optimize tumor therapy and customize treatment for individuals with different HLA types.

An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune joint disease maintained by aberrant immune responses involving CD4+ T helper (Th)1 and Th17 cells. In this study, we tested the therapeutic efficacy of Ligand Epitope Antigen Presentation System (LEAPS™) vaccines in two Th1 cell-driven mouse models of RA, cartilage proteoglycan (PG)-induced arthritis (PGIA) and PG G1-domain-induced arthritis (GIA). The immunodominant PG peptide PG70 was attached to a DerG or J immune cell binding peptide, and the DerG-PG70 and J-PG70 LEAPS vaccines were administered to the mice after the onset of PGIA or GIA symptoms. As indicated by significant decreases in visual and histopathological scores of arthritis, the DerG-PG70 vaccine inhibited disease progression in both PGIA and GIA, while the J-PG70 vaccine was ineffective. Splenic CD4+ cells from DerG-PG70-treated mice were diminished in Th1 and Th17 populations but enriched in Th2 and regulatory T (Treg) cells. In vitro spleen cell-secreted and serum cytokines from DerG-PG70-treated mice demonstrated a shift from a pro-inflammatory to an anti-inflammatory/regulatory profile. DerG-PG70 peptide tetramers preferentially bound to CD4+ T-cells of GIA spleen cells. We conclude that the DerG-PG70 vaccine (now designated CEL-4000) exerts its therapeutic effect by interacting with CD4+ cells, which results in an antigen-specific down-modulation of pathogenic T-cell responses in both the PGIA and GIA models of RA. Future studies will need to determine the potential of LEAPS vaccination to provide disease suppression in patients with RA.

Two Visual Training Paradigms Associated with Enhanced Critical Flicker Fusion Threshold.

Critical flicker fusion thresholds (CFFTs) describe when quick amplitude modulations of a light source become undetectable as the frequency of the modulation increases and are thought to underlie a number of visual processing skills, including reading. Here, we compare the impact of two vision-training approaches, one involving contrast sensitivity training and the other directional dot-motion training, compared to an active control group trained on Sudoku. The three training paradigms were compared on their effectiveness for altering CFFT. Directional dot-motion and contrast sensitivity training resulted in significant improvement in CFFT, while the Sudoku group did not yield significant improvement. This finding indicates that dot-motion and contrast sensitivity training similarly transfer to effect changes in CFFT. The results, combined with prior research linking CFFT to high-order cognitive processes such as reading ability, and studies showing positive impact of both dot-motion and contrast sensitivity training in reading, provide a possible mechanistic link of how these different training approaches impact reading abilities.

The L.E.A.P.S. approach to vaccine development.

The Ligand Epitope Antigen Presentation System (L.E.A.P.S.) approach to vaccine development utilizes immune peptides to promote the immunogenicity and influence the type of immune response generated towards epitopes in peptides which may be too small to elicit an immune response. The covalent attachment of these immune peptides to the antigenic peptide promotes the interaction of the epitope with T cells (T cell binding ligand (TCBL)) or antigen presenting cells (immune cell binding ligand (ICBL)) and ultimately promotes binding with the T cell receptor on CD4 or CD8 T cells. The, J, ICBL/TCBL peptide derived from the beta-2-microglobulin chain of MHC I molecules promotes Th1 type responses to the antigenic peptide while the, G, ICBL/TCBL peptide derived from the beta chain of MHC II molecules promotes Th2 types of responses. The efficacy of this approach has been demonstrated by characterization of the immune responses to L.E.A.P.S. vaccines and by elicitation of protection from infectious challenge with herpes simplex virus and other pathogens. The protection studies show that the L.E.A.P.S. approach allows customization of the immune response appropriate for inducing protection from disease. The theory, background, examples and studies of the mechanism of action of the L.E.A.P.S. vaccines will be discussed.

Ligand epitope antigen presentation system vaccines against herpes simplex virus.

The Ligand Epitope Antigen Presentation System (L.E.A.P.S.) approach to vaccine development allowed construction of immunogens from defined T cell epitopes from herpes simplex virus (HSV) proteins that conferred protection against lethal challenge by the virus. This technology utilizes specific peptides which bind to CD4, CD8 or other proteins on the surface of T cells (T cell binding ligand (TCBL)), macrophage and dendritic cells (immune cell binding ligand (ICBL)) to promote the immunogenicity of an epitope, activate T cell and other protective responses, and direct the immune response to either a Th1 or a Th2 type of response. The J TCBL/ICBL is a peptide from beta-2-microglobulin which binds to the CD8 protein and promotes Th1 responses and the G TCBL/ICBL is a peptide from the beta chain of MHC II molecules that binds to the CD4 protein and promotes Th2 responses. Epitopes from the ICP27 (H1, H2), glycoprotein B (gB) and glycoprotein D (gD) proteins of HSV-1 were attached to either the J TCBL/ICBL or the G TCBL/ICBL. The JH1, JH2, JgB and JgD vaccines elicited DTH responses without antibody but conferred protection upon lethal challenge. Th1 related antibody was produced after challenge of the JgB and JgD immunized mice. Immunization with the GH1, GgB or GgD vaccines did not yield protection. The GgB and GgD produced Th2 related antibodies upon virus challenge. Initiation of the immune response by the JgD vaccine was dependent on functional CD4, CD8 expressing cells and interferon gamma and delivery of protection was dependent upon CD4 and interferon gamma. The L.E.A.P.S. HSV vaccines appear to elicit the appropriate immune responses for protection and further work is being performed to develop the JgD vaccine for human use.