Examining Social Identities of Patient Diversity Through Cases Presented in a Therapeutics Course Series.

Objective. In pharmacy education, considerable debate surrounds the decision about whether didactic cases should include social identities, such as race, ethnicity, sexual orientation, gender identity, ability, spirituality, nationality, and socioeconomic status. In considering what and how much of these identities to include, the first step could be to measure their current inclusion. This study aimed to quantify the presence of these social identities in cases presented to student pharmacists in a three-semester course series.Methods. One hundred forty-four cases presented in a three-semester pharmacotherapeutics course series were reviewed. The primary objective was to quantify the inclusion of each social identity. The secondary objective was to assess whether the identities were needed to answer specific questions related to each case. Cases were reviewed by two independent study researchers; a third impartial reviewer settled disagreements.Results. Cases rarely explicitly included social identities. Race was explicitly stated in 15% of cases (n = 21). Gender identity was explicitly named in two cases (1%), but nearly all cases implied gender through pronouns. Gender was necessary to answer case questions in approximately 20% of cases (n=27). Socioeconomic status, ability, sexual orientation, and nationality were infrequently named among all cases, at rates of 6%, 5%, 1%, and 1%, respectively.Conclusion. This study found that didactic cases rarely explicitly state social identities. In determining the next steps for integrating social identities, pharmacy education must first take stock of how it currently acknowledges these identities.

Incidence of a negative hidden curriculum, cynicism, and burnout within pharmacy resident education: A nationwide survey.

INTRODUCTION: The term "hidden curriculum" (HC) is a set of ethical, moral, and value-based teachings communicated in a non-explicit manner. Recent literature has described increasing awareness of the prevalence of the HC and potential negative impact on medical learners; however, this information is lacking in pharmacy resident education. Consequently, we conducted a survey study of United States pharmacy residents to learn their perceptions concerning the HC in pharmacy residency training. METHODS: A nationwide survey of pharmacy residents was conducted in June 2019. The survey assessed the following: presence of negative HC (score 0 to 80), cynicism (score 0 to 25), burnout via Maslach Burnout Inventory depersonalization (MBI-D) (range 0 to 30), and emotional exhaustion via Maslach Burnout Inventory emotional exhaustion (MBI-EE) (range 0 to 54). Higher scores represent increased occurrences of each domain. RESULTS: The mean HC score was 20 (SD 14.7), mean cynicism score was 9 (SD 5.5), MBI-D was 5.5 (SD 4.5), and MBI-EE was 24.2 (SD 12.4). Of those completing an MBI score, 40.4% (82/203) reported burnout in one area, while 15.8% (32/203) reported burnout in both areas. Residents reporting burnout had higher mean HC and cynicism scores. CONCLUSIONS: Awareness to develop and grow cultures that minimize the presence of a negative HC is essential to improve postgraduate pharmacy training.

Possible dulaglutide-associated cholecystitis with safe continuation post cholecystectomy.

PURPOSE: Possible dulaglutide-induced cholecystitis, with successful resumption of dulaglutide after cholecystectomy, is discussed. SUMMARY: A 72-year-old White man was started on dulaglutide for outpatient management of type 2 diabetes, in addition to his existing antihyperglycemic regimen of metformin, glipizide, pioglitazone, and insulin glargine. His glycated hemoglobin (HbA1c) concentration improved from 8.2% to 7.2% with the addition of dulaglutide. Furthermore, the use of dulaglutide did not lead to weight loss. After 16 months of treatment with dulaglutide, he presented to the emergency room with nausea, loss of appetite, and progressive sharp, nonradiating right upper quadrant pain. Based on symptom presentation, laboratory workup, and computed tomography scan results, acute cholecystitis was diagnosed. He underwent a cholecystectomy to remove what was found to be a gangrenous gallbladder. Per documented surgical dictation from the cholecystectomy, the gallbladder was removed, but portions of the biliary tree were left intact. The patient was continued on dulaglutide postoperatively without recurrence of bile stones, biliary tree disease, or abdominal symptoms at 8 months after initial cholecystitis incident. CONCLUSION: A male patient with possible dulaglutide-induced cholecystitis was successfully continued on dulaglutide therapy post cholecystectomy without recurrent complications within the biliary tract.

Possible apixaban-induced leukocytoclastic vasculitis.

PURPOSE: The development of leukocytoclastic vasculitis (LCV) during apixaban therapy in a female patient being treated for deep vein thrombosis (DVT) is reported. SUMMARY: A 74-year-old Caucasian woman weighing 102 kg presented to a walk-in clinic with complaints of mild pain and swelling in her left leg for 2 weeks. She was diagnosed as having left lower-extremity DVT. The direct oral anticoagulant (DOAC) apixaban (10 mg twice daily for 7 days, then 5 mg twice daily for 3 months) was prescribed. At 1-week follow-up the patient stated that her DVT symptoms were slowly improving and reported that small areas of red rash had appeared bilaterally on her lower extremities. On day 23 of apixaban therapy, the patient presented to a walk-in clinic with a complaint that the rash had progressively worsened. The rash was diagnosed as LCV by dermatology consult. On day 24 of therapy, apixaban use was discontinued and the patient was initiated on rivaroxaban (20 mg daily) for the remainder of DVT treatment. LCV was found to be progressively improving on day 73, with trace petechiae. Rivaroxaban was used through the end of DVT treatment without further reports of LCV. CONCLUSION: A female patient who developed LCV while taking apixaban for treatment of DVT was successfully transitioned to rivaroxaban therapy, leading to resolution of LCV and successful completion of DVT treatment without recurrence of LCV.

Baby Boomers and Birth Certificates: Early-Life Socioeconomic Status and Cancer Risk in Adulthood.

BACKGROUND: Early-life socioeconomic status (SES) may play a role in cancer risk in adulthood. However, measuring SES retrospectively presents challenges. Parental occupation on the birth certificate is a novel method of ascertaining early-life SES that has not been applied in cancer epidemiology. METHODS: For a Baby-Boom cohort born from 1945-1959 in two Utah counties, individual-level Nam-Powers SES (Np-SES) was derived from parental industry/occupation reported on birth certificates. Neighborhood SES was estimated from average household income of census tract at birth. Cancer incidence was determined by linkage to Utah Cancer Registry records through the Utah Population Database. Hazard ratios (HR) for cancer risk by SES quartile were estimated using Cox proportional hazards regression. RESULTS: Females with low Np-SES at birth had lower risk of breast cancer compared with those in the highest Np-SES group [HRQ1/Q4 = 0.83; 95% confidence interval (CI), 0.72-0.97; HRQ2/Q4 = 0.81; 95% CI, 0.69-0.96]. Np-SES was inversely associated with melanoma (HRQ1/Q4 = 0.81; 95% CI, 0.67-0.98) and prostate cancer (HRQ1/Q4 = 0.70; 95% CI, 0.56-0.88). Women born into lower SES neighborhoods had significantly increased risk for invasive cervical cancer (HRQ1/Q4 = 1.44; 95% CI, 1.12-1.85; HRQ2/Q4 = 1.33; 95% CI, 1.04-1.72). Neighborhood SES had similar effects for melanoma and prostate cancers, but was not associated with female breast cancer. We found no association with SES for pancreas, lung, and colon and rectal cancers. CONCLUSIONS: Individual SES derived from parental occupation at birth was associated with altered risk for several cancer sites. IMPACT: This novel methodology can contribute to improved understanding of the role of early-life SES on cancer risk. Cancer Epidemiol Biomarkers Prev; 26(1); 75-84. ©2016 AACR.

Evolution of postural diversity in primates as reflected by the size and shape of the medial tibial facet of the talus.

OBJECTIVES: Comprehensive quantification of the shape and proportions of the medial tibial facet (MTF) of the talus (=astragalus) has been lacking for Primates and their closest relatives. In this study, aspects of MTF form were quantified and employed to test hypotheses about their functional and phylogenetic significance. The following hypotheses influence perceptions of primate evolutionary history but are due for more rigorous assessment: 1) A relatively large MTF distinguishes "prosimians" (strepsirrhines and tarsiers) from anthropoids and non-primate euarchontans; 2) the distinctive form of the "prosimian" MTF is a correlate of locomotor tendencies that emphasize use of vertical and small diameter supports in conjunction with inverted, abducted foot postures; and 3) the "prosimian" MTF form arose along the primate stem lineage and was present in the euprimate common ancestor. METHODS: Three-dimensional (3D) scanning was used to create scale digital models of tali (n = 378 specimens, 122 species) from which three types of variables capturing aspects of MTF form were computed: 1) MTF area relative to body mass and ectal facet area; 2) MTF shape (elliptical vs. non-elliptical); and 3) MTF dorsal restriction on the talar body (i.e., extensive vs. minimal exposure of non-articular area). Data were analyzed using both phylogenetic and traditional comparative methods including Phylogenetic Generalized Least Squares, Ordinary Least Squares, ANCOVA, ANOVA, and Bayesian Ancestral State Reconstruction (ASR). RESULTS: Extant "prosimians" are generally distinct from anthropoids and non-primate euarchontans in our quantitative representations of MTF form. MTF area (but not shape or dorsal restriction) correlates with fibular facet angle (FFa) of the talus, which has also been argued to reflect habitual pedal inversion. Among strepsirrhines, taxa that engage in grasp-leaping more frequently/effectively appear to have a relatively larger MTF than less acrobatic taxa. Directional models of evolutionary change better describe the phylogenetic distribution of MTF variation than do other models. ASR shows 1) little change in the MTF along the primate stem, 2) independent evolution of relatively large and dorsoplantarly deep MTFs in basal haplorhines and strepsirrhines, and 3) re-evolution of morphologies similar to non-euprimates in anthropoids. CONCLUSIONS: Results support the hypothesis that differences in MTF form between anthropoids and "prosimians" reflect greater use of inverted foot postures and grasp-leaping in the latter group. Although fossil "prosimians" do not have the extreme MTF dimensions that characterize many extant acrobatic leapers, these variables by themselves provide little additional behavioral resolution at the level of individual fossils due to strong phylogenetic signal. ASR suggests that some specialization for use of inverted foot postures (as required in a fine-branch niche) and modifications for grasp-leaping evolved independently in basal strepsirrhine and haplorhine lineages.

Use of low-dose prothrombin complex concentrate before lumbar puncture.

PURPOSE: The use of an off-label dose of four-factor prothrombin complex concentrate (PCC) for International Normalized Ratio (INR) reversal in a patient before a diagnostic lumbar puncture is reported. SUMMARY: A 57-year-old, 122-kg man arrived at the hospital with a possible diagnosis of meningitis and had an INR of >3 while on warfarin therapy. The patient initiated warfarin therapy in 2009 due to recurrent deep vein thrombosis. The patient required reversal of his elevated INR in order for a lumbar puncture to be safely performed (INR must be no higher than 1.4). Multiple units of fresh frozen plasma (FFP) were administered, with a subsequent INR decrease to 1.9. Additional units of FFP were given. The patient developed respiratory decompensation due to volume overload, partially caused by the administration of multiple units of FFP. As the INR remained above 1.4 but was less than 2, an alternative dosing strategy was used. A dose of 1020 units of factor IX, equaling about 10 mg/kg based on a maximum dosing weight of 100 kg, was administered. The two vials of PCC administered each contained 510 units of factor IX. No vitamin K was given. The patient's INR, checked 30 minutes after PCC administration, was 1.3, and the lumbar puncture was performed. The lumbar puncture was completed without complication, and the patient was restarted on therapeutic anticoagulation the following day. CONCLUSION: A 57-year-old patient was successfully treated with low-dose PCC to reverse an INR from 1.7 to 1.3 in order to perform a diagnostic lumbar puncture.

Rural - urban inequalities in late-stage breast cancer: spatial and social dimensions of risk and access.

Rural - urban inequalities in health and access to health care have long been of concern in health-policy formulation. Understanding these inequalities is critically important in efforts to plan a more effective geographical distribution of public health resources and programs. Socially and ethnically diverse populations are likely to exhibit different rural - urban gradients in health and well-being because of their varying experiences of place environments, yet little is known about the interplay between social and spatial inequalities. Using data from the Illinois State Cancer Registry, we investigate rural - urban inequalities in late-stage breast cancer diagnosis both for the overall population and for African-Americans, and the impacts of socioeconomic deprivation and spatial access to health care. Changes over time are analyzed from 1988 - 92 to 1998 - 2002, periods of heightened breast cancer awareness and increased access to screening. In both time periods, the risk of late-stage diagnosis is highest among patients living in the most urbanized areas, an indication of urban disadvantage. Multilevel modeling results indicate that rural - urban inequalities in risk are associated with differences in the demographic characteristics of area populations and differences in the social and spatial characteristics of the places in which they live. For African-American breast cancer patients, the rural - urban gradient is reversed, with higher risks among patients living outside the city of Chicago, suggesting a distinct set of health-related risks and place experiences that inhibit early breast cancer detection. Findings emphasize the need for combining spatial and social targeting in locating cancer prevention and treatment programs.

Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases.

Adenosine is a purine nucleoside with immunosuppressive activity that acts through cell surface receptors (A(1), A(2a), A(2b), A(3)) on responsive cells such as T lymphocytes. IL-2 is a major T cell growth and survival factor that is responsible for inducing Jak1, Jak3, and STAT5 phosphorylation, as well as causing STAT5 to translocate to the nucleus and bind regulatory elements in the genome. In this study, we show that adenosine suppressed IL-2-dependent proliferation of CTLL-2 T cells by inhibiting STAT5a/b tyrosine phosphorylation that is associated with IL-2R signaling without affecting IL-2-induced phosphorylation of Jak1 or Jak3. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reversed by the protein tyrosine phosphatase inhibitors sodium orthovanadate and bpV(phen). Adenosine dramatically increased Src homology region 2 domain-containing phosphatase-2 (SHP-2) tyrosine phosphorylation and its association with STAT5 in IL-2-stimulated CTLL-2 T cells, implicating SHP-2 in adenosine-induced STAT5a/b dephosphorylation. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reproduced by A(2) receptor agonists and was blocked by selective A(2a) and A(2b) receptor antagonists, indicating that adenosine was mediating its effect through A(2) receptors. Inhibition of STAT5a/b phosphorylation was reproduced with cell-permeable 8-bromo-cAMP or forskolin-induced activation of adenylyl cyclase, and blocked by the cAMP/protein kinase A inhibitor Rp-cAMP. Forskolin and 8-bromo-cAMP also induced SHP-2 tyrosine phosphorylation. Collectively, these findings suggest that adenosine acts through A(2) receptors and associated cAMP/protein kinase A-dependent signaling pathways to activate SHP-2 and cause STAT5 dephosphorylation that results in reduced IL-2R signaling in T cells.

Adenosine inhibits activation-induced T cell expression of CD2 and CD28 co-stimulatory molecules: role of interleukin-2 and cyclic AMP signaling pathways.

Adenosine is an immunosuppressive molecule that is associated with the microenvironment of solid tumors. Mouse T cells activated with anti-CD3 antibody in the presence of adenosine with or without coformycin (to prevent adenosine breakdown by adenosine deaminase) exhibited decreased tyrosine phosphorylation of some intracellular proteins and were inhibited in their ability to proliferate and synthesize interleukin (IL)-2. In addition, adenosine interfered with activation-induced expression of the co-stimulatory molecules CD2 and CD28. Activation-induced CD2 and CD28 expression was also diminished when T cells were activated in the presence of anti-IL-2 and anti-CD25 antibodies to neutralize IL-2 bioactivity. Collectively, these data suggest that CD2 and CD28 up-regulation following T cell activation is IL-2-dependent; and that adenosine inhibits activation-induced T cell expression of CD2 and CD28 by interfering with IL-2-dependent signaling. The inhibitory effect of adenosine on activation-induced CD2 and CD28 expression could not be attributed to cyclic AMP (cAMP) accumulation resulting from the stimulation of adenylyl cyclase-coupled adenosine receptors, even though cAMP at concentrations much higher than those generated following adenosine stimulation was inhibitory for both CD2 and CD28 expression. We conclude that adenosine interferes with IL-2-dependent T cell expression of co-stimulatory molecules via a mechanism that does not involve the accumulation of intracellular cAMP.

Development of an interleukin-12-deficient mouse model that is permissive for colonization by a motile KE26695 strain of Helicobacter pylori.

The identification of genes associated with colonization and persistence of Helicobacter pylori in the gastric mucosa has been limited by the lack of robust animal models that support infection by strains whose genomes have been completely sequenced. Here we report that an interleukin-12 (IL-12)-deficient mouse (IL-12(-/-) p40 subunit knockout in C57BL/6 mouse) is permissive for infection by a motile variant (KE88-3887) of The Institute For Genomic Research-sequenced strain (KE26695) of H. pylori. The IL-12-deficient mouse was also more permissive for colonization by the mouse-colonizing Sydney 1 strain of H. pylori than were wild-type C57BL/6 mice. Differences in colonization efficiency were demonstrated by mouse challenge with SS1 strains containing loss-of-function mutations in two genes (hspR and hrcA), whose products negatively regulate several heat shock genes. At 5 weeks postinfection, double-knockout mutants (SS1 hspR hrcA) efficiently colonized IL-12-deficient mice (5 of 5 animals compared to 4 of 10 for C57BL6 mice) and bacterial counts were higher in stomachs of IL-12-deficient mice (10(6) versus 10(5) CFU/g of stomach, respectively). IL-12-deficient mice were efficiently colonized by KE88-3887 (29 of 30), but not by nonmotile KE26695, and bacterial numbers (10(4) to 10(5) CFU/g of stomach) were unchanged over an 8-week period postinfection. In contrast, C57BL/6 mice were inefficiently colonized by KE88-3887 (8 of 20 animals with bacterial loads at the limit of detection, approximately 10(3) CFU/g), and infection did not persist much beyond 5 weeks. Cytokine responses (tumor necrosis factor alpha and gamma interferon), pathology, and antral-predominant infection were indistinguishable between IL-12-deficient and C57BL/6 mice. The increased permissiveness of the IL-12-deficient mouse for infection with H. pylori should facilitate whole-genome-based strategies to study genes associated with virulence and immune modulation.

Activation-induced expression of cell surface CD28 on mouse T lymphocytes is inhibited by cyclosporine A.

T-cell activation requires both T-cell receptor signaling and a costimulatory signal provided by CD28 which enhances and prolongs interleukin-2 (IL-2) production. To determine the effect of cyclosporine A (CsA) on constitutive and activation-induced CD28 expression, mouse T cells were exposed to CsA (0.1 microM) in the absence or presence of anti-CD3 monoclonal antibody (mAb). CD28 expression was then determined by flow cytometry. CsA treatment prevented activation-induced CD28 expression but did not affect constitutive CD28 expression. Inhibition of inducible CD28 expression by CsA was not rapidly reversible, requiring 48h of restimulation in the absence of CsA for CD28 expression to return to control levels. T cells activated in the presence of combined anti-IL-2 and anti-CD25 mAb (both 10 microg/mL) also exhibited reduced CD28 expression, suggesting that activation-induced CD28 expression is, at least in part, an IL-2-dependent process. However, the inhibitory effect of CsA on activation-induced CD28 expression was maintained in the presence of exogenous IL-2 (250 U/mL). We conclude that CsA, by inhibiting activation-induced expression of costimulatory CD28 molecules by T lymphocytes, may interfere with the ability of CD28 to provide an optimal costimulatory signal for sustained IL-2 production following T-cell activation.

Adenosine acts through an A3 receptor to prevent the induction of murine anti-CD3-activated killer T cells.

Adenosine, a purine nucleoside found at high levels in solid tumors, is able to suppress the recognition/adhesion and effector phases of killer lymphocyte-mediated tumor cell destruction. Here, we demonstrate that adenosine, at concentrations that are typically present in the extracellular fluid of solid tumors, exerts a profound inhibitory effect on the induction of mouse cytotoxic T cells, without substantially affecting T-cell viability. T-cell proliferation in response to mitogenic anti-CD3 antibody was impaired in the presence of 10 microM adenosine (plus coformycin to inhibit endogenous adenosine deaminase). Antigen-specific T-cell proliferation was similarly inhibited by adenosine. Anti-CD3-activated killer T (AK-T) cells induced in the presence of adenosine exhibited reduced major histocompatibility complex-unrestricted cytotoxicity against P815 mastocytoma cells in JAM and (51)Cr-release assays. Diminished tumoricidal activity correlated with reduced expression of mRNAs coding for granzyme B, perforin, Fas ligand and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), as well as with diminished Nalpha-CBZ-L-lysine thiobenzylester (BLT) esterase activity. Interleukin-2 and interferon-gamma synthesis by AK-T cells was also inhibited by adenosine. AK-T cells express mRNA coding for A(2A), A(2B) and A(3) receptors, but little or no mRNA coding for A(1) receptors. The inhibitory effect of adenosine on AK-T cell proliferation was blocked by an A(3) receptor antagonist (MRS1191) but not by an A(2) receptor antagonist (3,7-dimethyl-1-propargylxanthine [DMPX]). The A(3) receptor agonists (N(6)-2-(4-aminophenyl)ethyladenosine [APNEA] and N(6)-benzyl-5'-N-ethylcarboxamidoadenosine [N(6)-benzyl-NECA]) also inhibited AK-T cell proliferation. Adenosine, therefore, acts through an A(3) receptor to prevent AK-T cell induction. Tumor-associated adenosine may act through the same mechanism to impair the development of tumor-reactive T cells in cancer patients.