Curriculum mapping of accredited pharmacy programs in the United States.

INTRODUCTION: No current guidance exists to inform the content area credit hours for doctor of pharmacy (PharmD) programs in the United States (US). METHODS: Public websites were accessed for all Accreditation Council for Pharmacy Education (ACPE) accredited PharmD programs in the US to record the credit hours devoted to drug therapy, clinical skills, experiential learning, scholarship, social and administrative sciences, physiology/pathophysiology, pharmacogenomics, medicinal chemistry, pharmacology, pharmaceutics, and pharmacokinetics/pharmacodynamics in the didactic curricula. Due to the high prevalence of programs that integrate drug therapy, pharmacology, and medicinal chemistry into a single course, we subdivided programs based upon whether drug therapy courses were "integrated" or "non-integrated." A regression analyses was conducted to explore the relationship between each content area and North American Pharmacist Licensure Examination (NAPLEX) pass rates and residency match rates. RESULTS: Data were available for 140 accredited PharmD programs. Drug therapy had the highest credit hours in programs with both integrated and non-integrated drug therapy courses. Programs with integrated drug therapy courses had significantly more credit hours in experiential and scholarship and fewer credit hours in stand-alone courses for pathophysiology, medicinal chemistry, and pharmacology. Credit hours in content areas did not predict NAPLEX pass rate nor residency match success rate. CONCLUSIONS: This is the first comprehensive description of all ACPE accredited pharmacy schools with credit hours broken down by content areas. While content areas did not directly predict success criteria, these results may still be useful to describe curricular norms or inform the design of future pharmacy curricula.

Biotic Interactions and the Future of Fishes on Coral Reefs: The Importance of Trait-Based Approaches.

Biotic interactions govern the structure and function of coral reef ecosystems. As environmental conditions change, reef-associated fish populations can persist by tracking their preferred niche or adapting to new conditions. Biotic interactions will affect how these responses proceed and whether they are successful. Yet, our understanding of these effects is currently limited. Ecological and evolutionary theories make explicit predictions about the effects of biotic interactions, but many remain untested. Here, we argue that large-scale functional trait datasets enable us to investigate how biotic interactions have shaped the assembly of contemporary reef fish communities and the evolution of species within them, thus improving our ability to predict future changes. Importantly, the effects of biotic interactions on these processes have occurred simultaneously within dynamic environments. Functional traits provide a means to integrate the effects of both ecological and evolutionary processes, as well as a way to overcome some of the challenges of studying biotic interactions. Moreover, functional trait data can enhance predictive modeling of future reef fish distributions and evolvability. We hope that our vision for an integrative approach, focused on quantifying functionally relevant traits and how they mediate biotic interactions in different environmental contexts, will catalyze new research on the future of reef fishes in a changing environment.

Biosimilar Pegfilgrastim-cbqv Demonstrated Similar Immunogenicity to Pegfilgrastim in Healthy Subjects Across Three Randomized Clinical Studies.

INTRODUCTION: Biologic therapeutics can trigger immune responses in patients. As part of the totality of evidence that is required for regulatory approval of biosimilars, immunogenicity similarity must be assessed in the clinical programs. Pegfilgrastim-cbqv (UDENYCA®) is a pegfilgrastim biosimilar approved in the USA and European Union. This article demonstrates the similar immunogenicity of pegfilgrastim-cbqv compared with its reference product, pegfilgrastim (Neulasta®). METHODS: The immunogenicity of pegfilgrastim-cbqv was assessed in three clinical studies in healthy subjects (one specifically designed to evaluate immunogenicity similarity and two studies to assess pharmacokinetics and pharmacodynamics bioequivalence) using a tiered approach, in which plasma samples were tested for the presence of antidrug antibodies (ADAs) as well as ADA binding-specificity, titer and neutralizing activity. To assess the clinical impact of ADAs, pharmacokinetics, pharmacodynamics and safety profiles were compared between ADA-positive and -negative subjects. RESULTS: These studies demonstrated similar immunogenicity of pegfilgrastim-cbqv and pegfilgrastim. The small differences in ADA incidence between treatment groups observed in the immunogenicity study were driven by non-neutralizing, low-titer, polyethylene glycol (PEG)-reactive ADAs, which are commonly present in healthy subjects. No treatment-emergent neutralizing antibodies (NAbs) were detected in either treatment group, and there was no apparent impact of ADAs on pharmacokinetics, pharmacodynamics or safety. CONCLUSION: Pegfilgrastim-cbqv has similar immunogenicity to pegfilgrastim. The presented immunogenicity, pharmacokinetics, pharmacodynamics and safety data support the overall demonstration of no clinically meaningful differences between pegfilgrastim-cbqv and pegfilgrastim. CLINICAL TRIAL REGISTRATION: NCT02418104 (CHS-1701-04, April 2015), NCT02650973 (CHS-1701-05, February 2016) and NCT02385851 (CHS-1701-03, March 2015).

Anatomical basis of diverse jaw protrusion directionality in ponyfishes (Family Leiognathidae).

Protrusion of the oral jaws is a key morphological innovation that enhances feeding performance in fishes. The mechanisms of protrusion and the basis of variation in its magnitude are well studied, but little attention has been paid to the functional morphology of protrusion directionality, despite wide variation among teleost species from slightly dorsal to strongly ventral. Ponyfishes (Leiognathidae) comprise a group of 52 species that exhibit striking diversity in the directionality of jaw protrusion, providing a promising system for exploring its underlying basis in a single clade. We examined the anatomical basis of protrusion directionality by measuring eight traits associated with the size and positioning of oral jaw bones. Measurements were made on cleared and stained specimens of 20 ponyfish species, representing every major lineage within the family. Species fell into three nonoverlapping clusters with respect to directionality including dorsal, rostral, and ventral protruders. A key correlate of protrusion direction is the anterior-posterior position of the articular-quadrate jaw joint. As the joint position moves from a posterior to a more anterior location, the orientation of the relaxed mandible rotates from an almost horizontal resting position to an upright vertical posture. Abduction of the mandible from the horizontal position results in ventrally directed protrusion, while the more upright mandible rotates to a position that maintains dorsal orientation. The resting orientation of the premaxilla and maxilla, thus, vary consistently with protrusion direction. Mouth size, represented by length of the mandible and maxilla, is a second major axis of variation in ponyfishes that is independent of variation in protrusion directionality.

Do key innovations unlock diversification? A case-study on the morphological and ecological impact of pharyngognathy in acanthomorph fishes.

Key innovations may allow lineages access to new resources and facilitate the invasion of new adaptive zones, potentially influencing diversification patterns. Many studies have focused on the impact of key innovations on speciation rates, but far less is known about how they influence phenotypic rates and patterns of ecomorphological diversification. We use the repeated evolution of pharyngognathy within acanthomorph fishes, a commonly cited key innovation, as a case study to explore the predictions of key innovation theory. Specifically, we investigate whether transitions to pharyngognathy led to shifts in the rate of phenotypic evolution, as well as shifts and/or expansion in the occupation of morphological and dietary space, using a dataset of 8 morphological traits measured across 3,853 species of Acanthomorpha. Analyzing the 6 evolutionarily independent pharyngognathous clades together, we found no evidence to support pharyngognathy as a key innovation; however, comparisons between individual pharyngognathous lineages and their sister clades did reveal some consistent patterns. In morphospace, most pharyngognathous clades cluster in areas that correspond to deeper-bodied morphologies relative to their sister clades, whereas occupying greater areas in dietary space that reflects a more diversified diet. Additionally, both Cichlidae and Labridae exhibited higher univariate rates of phenotypic evolution compared with their closest relatives. However, few of these results were exceptional relative to our null models. Our results suggest that transitions to pharyngognathy may only be advantageous when combined with additional ecological or intrinsic factors, illustrating the importance of accounting for lineage-specific effects when testing key innovation hypotheses. Moreover, the challenges we experienced formulating informative comparisons, despite the ideal evolutionary scenario of multiple independent evolutionary origins of pharyngognathous clades, illustrates the complexities involved in quantifying the impact of key innovations. Given the issues of lineage specific effects and rate heterogeneity at macroevolutionary scales we observed, we suggest a reassessment of the expected impacts of key innovations may be warranted.

Pharmacokinetic and Pharmacodynamic Equivalence of Pegfilgrastim-cbqv and Pegfilgrastim in Healthy Subjects.

INTRODUCTION: Pegfilgrastim-cbqv was developed as a biosimilar of pegfilgrastim, a pegylated form of recombinant human granulocyte colony-stimulating factor approved for decreasing febrile neutropenia-associated infection in patients receiving myelosuppressive drugs. This multicenter, randomized, single-blind, partial-reference-replicated, three-sequence crossover study assessed pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv and pegfilgrastim in healthy subjects. METHODS: One hundred twenty-two subjects were randomized to one of three treatment sequences; each included one dose of pegfilgrastim-cbqv and two doses of pegfilgrastim separated by ≥ 28 days. The primary pharmacokinetic end points were area under the curve (AUC) from 0 to infinity (AUC0-∞) and maximum concentration (Cmax). The primary pharmacodynamic end points were maximum absolute neutrophil count (ANCmax) and ANC AUC from time 0 to the last measurable observation (ANC AUC0-last). Pharmacokinetic and pharmacodynamic bioequivalences were demonstrated if the 90% CI for the geometric mean ratio (GMR) of pegfilgrastim-cbqv to pegfilgrastim was within 80-125% for the primary end points. RESULTS: Pharmacokinetic bioequivalence criteria were met for Cmax (GMR 105.0; 90% CI 95.5-115.4) and AUC0-∞ (GMR 97.5; 90% CI 88.6-107.2). Pharmacodynamic bioequivalence criteria were met for ANCmax (GMR 99.6; 90% CI 96.2-103.2) and ANC AUC0-last (GMR 96.7; 90% CI 92.2-101.4). Adverse events occurred in 76.0%, 76.6%, and 73.1% of subjects for pegfilgrastim-cbqv, first pegfilgrastim, and second pegfilgrastim dosing periods across treatment sequences, respectively. Investigators found no drug-related serious adverse events. CONCLUSION: This study established pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv to pegfilgrastim. The treatments displayed similar safety profiles, including immunogenicity, with no unexpected safety findings. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov, NCT02650973, February 2016.

Correlated Evolution of Sex Allocation and Mating System in Wrasses and Parrotfishes.

In accordance with predictions of the size-advantage model, comparative evidence confirms that protogynous sex change is lost when mating behavior is characterized by weak size advantage. However, we lack comparative evidence supporting the adaptive significance of sex change. Specifically, it remains unclear whether increasing male size advantage induces transitions to protogynous sex change across species, as it can within species. We show that in wrasses and parrotfishes (Labridae) the evolution of protogynous sex change is correlated with polygynous mating and that the degree of male size advantage expressed by polygynous species influences transitions between different types of protogynous sex change. Phylogenetic reconstructions reveal strikingly similar patterns of sex allocation and mating system evolution with comparable lability. Despite the plasticity of sex-determination mechanisms in labrids, transitions trend toward monandry (all males derived from sex-changed females), with all observed losses of protogyny accounted for by shifts in the timing of sex change to prematuration. Likewise, transitions in mating system trend from the ancestral condition of lek-like polygyny toward greater male size advantage, characteristic of haremic polygyny. The results of our comparative analyses are among the first to confirm the adaptive significance of sex change as described by the size-advantage model.

The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis.

The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.

Colour pattern divergence in reef fish species is rapid and driven by both range overlap and symmetry.

Signal divergence is an important process underpinning the diversification of lineages. Research has shown that signal divergence is greatest in species pairs that possess high geographic range overlap. However, the influence of range-size differences within pairs is less understood. We investigated how these factors have shaped signal divergence within brightly coloured coral reef butterflyfishes (genus: Chaetodon). Using a novel digital imaging methodology, we quantified both colouration and pattern using 250 000 sample points on each fish image. Surprisingly, evolutionary age did not affect colour pattern dissimilarity between species pairs, with average differences arising in just 300 000 years. However, the effect of range overlap and range symmetry was significant. Species-pair colour patterns become more different with increasing overlap, but only when ranges are similar in size. When ranges differ markedly in area, species-pair colour patterns become more similar with increasing overlap. This suggests that species with small ranges may maintain non-colour-based species boundaries.

Evaluation of the Short-, Mid-, and Long-Term Effects of Tofacitinib on Lymphocytes in Patients With Rheumatoid Arthritis.

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Altered lymphocyte cell counts and a potential association with increased infection rates have been reported in RA patients treated with JAK inhibitors. This analysis was undertaken to evaluate the short-, mid-, and long-term effects of tofacitinib on lymphocytes and infection rates in patients with RA. METHODS: In this post hoc analysis, absolute lymphocyte counts (ALCs) were obtained from phase III studies (12-24 months; n = 717-958) and phase I/II/III/long-term extension studies of tofacitinib (≤117 months) (All RA population; n = 7,061); lymphocyte subset counts (LSCs) were from phase II studies (1.5-6 months' exposure; n = 236-486), an ORAL Sequel vaccine substudy (~22 months; n = 198), and an ORAL Sequel lymphocyte substudy (~50 months; n = 55-1,035) of tofacitinib. The reversibility of ALC/LSC changes was evaluated. The relationship of ALC and LSC to infections was analyzed in the All RA population. The value of monitoring ALC alone was assessed by examining correlations between ALCs and LSCs. RESULTS: Tofacitinib treatment resulted in an initial increase in ALC versus pretreatment baseline, which gradually declined to steady state by ~48 months. CD4+ and CD8+ T cell counts decreased over long-term treatment, and ALC and LSC changes were reversible upon treatment cessation. Patients with ALCs of <500 cells/mm3 had an increased risk of serious infections. There was no strong association between CD4+ T cell, CD8+ T cell, B cell, or natural killer cell counts and serious infection incidence rates. ALC and CD4+ or CD8+ T cell counts correlated well (R = 0.65-0.86). CONCLUSION: Our findings indicate that monitoring of ALC alone appears to be adequate to assess infection risk in tofacitinib-treated patients with RA.

Real-World Analysis of Dispensed International Units of Coagulation Factor VIII and Resultant Expenditures for Hemophilia A Patients: A Comparison Between Standard Half-Life and Extended Half-Life Products.

PURPOSE: To identify international units (IUs) dispensed and consequent expenditures for standard half-life (SHL) versus extended half-life (EHL) recombinant factor VIII (rFVIII) replacement products in hemophilia A patients in a real-world setting. DESIGN: Two U.S. claims databases were analyzed. METHODOLOGY: Number of IUs dispensed and quarterly expenditures for rFVIII products were collected from the Optum Clinformatics Data Mart and Truven Health MarketScan Databases. Truven claims were also analyzed for factor IUs dispensed and expenditures for patients with data for ≥3 months before and after switching to an EHL product. RESULTS: The Optum and Truven databases, respectively, included 276 (SHL, n=243; EHL, n=33) and 500 (SHL, n=409; EHL, n=91) hemophilia A patients. Median quarterly factor IUs dispensed in Optum were 10% higher with EHL versus SHL products over nine quarters, and 45% higher with EHL versus SHL products in Truven over 10 quarters. Median quarterly expenditures in the EHL cohort were 51% (individual quarterly medians range, 1%-101%) higher than in the SHL cohort in Optum and 122% higher (individual quarterly medians range, 1%-189%) in Truven. Twenty-nine Truven patients switched to an EHL product; median factor IUs dispensed varied quarterly. The lowest SHL and highest EHL values occurred in the quarter immediately before switching and the first quarter post-switch, respectively. Overall median quarterly expenditures were higher post-switch; this was consistent over seven quarters. CONCLUSION: We found higher expenditures over two years for hemophilia A patients using EHL versus SHL products. Switching to an EHL rFVIII product was associated with variable factor IUs dispensed and consistently higher expenditures.

Ecology shapes the evolutionary trade-off between predator avoidance and defence in coral reef butterflyfishes.

Antipredator defensive traits are thought to trade-off evolutionarily with traits that facilitate predator avoidance. However, complexity and scale have precluded tests of this prediction in many groups, including fishes. Using a macroevolutionary approach, we test this prediction in butterflyfishes, an iconic group of coral reef inhabitants with diverse social behaviours, foraging strategies and antipredator adaptations. We find that several antipredator traits have evolved adaptively, dependent primarily on foraging strategy. We identify a previously unrecognised axis of diversity in butterflyfishes where species with robust morphological defences have riskier foraging strategies and lack sociality, while species with reduced morphological defences feed in familiar territories, have adaptations for quick escapes and benefit from the vigilance provided by sociality. Furthermore, we find evidence for the constrained evolution of fin spines among species that graze solely on corals, highlighting the importance of corals, as both prey and structural refuge, in shaping fish morphology.

Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal.

Impact of Contextual Factors on Interventions to Reduce Acute Care Transfers II Implementation and Hospital Readmission Rates.

OBJECTIVES: Identify contextual and implementation factors impacting the effectiveness of an organizational-level intervention to reduce preventable hospital readmissions from affiliated skilled nursing facilities (SNFs). DESIGN: Observational study of the implementation of Interventions to Reduce Acute Care Transfers tools in 3 different cohorts. SETTING: SNFs. PARTICIPANTS: SNFs belonging to 1 of 2 corporate entities and a group of independent SNFs that volunteered to participate in a Quality Improvement Organization (QIO) training program. INTERVENTION: Two groups of SNFs received INTERACT II training and technical assistance from corporate staff, and 1 group of SNFs received training from QIO staff. MEASUREMENTS: Thirty-day acute care hospital readmissions from Medicare fee-for-service claims, contextual factors using the Model for Understanding Success in Quality framework. RESULTS: All 3 cohorts were able to deliver the INTERACT training program to their constituent facilities through regional events as well as onsite technical assistance, but the impact on readmission rates varied. Facilities supported by the QIO and corporation A were able to achieve statistically significant reductions in 30-day readmission rates. A review of contextual factors found that although all cohorts were challenged by staff turnover and workload, corporation B facilities struggled with a less mature quality improvement (QI) culture and infrastructure. CONCLUSIONS: Both corporations demonstrated a strong corporate commitment to implementing INTERACT II, but differences in training strategies, QI culture, capacity, and competing pressures may have impacted the effectiveness of the training. Proactively addressing these factors may help long-term care organizations interested in reducing acute care readmission rates increase the likelihood of QI success.

The Safety and Immunogenicity of Live Zoster Vaccination in Patients With Rheumatoid Arthritis Before Starting Tofacitinib: A Randomized Phase II Trial.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster, and vaccination is recommended for patients ages 50 years and older, prior to starting treatment with biologic agents or tofacitinib. Tofacitinib is an oral JAK inhibitor for the treatment of RA. We evaluated its effect on the immune response and safety of live zoster vaccine (LZV). METHODS: In this phase II, 14-week, placebo-controlled trial, patients ages 50 years and older who had active RA and were receiving background methotrexate were given LZV and randomized to receive tofacitinib 5 mg twice daily or placebo 2-3 weeks postvaccination. We measured humoral responses (varicella zoster virus [VZV]-specific IgG level as determined by glycoprotein enzyme-linked immunosorbent assay) and cell-mediated responses (VZV-specific T cell enumeration, as determined by enzyme-linked immunospot assay) at baseline and 2 weeks, 6 weeks, and 14 weeks postvaccination. End points included the geometric mean fold rise (GMFR) in VZV-specific IgG levels (primary end point) and T cells (number of spot-forming cells/106 peripheral blood mononuclear cells) at 6 weeks postvaccination. RESULTS: One hundred twelve patients were randomized to receive tofacitinib (n = 55) or placebo (n = 57). Six weeks postvaccination, the GMFR in VZV-specific IgG levels was 2.11 in the tofacitinib group and 1.74 in the placebo group, and the VZV-specific T cell GMFR was similar in the tofacitinib group and the placebo group (1.50 and 1.29, respectively). Serious adverse events occurred in 3 patients in the tofacitinib group (5.5%) and 0 patients (0.0%) in the placebo group. One patient, who lacked preexisting VZV immunity, developed cutaneous vaccine dissemination 2 days after starting tofacitinib (16 days postvaccination). This resolved after tofacitinib was discontinued and the patient received antiviral treatment. CONCLUSION: Patients who began treatment with tofacitinib 2-3 weeks after receiving LZV had VZV-specific humoral and cell-mediated immune responses to LZV similar to those in placebo-treated patients. Vaccination appeared to be safe in all of the patients except 1 patient who lacked preexisting VZV immunity.

The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by infiltration of immune cells into the affected synovium, release of inflammatory cytokines and degradative mediators, and subsequent joint damage. Both innate and adaptive arms of the immune response play a role, with activation of immune cells leading to dysregulated expression of inflammatory cytokines. Cytokines work within a complex regulatory network in RA, signalling through different intracellular kinase pathways to modulate recruitment, activation and function of immune cells and other leukocytes. As our understanding of RA has advanced, intracellular signalling pathways such as Janus kinase (JAK) pathways have emerged as key hubs in the cytokine network and, therefore, important as therapeutic targets. Tofacitinib is an oral JAK inhibitor for the treatment of RA. Tofacitinib is a targeted small molecule, and an innovative advance in RA therapy, which modulates cytokines critical to the progression of immune and inflammatory responses. Herein we describe the mechanism of action of tofacitinib and the impact of JAK inhibition on the immune and inflammatory responses in RA.

JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines.

The inflammatory diseases ulcerative colitis and Crohn's disease constitute the two main forms of inflammatory bowel disease (IBD). They are characterized by chronic, relapsing inflammation of the gastrointestinal tract, significantly impacting on patient quality of life and often requiring prolonged treatment. Existing therapies for IBD are not effective for all patients, and an unmet need exists for additional therapies to induce and maintain remission. Here we describe the mechanism of action of the Janus kinase (JAK) inhibitor, tofacitinib, for the treatment of IBD and the effect of JAK inhibition on the chronic cycle of inflammation that is characteristic of the disease. The pathogenesis of IBD involves a dysfunctional response from the innate and adaptive immune system, resulting in overexpression of multiple inflammatory cytokines, many of which signal through JAKs. Thus JAK inhibition allows multiple cytokine signaling pathways to be targeted and is expected to modulate the innate and adaptive immune response in IBD, thereby interrupting the cycle of inflammation. Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated as a targeted immunomodulator for IBD. Clinical development of tofacitinib and other JAK inhibitors is ongoing, with the aspiration of providing new treatment options for IBD that have the potential to deliver prolonged efficacy and clinically meaningful patient benefits.

The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis.

OBJECTIVE: To evaluate tofacitinib's effect upon pneumococcal and influenza vaccine immunogenicity. METHODS: We conducted two studies in patients with rheumatoid arthritis using the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and the 2011-2012 trivalent influenza vaccine. In study A, tofacitinib-naive patients were randomised to tofacitinib 10 mg twice daily or placebo, stratified by background methotrexate and vaccinated 4 weeks later. In study B, patients already receiving tofacitinib 10 mg twice daily (with or without methotrexate) were randomised into two groups: those continuing ('continuous') or interrupting ('withdrawn') tofacitinib for 2 weeks, and then vaccinated 1 week after randomisation. In both studies, titres were measured 35 days after vaccination. Primary endpoints were the proportion of patients achieving a satisfactory response to pneumococcus (twofold or more titre increase against six or more of 12 pneumococcal serotypes) and influenza (fourfold or more titre increase against two or more of three influenza antigens). RESULTS: In study A (N=200), fewer tofacitinib patients (45.1%) developed satisfactory pneumococcal responses versus placebo (68.4%), and pneumococcal titres were lower with tofacitinib (particularly with methotrexate). Similar proportions of tofacitinib-treated and placebo-treated patients developed satisfactory influenza responses (56.9% and 62.2%, respectively), although fewer tofacitinib patients (76.5%) developed protective influenza titres (≥1:40 in two or more of three antigens) versus placebo (91.8%). In study B (N=183), similar proportions of continuous and withdrawn patients had satisfactory responses to PPSV-23 (75.0% and 84.6%, respectively) and influenza (66.3% and 63.7%, respectively). CONCLUSIONS: Among patients starting tofacitinib, diminished responsiveness to PPSV-23, but not influenza, was observed, particularly in those taking concomitant methotrexate. Among existing tofacitinib users, temporary drug discontinuation had limited effect upon influenza or PPSV-23 vaccine responses. TRIAL REGISTRATION NUMBERS: NCT01359150, NCT00413699.

Using a Small Workgroup to Jump-start a Community-Wide Coalition to Reduce Preventable Hospital Readmissions.

Unplanned hospital readmissions are common and often preventable. A review of Medicare discharge data identified a geographical area with higher than expected readmission rates. The state Medicare quality improvement organization (QIO) used community organizing techniques to assess provider engagement and hypothesized that a small workgroup of high impact providers could address some root causes for preventable readmissions, achieve quick wins, and reinvigorate the broader community-wide coalition. Seven of the eight facilities targeted by the QIO actively engaged and began rapid cycle initiatives to improve the patient transfer process between providers. Monthly, 2-hr structured meetings were supplemented by additional ad hoc meetings convened by participants. Effectiveness of the intervention was measured by workgroup functioning, the implementation of multiple initiatives spread from the small workgroup to the broader provider coalition, and reductions in readmissions to the anchor hospital system from the participating skilled nursing facilities. The community impact of the workgroup initiative is shown by a decline in community readmission rates for Medicare beneficiaries.

The role of peripheral endemism in species diversification: evidence from the coral reef fish genus Anampses (Family: Labridae).

We examined how peripherally isolated endemic species may have contributed to the biodiversity of the Indo-Australian Archipelago biodiversity hotspot by reconstructing the evolutionary history of the wrasse genus Anampses. We identified three alternate models of diversification: the vicariance-based 'successive division' model, and the dispersal-based 'successive colonisation' and 'peripheral budding' models. The genus was well suited for this study given its relatively high proportion (42%) of endemic species, its reasonably low diversity (12 species), which permitted complete taxon sampling, and its widespread tropical Indo-Pacific distribution. Monophyly of the genus was strongly supported by three phylogenetic analyses: maximum parsimony, maximum likelihood, and Bayesian inference based on mitochondrial CO1 and 12S rRNA and nuclear S7 sequences. Estimates of species divergence times from fossil-calibrated Bayesian inference suggest that Anampses arose in the mid-Eocene and subsequently diversified throughout the Miocene. Evolutionary relationships within the genus, combined with limited spatial and temporal concordance among endemics, offer support for all three alternate models of diversification. Our findings emphasise the importance of peripherally isolated locations in creating and maintaining endemic species and their contribution to the biodiversity of the Indo-Australian Archipelago.