Time and NP Practice: Naming,Claiming, and Explaining the Role of Nurse Practitioners

This is a new era in primary health care with models of care focused less on number of patients seen per hour to one grounded in both patient satisfaction and outcome-based care. Nurse practitioners (NPs) are well positioned to achieve high marks under such criteria provided they can make the case for what they actually do. Nursing’s profession-based philosophy of care underpins NP practice and contributes to good outcomes. Naming, claiming, and explaining the role of NPs are 3 actions steps that NPs are empowered to enact right now.     

Interactions between persons—Knowledge,decision making,and the co‐production of practice

There is now broad agreement that ideas like person‐centred care, patient expertise and shared decision‐making are no longer peripheral to health discourse, fine ideals or merely desirable additions to sound, scientific clinical practice. Rather, their incorporation into our thinking and planning of health and social care is essential if we are to respond adequately to the problems that confront us: they need to be seen not as “ethical add‐ons” but core components of any genuinely integrated, realistic and conceptually sound account of healthcare practice. This, the tenth philosophy thematic edition of the journal, presents papers conducting urgent research into the social context of scientific knowledge and the significance of viewing clinical knowledge not as something that “sits within the minds” of researchers and practitioners, but as a relational concept, the product of social interactions. It includes papers on the nature of reasoning and evidence, the on‐going problems of how to ‘integrate’ different forms of scientific knowledge with broader, humanistic understandings of reasoning and judgement, patient and community perspectives. Discussions of the epistemological contribution of patient perspectives to the nature of care, and the crucial and still under‐developed role of phenomenology in medical epistemology, are followed by a broad range of papers focussing on shared decision‐making, analysing its proper meaning, its role in policy, methods for realising it and its limitations in real‐world contexts.     

Providing Culturally Sensitive Palliative Care in the Desert—The Experience, the Need, the Challenges, and the Solution

The Bedouin population of the Negev region in Israel consists of 180,000 Muslims, half of whom live in six townships. The other half is dispersed in small temporary settlements (huts, tents) with no running water or electricity. Accessibility is quite difficult, with no paved roads or any form of motorized public transportation. For patients with advanced illnesses near the end of life, adequate palliative treatment is not available in their rural homestead. A mobile palliative care unit (MPCU) has been established, with the aims of delivering palliative care to terminal patients living in remote regions not easily accessible to the community health care teams and to provide palliative care consultation services to the local primary care teams. The mobile unit consists of a core team of a nurse, a social worker, a physician, and a Bedouin driver-interpreter/translator. The MPCU cares for about 30 patients at any given time, including four to six Bedouins living in rural homesteads, four to six Bedouins living in townships, and the remainder Jewish patients living in the surrounding settlements. One hundred patients were cared for and about 1800 home visits were conducted during the past year, including 15% by the whole mobile unit team, 15% by the physician alone, 25% by the nurse alone, and 25% by the unit's nurse together with the local primary clinic nurse. The average distance covered per home visit was around 70 km. Our experience in establishing a culturally sensitive MPCU can be a model to provide palliative care services in remote areas.     

Autoantibodies,autoimmune disease,and the birth of immune diagnostics

The appearance of autoantibody to DNA followed sequentially by the disappearance of anti-DNA and appearance of DNA antigen in a patient with systemic lupus erythematosus demonstrated that autoantibodies participate in immune complex–mediated pathogenesis. Continuing studies showed that autoantibodies are also useful biomarkers in clinical diagnosis and important reagents for elucidating the structure and function of intracellular proteins in cell biology. Recently, autoantibodies to tumor-associated antigens have been identified in cancer, and these findings have expanded the field of cancer immunodiagnostics.In 1964, a young man with systemic lupus erythematosus (SLE) presented at the hospital of Rockefeller University in New York City with an acute exacerbation of his illness. This was brought on by his falling asleep under a sunlamp. He had a generalized erythematous sunburn rash, joint pain, high fever, and markedly increased proteinuria (1). He was hospitalized, treated with large doses of prednisone, and, after several weeks, went into remission (Figure ​(Figure1A). Serum1A). Serum specimens had been obtained during his previous outpatient visits when his illness was relatively stable, and more specimens were collected during his hospitalization. These serial serum specimens were examined by double diffusion analysis in agarose for antibodies to DNA. The presence of antibodies was indicated by the appearance of immunoprecipitin lines (Figure ​(Figure1B).1B). Open in a separate windowFigure 1Identification of DNA antibodies in a patient with systemic lupus erythematosus.A patient with SLE experienced an acute exacerbation of illness with continuous daily fever of 40°C to 42°C for several weeks with increased proteinuria (A). Sequential serum samples showed the presence of autoantibody to DNA, which was replaced by circulating DNA antigen during the disease flare. (B) Immunodiffusion studies demonstrating that pre-flare serum samples from 2-14 and 2-19 contained antibody to DNA (i, upper set of wells). In the lower set of wells, the central well was filled with serum from 2-19 (ii, containing autoantibody to DNA). Precipitin reactions were observed between this serum and those of 4-18 and 4-26. Chemical studies confirmed the presence of DNA in the latter two samples. Absence of either antibody to DNA or DNA antigen was observed at 3-26, a period of transition from antibody excess to antigen excess. The time line in A shows a period of eight months in the patient’s history and is not calendar time. Adapted from ref. 1. Immunologists in the 1950s and early 1960s had shown in experimental animals that antigen-antibody complexes produced vasculitis, including glomerulonephritis (2, 3), and the search was on for evidence of this form of pathogenic mechanism in autoimmune diseases. In the case of the SLE patient, six serum samples, collected on different dates, were set up against a central well containing solubilized DNA. Serum samples obtained before the episode of sustained high fever (February 14 and 19, 1964 [2-14 and 2-19]) contained precipitating antibody to DNA, but the antibody could not be detected in sera collected during disease flare (4-18 and 4-26). When this same set of samples was reacted against the pre-flare serum (from 2-19) in the central well, those obtained during disease flare (4-18 and 4-26) demonstrated precipitin reactions against factors in the serum of 2-19 (Figure ​(Figure1B,1B, lower set of wells). It was shown in other experiments that the sera of 4-18 and 4-26 contained DNA antigen and that the precipitin lines were DNA–anti-DNA reactions and were capable of fixing complement. These observations confirmed the presence of immune complex disease in autoimmunity and that autoantibodies to cellular antigens recognized as non-self by the immune system were involved. The sequential presence of antibody, absence of detectable antigen or antibody in the 3-26 specimen, and appearance of antigen would be in line with the immunochemistry of antigen-antibody reactions in solution related to phases of antibody excess, antigen-antibody equivalence, and antigen excess, respectively. These studies were conducted while I was in the laboratory of Dr. Henry G. Kunkel (1916–1983) of Rockefeller University. The University Hospital was funded by a General Clinical Research Center grant from the NIH, and patients were often hospitalized for several weeks for extended immunological studies. For investigators, those were the halcyon days of clinical research.     

Hereditary osteopetrosis of the rabbit; X-ray,hematologic, and chemical observations

The results of x-ray, hematologic, and chemical studies on cases of hereditary osteopetrosis of the rabbit are described and the resemblance of the findings to those of the severe juvenile form of human osteopetrosis is pointed out. The outstanding feature of the x-ray examinations was the homogeneous dense appearance of the entire skeleton. This condition was present at birth. In older cases there was evidence of some differentiation of bone structure. The hematologic studies showed that the disease was characterized by the development of a macrocytic anemia, thrombocytopenia, and a moderate myeloid leucocytosis. Other abnormal findings included high reticulocyte and normoblast counts, anisocytosis and poikllocytosis, and degenerative changes of the neutrophiles and lymphocytes. The chemical studies showed very low serum calcium values; serum phosphorus values were low during the first 4 weeks of life but were somewhat higher than normal levels in older cases. The serum phosphatase values were elevated. The blood sugar content was generally low. The blood cholesterol values were generally high. The liver glycogen values were small especially in older cases and those for muscle glycogen were somewhat smaller than normal values.     

A Phase I,Randomized, Double‐Blind,Placebo‐Controlled,Single‐Dose and Multiple‐Rising‐Dose Study of the BTK Inhibitor TAK‐020 in Healthy Subjects

Bruton’s tyrosine kinase (BTK) is a target for treatment of hematologic malignancies and autoimmune diseases. TAK‐020 is a highly selective covalent BTK inhibitor that inhibits both B cell receptor and fragment crystallizable receptor signaling. We assessed the safety/tolerability and pharmacokinetics/pharmacodynamics (PDs) of TAK‐020 in healthy subjects. Each cohort of the single‐rising dose (n = 72; 9 cohorts) and the multiple‐rising dose (n = 48; 6 cohorts) portions of the study comprised six TAK‐020‐treated and two placebo‐treated, subjects aged 18–55 years (inclusive). The PD effects were assessed by measuring BTK occupancy and the inhibition of fragment crystallizable epsilon receptor 1 (FcεRI)‐mediated activation of basophils. Overall, treatment‐emergent adverse events (TEAEs) were similar to placebo; there were no serious TEAEs or no TEAEs leading to discontinuation. TAK‐020 was rapidly absorbed (median time to maximum plasma concentration (T_max) 45–60 minutes) with a half‐life of ~ 3–9 hours at doses ≥ 2.5 mg. TAK‐020 exposure was generally dose proportional for single doses ≤ 70 mg and after multiple doses of ≤ 60 mg once daily. Target occupancy was dose dependent, with doses ≥ 2.5 mg yielding maximum and sustained occupancy > 70% for > 96 hours. Single doses ≥ 4.4 mg reduced FcεRI‐mediated activation of basophils by > 80% and comparable inhibition was observed with daily dosing ≥3.75 mg for 9 days. Inhibition persisted for 24–72 hours postdose and the duration generally increased with dose. TAK‐020 was generally well‐tolerated in healthy subjects after single and multiple doses and demonstrated target engagement and pathway modulation. The PD effects outlasted drug exposures, as expected for covalent inhibition of BTK.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ First‐generation Bruton’s tyrosine kinase inhibitors (BTKis; e.g., ibrutinib and acalabrutinib) are effective therapeutics for hematologic malignancies (e.g., chronic lymphocytic leukemia and mantle cell lymphoma); however, treatment‐emergent adverse events that resulted from off‐target effects have restricted the application of these drugs to nonmalignant indications.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ A new generation of BTKis (TAK‐020, evobrutinib, etc.) with greater selectivity was developed with the hope that their safety and tolerability profiles would enable treatment of nonmalignant conditions.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ BTK saturation and inhibition by TAK‐020 was safe and well‐tolerated by healthy subjects, supporting additional investigation in nonmalignant conditions.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ These results indicate that the selective inhibition of BTK could be utilized to safely treat nonmalignant pathologies mediated by hematopoietic cells of the B and myeloid lineages.

TAK‐020 is an orally available, small‐molecule, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), the expression of which is restricted to B cells, neutrophils, basophils, monocytes, mast cells, and osteoclasts. ¹ , ² , ³ , ⁴ BTK plays a critical role in B cell receptor activation, which results in proliferation and phenotypic differentiation of immature B cells into antibody‐secreting cells and in Fc gamma and fragment crystallizable epsilon (Fcε) receptor signaling by mediating activation of immunoreceptor tyrosine‐based activation motifs in multiple cell types. ¹ , ² , ⁵ The complete absence of BTK activity is associated with primary immunodeficiency, X‐linked agammaglobulinemia, and no other dominant phenotype, ⁶ indicating that the effect of BTK inhibition could be well‐tolerated by patients.First‐generation BTK inhibitors (BTKis; e.g., ibrutinib and acalabrutinib) are effective therapeutics for hematologic malignancies, such as chronic lymphocytic leukemia and mantle cell lymphoma. Because of adverse reactions (e.g., atrial fibrillation and cytopenia), which are uncharacteristic of patients with X‐linked agammaglobulinemia and perceived to result from off‐target effects, BTKis have limited application to nonmalignant indications. Therefore, a new generation of BTKi (e.g., TAK‐020 and evobrutinib) is being developed on the therapeutic premise that greater selectivity for BTK would yield tolerability profiles that permitted the exploration of their use in nonmalignant indications. ⁷ , ⁸ A first‐in‐human, phase I, double‐blind, placebo‐controlled study demonstrated that evobrutinib was well‐tolerated, showed linear and time‐independent pharmacokinetics (PKs), and induced long‐lasting BTK inhibition in healthy subjects; studies were initiated for the treatment of rheumatoid arthritis, systemic lupus erythematosus, and relapsed‐remitting multiple sclerosis.TAK‐020 engages its target rapidly and remains covalently bound, even after plasma concentrations are undetectable, and is efficacious in a rat collagen‐induced arthritis model of autoimmune disease with a median effective dose of 0.31 mg/kg per day. At the human equivalent of the median effective dose (3 mg/day), it was predicted that therapeutic levels of > 90% BTK occupancy could be achieved in the peripheral blood for the majority of the dosing interval.In nonclinical studies, TAK‐020 (as an oral solution) was absorbed rapidly and extensively after oral administration, with peak plasma concentrations generally occurring within 2 hours postdose. The oral bioavailability of TAK‐020 in animals was low (13.2% in rats and 8.17% in dogs). Absorption could be modulated by P‐glycoprotein. Terminal disposition phase elimination half‐life (t_1/2z) of TAK‐020 after oral administration was 4.4 to 7.3 hours in rats and 3.8 to 6.7 hours in dogs.The nonclinical safety, tolerability, and pharmacodynamic (PD) profiles of TAK‐020 suggest that it may have the potential to address the unmet needs of patients suffering from autoantibody‐mediated diseases, such as myasthenia gravis and immune thrombocytopenia.ObjectivesThe objectives of this study were to characterize the safety and tolerability of TAK‐020 after single‐rising and multiple‐rising oral doses (SRD and MRD, respectively) in healthy subjects. The secondary objectives were to characterize the PKs and PDs of TAK‐020.