Factors influencing deprescribing in primary care for those towards the end of life: A qualitative interview study with patients and healthcare practitioners.

BACKGROUND: For people with limited lifetime expectancy, the benefit of many medications may be outweighed by their potential harms. Despite the relevance of reducing unnecessary medication use, deprescribing is poorly enacted in primary care practice. AIM: This study aims to describe factors, as identified by primary care professionals and patients, that influence deprescribing in the last phase of life. DESIGN: Semi-structured interviews were conducted and analysed using a thematic approach. SETTING/PARTICIPANTS: This study was performed in primary care settings, including general practices, hospices and community care teams in The Netherlands. Purposefully identified primary care professionals (general practitioners, pharmacists, nurses) and patients with limited lifetime expectancy due to advanced chronic illness or cancer and their caretakers were interviewed. RESULTS: Three themes emerged detailing factors influencing deprescribing in the last phase of life in primary care: (1) non-maleficence, the wish to avoid additional psychological or physical distress; (2) reactive care, the lack of priority and awareness of eligible patients; and (3) discontinuity of care within primary care and between primary care and specialty care. CONCLUSIONS: Deprescribing is an incremental process, complicated by the unpredictability of life expectancy and attitudes of patients and health care professionals that associate continued medication use with clinical stability. Opportunities to facilitate the deprescribing process and its acceptance include the routinely systematic identification of patients with limited life expectancy and potentially inappropriate medications, and normalisation of deprescribing as component of regular primary care, occurring for all patients and continuing into end-of-life care.

A meta-analysis on the role older adults with cancer favour in treatment decision making.

INTRODUCTION: In the complex setting of oncological treatment decision making, balancing professional guidance while respecting patient involvement can be a challenge. We set out to assess the role adults with cancer favour in treatment decision making (TDM), including differences across age groups and change over time. MATERIALS AND METHODS: A systematic search was performed in MEDLINE and Embase, for studies on role preference of (older) adults with cancer in oncological treatment decision making. A meta-analysis was conducted based on Control Preference Scale (CPS) data, a questionnaire on patient role preference in TDM. RESULTS: This meta-analysis includes 33 studies reporting CPS data comprising 17,197 adults with cancer. Mean age was 60.6 years old for studies that specified age (24 studies, 6155 patients). During the last decade, patients' role preference shifted towards significantly more active involvement in TDM (p = 0.006). No age-dependent subgroup differences have been identified; both younger and older adults, defined as, respectively, below and above 65 years old, favour active involvement in treatment decision making. DISCUSSION: Over time, adults with cancer have shifted towards more active role preference in treatment decision making. In current cancer care, a large majority prefers taking an active role, irrespective of age.

Inter-domain Cooperation in INCENP Promotes Aurora B Relocation from Centromeres to Microtubules.

The chromosomal passenger complex is essential for error-free chromosome segregation and proper execution of cytokinesis. To coordinate nuclear division with cytoplasmic division, its enzymatic subunit, Aurora B, relocalizes from centromeres in metaphase to the spindle midzone in anaphase. In budding yeast, this requires dephosphorylation of the microtubule-binding (MTB) domain of the INCENP analog Sli15. The mechanistic basis for this relocalization in metazoans is incompletely understood. We demonstrate that the putative coiled-coil domain within INCENP drives midzone localization of Aurora B via a direct, electrostatic interaction with microtubules. Furthermore, we provide evidence that the CPC multimerizes via INCENP's centromere-targeting domain (CEN box), which increases the MTB affinity of INCENP. In (pro)metaphase, the MTB affinity of INCENP is outcompeted by the affinity of its CEN box for centromeres, while at anaphase onset­when the histone mark H2AT120 is dephosphorylated­INCENP and Aurora B switch from centromere to microtubule localization.

Mps1 promotes rapid centromere accumulation of Aurora B.

Aurora B localization to mitotic centromeres, which is required for proper chromosome alignment during mitosis, relies on Haspin-dependent histone H3 phosphorylation and on Bub1-dependent histone H2A phosphorylation--which interacts with Borealin through a Shugoshin (Sgo) intermediate. We demonstrate that Mps1 stimulates the latter recruitment axis. Mps1 activity enhances H2A-T120ph and is critical for Sgo1 recruitment to centromeres, thereby promoting Aurora B centromere recruitment in early mitosis. Importantly, chromosome biorientation defects caused by Mps1 inhibition are improved by restoring Aurora B centromere recruitment. As Mps1 kinetochore localization reciprocally depends on Aurora B, we propose that this Aurora B-Mps1 recruitment circuitry cooperates with the Aurora B-Haspin feedback loop to ensure rapid centromere accumulation of Aurora B at the onset of mitosis.

Cell division control by the Chromosomal Passenger Complex.

The Chromosomal Passenger Complex (CPC) consisting of Aurora B kinase, INCENP, Survivin and Borealin, is essential for genomic stability by controlling multiple processes during both nuclear and cytoplasmic division. In mitosis it ensures accurate segregation of the duplicated chromosomes by regulating the mitotic checkpoint, destabilizing incorrectly attached spindle microtubules and by promoting the axial shortening of chromosomal arms in anaphase. During cytokinesis the CPC most likely prevents chromosome damage by imposing an abscission delay when a chromosome bridge connects the two daughter cells. Moreover, by controlling proper cytoplasmic division, the CPC averts tetraploidization. This review describes recent insights on how the CPC is capable of conducting its various functions in the dividing cell to ensure chromosomal stability.

A positive feedback loop involving Haspin and Aurora B promotes CPC accumulation at centromeres in mitosis.

Haspin phosphorylates histone H3 at Thr3 (H3T3ph) during mitosis [1, 2], providing a chromatin binding site for the chromosomal passenger complex (CPC) at centromeres to regulate chromosome segregation [3-5]. H3T3ph becomes increasingly focused at inner centromeres during prometaphase [1, 2], but little is known about how its level or location and the consequent chromosomal localization of the CPC are regulated. In addition, CPC binding to shugoshin proteins contributes to centromeric Aurora B localization [5, 6]. Recruitment of the shugoshins to centromeres requires the phosphorylation of histone H2A at Thr120 (H2AT120ph) by the kinetochore kinase Bub1 [7], but the molecular basis for the collaboration of this pathway with H3T3ph has been unclear. Here, we show that Aurora B phosphorylates Haspin to promote generation of H3T3ph and that Aurora B kinase activity is required for normal chromosomal localization of the CPC, indicating an intimate linkage between Aurora B and Haspin functions in mitosis. We propose that Aurora B activity triggers a CPC-Haspin-H3T3ph feedback loop that promotes generation of H3T3ph on chromatin. We also provide evidence that the Bub1-shugoshin-CPC pathway supplies a signal that boosts the CPC-Haspin-H3T3ph feedback loop specifically at centromeres to produce the well-known accumulation of the CPC in these regions.

Aurora B potentiates Mps1 activation to ensure rapid checkpoint establishment at the onset of mitosis.

The mitotic checkpoint prevents mitotic exit until all chromosomes are attached to spindle microtubules. Aurora B kinase indirectly invokes this checkpoint by destabilizing incorrect attachments; however, a more direct role remains controversial. In contrast, activity of the kinase Mps1 is indispensible for the mitotic checkpoint. Here we show that Aurora B and Hec1 are needed for efficient Mps1 recruitment to unattached kinetochores, allowing rapid Mps1 activation at the onset of mitosis. Live monitoring of cyclin B degradation reveals that this is essential to establish the mitotic checkpoint quickly at the start of mitosis. Delayed Mps1 activation and checkpoint establishment upon Aurora B inhibition or Hec1 depletion are rescued by tethering Mps1 to kinetochores, demonstrating that Mps1 recruitment is the primary role of Aurora B and Hec1 in mitotic checkpoint signalling. These data demonstrate a direct role for Aurora B in initiating the mitotic checkpoint rapidly at the onset of mitosis.