Impact of informational and relational continuity for people with palliative care needs: a mixed methods rapid review.

OBJECTIVE: To identify and synthesise existing literature exploring the impact of relational and informational continuity of care on preferred place of death, hospital admissions and satisfaction for palliative care patients in qualitative, quantitative and mixed methods literature. DESIGN: A mixed methods rapid review. METHODS: PUBMED, PsychINFO, CINAHL were searched from June 2008 to June 2018 in order to identify original peer reviewed, primary qualitative, quantitative or mixed methods research exploring the impact of continuity of care for people receiving palliative care. Synthesis methods as outlined by the Cochrane Qualitative and Implementation Methods Group were applied to qualitative studies while meta-analyses for quantitative data were planned. OUTCOMES: The impact of interventions designed to promote continuity of care for people receiving palliative care on the following outcomes was explored: achieving preferred place of death, satisfaction with care and avoidable hospital admissions. RESULTS: 18 eligible papers were identified (11 qualitative, 6 quantitative and 1 mixed methods papers). In all, 1951 patients and 190 family caregivers were recruited across included studies. Meta-analyses were not possible due to heterogeneity in outcome measures and tools used. Two studies described positive impact on facilitating preferred place of death. Four described a reduction in avoidable hospital admissions. No negative impacts of interventions designed to promote continuity were reported. Patient satisfaction was not assessed in quantitative studies. Participants described a significant impact on their experiences as a result of the lack of informational and relational continuity. CONCLUSIONS: This rapid review highlights the impact that continuity of care can have on the experiences of patients receiving palliative care. The evidence for the impact of continuity on place of death and hospital admissions is limited. Methods for enhancing, and recording continuity should be considered in the design and development of future healthcare interventions to support people receiving palliative care.

A two-state model for Ca2+/CaM-dependent protein kinase II (alphaCaMKII) in response to persistent Ca2+ stimulation in hippocampal neurons.

Persistent elevation of the intracellular free Ca(2+) concentration [Ca(2+)](i) is neurotoxic and therefore it is important to understand how it affects downstream components of the Ca(2+) signaling pathway. The response of calmodulin (CaM) and alphaCa(2+)/CaM-dependent protein kinase II (alphaCaMKII), to intracellular Ca(2+) overload in hippocampal neurons is studied by confocal imaging of fluorescently tagged proteins. Transient and persistent redistribution of CaM and alphaCaMKII together is seen from the cytosol to dendritic and somatic punctae. Typical persistent redistribution occurs following a lag of 138+/-(S.E.M.) 12 s and is complete at 460+/-(S.E.M.) 34 s (n=18), lack of Thr(286)-autophosphorylation of alphaCaMKII however promotes the formation of early transient punctae (peak at 40 s). In contrast, the T286D-mimick of phospho-Thr(286)-alphaCaMKII forms punctae with a delay >10 min, indicating that Thr(286)-autophosphorylation is antagonistic to CaMKII clustering. A two-state model is proposed in which phospho-Thr(286)-alphaCaMKII, formed immediately upon Ca(2+) stimulation, is primarily responsible for target interactions and memory functions of alphaCaMKII. However, a distinct clustering form denoted alphaCaMKII(c), generated upon persistent intracellular free Ca(2+) elevation, is deposited in the punctae which are made of self-interacting CaM/CaMKII complexes. Punctate deposition disables both the interactions and the activity of CaMKII.

Ca2+/calmodulin-dependent activation and inactivation mechanisms of alphaCaMKII and phospho-Thr286-alphaCaMKII.

Thr(286) autophosphorylation is important for the role of alphaCaMKII in learning and memory. Phospho-Thr(286)-alphaCaMKII has been described to have two types of activity: Ca(2+)-independent partial activity and Ca(2+)/calmodulin-activated full activity. We investigated the mechanism of switching between the two activities in order to relate them to the physiological functioning of alphaCaMKII. Using a fluorometric coupled enzyme assay and smooth muscle myosin light chain (MLC) as substrate, we found that (1) Ca(2+)-independent activity of phospho-Thr(286)-alphaCaMKII represents 5.0 (+/-3.7)% of the activity measured in the presence of optimal concentrations of Ca(2+) and calmodulin and (2) Ca(2+) in the presence of calmodulin activates the enzyme with a K(m) of 137 (+/-56) nM and a Hill coefficient n = 1.8 (+/-0.3). In contrast, unphosphorylated alphaCaMKII has a K(m) for Ca(2+) in the presence of calmodulin of 425 (+/-119) nM and a Hill coefficient n = 5.4 (+/-0.4). Thus, the activity of phospho-Thr(286)-alphaCaMKII is essentially Ca(2+)/calmodulin dependent with MLC as substrate. In physiological terms, our data suggest that alphaCaMKII is only activated in stimulated neurones whereas Ca(2+)/calmodulin activation of phospho-Thr(286)-alphaCaMKII can occur in resting cells (approximately 100 nM [Ca(2+)]). Stopped-flow experiments using Ca(2+)/TA-cal [Ca(2+)/2-chloro-(epsilon-amino-Lys(75))-[6-[4-(N,N-diethylamino)phenyl]-1,3,5-triazin-4-yl]calmodulin] showed that at 100 nM [Ca(2+)] partially Ca(2+)-saturated Ca(2+)/cal.phospho-Thr(286)-alphaCaMKII complexes existed. These are likely to account for the activity of the phospho-Thr(286)-alphaCaMKII enzyme at resting [Ca(2+)]. Ca(2+) dissociation measurements by a fluorescent Ca(2+) chelator revealed that the limiting Ca(2+) dissociation rate constants were 1.5 s(-1) from the Ca(2+)/cal.alphaCaMKII and 0.023 s(-1) from the Ca(2+)/cal.phospho-Thr(286)-alphaCaMKII complex, accounting for the differences in the Ca(2+) sensitivities of the Ca(2+)/cal.alphaCaMKII and Ca(2+)/cal.phospho-Thr(286)-alphaCaMKII enzymes.