Intrahospital transport of critically ill patients: Nurse anaesthetists' and specialist ICU nurses' experiences.

BACKGROUND: Intrahospital transport (IHT) is often performed by nurse anaesthetists and specialist intensive care nurses. Studies have shown that IHT increases the risk of mortality and morbidity, with up to 71% negative incidents. Using checklists when preparing for an IHT is important. Several international guidelines exist to ensure IHT safety and reduce the risk of complications. However, existing guidelines are often problematic in clinical practice. AIM: This study aimed to describe the experiences of nurse anaesthetists and specialized intensive care nurses during the IHT of adult patients with critical illnesses. STUDY DESIGN: This study adopted a mixed-methods approach. METHODS: Data were collected through a questionnaire completed by 66 nurses with specialist education in anaesthesia or intensive care. The data were analysed with qualitative content analysis, and the quantitative data were analysed with descriptive statistics. RESULTS: Two categories with two subcategories each emerged from the analysis of the responses of nurse anaesthetists and specialist intensive care nurses regarding their IHT experiences: creating good circumstances (subcategories: being risk-conscious and the importance of meticulous preparations) and the importance of routines and education (subcategories: following guidelines and having adequate training). CONCLUSION: IHT was described as a high risk for patient safety and complications. Routines with good compliance and education can positively impact patient safety during IHT. Checklists and scenario training can better prepare nurse anaesthetists and specialist intensive care nurses to manage complications that may arise during IHT, resulting in safer patient care. RELEVANCE FOR CLINICAL PRACTICE: The findings underscore the importance of written guidelines for IHT, emphasizing awareness and adherence by the entire team. Careful pre-IHT preparations, coupled with an understanding of potential risks, are vital for ensuring patient safety. Clinical training and discussions following incidents during IHT play a crucial role in raising the collective awareness of patient safety within the entire team.

Struggling in the dehumanized world of COVID-An exploratory mixed-methods study of frontline healthcare workers' experiences.

AIM: To explore healthcare workers' experiences of the changed caring reality during the COVID-19 pandemic in Sweden. DESIGN: An online fully mixed-methods design. METHODS: A web-based self-reported questionnaire with fixed and open-ended answers collected data from March to April 2021, analysed in three steps. First, free-text questions were analysed by qualitative content analysis. Then quantitative linear regression analyses using models covering stress and coping mechanisms were conducted. Finally, a meta-inference of qualitative and quantitative data emerged a new comprehensive understanding. The COREQ guidelines were used for reporting. RESULTS: Meta-inferenced results of quantitative and qualitative findings show the pandemic was a traumatic experience for healthcare workers. Main theme; When work became a frightening experience in a dehumanized reality, comprised four themes: Entering unprepared into a frightful, incomprehensible world; Sacrificing moral values and harbouring dilemmas in isolation; Lack of clear management; and Reorient in togetherness and find meaning in a changed reality. Qualitative results comprised four categories; Working in a dehumanized world; Living in betrayal of ones' own conscience; Lack of structure in a chaotic time and Regaining vitality together. Subdimensions comprehensibility and meaningfulness were associated significantly with post-traumatic stress disorder in multiple regression analysis. In multiple regression analysis, sense of coherence was the most prominent coping strategy. CONCLUSIONS: Forcing oneself to perform beyond one's limit, sacrificing moral values and lacking management was a traumatic experience to healthcare workers during the pandemic. Reorienting as a way of coping was possible in togetherness with colleagues. There is an urgency of interventions to meet the needs among healthcare workers who took on a frontline role during the COVID-19 pandemic and to prevent mental health illness in future crisis. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. SUMMARY: The pandemic outbreak exposed frontline healthcare workers to unparallelled stress shown as negative for their mental health in several meta-analyses and systematic reviews. In-depth understanding on experiences and how symptoms of post-traumatic stress disorder relate to coping mechanisms have been scarcely explored. This study contributes to understanding on healthcare workers' experiences and the relation between lower sense of coherence and increased risk of developing symptoms of post-traumatic stress disorder. IMPLICATIONS FOR PRACTICE/POLICY: This study might guide how to prepare for resilience in future emergencies.

Intensive care nurses' experiences of caring for patients during the COVID-19 pandemic based on an analysis of blog posts.

BACKGROUND: In 2019, coronavirus disease 2019 (COVID-19) broke out worldwide, leading to a pandemic. Studies have shown that COVID-19 patients in intensive care units (ICUs) require more nursing care than other patients. ICU nurses who care for patients with COVID-19 have shown signs of psychological and physical strain. AIM: The aim of this study was to illuminate ICU nurses' experiences of caring for patients with COVID-19 in ICUs during the first wave of the pandemic. STUDY DESIGN: A qualitative, descriptive and inductive approach was used. A total of 70 blog posts from 13 bloggers in the United States, Great Britain, Finland and Sweden were analysed using qualitative inductive manifest content analysis. RESULTS: The results reveal an overall theme: 'An overturned existence under extreme conditions'. Furthermore, three categories-'the virus caused changes in work and private lives', 'unreasonable demands', and to hold on to caring ideals thanks to the support of others'-and seven subcategories were identified. CONCLUSIONS: Caring for patients with COVID-19 during the first wave of the pandemic was demanding because of a lack of knowledge about the disease and the severity of the illness. This led to ICU nurses experiencing extreme conditions that affected various aspects of their lives. Support from colleagues and teamwork were revealed to be particularly important for how nurses dealt with the demands of working during a pandemic, as was sufficient recovery time between work shifts. RELEVANCE TO CLINICAL PRACTICE: Work in ICUs was challenging and demanding, even before the pandemic. This study contributes to an understanding of the complex work environment that existed in hospitals during the first wave of the COVID-19 pandemic. The knowledge obtained from this study can be used to revise working conditions and identify health interventions for ICU nurses.

Caring through barriers-Newly graduated registered nurses' lived experiences in emergency departments during the COVID-19 pandemic.

AIM: To illuminate the meaning of newly graduated registered nurses' experiences of caring for patients in emergency departments during the COVID-19 pandemic. DESIGN: A phenomenological hermeneutical study guided by Lindseth and Norberg. METHODS: In-depth one-on-one interviews with 14 nurses from five hospitals were conducted from March to November 2020 and analysed using thematic analysis. The consolidated criteria for reporting qualitative research (COREQ) were used as the reporting guideline. RESULTS: The findings comprise one main theme Caring through barriers and three themes with sub-themes. In the first theme, having intention to care, participants revealed their dedication to care for patients during the pandemic despite extensive stress, little experience and skills. The second theme, with tied hands in human suffering, illuminates experiences of being disconnected from the patient, overwhelmed by responsibility and unable to relieve suffering. The third theme, feeling inadequate, reveals experiences of lack of support and doubts meaning less space to develop into the nurse one wants to be. CONCLUSION: Findings reveal a new understanding of new nurses' experiences during times of crisis. The essence of caring in the emergency department during the pandemic can be explained as mediated through spatial, temporal and emotional barriers preventing new nurses from providing holistic care. IMPACT: The results may be used as anticipatory guidance for new nurses and inform targeted support interventions to support new nurses entering the profession in crisis conditions. PUBLIC CONTRIBUTION: This study involved new nurses in semi-structured interviews.

Efficacy of topical lidocaine-prilocaine (EMLA®) for management of infant pain during pneumococcal vaccination: A randomized controlled trial.

Few studies have evaluated whether topical anesthetic cream reduces pain during pneumococcal vaccination. This is crucial, since effective pain management should be evidence-based. Previous studies have shown that topical lidocaine-prilocaine (EMLA®) reduces vaccination-related pain, measured using pain-rating instruments and observation of crying time. This intervention study aimed to compare the efficacy of topical lidocaine-prilocaine cream with that of the standard of care on the expression of pain during the first pneumococcal vaccination administered at age 3 months under the Swedish national vaccination program. A randomized controlled trial included 72 infants receiving their first pneumococcal vaccination (Prevenar 13®). The study showed that topical lidocaine-prilocaine before pneumococcal vaccination significantly reduced infants' expression of pain according to the Face, Legs, Activity, Cry, Consolability (FLACC) score (P = .006) and increased latency to cry (P = .001). There were no statistically significant differences in the total crying time (P = .146) between the groups. Topical lidocaine-prilocaine cream reduced pain expression and increased latency to cry in infants receiving their first pneumococcal vaccine. Systematic efforts are needed to successfully implement the use of topical anesthetic cream and other effective non-pharmacological pain-relieving strategies during infant vaccination procedures.

Battling extraordinary situations and conflicting emotions-A qualitative study of being a newly graduated Registered Nurse in the emergency department during the COVID-19 pandemic.

AIM: To describe newly graduated registered nurses' (NGRNs') experiences of encountering stress in emergency departments (EDs) during the COVID-19 pandemic. DESIGN: A qualitative descriptive study. METHODS: Data from 14 in-depth interviews with NGRNs working in an ED for 3-36 months after graduation was analysed by the means of qualitative content analysis as described by Graneheim and Lundman. Interviews were conducted from March to November 2020 covering the first two waves of the pandemic. RESULTS: Data revealed three categories and nine subcategories comprised in the theme Battling extraordinary situations and conflicting emotions. Empowered by acknowledging themselves as important caregivers during the pandemic NGRNs struggle against limitations and exert themselves beyond their known limit. External stressors due to work overload in combination with understaffing force NGRNs into the role of the experienced nurse prematurely and internal stressors derives from part taking in less qualitative care.

Paradoxes of person-centred care: A discussion paper.

Aim: Previous research has mainly focused on the advantages of PCC and less on its disadvantages. Hence, there is a need to further explore the recent research regarding PCC from both sides. Therefore, the aim of this paper is to elucidate the advantages and disadvantages of PCC. Design: Discussion paper. Methods: We searched relevant literature published January 2000-March 2018 in PubMed, Medline, CHINAL, Scopus and Web of Science. Results: The results showed that PCC can contribute to improved health and well-being, improved mutual interaction in relationships, improved cost-effectiveness and improved work environment, while the disadvantages can involve increased personal and financial costs, exclusion of certain groups, increased personal and financial costs, exclusion of staff's personhood and unfairness due to empathy. An analysis of the existing literature on PCC showed paradoxes, which call for further investigation.

Telephone nurses' use of a decision support system: An observational study.

Telephone nurses give advice and support and make assessments based on verbal communication only. Web-based decision support systems are often used to increase patient safety and make medically correct assessments. The aim of the present this study was to describe factors affecting the use of a decision support system and experiences with this system among telephone nurses in Swedish primary health care. Observations and semistructured interviews were conducted. Six registered nurses with at least 1 year of experience of telephone nursing participated. Field notes and interviews were analyzed by qualitative content analysis. The main findings of the present this study were factors that decrease the decision support system use or promote deviation from decision support system use, factors that are positive for decision support system use and the decision support system complicates the work. Underuse and deviations from decision support systems can be a safety risk, because decisions are based on too little information. Further research with observations of telephone nurses' use of decision support systems is needed to develop both telephone nursing and decision support systems.

Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden.

Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patient's TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.

"Same same or different?" A review of reviews of person-centered and patient-centered care.

OBJECTIVE: To provide a synthesis of already synthesized literature on person-centered care and patient-centered care in order to identify similarities and differences between the two concepts. METHODS: A synthesis of reviews was conducted to locate synthesized literature published between January 2000 and March 2017. A total of 21 articles deemed relevant to this overview were synthesized using a thematic analysis. RESULTS: The analysis resulted in nine themes present in person-centered as well as in patient-centered care: (1) empathy, (2), respect (3), engagement, (4), relationship, (5) communication, (6) shared decision-making, (7) holistic focus, (8), individualized focus, and (9) coordinated care. The analysis also revealed that the goal of person-centered care is a meaningful life while the goal of patient-centered care is a functional life. CONCLUSIONS: While there are a number of similarities between the two concepts, the goals for person-centered and patient-centered care differ. The similarities are at the surface and there are important differences when the concepts are regarded in light of their different goals. PRACTICE IMPLICATIONS: Clarification of the concepts may assist practitioners to develop the relevant aspects of care. Person-centered care broadens and extends the perspective of patient-centered care by considering the whole life of the patient.

Previous work experience and age do not affect final semester nursing student self-efficacy in communication skills.

BACKGROUND: With the continuing increase in the older population, being able to communicate with the elderly is one of the many important skills in caring for older people. Therefore, student nurses need support during education to be prepared with the necessary communication skills to meet these demands. OBJECTIVE: The aim of this study was to describe the development of communication skills during nursing education. DESIGN: A quantitative descriptive and comparative study. SETTINGS: The nursing programme at a university in an urban area of Sweden. PARTICIPANTS: Student nurses in the first and third year in a nursing programme in Sweden in 2015. METHODS: Data were collected with a self-efficacy questionnaire and analysed with descriptive and comparative statistics. RESULTS: The student nurses in the final semester had a higher self-rated ability to communicate with older people than students in the second semester of the education year. There was also a difference in self efficacy between students with or without former experience of health care work or work in care with older persons in the second semester. However, these differences were not seen in the final semester. The age of the students did not affect the self-efficacy rate in either semester. CONCLUSIONS: Student nurses in the present study scored themselves relatively highly, while student nurses in previous studies expressed a need for more communication skills training. Further studies with observations of student nurses' actual communicative skills in clinical and simulations settings are needed, to pinpoint weak spots and targets for such an education.

The care of and communication with older people from the perspective of student nurses. A mixed method study.

BACKGROUND: Undergraduate nurse education needs to prepare student nurses to meet the demands and to have the necessary communication skills for caring for an increasing older population. The challenges involve how best to support and empower student nurses to learn the communication skills needed to care for older people. OBJECTIVE: The aim of this study was to investigate student nurses' views on the care of and communication with older people. DESIGN: A descriptive study with a mixed-method approach was conducted. METHODS: Quantitative and qualitative data were collected from a questionnaire completed by third-year Swedish student nurses in 2015. RESULTS: The student nurses reported positive attitudes to the care of and communication with older people. The findings focus on the central aspects related to relationship building, techniques for communication and external prerequisites. CONCLUSIONS: Despite positive attitudes, student nurses had a limited view of communication with older people. Educators need to increase student nurses' capacity to communicate effectively with older people. Educational interventions to improve and evaluate the communication competency of nurses and student nurses are needed.

Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells.

Oligodendrocyte (OL) death may contribute to white matter pathology, a common cause of network dysfunction and persistent cognitive problems in patients with traumatic brain injury (TBI). Oligodendrocyte progenitor cells (OPCs) persist throughout the adult CNS and may replace dead OLs. OL death and OPCs were analyzed by immunohistochemistry of human brain tissue samples, surgically removed due to life-threatening contusions and/or focal brain swelling at 60.6 ± 75 hours (range 4-192 hours) postinjury in 10 severe TBI patients (age 51.7 ± 18.5 years). Control brain tissue was obtained postmortem from 5 age-matched patients without CNS disorders. TUNEL and CC1 co-labeling was used to analyze apoptotic OLs, which were increased in injured brain tissue (p < 0.05), without correlation with time from injury until surgery. The OPC markers Olig2, A2B5, NG2, and PDGFR-α were used. In contrast to the number of single-labeled Olig2, A2B5, NG2, and PDGFR-α-positive cells, numbers of Olig2 and A2B5 co-labeled cells were increased in TBI samples (p < 0.05); this was inversely correlated with time from injury to surgery (r = -0.8, p < 0.05). These results indicate that severe focal human TBI results in OL death and increases in OPCs postinjury, which may influence white matter function following TBI.

Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages.

BACKGROUND: Imatinib mesylate (Glivec®, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). AIM: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. METHODS AND RESULTS: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p<0.05), acetylated LDL (p<0.01), and copper-modified oxidized LDL (p<0.01), respectively. Gel-based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. CONCLUSION: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes.

In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia.

BACKGROUND: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. METHODS: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. RESULTS: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. CONCLUSIONS: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line.

OBJECTIVE: The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib]. MATERIALS AND METHODS: ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G, and 1582G>A were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity. RESULTS: Wild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C, and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity. CONCLUSION: These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C, and 1574T>G increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.

The neurological wake-up test does not alter cerebral energy metabolism and oxygenation in patients with severe traumatic brain injury.

BACKGROUND: The neurological wake-up test (NWT) is used to monitor the level of consciousness in patients with traumatic brain injury (TBI). However, it requires interruption of sedation and may elicit a stress response. We evaluated the effects of the NWT using cerebral microdialysis (MD), brain tissue oxygenation (PbtiO2), jugular venous oxygen saturation (SjvO2), and/or arterial-venous difference (AVD) for glucose, lactate, and oxygen in patients with severe TBI. METHODS: Seventeen intubated TBI patients (age 16-74 years) were sedated using continuous propofol infusion. All patients received intracranial pressure (ICP) and cerebral perfusion pressure (CPP) monitoring in addition to MD, PbtiO2 and/or SjvO2. Up to 10 days post-injury, ICP, CPP, PbtiO2 (51 NWTs), MD (49 NWTs), and/or SjvO2 (18 NWTs) levels during propofol sedation (baseline) and NWT were compared. MD was evaluated at a flow rate of 1.0 µL/min (28 NWTs) or the routine 0.3 µL/min rate (21 NWTs). RESULTS: The NWT increased ICP and CPP levels (p < 0.05). Compared to baseline, interstitial levels of glucose, lactate, pyruvate, glutamate, glycerol, and the lactate/pyruvate ratio were unaltered by the NWT. Pathological SjvO2 (<50 % or >71 %; n = 2 NWTs) and PbtiO2 (<10 mmHg; n = 3 NWTs) values were rare at baseline and did not change following NWT. Finally, the NWT did not alter the AVD of glucose, lactate, or oxygen. CONCLUSIONS: The NWT-induced stress response resulted in increased ICP and CPP levels although it did not negatively alter focal neurochemistry or cerebral oxygenation in TBI patients.

Monitoring and sedation differences in the management of severe head injury and subarachnoid hemorrhage among neurocritical care centers.

BACKGROUND: The emergence of specialized neurocritical care (NCC) centers has been associated with an improved survival of patients with severe traumatic brain injury or subarachnoid hemorrhage. However, there are no established guidelines on sedation strategy or the frequency of evaluating the level of consciousness using the neurological wake-up test (NWT) in sedated NCC patients. OBJECTIVES: The aim was to compare the (1) monitoring techniques, (2) sedation principles, and (3) the use of the NWT in patients with severe traumatic brain injury or subarachnoid hemorrhage in 16 NCC centers. METHOD: A systematic survey of all 16 centers providing NCC in Scandinavia was performed using a questionnaire regarding the routine primary choice of sedative and analgesic compounds, monitoring techniques, and the frequency of the NWT, sent to the director of each center during 1999, 2004, and 2009. RESULTS: The response rate was 100%. Except for one center in 1999, all included centers routinely used monitoring of intracranial and cerebral perfusion pressure. In contrast, newer monitoring techniques such as microdialysis, jugular bulb oximetry, and brain tissue oxygenation were infrequently used throughout the survey period. Approximately half of the NCC centers used propofol infusion as the primary sedative, whereas the remaining centers used midazolam infusion, and there was a marked variation in the choice of analgesia in each evaluated year. The NWT was never used in 50% of centers and ≥six times daily in one center from 1999 to 2009. Most differences among the NCC centers remained unchanged over the evaluated 10-year period. DISCUSSION: Although Scandinavian countries have similar healthcare systems, there were marked differences among the participating NCC centers in the choice of monitoring tools and sedatives and the routine use of the NWT. These differences likely reflect different clinical management traditions and a lack of evidence-based guidelines in routine NCC.

ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro.

Single-nucleotide polymorphisms (SNPs) in the gene coding for the efflux-transport protein ABCB1 (P-glycoprotein) are commonly inherited as haplotypes. ABCB1 SNPs and haplotypes have been suggested to influence the pharmacokinetics and therapeutic outcome of the tyrosine kinase inhibitor (TKI) imatinib, used for treatment of chronic myeloid leukemia (CML). However, no consensus has yet been reached with respect to the significance of variant ABCB1 in CML treatment. Functional studies of variant ABCB1 transport of imatinib as well as other TKIs might aid the interpretation of results from in vivo association studies, but are currently lacking. The aim of this study was to investigate the consequences of ABCB1 variant haplotypes for transport and efficacy of TKIs (imatinib, its major metabolite N-desmethyl imatinib [CGP74588], dasatinib, nilotinib, and bosutinib) in CML cells. Variant haplotypes - including the 61A>G, 1199G>A, 1236C>T, 1795G>A, 2677G>T/A, and 3435T>C SNPs - were constructed in ABCB1 complementary DNA and transduced to K562 cells using retroviral gene transfer. The ability of variant cells to express ABCB1 protein and protect against TKI cytotoxicity was investigated. It was found that dasatinib and the imatinib metabolite CGP74588 are effectively transported by ABCB1, while imatinib, nilotinib, and bosutinib are comparatively weaker ABCB1 substrates. None of the investigated haplotypes altered the protective effect of ABCB1 expression against TKI cytotoxicity. These findings imply that the ABCB1 haplotypes investigated here are not likely to influence TKI pharmacokinetics or therapeutic efficacy in vivo.

Structural characteristics determine the cause of the low enzyme activity of two thiopurine S-methyltransferase allelic variants: a biophysical characterization of TPMT*2 and TPMT*5.

The enzyme thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurine drugs used to treat acute lymphoblastic leukemia and inflammatory bowel disease. Thus far, at least 29 variants of the TPMT gene have been described, many of which encode proteins that have low enzyme activity and in some cases become more prone to aggregation and degradation. Here, the two naturally occurring variants, TPMT*2 (Ala80 → Pro) and TPMT*5 (Leu49 → Ser), were cloned and expressed in Escherichia coli. Far-UV circular dichroism spectroscopy showed that TPMT*2 was substantially destabilized whereas TPMT*5 showed much greater stability comparable to that of wild-type TPMT (TPMTwt). The extrinsic fluorescent molecule anilinonaphthalene sulfonate (ANS) was used to probe the tertiary structure during thermal denaturation. In contrast to TPMTwt, neither of the variants bound ANS to a large extent. To explore the morphology of the TPMT aggregates, we performed luminescent conjugated oligothiophene staining and showed fibril formation for TPMT*2 and TPMT*5. The differences in the flexibility of TPMTwt, TPMT*2, and TPMT*5 were evaluated in a limited proteolysis experiment to pinpoint stable regions. Even though there is only one amino acid difference between the analyzed TPMT variants, a clear disparity in the cleavage patterns was observed. TPMT*2 displays a protected region in the C-terminus, which differs from TPMTwt, whereas the protected regions in TPMT*5 are located mainly in the N-terminus close to the active site. In conclusion, this in vitro study, conducted to probe structural changes during unfolding of TPMT*2 and TPMT*5, demonstrates that the various causes of the low enzyme activity in vivo could be explained on a molecular level.