The epidemiology and prehospital care of motorcycle crashes in a sub-Saharan African urban center.

OBJECTIVE: Road traffic crashes (RTCs) are common among motorcyclists in Kigali, Rwanda. The Service d'Aide Medicale Urgente (SAMU), a prehospital ambulance service, responds to many of these crashes. We aimed to describe motorcycle-related RTCs managed by SAMU. METHODS: SAMU clinical data including demographic information, injury characteristics, and management details were analyzed descriptively for all motorcycle crashes occurring between December 2012 and July 2016. RESULTS: Every patient included in this study was injured. These patients all called the ambulance for their injuries after a motorcycle crash. There were 2,912 motorcycle-related RTCs over the study period, representing 26% of all patients managed by SAMU. The incidence of motorcycle crashes in Kigali was 258 crashes per 100,000 people over the 3.5-year study period. The average age was 30 years and 80% were males. The most common injuries were to the lower extremities (n = 958, 33%), head (n = 878, 30%), or upper extremities (n = 453, 16%). Injuries often resulted in fractures of extremities (n = 740, 25%) and external hemorrhage anywhere in the body (unspecified region; n = 660, 23%), yet few were severe based on the Kampala Trauma Score (n = 23, 2%) and Glasgow Coma Scale (n = 42, 1.5%). The most common interventions were provision of diclofenac (n = 1,526, 52.5%), peripheral intravenous (IV) access (n = 1,217, 42%), and administration of IV fluids (n = 1,048, 36%). CONCLUSION: Motorcycle-related RTCs represent a large burden of disease for patients treated by SAMU in Kigali, Rwanda. Young men are most at risk of injury, which imposes a financial strain on society. Though injuries occurred frequently, critical trauma cases from motorcycle crashes were uncommon. This may be a result of several initiatives in Rwanda to improve road safety.

Determinants of selection into buprenorphine/naloxone among people initiating opioid agonist treatment in British Columbia.

BACKGROUND: Studies assessing the comparative effectiveness of methadone versus buprenorphine/naloxone for opioid use disorder in real-world settings are rare - challenged by structural differences in delivery across settings and factors influencing treatment selection. We identified determinants of selection into buprenorphine/naloxone and quantified contributions of individual and provider-level covariates in a setting delivering both medications within the same healthcare settings. METHODS: Utilizing linked health administrative datasets, we conducted a retrospective cohort study of people with opioid use disorder (PWOUD) receiving opioid agonist treatment (OAT) in British Columbia, Canada, from 2008-2017. Determinants of buprenorphine/naloxone selection were identified using a generalized linear mixed model with random intercept terms for providers and individuals. We determined the influence of individual demographics, clinical history, measures of provider experience and preference, and dates of key policy changes. RESULTS: A total of 39,605 individuals experienced 178,976 OAT episodes (methadone:139,439(77.9 %);buprenorphine/naloxone:39,537(22.1 %)). Male sex, less OAT experience, younger age, mental health conditions and chronic pain were associated with higher odds of buprenorphine/naloxone prescription. For providers, higher client-attachment, more complex OAT case-mixes, and higher buprenorphine/naloxone prescribing-preference were also associated with higher odds of buprenorphine/naloxone prescription. Observed individual-level covariates explained 9.7 % of variance in odds of buprenorphine/naloxone selection, while observed provider-level covariates explained 20.0 %. Controlling for covariates, residual unmeasured between-individual variance accounted for 18.5 % of the explained variation in the odds of buprenorphine/naloxone selection, while unmeasured between-provider variance accounted for 28.4 %. CONCLUSION: Provider characteristics were more influential in selection of buprenorphine/naloxone over methadone informing subsequent analyses of comparative effectiveness of these regimens.

Pain self-management training increases self-efficacy, self-management behaviours and pain and depression outcomes.

BACKGROUND: Self-management practices among patients with medical and psychiatric comorbidity is not well understood. We assessed the effects of a combined pharmacological and behavioural intervention on self-efficacy to manage symptoms and self-management behaviours in patients with pain and comorbid depression. METHODS: Longitudinal analysis of self-management behaviours and their relationship with outcomes in a 12-month trial of 250 primary care patients with chronic musculoskeletal pain and comorbid depression. Participants were randomized to either usual care or an intervention that consisted of optimized antidepressant therapy followed by six sessions of a pain self-management (PSM) programme. RESULTS: Participants in the intervention group significantly increased the time spent performing self-management behaviours including strengthening and stretching exercises, progressive muscle relaxation and visualization at 12 months. Moreover, intervention participants reported greater self-efficacy to manage their pain and depression. The number of pain self-management sessions received showed a dose-response relationship with improvement in both pain and depression severity. CONCLUSION: A combined intervention increased patient self-management behaviours and self-efficacy to manage symptoms among primary care patients with chronic musculoskeletal pain and depression. Receipt of the full dose of the entire PSM programme was related to improvements in pain interference and depression severity. WHAT DOES THIS STUDY ADD?: A nurse-led six-session PSM programme increased self-efficacy as well as specific behaviours such as strengthening and stretching exercises, progressive muscle relaxation and visualization. There was a dose-response in that attending a greater proportion of the PSM sessions led to greater improvement in both pain and depression outcomes.

The 'Expanded HIV care in opioid substitution treatment' (EHOST) cluster-randomized, stepped-wedge trial: A study protocol.

The public health response to HIV/AIDS has turned its focus onto optimizing health care system delivery to maximize case identification, access and sustained engagement in antiretroviral treatment (ART). Opioid Agonist Treatment (OAT) provides a critical opportunity for HIV testing and linkage to ART. The EHOST study is a cluster-randomized, stepped-wedge trial to evaluate a prescriber-focused intervention to increase HIV testing rates, and optimize ART engagement and retention outcomes among individuals engaged in OAT. The study will encompass all drug treatment clinics currently admitting patients for the treatment of opioid use disorder across the province of British Columbia, encompassing an estimated 90% of the OAT caseload. The trial will be executed over a 24-month period, with groups of clinics receiving the intervention in 6-month intervals. Evaluation of the proposed intervention's effectiveness will focus on three primary outcomes: (i) the HIV testing rate among those not known to be HIV positive; (ii) the rate of ART initiation among those not on ART; and (iii) the rate of ART continuation among those on ART. A difference-in-differences analytical framework will be applied to estimate the intervention's effect. This approach will assess site-specific changes in primary outcomes across clusters while adjusting for potential residual heterogeneity in patient case mix, volume, and quality of care across clinics. Statistical analysis of outcomes will be conducted entirely with linked population-level administrative health datasets. Facilitated by established collaborations between key stakeholders across the province, the EHOST intervention promises to optimize HIV testing and care within a marginalized and hard-to-reach population.

Trends in prevalent and incident opioid receipt: an observational study in Veterans Health Administration 2004-2012.

BACKGROUND: Improved understanding of temporal and regional trends may support safe and effective prescribing of opioids. OBJECTIVE: We describe national, regional, and facility-level trends and variations in opioid receipt between fiscal years (FY) 2004 and 2012. DESIGN: Observational cohort study using Veterans Health Administration (VHA) administrative databases. PARTICIPANTS: All patients receiving primary care within 137 VHA healthcare systems during a given study year and receiving medications from VHA one year before and during a given study year. MAIN MEASURES: Prevalent and incident opioid receipt during each year of the study period. KEY RESULTS: The overall prevalence of opioid receipt increased from 18.9% of all veteran outpatients in FY2004 to 33.4% in FY2012, a 76.7% relative increase. In FY2012, women had higher rates of prevalent opioid receipt than men (42.4% vs. 32.9%), and the youngest veterans (18-34 years) had higher prevalent opioid receipt compared to the oldest veterans (≥ 80 years) (47.6% vs. 17.9%). All regions in the United States saw increased rates of prevalent opioid receipt during this time period. Prevalence rates varied widely by facility: in FY2012, the lowest-prescribing facility had a rate of 13.5%, and the highest of 50.8%. Annual incident opioid receipt increased from 8.8% in FY2004 to 10.2% in FY2011, with a decline to 9.8% in FY2012. Incident prescribing increased at some facilities and decreased at others. Facilities with high prevalent prescribing tended to have flat or decreasing incident prescribing rates during the study time frame. CONCLUSIONS: Rates of opioid receipt increased throughout the study time frame, with wide variation in prevalent and incident rates across geographical region, sex, and age groups. Prevalence and incidence rates reflect distinct prescribing practices. Areas with the highest prevalence tended to have lower increases in incident opioid receipt over the study period. This likely reflects facility-level variations in prescribing practices as well as baseline rates of prevalent use. Future work assessing opioid prescribing should employ methodologies to account for and interpret both prevalent and incident opioid receipt.

Cost-effectiveness analysis along the continuum of HIV care: how can we optimize the effect of HIV treatment as prevention programs?

The cascade of HIV care has been proposed as a useful tool to monitor health system performance across the key stages of HIV care delivery to reduce morbidity, mortality, and HIV transmission, the focal points of HIV Treatment as Prevention campaigns. Interventions to improve the cascade at its various stages may vary substantially in their ability to deliver health value per amount expended. In order to meet global antiretroviral treatment access targets, there is an urgent need to maximize the value of health spending by prioritizing cost-effective interventions. We executed a literature review on economic evaluations of interventions to improve specific stages of the cascade of HIV care. In total, 33 articles met the criteria for inclusion in the review, 22 (67 %) of which were published within the last 5 years. Nonetheless, substantial gaps in our knowledge remain, particularly for interventions to improve linkage and retention in HIV care in developed and developing-world settings and generalized and concentrated epidemics. We make the case here that the attention of scientists and policymakers needs to turn to the development, implementation, and rigorous evaluation of interventions to improve the various stages of the cascade of HIV care.

Communicating about opioids for chronic pain: a qualitative study of patient attributions and the influence of the patient-physician relationship.

BACKGROUND: Chronic pain poses numerous challenges for patients and providers, particularly when opioid treatment is discussed. Despite accounts of antagonistic patient-provider communication, little is known about how communication about opioids unfolds during clinic visits and, importantly, how the relationship history of a patient and physician shapes this communication. This study's objective was to advance understanding of communication about opioid treatment by recording primary care clinic visits and conducting in-depth interviews with patients to gain insight into the patient­provider relationship and its influence on clinical communication. METHOD: Forty patients with chronic pain were audio recorded during their primary care clinic appointments and then interviewed about their pain care and relationships with their providers. Ten patients were excluded from analysis because pain was not discussed during the clinic visit. RESULTS: Qualitative analysis revealed that patients responded in markedly different ways to similar physician treatment decisions about opioids. Some patients attributed limiting or denying opioids to physicians' distrust or lack of caring. Others attributed these limitations to acting out of genuine concern for patients' health. These attributions appeared to be shaped by features of the patient­physician relationship as described by patients. Results are discussed within the framework of attribution theory. CONCLUSIONS: Understanding how patients and providers discuss opioid treatment is critical for optimal pain treatment. Physicians might be able to improve communication by re-framing treatment discussions about opioids around external factors, such as benefits and harms, and engaging in communication that fosters a strong therapeutic alliance and emphasizes concern for the patient.

The spectrum of clinical manifestations, outcome and treatment of pericardial tamponade in patients with systemic lupus erythematosus: a retrospective study and literature review.

Pericardial effusions causing pericardial tamponade are rare in patients with systemic lupus erythematosus (SLE). The goal of this study is to describe in detail the clinical and laboratory characteristics of a group of patients with pericardial effusions and pericardial tamponade secondary to SLE. We retrospectively reviewed the records of 71 patients with SLE, admitted to our Hospital between 1985 and 2006 with a diagnosis of pericarditis, pericardial effusion and tamponade. Clinical features in the patients with tamponade were compared with those with pericardial effusions without tamponade. Pericardial effusion and SLE was confirmed in 41 patients. Pericardial tamponade occurred in nine of these patients (21.9%) at the time of presentation. All tamponade patients were women. Patients with pericardial effusions who developed tamponade had a statistically significant (P = 0.05) lower C4 level as compared with patients who did not develop tamponade. A pericardial window was required in five patients even though the patients were receiving high-dose corticosteroids. In the present series, all patients with tamponade were treated with high-dose corticosteroids though five of nine patients required a pericardial window in contrast to previous studies. A low C4 level at presentation was predictive of the development of tamponade physiology.

Both phosphorylation and caspase-mediated cleavage contribute to regulation of the Ste20-like protein kinase Mst1 during CD95/Fas-induced apoptosis.

The serine/threonine kinase Mst1, a mammalian homolog of the budding yeast Ste20 kinase, is cleaved by caspase-mediated proteolysis in response to apoptotic stimuli such as ligation of CD95/Fas or treatment with staurosporine. Furthermore, overexpression of Mst1 induces morphological changes characteristic of apoptosis in human B lymphoma cells. Mst1 may therefore represent an important target for caspases during cell death which serves to amplify the apoptotic response. Here we report that Mst1 has two caspase cleavage sites, and we present evidence indicating that cleavage may occur in an ordered fashion and be mediated by distinct caspases. We also show that caspase-mediated cleavage alone is insufficient to activate Mst1, suggesting that full activation of Mst1 during apoptosis requires both phosphorylation and proteolysis. Another role of phosphorylation may be to influence the susceptibility of Mst1 to proteolysis. Autophosphorylation of Mst1 on a serine residue close to one of the caspase sites inhibited caspase-mediated cleavage in vitro. Finally, Mst1 appears to function upstream of the protein kinase MEKK1 in the SAPK pathway. In conclusion, Mst1 activity is regulated by both phosphorylation and proteolysis, suggesting that protein kinase and caspase pathways work in concert to regulate cell death.

Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes.

Although many effects of leptin are mediated through the central nervous system, leptin can regulate metabolism through a direct action on peripheral tissues, such as fat and liver. We show here that leptin, at physiological concentrations, acts through an intracellular signaling pathway similar to that activated by insulin in isolated primary rat hepatocytes. This pathway involves stimulation of phosphatidylinositol 3-kinase (PI3K) binding to insulin receptor substrate-1 and insulin receptor substrate-2, activation of PI3K and protein kinase B (AKT), and PI3K-dependent activation of cyclic nucleotide phosphodiesterase 3B, a cAMP-degrading enzyme. One important function of this signaling pathway is to reduce levels of cAMP, because leptin-mediated activation of both protein kinase B and phosphodiesterase 3B is most marked following elevation of cAMP by glucagon, and because leptin suppresses glucagon-induced cAMP elevation in a PI3K-dependent manner. There is little or no expression of the long form leptin receptor in primary rat hepatocytes, and these signaling events are probably mediated through the short forms of the leptin receptor. Thus, leptin, like insulin, induces an intracellular signaling pathway in hepatocytes that culminates in cAMP degradation and an antagonism of the actions of glucagon.

Expression of the casein kinase 2 subunits in Chinese hamster ovary and 3T3 L1 cells provides information on the role of the enzyme in cell proliferation and the cell cycle.

In order to investigate the in vivo functions of protein kinase CK2 (CK2), the expression of Myc-tagged versions of the subunits, Myc-CK2alpha and Myc-CK2beta, was carried out in Chinese hamster ovary cells (CHO cells) and in 3T3 L1 fibroblasts. Cell proliferation in these cells was examined. CHO cells that transiently overexpressed the Myc-CK2beta subunit exhibited a severe growth defect, as shown by a much lower value of [(3)H]thymidine incorporation than the vector controls, and a rounded shrunken morphology. In contrast, cells overexpressing Myc-tagged CK2alpha showed a slightly but consistently higher value of [(3)H]thymidine incorporation than the controls. The defect in cell growth and changes in morphology caused by Myc-CK2beta overexpression were partially rescued by coexpression of Myc-tagged CK2alpha. In parallel to the studies in CHO cells, the stable transfection of Myc-CK2alpha and Myc-CK2beta subunits was achieved in 3T3 L1 fibroblast cells. Similarly, the ectopic expression of Myc-CK2beta, but not Myc-CK2alpha, caused a growth defect. By measuring [(3)H]thymidine incorporation, it was found that expression of Myc-CK2beta prolonged the G(1) phase and inhibited up-regulation of cyclin D1 expression during G(1). In addition, a lower mitotic index and lower mitotic cyclin-dependent kinase activities were detected in Myc-CK2beta-expressing cells. Detailed analysis of stable cells that were synchronously released into the cell cycle revealed that the expression of Myc-CK2beta inhibited cells entering into mitosis and prevented the activation of mitotic cyclin-dependent kinases. Taken together, results from both transient and stable expression of CK2 subunits strongly suggest that CK2 may be involved in the control of cell growth and progression of the cell cycle.

Mitogen-activated protein kinase kinase activity is required for the G(2)/M transition of the cell cycle in mammalian fibroblasts.

The mitogen-activated protein kinase (MAPK) cascade is required for mitogenesis in somatic mammalian cells and is activated by a wide variety of oncogenic stimuli. Specific roles for this signaling module in growth were dissected by inhibiting MAPK kinase 1 (MAPKK1) activity in highly synchronized NIH 3T3 cells. In addition to the known role of this kinase in cell-cycle entry from G(0), the level of MAPKK activity was observed to affect the kinetics of progression through both the G(1) and G(2) phases of the cell cycle in NIH 3T3 cells. Ectopic expression of dominant-negative forms of MAPKK1, which was previously shown to inhibit G(0)/G(1) progression, was found to also delay progression of cells through G(2). In addition, treatment of cells with the specific MAPKK inhibitor PD 98059 during a synchronous S phase arrested the cells in the following G(2) phase. These data demonstrate a novel role for the MAPK cascade in progression from G(2) into mitosis in NIH 3T3 cells.

Protein phosphorylation and signal transduction.

It is now generally accepted that protein phosphorylation-dephosphorylation has a role in the regulation of essentially all cellular functions. Thus, it is of interest that this process is involved in signal transduction. Nonetheless, the extent to which protein phosphorylation participates in signaling is truly remarkable. Almost every known signaling pathway eventually impinges on a protein kinase, or in some instances, a protein phosphatase. The diversity of these enzymes is noteworthy, and it is of interest that many biotechnology companies are eyeing them as potentially important targets for drugs. Such drugs may have important therapeutic applications, and in any event, they certainly will be useful to investigators who study signal transduction. Indeed, this already has been proven to be true.

Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice.

Although the precise mechanisms contributing to insulin resistance and type 2 diabetes are unknown, it is believed that defects in downstream components of the insulin signaling pathway may be involved. In this work, we hypothesize that a serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), may be pertinent in this regard. To test this hypothesis, we examined GSK-3 activity in two inbred mouse strains known to be susceptible (C57BL/6J) or resistant (A/J) to diet-induced obesity and diabetes. Examination of GSK-3 in fat, liver, and muscle tissues of C57BL/6J mice revealed that GSK-3 activity increased twofold in the epididymal fat tissue and remained unchanged in muscle and liver of mice fed a high-fat diet, compared with their low-fat diet-fed counterparts. In contrast, GSK-3 activity did not change in the epididymal fat tissue of A/J mice, regardless of the type of diet they were fed. In addition, both basal and diet-induced GSK-3 activity was higher (2.3- and 3.2-fold, respectively) in the adipose tissue of C57BL/6J mice compared with that in A/J mice. Taken together, our studies suggest an unsuspected link between increased GSK-3 activity and development of insulin resistance and type 2 diabetes in fat tissue of C57BL/6J mice, and implicate GSK-3 as a potential factor contributing to susceptibility of C57BL/6J mice to diet-induced diabetes.

p90(RSK) is a serum-stimulated Na+/H+ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of Na+/H+ exchanger isoform-1.

The Na+/H+ exchanger isoform-1 (NHE-1) is the key member of a family of exchangers that regulates intracellular pH and cell volume. Activation of NHE-1 by growth factors is rapid, correlates with increased NHE-1 phosphorylation and cell alkalinization, and plays a role in cell cycle progression. By two-dimensional tryptic peptide mapping of immunoprecipitated NHE-1, we identify serine 703 as the major serum-stimulated amino acid. Mutation of serine 703 to alanine had no effect on acid-stimulated Na+/H+ exchange but completely prevented the growth factor-mediated increase in NHE-1 affinity for H+. In addition, we show that p90 ribosomal S6 kinase (p90(RSK)) is a key NHE-1 kinase since p90(RSK) phosphorylates NHE-1 serine 703 stoichiometrically in vitro, and transfection with kinase-inactive p90(RSK) inhibits serum-induced phosphorylation of NHE-1 serine 703 in transfected 293 cells. These findings establish p90(RSK) as a serum-stimulated NHE-1 kinase and a mediator of increased Na+/H+ exchange in vivo.

Crosstalk between protein kinase A and growth factor receptor signaling pathways in arterial smooth muscle.

Crosstalk between the cyclic AMP-dependent protein kinase (PKA) and growth factor receptor signaling is one of many emerging concepts of crosstalk in signal transduction. Understanding of PKA crosstalk may have important implications for studies of crosstalk between other, less well known, signaling pathways. This review focuses on PKA crosstalk in arterial smooth muscle. Proliferation and migration of arterial smooth muscle cells (SMCs) contribute to the thickening of the blood vessel wall that occurs in many types of cardiovascular disease. PKA potently inhibits SMC proliferation by antagonizing the major mitogenic signaling pathways induced by growth factors in SMCs. PKA also inhibits growth factor-induced SMC migration. An intricate crosstalk between PKA and the mitogen-activated protein kinase (MAPK/ERK) pathway, the p70 S6 kinase pathway and cyclin-dependent kinases has been described. Further, PKA regulates expression of growth regulatory molecules. The result of PKA activation in SMCs is the potent inhibition of cell cycle traverse and SMC migration. In this review, we discuss recent advances in our understanding of the crosstalk between PKA and signaling pathways induced by growth factor receptors in SMCs, and where relevant, in other cell types in which interesting examples of PKA crosstalk have been described.

CK2, a protein kinase of the next millennium.

Protein kinase CK2 is a ubiquitous eukaryotic protein kinase composed of two catalytic subunits, alpha and/or alpha', and two regulatory subunits, beta. In order to define similarities and dissimilarities between the alpha and alpha' catalytic subunits, which might account for their particular cellular functions, different forms of the enzyme were expressed in Sf9 cells and their properties determined. Both catalytic subunits were expressed separately, and also along with the regulatory beta subunit, in order to obtain free alpha and alpha', as well as alpha2beta2 and alpha'2beta2 forms. Our results confirm that the beta subunit acts to stabilize the alpha and alpha' subunits and also influences the substrate specificity and kinetic properties of the enzyme. Although significant differences between the specificities of holoenzymes alpha2beta2 and alpha'2beta2 as determined using a number of substrates were not detected, autophosphorylation studies on alpha2beta2 and alpha'2beta2 revealed significant differences in this property. The regulatory subunit beta was phosphorylated less rapidly by the alpha' subunit than by the alpha subunit, and the extent of phosphorylation of beta by alpha was also greater than that of beta by alpha'. It was also noted that the thermo-stability and the extent of its activation by NaCl were greater for alpha2beta2 than for alpha'2beta2. These different properties may relate to distinct functions of the two form of CK2.