Randomized trial of the safety and efficacy of anti-SARS-CoV-2 mAb in the treatment of patients with nosocomial COVID-19 (CATCO-NOS).

Background: Patients with nosocomial acquisition of COVID-19 have poor outcomes but have not been included in therapeutic trials to date. Methods: A pragmatic open-label randomized controlled trial of anti-SARS-CoV-2 monoclonal antibodies (mAb) was performed in hospitalized patients with nosocomial COVID-19 infection in acute care hospitals spanning a provincial health care network. Participants within 5 days of first positive test or symptom onset were randomized to standard of care (SOC) plus a single dose intravenous mAb treatment (bamlanivimab or casirivimab/imdevimab) or SOC alone on a 2:1 basis. The primary study endpoint was the need for invasive mechanical ventilation (IMV) or inpatient mortality by day 60 after randomization. Results: Forty-six participants were enrolled from 13 hospitals between February 14 and October 8, 2021: 31 in the mAb and 15 in the SOC arm. IMV or inpatient mortality up to day 60 occurred in 4 (12.9%) participants in the mAb versus 3 in the SOC arm (20.0%), difference of -7.1% (95% CI -22.5 to 13.4, p = 0.67). The study was terminated early due to lack of equipoise as effectiveness of anti-viral therapies and mAb was published in similar high-risk patient populations. Conclusions: The trial was underpowered to detect meaningful differences given its early termination. The study does highlight the feasibility of undertaking trials in this patient population using a pragmatic approach allowing for trial participation and treatment access across a large health care network and may serve as a template for future designs.

Historique: Les patients qui contractent une COVID-19 nosocomiale ont de mauvais résultats cliniques, mais n'ont pas fait partie des études thérapeutiques jusqu'à présent. Méthodologie: Les chercheurs ont mené une étude randomisée et contrôlée ouverte et pragmatique des anticorps monoclonaux (AcM) anti-SRAS-CoV-2 auprès de patients hospitalisés qui ont contracté une COVID-19 nosocomiale dans les hôpitaux de soins aigus d'un réseau de santé provincial. Dans les cinq jours suivant un premier test positif ou l'apparition des symptômes, les participants ont été divisés de manière randomisée entre la norme des soins (NdS) combinée à une monodose de traitement aux AcM par voie intraveineuse (bamlanivimab ou casirivimab-imdevimab) ou la NdS seule sur une base de deux pour un. Le critère d'évaluation primaire de l'étude était la ventilation mécanique invasive (VMI) ou la mortalité en milieu hospitalier le 60e jour après la randomisation. Résultats: Au total, 46 participants de 13 hôpitaux ont été inclus entre le 14 février et le 8 octobre 2021, soit 31 patients du volet des AcM et 15 du volet de la NdS. La VMI ou la mortalité en milieu hospitalier jusqu'au 60e jour a été observée chez quatre participants au volet des AcM (12,9 %) et trois participants du volet de la NdS (20,0 %), soit une différence de −7,1 % (IC à 95 %, −22,5 à 13,4, p = 0,67). L'étude a été interrompue précocement à cause de l'absence d'équilibre clinique, car des données sur l'efficacité des traitements antiviraux et des AcM ont été publiées au sujet de populations semblables de patients à haut risque. Conclusions: L'échantillon à l'étude était insuffisant pour déceler des différences significatives compte tenu de son interruption précoce. Cette recherche fait ressortir la faisabilité d'études auprès de cette population de patients au moyen d'une approche pragmatique pour y inclure des participants et accéder au traitement dans un vaste réseau de soins et pourrait servir de modèle pour concevoir d'autres études.

The Alberta Telestewardship Network: Building a platform to enable capacity building in antimicrobial stewardship-results of an initial pilot study.

Background: Resources to improve antimicrobial stewardship (AS) are limited, but a telestewardship platform can enable capacity building and scalability. The Alberta Telestewardship Network (ATeleNet) was designed to focus on outreach across the province of Alberta, Canada, and facilitate AS activities. Methods: Outreach occurred virtually between pharmacists and physicians in hospital and long-term care settings throughout Alberta via secure, enterprise video conferencing software on both desktop and mobile devices. We used a quantitative questionnaire adapted from the telehealth usability questionnaire to capture the health provider's experience during each session. The questionnaire consisted of 39 questions, and a 5-point Likert scale was used to assess the degree of agreement and collate responses into a descriptive analysis. Results: A total of 33 pilot consultations were completed between July 6, 2020 and December 15, 2021. The majority (22, 85%) of respondents agreed that video conference-based virtual sessions are an acceptable means to provide health care and that they were able to express themselves effectively to other health care professionals (23, 88%). Respondents agreed the system was simple to use (23, 96%), and that they could become productive quickly using the system (23, 88%). Overall, 24 (92%) respondents were satisfied or very satisfied with the virtual care platform. Conclusions: We implemented and evaluated a telehealth consultation and collaborative care service between AS providers at multiple centres. AHS has since prioritized similar workflows, including access to specialists in acute care, as part of their virtual health strategy. Evaluation results will be shared with provincial stakeholders for further strategic planning and deployment.

Historique: Les ressources pour améliorer la gérance antimicrobienne (GA) sont limitées, mais une plateforme de télégérance peut favoriser le renforcement des capacités et l'échelonnabilité. L'Alberta Telestewardship Network (réseau de télégérance de l'Alberta, ou ATeleNet) a été conçu pour mettre l'accent sur le rayonnement dans la province de l'Alberta, au Canada et pour faciliter les activités de GA. Méthodologie: Le rayonnement s'est produit virtuellement entre des pharmaciens et des médecins d'établissements hospitaliers et d'établissements de soins de longue durée de l'Alberta par logiciel de visioconférence sécurisé sur des ordinateurs de bureau et des appareils mobiles. Les chercheurs ont utilisé un questionnaire quantitatif adapté du questionnaire sur la convivialité de la télésanté pour saisir l'expérience du dispensateur de soins lors de chaque séance. Le questionnaire était composé de 39 questions, et une échelle de Likert de cinq points a permis d'évaluer le degré d'entente et de recueillir les réponses dans une analyse descriptive. Résultats: Au total, les chercheurs ont effectué 33 consultations pilotes entre le 6 juillet 2020 et le 15 décembre 2021. La majorité des répondants (n = 22, 85 %) ont convenu que les séances en visioconférence représentaient un moyen acceptable de fournir des soins de santé et leur permettaient de s'exprimer avec efficacité auprès des autres professionnels de la santé (n = 23, 88 %). Les répondants ont indiqué que le système était facile à utiliser (n = 23, 96 %), et qu'ils pouvaient vite devenir productifs (n = 23, 88 %). Dans l'ensemble, 24 répondants (92 %) étaient satisfaits ou très satisfaits de la plateforme de soins virtuels. Conclusions: Les chercheurs ont lancé et évalué une consultation en télésanté et un service de soins coopératifs entre fournisseurs de GA de multiples centres. Depuis, les Services de santé de l'Alberta ont priorisé des processus de travail semblables dans leur stratégie de santé virtuelle, y compris pour l'accès à des spécialistes en soins aigus. Les résultats de l'évaluation seront transmis à des intervenants provinciaux en vue d'une planification et d'un déploiement stratégiques.

Efficacy and safety of antimicrobial stewardship prospective audit and feedback in patients hospitalised with COVID-19 (COVASP): a pragmatic, cluster-randomised, non-inferiority trial.

BACKGROUND: The COVID-19 pandemic has been associated with increased antimicrobial use despite low rates of bacterial co-infection. Prospective audit and feedback is recommended to optimise antibiotic prescribing, but high-quality evidence supporting its use for COVID-19 is absent. We aimed to study the efficacy and safety of prospective audit and feedback in patients admitted to hospital for the treatment of COVID-19. METHODS: COVASP was a prospective, pragmatic, non-inferiority, small-unit, cluster-randomised trial comparing prospective audit and feedback plus standard of care with standard of care alone in adults admitted to three hospitals in Edmonton, AB, Canada, with COVID-19 pneumonia. All patients aged at least 18 years who were admitted from the community to a designated study bed with microbiologically confirmed SARS-CoV-2 infection in the preceding 14 days were included if they had an oxygen saturation of 94% or lower on room air, required supplemental oxygen, or had chest-imaging findings compatible with COVID-19 pneumonia. Patients were excluded if they were transferred in from another acute care centre, enrolled in another clinical trial that involved antibiotic therapy, expected to progress to palliative care or death within 48 h of hospital admission, or managed by any member of the research team within 30 days of enrolment. COVID-19 unit and critical care unit beds were stratified and randomly assigned (1:1) to the prospective audit and feedback plus standard of care group or the standard of care group. Patients were masked to their bed assignment but the attending physician and study team were not. The primary outcome was clinical status on postadmission day 15, measured using a seven-point ordinal scale. We used a non-inferiority margin of 0·5. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT04896866, and is now closed. FINDINGS: Between March 1 and Oct 29, 2021, 1411 patients were screened and 886 were enrolled: 457 into the prospective audit and feedback plus standard of care group, of whom 429 completed the study, and 429 into the standard of care group, of whom 404 completed the study. Baseline characteristics were similar for both groups, with an overall mean age of 56·7 years (SD 17·3) and a median baseline ordinal scale of 4·0 (IQR 4·0-5·0). 301 audit and feedback events were recorded in the intervention group and 215 recommendations were made, of which 181 (84%) were accepted. Despite lower antibiotic use in the intervention group than in the control group (length of therapy 364·9 vs 384·2 days per 1000 patient days), clinical status at postadmission day 15 was non-inferior (median ordinal score 2·0 [IQR 2·0-3·0] vs 2·0 [IQR 2·0-4·0]; p=0·37, Mann-Whitney U test). Neutropenia was uncommon in both the intervention group (13 [3%] of 420 patients) and the control group (20 [5%] of 396 patients), and acute kidney injury occurred at a similar rate in both groups (74 [18%] of 421 patients in the intervention group and 76 [19%] of 399 patients in the control group). No intervention-related deaths were recorded. INTERPRETATION: This cluster-randomised clinical trial shows that prospective audit and feedback is safe and effective in optimising and reducing antibiotic use in adults admitted to hospital with COVID-19. Despite many competing priorities during the COVID-19 pandemic, antimicrobial stewardship should remain a priority to mitigate the overuse of antibiotics in this population. FUNDING: None.

Efficacy and safety of antimicrobial stewardship prospective audit and feedback in patients hospitalized with COVID-19: A protocol for a pragmatic clinical trial.

BACKGROUND: The use of broad-spectrum antibiotics is widespread in patients with COVID-19 despite a low prevalence of bacterial co-infection, raising concerns for the accelerated development of antimicrobial resistance. Antimicrobial stewardship (AMS) is vital but there are limited randomized clinical trial data supporting AMS interventions such as prospective audit and feedback (PAF). High quality data to demonstrate safety and efficacy of AMS PAF in hospitalized COVID-19 patients are needed. METHODS AND DESIGN: This is a prospective, multi-center, non-inferiority, pragmatic randomized clinical trial evaluating AMS PAF intervention plus standard of care (SOC) versus SOC alone. We include patients with microbiologically confirmed SARS-CoV-2 infection requiring hospital admission for severe COVID-19 pneumonia. Eligible ward beds and critical care unit beds will be randomized prior to study commencement at each participating site by computer-generated allocation sequence stratified by intensive care unit versus conventional ward in a 1:1 fashion. PAF intervention consists of real time review of antibacterial prescriptions and immediate written and verbal feedback to attending teams, performed by site-based AMS teams comprised of an AMS pharmacist and physician. The primary outcome is clinical status at post-admission day 15 measured using a 7-point ordinal scale. Patients will be followed for secondary outcomes out to 30 days. A total of 530 patients are needed to show a statistically significant non-inferiority, with 80% power and 2.5% one-sided alpha assuming standard deviation of 2 and the non-inferiority margin of 0.5. DISCUSSION: This study protocol presents a pragmatic clinical trial design with small unit cluster randomization for AMS intervention in hospitalized COVID-19 that will provide high-level evidence and may be adopted in other clinical situations. TRIAL REGISTRATION: This study is being performed at the University of Alberta and is registered at ClinicalTrials.gov (NCT04896866) on May 17, 2021.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Effect of prospective audit and feedback on inpatient fluoroquinolone use and appropriateness of prescribing.

We report the effect of prospective audit and feedback (PAF) on inpatient fluoroquinolone (FQN) prescriptions. During the PAF period, FQN use decreased from 39.19 to 29.58 days of therapy per 1,000 patient days (P < .001) and appropriateness improved from 68% to 88% (P < .001). High-yield indications to target included noninfectious urinary tract and respiratory presentations.

Effectiveness of a simple intervention for prevention of catheter-associated urinary tract infections on a medical hospital unit.

BACKGROUND: Urinary tract infections (UTI) are one of the most common hospital-acquired infections with 80% as a result of urinary catheterisation. AIM/OBJECTIVE: This study examined the impact of a simple intervention consisting of a daily chart reminder in patients with indwelling urinary catheters (IUC) on the duration of catheter use and the incidence of catheter-associated UTIs (CAUTIs). METHODS: The trial used a prospective pretest-post-test design with a control group over a six-month period conducted on two medical units of a community teaching hospital. We included all patients admitted to two medical units between 1 June and 30 November 2016 who had an IUC inserted at the study site. During the intervention phase, a sticker was placed in the charts of patients with urinary catheters reminding physicians to assess for catheter removal if not clinically necessary. RESULTS: A total of 195 patients participated in this study (112 control unit, 83 intervention unit). There was a decrease in the duration of IUC use on the intervention unit from 11.7 days to 7.5 days (P = 0.0028). There was a decrease in repeated catheterisation from 11.1% to 2.1% (P = 0.0882), and CAUTIs from 17.5% to 4.6% (P = 0.0552) but this did not reach statistical significance. DISCUSSION: The implementation of a daily IUC reminder sticker in patient charts was associated with a significant reduction in the mean duration of indwelling catheter use with a trend towards a reduction in the frequency of repeated urinary catheterisation and rate of CAUTIs.

Impact of an Unsolicited, Standardized Form-Based Antimicrobial Stewardship Intervention to Improve Guideline Adherence in the Management of Staphylococcus aureus Bacteremia.

BACKGROUND: Antimicrobial stewardship programs (ASPs) improve Staphylococcus aureus bacteremia (SAB) management. The objective of the current study was to evaluate the effect of unsolicited prospective audit and feedback (PAF) using a standardized SAB bundle form on the management of SAB. METHODS: Multicenter, pre-post quasi-experimental study of inpatients with SAB. The ASP developed an evidence-based SAB management bundle that included recommendations for infectious diseases consultation, blood culture clearance, appropriate empiric and definitive therapy, echocardiography, adequate treatment duration, and source control where applicable. ASP pharmacists performed PAF using a standardized form outlining bundle components. The primary outcome was bundle component adherence. Secondary outcomes were length of stay, 30-day readmission rate, and in-hospital and 30-day mortality rates. RESULTS: A total of 199 patients were included (preintervention group, 62; intervention group, 137). Bundle implementation with PAF resulted in significant improvements in infectious diseases consultation (56.5% in preintervention vs 93.4% in intervention group), appropriate definitive antibiotic therapy (83.9% vs 99.3%), ordering echocardiography (72.6% vs 95.6%), and adequate treatment duration (87.0% vs 100%) (all P < .001). Overall bundle adherence increased by 43.8% (P < .001). Readmission and 30-day mortality rates decreased, but this difference did not reach statistical significance. CONCLUSIONS: Unsolicited PAF using a standardized SAB management bundle significantly improved adherence to evidence-based recommendations. This simple yet effective ASP-driven intervention can ensure consistent management of a highly morbid infection.

Assessment of HIV Knowledge in Correctional Facility Health Care Workers: A Pilot Study of an Educational Intervention.

HIV rates are disproportionately higher in the incarcerated compared to the general population. Unfortunately, HIV sero-positive inmates report perceived discrimination and missed antiretroviral doses. Correctional facility nursing competency in HIV management may mitigate these concerns. Using validated knowledge instruments, the authors measured baseline HIV knowledge in correctional facility nurses from 3 correctional facilities in Alberta, Canada, and quantified changes after a targeted educational workshop. Basic HIV knowledge increased significantly, whereas perceived need for further HIV education significantly decreased postintervention. This study demonstrates that correctional facility nurses may not receive ideal HIV education during employment and that targeted HIV workshops can significantly increase knowledge and confidence when caring for affected individuals.

Macrolide use in the treatment of critically ill patients with pneumonia: Incidence, correlates, timing and outcomes.

BACKGROUND: Macrolide antibiotics are commonly used to treat pneumonia despite increasing antimicrobial resistance. Evidence suggests that macrolides may also decrease mortality in severe sepsis via immunomodulatory properties. OBJECTIVE: To evaluate the incidence, correlates, timing and mortality associated with macrolide-based treatment. METHODS: A population-based cohort of critically ill adults with pneumonia at five intensive care units in Edmonton, Alberta, was prospectively followed over two years. Data collected included disease severity (Acute Physiology and Chronic Health Evaluation [APACHE] II score), pneumonia severity (Pneumonia Severity Index score), comorbidities, antibiotic treatments at presentation and time to effective antibiotic. The independent association between macrolide-based treatment and 30-day all-cause mortality was examined using multivariable Cox regression. A secondary exploratory analysis examined time to effective antimicrobial therapy. RESULTS: The cohort included 328 patients with a mean Pneumonia Severity Index score of 116 and a mean APACHE II score of 17; 84% required invasive mechanical ventilation. Ninety-one (28%) patients received macrolide-based treatments, with no significant correlates of treatment except nursing home residence (15% versus 30% for nonresidents [P=0.02]). Overall mortality was 54 of 328 (16%) at 30 days: 14 of 91 (15%) among patients treated with macrolides versus 40 of 237 (17%) for nonmacrolides (adjusted HR 0.93 [95% CI 0.50 to 1.74]; P=0.8). Patients who received effective antibiotics within 4 h of presentation were less likely to die than those whose treatment was delayed (14% versus 17%; adjusted HR 0.50 [95% CI 0.27 to 0.94]; P=0.03). CONCLUSIONS: Macrolide-based treatment was not associated with lower 30-day mortality among critically ill patients with pneumonia, although receipt of effective antibiotic within 4 h was strongly predictive of survival. Based on these results, timely effective treatment may be more important than choice of antibiotics.

HISTORIQUE: Les macrolides sont souvent utilisés pour soigner la pneumonie, malgré une résistance croissante aux antimicrobiens. Selon les données probantes, les macrolides réduiraient également la mortalité en cas de septicémie sévère, en raison de ses propriétés immunomodulatoires. OBJECTIF: Évaluer l'incidence, les corrélats, les délais et la mortalité associés à un traitement fondé sur les macrolides. MÉTHODOLOGIE: Pendant deux ans, les chercheurs ont procédé au suivi rétrospectif d'une cohorte en population d'adultes atteints d'une grave pneumonie, hospitalisés dans cinq unités de soins intensifs d'Edmonton, en Alberta. Ils ont colligé la gravité de la maladie (indice APACHE II d'évaluation de la physiologie aiguë et de la santé chronique), la gravité de la pneumonie (indice de gravité de la pneumonie), les comorbidités, les traitements antibiotiques à la présentation et le délai avant la prise efficace d'antibiotiques. Ils ont examiné l'association indépendante entre le traitement aux macrolides et le décès au bout de 30 jours toutes causes confondues au moyen de la régression de Cox multivariable. Ils ont utilisé une analyse exploratoire secondaire pour examiner le délai avant un traitement antimicrobien efficace. RÉSULTATS: La cohorte se composait de 328 patients dont l'indice moyen de gravité de la pneumonie se situait à 116 et l'indice APACHE II moyen à 17; 84 % d'entre eux ont eu besoin d'une ventilation mécanique. Quatre-vingt-onze patients (28 %) ont reçu des traitements aux macrolides, sans corrélats significatifs du traitement à part le fait d'habiter dans un centre d'hébergement et de soins de longue durée (15 % par rapport à 30 % pour les non-résidents [P=0,02]). La mortalité globale correspondait à 54 cas sur 328 patients (16 %) au bout de 30 jours, soit 14 des 91 patients (15 %) traités aux macrolides par rapport à 40 des 237 (17 %) n'en ayant pas pris (RR rajusté de 0,93 [95 % IC 0,50 à 1,74]; P=0,8). Les patients qui prenaient des antibiotiques efficaces dans les quatre heures suivant leur présentation étaient moins susceptibles de mourir que ceux dont le traitement était retardé (14 % par rapport à 17 %; RR rajusté 0,50 [95 % IC 0,27 à 0,94]; P=0,03). CONCLUSIONS: Le traitement aux macrolides ne s'associait pas à une réduction du taux de mortalité au bout de 30 jours chez les patients atteints d'une grave pneumonie, mais la prise d'antibiotiques efficaces dans les quatre heures était fortement prédictive de la survie. D'après ces résultats, l'administration rapide d'un traitement efficace serait plus importante que le choix d'antibiotique.

Patient-level evaluation of community-based, multifactorial intervention to prevent diabetic nephropathy in northern alberta, Canada.

OBJECTIVE: To examine whether patients with type 2 diabetes enrolled in community-based clinics uniformly benefit from interventions designed to achieve multiple risk factor targets. METHODS: Using data from community-based clinics in Alberta, Canada, we examined whether patients achieved targets for blood pressure (<130/80 mm Hg), A1c (≤7%), low-density lipoprotein (LDL) cholesterol (<2.5 mmol/L), weight reduction, exercising, smoking cessation, and meal plan management among 235 patients between 2004 to 2007 with a 1-year follow-up. The effectiveness of the clinics was assessed by the number of targets achieved by individual patients. Patients achieving different degrees of success (0-2, 3-4, and ≥5 targets) were compared. RESULTS: Mean age of patients at baseline was 62 years (standard deviation [SD], 12 years), 43% were female, 77% had a history of cardiovascular disease, and mean diabetes duration was 9 years (SD, 9 years). Overall, 47 patients achieved 0 to 2 targets (group 1), 132 achieved 3 to 4 targets (group 2), and 56 achieved ≥5 targets (group 3) out of 7 targets. More patients in group 1 were male and had longer diabetes duration and were more likely to smoke or use insulin. Despite reductions in A1c in all groups and similar use of antihypertensives, there was no improvement in weight or systolic blood pressure (which actually increased) in group 1. Successful patients (group 3) were more likely to report adherence with exercise and a meal plan. CONCLUSIONS: Despite equally intensive, target-driven pharmacotherapy, this community-based multifactorial intervention was less effective among a subset of patients who did not adhere to lifestyle changes. Strategies to effectively address lifestyle factors will be important as this intervention is refined.

Ectophosphorylation of CD36 regulates cytoadherence of Plasmodium falciparum to microvascular endothelium under flow conditions.

The adhesion of Plasmodium falciparum-infected erythrocytes (IRBCs) to human dermal microvascular endothelial cells (HDMECs) under flow conditions is regulated by a Src family kinase- and alkaline phosphatase (AP)-dependent mechanism. In this study, we showed that the target of the phosphatase activity is the ectodomain of CD36 at threonine-92 (Thr92). Mouse fibroblasts (NIH 3T3 cells) transfected with wild-type CD36 or a mutant protein in which Thr92 was substituted by Ala supported the rolling and adhesion of IRBCs. However, while the Src family kinase inhibitors PP1 and PP2 and the specific AP inhibitor levamisole significantly reduced IRBC adhesion to wild-type CD36 transfectants as with HDMECs, the inhibitors had no effect on IRBC adhesion to the mutant cells. Using a phosphospecific antibody directed at a 12-amino-acid peptide spanning Thr92, we demonstrated directly that CD36 was constitutively phosphorylated and could be dephosphorylated by exogenous AP. Endothelial CD36 was likewise constitutively phosphorylated. The phosphospecific antibody inhibited IRBC adhesion to HDMECs that could be reversed by preincubating the antibody with the phosphorylated but not the nonphosphorylated peptide. Pretreatment of HDMECs with AP abrogated the effect of PP1 on IRBC adhesion. Collectively, these results are consistent with a critical role for CD36 dephosphorylation through Src family kinase activation in regulating IRBC adhesion to vascular endothelium.

Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria.

Haemoglobin C, which carries a glutamate-to-lysine mutation in the beta-globin chain, protects West African children against Plasmodium falciparum malaria. Mechanisms of protection are not established for the heterozygous (haemoglobin AC) or homozygous (haemoglobin CC) states. Here we report a marked effect of haemoglobin C on the cell-surface properties of P. falciparum-infected erythrocytes involved in pathogenesis. Relative to parasite-infected normal erythrocytes (haemoglobin AA), parasitized AC and CC erythrocytes show reduced adhesion to endothelial monolayers expressing CD36 and intercellular adhesion molecule-1 (ICAM-1). They also show impaired rosetting interactions with non-parasitized erythrocytes, and reduced agglutination in the presence of pooled sera from malaria-immune adults. Abnormal cell-surface display of the main variable cytoadherence ligand, PfEMP-1 (P. falciparum erythrocyte membrane protein-1), correlates with these findings. The abnormalities in PfEMP-1 display are associated with markers of erythrocyte senescence, and are greater in CC than in AC erythrocytes. Haemoglobin C might protect against malaria by reducing PfEMP-1-mediated adherence of parasitized erythrocytes, thereby mitigating the effects of their sequestration in the microvasculature.