Evaluating Diagnostic Algorithms for Heparin-Induced Thrombocytopenia using Two Combined Automated Rapid Immunoassays.

Heparin-induced thrombocytopenia (HIT) is an autoimmune disorder caused by antibodies against platelet factor 4 (PF4) and heparin complexes. Rapid immunoassays (IAs) for detection of these antibodies mark a milestone in HIT diagnosis, despite a higher false-positive rate compared with functional platelet-activation assays. However, combining different rapid IAs may help to improve their diagnostic specificity. Here, we compared the individual performance of the latex immunoturbidimetric assay (LIA; HemosIL HIT-Ab [PF4-H]; sensitivity 91.7%, specificity 68.4%) and chemiluminescence immunoassay (CLIA; HemosIL AcuStarHIT-Ab [PF4-H]; sensitivity 92.4%, specificity 85.8%) with their combined performance using two unique diagnostic algorithms in a single prospective cohort of suspected HIT patients. Using the simultaneous algorithm adapted from Warkentin et al, the combined LIA-CLIA had a sensitivity of 99.0% and specificity of 64.3%. The sequential algorithm adapted from Rittener-Ruff et al was applied in two theoretical scenarios to reflect real-world circumstances in diagnostic laboratories where access to clinical information is limited: (1) assuming all patients had an intermediate 4Ts score and (2) assuming all patients had a high 4Ts score. This algorithm correctly predicted HIT in 94.5% (high 4Ts) and 96.0% (intermediate 4Ts) and excluded HIT in 82.6% (high 4Ts) and 80.1% (intermediate 4Ts) of patients in either scenario, respectively. Although both combined algorithms improved diagnostic performance of individual IAs, the simultaneous algorithm showed fewer false predictions (7.9%) than the sequential algorithm (intermediate 4Ts: 37.6% and high 4Ts: 41.5%) and proved more practical as it does not rely on physician evaluations. Our findings highlight the importance of accounting for clinician and interlaboratory variability when evaluating diagnostic tests for HIT.

Working viscosity and non-Newtonian behavior of silicone denture liners.

PURPOSE: To evaluate flow profile and non-Newtonian behavior of 10 different silicone lining materials. METHODS: Ten commercially available silicone lining materials were selected for evaluation. The flow profile and non-Newtonian behavior of each material was measured using a shark fin testing method. Fin height and resultant base thickness were measured with a digital caliper and compared with one-way ANOVA and Student-Newman-Keuls post hoc test and fin base by Kruskal-Wallis one-way ANOVA on ranks with Dunn post hoc test with significance at P< 0.05 for both. RESULTS: Shark fin heights ranged from 9.62 ± 0.86 mm [Reline II (Soft)] to 25.54 ± 0.43 mm [Sofreliner (Medium)]. Shark fin bases ranged from 2.57 ± 0.51 mm [Sofreliner (Medium)] to 10.31 ± 0.57 mm [Reline II (Soft)]. Statistically significant differences were found between certain samples' shark fin heights as well as resultant bases (P< 0.05) indicating different rheological properties. CLINICAL SIGNIFICANCE: Silicone liner materials differ significantly with respect to flow profile and non-Newtonian behavior. While a high flow profile (low viscosity) of an elastomeric impression material improves accuracy, it may be a detriment to a denture lining material that must achieve a critical minimum thickness to provide resilience. Likewise, a low flow profile (high viscosity) material may also pose a disadvantage, requiring excessive compression and possible tissue distortion to achieve the same critical thickness. The results of this study should be considered when selecting the appropriate material for clinical application. Additional studies are indicated to further quantify rheological properties as well as correlate them to physical properties after the complete cure of the material.

Nature-Based Solution to Eliminate Cyanotoxins in Water Using Biologically Enhanced Biochar.

Climate change and high eutrophication levels of freshwater sources are increasing the occurrence and intensity of toxic cyanobacterial blooms in drinking water supplies. Conventional water treatment struggles to eliminate cyanobacteria/cyanotoxins, and expensive tertiary treatments are needed. To address this, we have designed a sustainable, nature-based solution using biochar derived from waste coconut shells. This biochar provides a low-cost porous support for immobilizing microbial communities, forming biologically enhanced biochar (BEB). Highly toxic microcystin-LR (MC-LR) was used to influence microbial colonization of the biochar by the natural lake-water microbiome. Over 11 months, BEBs were exposed to microcystins, cyanobacterial extracts, and live cyanobacterial cells, always resulting in rapid elimination of toxins and even a 1.6-1.9 log reduction in cyanobacterial cell numbers. After 48 h of incubation with our BEBs, the MC-LR concentrations dropped below the detection limit of 0.1 ng/mL. The accelerated degradation of cyanotoxins was attributed to enhanced species diversity and microcystin-degrading microbes colonizing the biochar. To ensure scalability, we evaluated BEBs produced through batch-scale and continuous-scale pyrolysis, while also guaranteeing safety by maintaining toxic impurities in biochar within acceptable limits and monitoring degradation byproducts. This study serves as a proof-of-concept for a sustainable, scalable, and safe nature-based solution for combating toxic algal blooms.

The extinct Sicilian wolf shows a complex history of isolation and admixture with ancient dogs.

The Sicilian wolf remained isolated in Sicily from the end of the Pleistocene until its extermination in the 1930s-1960s. Given its long-term isolation on the island and distinctive morphology, the genetic origin of the Sicilian wolf remains debated. We sequenced four nuclear genomes and five mitogenomes from the seven existing museum specimens to investigate the Sicilian wolf ancestry, relationships with extant and extinct wolves and dogs, and diversity. Our results show that the Sicilian wolf is most closely related to the Italian wolf but carries ancestry from a lineage related to European Eneolithic and Bronze Age dogs. The average nucleotide diversity of the Sicilian wolf was half of the Italian wolf, with 37-50% of its genome contained in runs of homozygosity. Overall, we show that, by the time it went extinct, the Sicilian wolf had high inbreeding and low-genetic diversity, consistent with a population in an insular environment.

Interventions to increase sleep duration in young people: A systematic review.

This systematic review explored the outcomes of current interventions to increase sleep duration in healthy young people (14-25 years). Nine databases were systematically searched, and 26 studies were included in this review. Quality assessment of the included studies was evaluated using two tools: the Newcastle-Ottawa scale, and Cochrane Risk of Bias. The interventions incorporated a range of strategies including behavioral (46.2%), educational (26.9%), a combination of behavioral and educational (15.4%), and other strategies such as physical therapy (11.5%). The findings indicate that behavioral and combination interventions were consistently effective in increasing sleep duration in healthy young people. Educational interventions alone were less effective at increasing young people's sleep duration. Of all the included studies, only one randomized control trial but none of the non-randomized trials were rated as good quality. Our findings suggest a combination of strategies with an emphasis on personalization of intervention could possibly maximize the chances of success at improving sleep duration in healthy young people. More high-quality studies with long-term assessments (≥ 6 months) should be conducted to test the efficacy and durability of interventions to increase sleep duration in young people, as well as the clinical implications to mental and physical health.

Investigation of anti-PF4 versus anti-PF4/heparin reactivity using fluid-phase enzyme immunoassay for 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, vaccine-induced immune thrombotic thrombocytopenia, and spontaneous HIT.

BACKGROUND: Four platelet-activating anti-platelet factor 4 (PF4) disorders have been recognized: classic heparin-induced thrombocytopenia (cHIT), autoimmune heparin-induced thrombocytopenia (aHIT), spontaneous heparin-induced thrombocytopenia (SpHIT), and vaccine-induced immune thrombotic thrombocytopenia (VITT). All test immunoglobulin G (IgG) positive using solid-phase enzyme immunoassay (solid-EIA) against PF4/heparin (PF4/H) and/or PF4 alone. Fluid-phase EIA (fluid-EIA) should better discriminate between anti-PF4 and anti-PF4/H antibodies since conformationally altered PF4 bound to solid phase is avoided. OBJECTIVES: To compare anti-PF4 vs anti-PF4/H antibody profiles for anti-PF4 disorders using solid- and fluid-EIA. METHODS: We developed a novel fluid-EIA to measure anti-PF4 vs anti-PF4/H antibodies. RESULTS: Using fluid-EIA, 27 of 27 (100%) cHIT sera tested IgG positive with PF4/H, but only 4 of 27 (14.8%) tested positive against PF4 alone; all 27 exhibited heparin-enhanced binding. In contrast, 17 of 17 (100%) VITT sera tested IgG positive against PF4 alone, with markedly reduced binding against PF4/H; this distinct VITT antibody profile was not evident using solid-EIA. All 15 aHIT sera and all 11 SpHIT sera tested IgG positive against PF4 alone, with variable reactivity in PF4/H-EIA (heparin-enhanced binding in 14 of 15 and 10 of 11 aHIT and SpHIT sera, respectively). Remarkably, 1 SpHIT patient with a VITT-mimicking fluid-EIA profile (PF4 >> PF4/H) also clinically resembled patients with VITT (postviral cerebral vein/sinus thrombosis), with anti-PF4 reactivity correlating inversely with platelet count recovery; moreover, the single aHIT patient with a VITT-mimicking fluid-EIA profile also developed postviral cerebral vein/sinus thrombosis. CONCLUSION: cHIT and VITT sera showed opposite fluid-EIA profiles (cHIT: PF4/H >> PF4, with most testing negative against PF4 alone; VITT: PF4 >> PF4/H, with most testing negative against PF4/H). In contrast, all aHIT and SpHIT sera reacted against PF4 alone but with variable (usually enhanced) reactivity against PF4/H. VITT-mimicking clinical/serologic profiles occurred in only a minority of patients with SpHIT and aHIT.

Nursing Care Delivery Models and Intraprofessional Collaborative Care: Canadian Nurse Leaders' Perspectives.

Introduction: There are many different types of nursing care delivery models used to organize and provide care in hospitals. These models are comprised of different organizational structures and staffing skill mixes. Objective: The aim of this study was to explore how nursing care delivery models promote intraprofessional collaborative care in acute care hospitals from the perspectives of nurse leaders. Methods: A qualitative descriptive approach was used for this study. Telephone interviews were conducted between January 2021 and August 2021 using an interview guide comprised of semi-structured and structured questions. Using a purposeful sampling technique, ten leaders from nine hospital systems, representing both urban and rural hospitals in the province of Ontario, Canada, participated in the study. Content analysis was conducted resulting in two overarching themes. Results: The first theme, Fluidity of the Model addresses the flexibility of the models and the impact of contextual factors such as changes in nurses' scope of practice, government funding changes, staffing mix, and organizational policies and rules. The second theme, Tools of the Trade describes the resources that hospitals implement to promote intraprofessional collaboration that indirectly impacts on patient safety. Conclusion: Nursing care delivery models need to be flexible and adaptable. All nursing care delivery models in this study used various tools to promote intraprofessional collaborative care.

The clinical and laboratory diagnosis of vaccine-induced immune thrombotic thrombocytopenia.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious adverse syndrome occurring 5 to 30 days after adenoviral vector COVID-19 vaccination. Therefore, a practical evaluation of clinical assessments and laboratory testing for VITT is needed to prevent significant adverse outcomes as the global use of adenoviral vector vaccines continues. We received the clinical information and blood samples of 156 patients in Canada with a suspected diagnosis of VITT between April and July 2021. The performance characteristics of various diagnostic laboratory tests were evaluated against the platelet factor 4 (PF4)-14C-serotonin release assay (SRA) including a commercial anti-PF4/heparin immunoglobulin G (IgG)/IgA/IgM enzyme immunoassay (EIA, PF4 Enhanced; Immucor), in-house IgG-specific anti-PF4 and anti-PF4/heparin-EIAs, the standard SRA, and the PF4/heparin-SRA. Of those, 43 (27.6%) had serologically confirmed VITT-positive based on a positive PF4-SRA result and 113 (72.4%) were VITT-negative. The commercial anti-PF4/heparin EIA, the in-house anti-PF4-EIA, and anti-PF4/heparin-EIA were positive for all 43 VITT-confirmed samples (100% sensitivity) with a few false-positive results (mean specificity, 95.6%). These immunoassays had specificities of 95.6% (95% confidence interval [CI], 90.0-98.6), 96.5% (95% CI, 91.2-99.0), and 97.4% (95% CI, 92.4-99.5), respectively. Functional tests, including the standard SRA and PF4/heparin-SRA, had high specificities (100%), but poor sensitivities for VITT (16.7% [95% CI, 7.0-31.4]; and 46.2% [95% CI, 26.6-66.6], respectively). These findings suggest EIA assays that can directly detect antibodies to PF4 or PF4/heparin have excellent performance characteristics and may be useful as a diagnostic test if the F4-SRA is unavailable.

Climate change impacts on the mental health and wellbeing of young people: A scoping review of risk and protective factors.

BACKGROUND/RATIONALE: The impact of climate change on the mental health of young people is poorly understood. Emerging evidence suggests that exposure to climate change exerts a disproportionate mental health burden on young people. An understanding of the risk factors (RFs) and protective factors (PFs) that affect the likelihood of mental health impacts arising from exposure to climate change is required to support youth wellbeing. AIMS/OBJECTIVES: This review scopes the current research on what and how RFs and PFs are related to the mental health impacts of both direct and indirect exposure to climate change for young people. RFs and PFs were reviewed through the lens of ecological system theory. METHODS: We conducted systematic searches in four databases: PubMed, PsycInfo, Web of Science, and Scopus. Grey literature searches were conducted in ProQuest Dissertations, GreyLit.org, OpenGrey, and relevant organisations' websites. We included 92 empirical studies focused on the RFs and PFs of the mental wellbeing under the impact of climate change of young people (0-24). We extracted data on study characteristics, type of climate change event, mental health outcomes, RFs and PFs, and associated ecological system level. RESULTS: The current evidence base focuses predominantly on young people's experience of PTSD (k = 59), depression (k = 26), or anxiety (k = 17) mainly following exposure to singular climate change-related natural disaster events. Only four studies explored the impacts of climate change in general. Majority of the studies investigated RFs and PFs at the individual level and at the micro-system level. CONCLUSIONS: Several RFs and PFs were identified, such as coping strategies, family factors (e.g. parenting style), social support, community connection, and cultural identity. Positioning the mental health impacts of singular events within the broader context of ongoing and escalating climate change impacts will better inform the development of interventions that seek to build resilience among young people.

Post-cardiac surgery thrombotic thrombocytopenic purpura: presence of anti-ADAMTS13 autoantibodies at preoperative baseline.

Thrombotic thrombocytopenic purpura (TTP) rarely complicates acute inflammatory conditions such as surgery, including post-cardiac surgery. Review of 32 previously-reported cases of post-cardiac surgery TTP indicates that this disorder often occurs as early as 2-3 days following surgery, which seems too soon to implicate new formation of anti-ADAMTS13 autoantibodies as a consequence of surgery itself. We diagnosed post-cardiac surgery TTP in a 60-year-old female that began approximately 3 days post-coronary artery bypass surgery in which anti-ADAMTS13 autoantibodies were implicated. We therefore investigated whether anti-ADAMTS13 autoantibodies were also present in a preoperative blood sample. Inhibitory (neutralizing) anti-ADAMTS13 autoantibodies were detectable in the preoperative blood sample, suggesting that the role of surgery in precipitating TTP might be due to effects such as abrupt increase in postoperative von Willebrand factor levels and associated proinflammatory factors, rather than effects of surgery itself leading to the formation of de novo anti-ADAMTS13 autoantibodies.

Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement.

Optimization of a series of azabenzimidazoles identified from screening hit 2 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 6 bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles 38 and 39. These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 in vivo.

Nursing care delivery models and outcomes: A literature review.

OBJECTIVE: The purpose of this literature review was to determine the types of nursing care delivery models currently being used in acute care hospitals to determine the effectiveness of the model and the outcomes being measured. METHOD: A literature search was conducted, and databases searched included CINAHL, Nursing and Allied Health, Medline, EMBASE, ProQuest Theses, and Dissertations for the years 2000-2020. Sixteen studies were retrieved. Patient outcomes measured included falls, adverse events, and infections. Nursing outcomes measured included satisfaction, communication, and perceived quality of care. RESULTS: Findings from this review showed there was no single model of nursing care delivery that resulted in positive patient or nurse outcomes, thus a "one size fits all" approach to selecting or utilizing a model of care is not realistic. CONCLUSION: Given the number of nursing care delivery models that were hybrids, clearer descriptions of each model and further research on patient and nursing outcomes is warranted.

Collaboration among nurses when transitioning older adults between hospital and community settings: a scoping review.

BACKGROUND: The transitioning of older patients between healthcare sectors requires the provision of high-quality nursing care. Collaboration among nurses is identified as an essential element of transitional care, yet nurse-nurse collaboration has received little attention. AIM: The aim of this study was to examine the extent, range and nature of nurse-nurse collaboration when transitioning older patients between hospital and community settings, and to identify gaps in the literature. METHODS: Arksey and O'Malley's (International Journal of Social Research Methodology, 8, 2005 and 19) framework was used to undertake a scoping review to answer the research questions: how do nurses collaborate together when transitioning older patients from hospital to community settings and what are the facilitators, barriers and outcomes of nurse-nurse collaboration when transitioning older patients between sectors? The Nurse-Nurse Collaboration Scale (NNCS) subdomains informed the identification of selected studies. RESULTS: Twelve papers were included with most coming from Scandinavian countries and the majority using qualitative methodologies. Communication, coordination and professionalism were found to be both facilitators and barriers of nurse-nurse collaboration. Gaps in the literature included conflict management, and the outcomes of collaboration which was only reported in one study. CONCLUSIONS: The findings indicate there is limited study of collaboration among nurses when transitioning older patients between hospital and community settings. Future research should address the impact of conflict on nurses working in collaborative practice as well as conducting intervention studies to examine the outcomes of nurse-nurse collaboration.

Characteristics of Anti-SARS-CoV-2 Antibodies in Recovered COVID-19 Subjects.

Coronavirus Disease 2019 (COVID-19) is a global pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While detection of SARS-CoV-2 by polymerase chain reaction with reverse transcription (RT-PCR) is currently used to diagnose acute COVID-19 infection, serological assays are needed to study the humoral immune response to SARS-CoV-2. Anti-SARS-CoV-2 immunoglobulin (Ig)G/A/M antibodies against spike (S) protein and its receptor-binding domain (RBD) were characterized in recovered subjects who were RT-PCR-positive (n = 153) and RT-PCR-negative (n = 55) using an enzyme-linked immunosorbent assay (ELISA). These antibodies were also further assessed for their ability to neutralize live SARS-CoV-2 virus. Anti-SARS-CoV-2 antibodies were detected in 90.9% of resolved subjects up to 180 days post-symptom onset. Anti-S protein and anti-RBD IgG titers correlated (r = 0.5157 and r = 0.6010, respectively) with viral neutralization. Of the RT-PCR-positive subjects, 22 (14.3%) did not have anti-SARS-CoV-2 antibodies; and of those, 17 had RT-PCR cycle threshold (Ct) values > 27. These high Ct values raise the possibility that these indeterminate results are from individuals who were not infected or had mild infection that failed to elicit an antibody response. This study highlights the importance of serological surveys to determine population-level immunity based on infection numbers as determined by RT-PCR.

Platelet-activating immune complexes identified in critically ill COVID-19 patients suspected of heparin-induced thrombocytopenia.

BACKGROUND: Thrombocytopenia and thrombosis are prominent in coronavirus disease 2019 (COVID-19), particularly among critically ill patients; however, the mechanism is unclear. Such critically ill COVID-19 patients may be suspected of heparin-induced thrombocytopenia (HIT), given similar clinical features. OBJECTIVES: We investigated the presence of platelet-activating anti-platelet-factor 4 (PF4)/heparin antibodies in critically ill COVID-19 patients suspected of HIT. PATIENTS/METHODS: We tested 10 critically ill COVID-19 patients suspected of HIT for anti-PF4/heparin antibodies and functional platelet activation in the serotonin release assay (SRA). Anti-human CD32 antibody (IV.3) was added to the SRA to confirm FcγRIIA involvement. Additionally, SARS-CoV-2 antibodies were measured using an in-house ELISA. Finally, von Willebrand factor (VWF) antigen and activity were measured along with A Disintegrin And Metalloprotease with ThromboSpondin-13 Domain (ADAMTS13) activity and the presence of anti-ADAMTS13 antibodies. RESULTS: Heparin-induced thrombocytopenia was excluded in all samples based on anti-PF4/heparin antibody and SRA results. Notably, six COVID-19 patients demonstrated platelet activation by the SRA that was inhibited by FcγRIIA receptor blockade, confirming an immune complex (IC)-mediated reaction. Platelet activation was independent of heparin but inhibited by both therapeutic and high dose heparin. All six samples were positive for antibodies targeting the receptor binding domain (RBD) or the spike protein of the SARS-CoV-2 virus. These samples also featured significantly increased VWF antigen and activity, which was not statistically different from the four COVID-19 samples without platelet activation. ADAMTS13 activity was not severely reduced, and ADAMTS13 inhibitors were not present, thus ruling out a primary thrombotic microangiopathy. CONCLUSIONS: Our study identifies platelet-activating ICs as a novel mechanism that contributes to critically ill COVID-19.

Seat Assignments With Physical Distancing in Single-Destination Public Transit Settings.

While the importance of physical (social) distancing in reducing the spread of COVID-19 has been well-documented, implementing similar controls in public transit remains an open question. For instance, in the United States, guidance for maximum seating capacity in single-destination public transit settings, such as school buses, is only dependent on the physical distance between passengers. In our estimation, the available models/guidance are suboptimal/inefficient since they do not account for the possibility of passengers being from the same household. This paper discusses and addresses the aforementioned limitation through two types of physical distancing models. First, a mixed-integer programming model is used to assign passengers to seats based on the reported configuration of the vehicle and desired physical distancing requirement. In the second model, we present a heuristic that allows for household grouping. Through several illustrative scenarios, we show that seating assignments can be generated in near real-time, and the household grouping heuristic increases the capacity of the transit vehicles (e.g., airplanes, school buses, and trains) without increasing the risk of infection. A running application and its source code are available to the public to facilitate adoption and to encourage enhancements.

Serotonin-release assay-positive but platelet factor 4-dependent enzyme-immunoassay negative: HIT or not HIT?

IgG-specific and polyspecific PF4-dependent enzyme-immunoassays (EIAs) have exceptionally high sensitivity (≥99%) for diagnosis of heparin-induced thrombocytopenia (HIT), a drug reaction caused by platelet-activating antibodies detectable by serotonin-release assay (SRA). The IgG-specific EIAs are recommended for screening, as their high sensitivity is accompanied by relatively high specificity vis-à-vis polyspecific EIAs. We investigated the frequency of SRA-positive/EIA-negative (SRA+/EIA-) HIT, prompted by referral to our reference HIT laboratory of serial blood samples from a patient ("index case") with false-negative IgG-specific EIAs. Despite initial clinical suspicion for HIT, repeat negative IgG-specific EIAs prompted heparin resumption, which triggered recurrent thrombocytopenia and near-fatal cardiac arrest, indicating likely post-heparin HIT-associated anaphylactoid reaction. Further investigations revealed a strong-positive SRA, whether performed with heparin alone, PF4 alone, or PF4/heparin, with inhibition by Fc receptor-blocking monoclonal antibody (indicating IgG-mediated platelet activation); however, five different IgG-specific immunoassays yielded primarily negative (or weak-positive) results. To investigate the frequency of SRA+/EIA- HIT, we reviewed the laboratory and clinical features of patients with this serological profile during a 6-year period in which our reference laboratory investigated for HIT using both SRA and IgG-specific EIA. Although ~0.2% of 8546 patients had an SRA+/EIA- profile, further review of 15 such cases indicated clerical/laboratory misclassification or false-positive SRA in all, with no SRA+/EIA- HIT case identified. We conclude that while SRA+/EIA- HIT is possible-as shown by our index case-this clinical picture is exceptionally uncommon. Moreover, the requirement for a positive EIA is a useful quality control maneuver that reduces risk of reporting a false-positive SRA result.

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies.

A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.

Collaboration among Registered Nurses and Licensed Practical Nurses: A Scoping Review of Practice Guidelines.

Professional associations, nurse scholars, and practicing nurses suggest that intraprofessional collaboration between nurses is essential for the provision of quality patient care. However, there is a paucity of evidence describing collaboration among nurses, including the outcomes of collaboration to support these claims. The aim of this scoping review was to examine nursing practice guidelines that inform the registered nurse (RN) and registered/licensed practical nurse (R/LPN) collaborative practice in acute care, summarize and disseminate the findings, and identify gaps in the literature. Ten practice guidelines, all published in Canada, were included in the final scoping review. The findings indicate that many of the guidelines were not evidence informed, which was a major gap. Although the guidelines discussed the structures needed to support intraprofessional collaboration, and most of the guidelines mention that quality patient care is the desired outcome of intraprofessional collaboration, outcome indicators for measuring successful collaborative practice were missing in many of the guidelines. Conflict resolution is an important process component of collaborative practice; yet, it was only mentioned in a few of the guidelines. Future guidelines should be evidence informed and provide outcome indicators in order to measure if the collaborative practice is occurring in the practice setting.

Combination of two complementary automated rapid assays for diagnosis of heparin-induced thrombocytopenia (HIT).

BACKGROUND: HIT diagnosis typically uses complementary diagnostic assays (eg, a PF4-dependent enzyme-immunoassay [EIA] and a platelet activation assay such as the serotonin-release assay [SRA]). OBJECTIVES: To determine whether the combination of two automated assays-a latex immunoturbidimetric assay (LIA) that evaluates competitive inhibition of a HIT-like monoclonal antibody and a chemiluminescence immunoassay (CLIA) for detecting anti-PF4/heparin IgG-optimizes diagnostic sensitivity while also yielding good specificity, particularly at high assay reactivities. PATIENTS/METHODS: We determined operating characteristics using combined LIA/CLIA results from a HIT observational trial (n = 430; derivation cohort) and 147 consecutive patients with HIT (n = 147; supplementary derivation cohort). We also evaluated 678 consecutive samples referred for HIT testing (replication cohort). LIA/CLIA reactivities were scored individually as "negative" (<1.00 U/mL, 0 points), "weak" (1.00-4.99 U/mL, 1 point), "moderate" (5.00-15.99 U/mL, 2 points) and "strong" (≥16.00 U/mL, 3 points), thus contributing up to 6 points (maximum) when LIA/CLIA results were combined. We also examined whether higher LIA/CLIA scores predicted presence of platelet-activating antibodies by conventional and modified (PF4- or PF4/heparin-enhanced) SRA. RESULTS: Combined LIA/CLIA testing yielded high diagnostic sensitivity (~99%) similar to EIA. Interpretation of LIA/CLIA results using the 6-point scale indicated progressively greater likelihood for the presence of platelet-activating antibodies with increasing scores (semi-quantitative reactivity). A LIA/CLIA score ≥ 4 points predicted the presence of platelet-activating antibodies by SRA or PF4-enhanced SRA with high probability (~98%). CONCLUSION: Combined LIA/CLIA testing optimizes diagnostic sensitivity, with progressively greater probability of detecting platelet-activating antibodies with higher assay reactivity that reaches 98% when both automated assays yield moderate or strong results.