Academic drug discovery: Challenges and opportunities.

There are many different approaches to drug discovery in academia, some of which are based broadly on the industrial model of discovering novel targets and then conducting screening within academic drug discovery centres to identify hit molecules. Here we describe our approach to drug discovery, which makes more efficient use of the capabilities and resources of the different stakeholders. Specifically, we have created a large portfolio of drug projects and conducted small amounts of derisking work to ensure projects are investment ready. In this feature we will describe this model, including its limitations and advantages, since we believe the ideas and concepts will be of interest to other academic institutions and consortia.

Respiratory rate monitoring and early detection of deterioration practices.

BACKGROUND: Growing evidence points to respiratory rate (RR) being the most important vital sign for early detection of patient deterioration. However, RR is the vital sign most likely to be inaccurate or missed. AIMS: To measure prevalence of early detection of deterioration protocols, examine whether RR was perceived as the leading indicator of deterioration, and understand RR monitoring practices used by nurses around the world. METHODS: A double-blinded survey of nurses in Asia Pacific, Middle East, and Western Europe. FINDINGS: 161 nurses responded. Most (80%) reported having an initiative for early detection of patient deterioration; 12% indicated RR was the most important indicator of deterioration, 27% captured RR for all medical/surgical patients, and 56% take 60 seconds or longer to measure RR. CONCLUSION: Nurses across all regions generally underestimated the importance of capturing an accurate RR for all patients' multiple times per day. This study reinforces the need to enhance international nursing education regarding the importance of RR.

Budget Impact of the Vest™ High Frequency Chest Wall Oscillation System for Managing Airway Clearance in Patients with Complex Neurological Disorders: A US Healthcare Payers' Perspective Analysis.

OBJECTIVE: As a recognized therapy to improve airway clearance, high-frequency chest wall oscillation (HFCWO) is used to manage reduced vital capacity in patients with complex neuromuscular disorders (cNMD). This study aimed to investigate the budget impact of HFCWO versus chest wall physical therapy (CWPT) from a US-commercial payer perspective. METHODS: In combination with a previously developed cost-effectiveness model, a budget impact model was developed to evaluate the incremental budgetary impact associated with introducing a HFCWO device over a 5-year time horizon. The model compared the cost implications associated with the commonly used CWPT procedure, as the current scenario, with a new scenario consisting of 80% of market share for HFCWO. The resource use and costs included in the analyses were costs associated with the HFCWO device (Vest™ System) and its consumables, patient training, and medical services such as hospitalization, medications, emergency room, and outpatient visits. The primary outcome measures included total and incremental budgetary impact per member per year (PMPY). RESULTS: In a hypothetical plan of 1,000,000 members (men: 49.2%), 2099 patients with cNMD were estimated to be eligible to receive airway clearance services over 5 years. The new scenario (HFCWO and CWPT [US$24 PMPY]) was cost-saving compared with the current scenario (CWPT only [$34 PMPY]) with a cost reduction of US$9.46 PMPY. The model estimated a net cost-saving of US$1,594,131 and US$9,591,343 over 1 and 5 years, respectively. CONCLUSION: This study suggests the HFCWO technique to manage the reduction in vital capacity in patients with cNMD would lead to favorable budget impact results.

Incontinence and Incontinence-Associated Dermatitis in Acute Care: A Retrospective Analysis of Total Cost of Care and Patient Outcomes From the Premier Healthcare Database.

PURPOSE: To evaluate the prevalence of incontinence and treatment of incontinence-associated dermatitis (IAD) and associations with outcomes including total cost of care, length of stay (LOS), 30-day readmission, sacral area pressure injuries present on admission and hospital acquired pressure injuries, and progression of all sacral area pressure injuries to a higher stage. DESIGN: Retrospective analysis. SUBJECTS AND SETTINGS: Data were retrieved from the Premier Healthcare Database and comprised more than 15 million unique adult patient admissions from 937 hospitals. Patients were 18 years or older and admitted to a participating hospital between January 1, 2016, and December 31, 2019. METHODS: Given the absence of an IAD International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code, we categorized patients treated for IAD by selecting patients with a documented incontinence ICD-10-CM code and a documented charge for dermatology products used to treat IAD. The t test and χ2 tests determined whether incontinence and treatment for IAD were associated with outcomes. RESULTS: Incontinence prevalence was 1.5% for the entire sample; prevalence rate for IAD among incontinent patients was 0.7%. As compared to continent patients, incontinent patients had longer LOS (6.4 days versus 4.4 days), were 1.4 times more likely to be readmitted, 4.7 times more likely to have a sacral pressure injury upon admission pressure injury, 5.1 times more likely to have a sacral hospital-acquired pressure injury, and 5.8 times more likely to have a sacral pressure injury progress to a severe stage. As compared to incontinent patients without IAD treatment, those with IAD treatment had longer LOS (9.7 days versus 6.4 days), were 1.3 times more likely to be readmitted, and were 2.0 times more likely to have a sacral hospital-acquired pressure injury. Total index hospital costs were 1.2 times higher for incontinent patients and 1.3 times higher for patients with IAD treatment. CONCLUSIONS: Incontinence and IAD prevalence are substantially lower than past research due to underreporting of incontinence. The lack of an ICD-10-CM code for IAD further exacerbates the underreporting of IAD. Despite low prevalence numbers, our results show higher health care costs and worse outcomes for incontinent patients and patients with IAD treatment.

Analysis of Glyphosate Residues in Foods from the Canadian Retail Markets between 2015 and 2017.

Underlying the risk management of pesticides to protect human health and to facilitate trade among nations are sound scientific data on the levels of compliance with standards set by governments and internationally from monitoring of the levels of pesticides in foods. Although glyphosate is among the universally used pesticides in the world, monitoring has been hampered by the analytical difficulties in dealing with this highly polar compound. Starting in 2015, using liquid chromatography/tandem mass spectrometry (LC-MS/MS) that permits accurate and reproducible determination of glyphosate, the prevalence, concentrations, and compliance rates were determined. In this work, the glyphosate residues contents of 7955 samples of fresh fruits and vegetables, milled grain products, pulse products, and finished foods collected from April 2015 to March 2017 in the Canadian retail market are reported. A total of 3366 samples (42.3%) contained detectable glyphosate residues. The compliance rate with Canadian regulations was 99.4%. There were 46 noncompliant samples. Health Canada determined that there was no long-term health risk to Canadian consumers from exposure to the levels of glyphosate found in the samples of a variety of foods surveyed. The high level of compliance (99.4% of samples with the Canadian regulatory limits) and the lack of a health risk for noncompliant samples indicate that, with respect to glyphosates, the food available for sale in Canada is safe.

Biorefining of platinum group metals from model waste solutions into catalytically active bimetallic nanoparticles.

Bacteria can fabricate platinum group metal (PGM) catalysts cheaply, a key consideration of industrial processes and waste decontaminations. Biorecovery of PGMs from wastes is promising but PGM leachates made from metallic scraps are acidic. A two-step biosynthesis 'pre-seeds' metallic deposits onto bacterial cells benignly; chemical reduction of subsequent metal from acidic solution via the seeds makes bioscaffolded nanoparticles (NPs). Cells of Escherichia coli were seeded using Pd(II) or Pt(IV) and exposed to a mixed Pd(II)/Pt(IV) model solution under H2 to make bimetallic catalyst. Its catalytic activity was assessed in the reduction of Cr(VI), with 2 wt% or 5 wt% preloading of Pd giving the best catalytic activity, while 1 wt% seeds gave a poorer catalyst. Use of Pt seeds gave less effective catalyst in the final bimetallic catalyst, attributed to fewer and larger initial seeds as shown by electron microscopy, which also showed a different pattern of Pd and Pt deposition. Bimetallic catalyst (using cells preloaded with 2 wt% Pd) was used in the hydrogenation of soybean oil which was enhanced by ~fourfold using the bimetallic catalyst made from a model waste solution as compared to 2 wt% Pd preloaded cells alone, with a similar selectivity to cis C18:1 product as found using a Pd-Al2 O3 commercial catalyst.

Challenges developing evidence-based algorithms for the trauma reception and resuscitation project.

A project based at the Alfred Emergency and Trauma Centre in Melbourne, Australia aimed to standardise trauma resuscitation, documentation and interventions by developing best practice algorithms. The primary study objective was to demonstrate a reduction in management errors using a real-time computer based algorithm (the study group) compared to the control group in an open randomised controlled interventional study. A baseline control group was also used for comparison with usual (current) practice. In order to examine the existing evidence and algorithms in trauma care, nine teams of emergency nurses and doctors were formed. Specific literature searches performed by each team revealed a paucity of evidence supporting clinical practice in the trauma setting for procedures. Subsequently, the multidisciplinary teams worked together and developed algorithms based on best practice. The process revealed three main areas of challenges in the development of algorithms: (i) clinical, (ii) research and (iii) nursing challenges. The completion of the project demonstrated benefits in the real-time computer based algorithm with a reduction in the error rate per patient from the baseline control group to the intervention study group (2.30 vs. 2.13, p=0.04) and error-free resuscitations increasing from 16% to 21.8% (p=.049). This project supported the implementation of a real-time computer based algorithm system with improved protocol compliance and reduced errors and morbidity.

Trauma resuscitation errors and computer-assisted decision support.

HYPOTHESIS: This project tested the hypothesis that computer-aided decision support during the first 30 minutes of trauma resuscitation reduces management errors. DESIGN: Ours was a prospective, open, randomized, controlled interventional study that evaluated the effect of real-time, computer-prompted, evidence-based decision and action algorithms on error occurrence during initial resuscitation between January 24, 2006, and February 25, 2008. SETTING: A level I adult trauma center. PATIENTS: Severely injured adults. MAIN OUTCOME MEASURES: The primary outcome variable was the error rate per patient treated as demonstrated by deviation from trauma care algorithms. Computer-assisted video audit was used to assess adherence to the algorithms. RESULTS: A total of 1171 patients were recruited into 3 groups: 300 into a baseline control group, 436 into a concurrent control group, and 435 into the study group. There was a reduction in error rate per patient from the baseline control group to the study group (2.53 to 2.13, P = .004) and from the control group to the study group (2.30 to 2.13, P = .04). The difference in error rate per patient from the baseline control group to the concurrent control group was not statistically different (2.53 to 2.30, P = .21). A critical decision was required every 72 seconds, and error-free resuscitations were increased from 16.0% to 21.8% (P = .049) during the first 30 minutes of resuscitation. Morbidity from shock management (P = .03), blood use (P < .001), and aspiration pneumonia (P = .046) were decreased. CONCLUSIONS: Computer-aided, real-time decision support resulted in improved protocol compliance and reduced errors and morbidity. Trial Registration clinicaltrials.gov Identifier: NCT00164034.

Clinical handover in the trauma setting: a qualitative study of paramedics and trauma team members.

BACKGROUND: Clinical handover between paramedics and the trauma team is undertaken in a time-pressured environment. Paramedics are often required to handover complex problems to a multitude of staff. There is evidence that information loss occurs at this transition. The aims of this project were to (1) develop a minimum dataset to assist paramedics provide handover; (2) identify attributes of effective and ineffective handover; (3) determine the feasibility of advanced data transmission; and (4) identify how to best display data in trauma bays. METHODS: Qualitative study of paramedics and trauma team members. A thematic analysis was undertaken using grounded theory. RESULTS: Ten paramedics and 17 trauma team members were interviewed. A minimum dataset modified on an existing template was developed to include fields required by the trauma team to inform immediate treatment. Respondents stated that an effective handover was one which was delivered succinctly and in a structured manner, and contained only vital data necessary to direct immediate treatment. Advanced transmission of data to the receiving hospital was widely supported. While computers carried by paramedics were capable of exporting data to the receiving hospital, barriers such as time constraints, workflow issues and infection control issues impeded the ability to do this in the current environment. DISCUSSION: There is support for the adoption and further evaluation of a handover template. It can provide valuable structure to the face-to-face handover, and experience from other specialties suggests it can reduce information loss. Strategies to enable information to be transmitted in advance of the patients' arrival must address concerns voiced by paramedics.

Assessing clinical handover between paramedics and the trauma team.

INTRODUCTION: The aim of effective clinical handover is seamless transfer of information between care providers. Handover between paramedics and the trauma team provides challenges in ensuring that information loss does not occur. Handover is often time-pressured and paramedics' clinical notes are often delayed in reaching the trauma team. Documentation by trauma team members must be accurate. This study evaluated information loss and discordance as patients were transferred from the scene of an incident to the Trauma Centre. METHODS: Twenty-five trauma patients presenting by ambulance to a tertiary Emergency and Trauma Centre were randomly selected. Audiotaped (pre-hospital) and videotaped (in-hospital) handover was compared with written documentation. RESULTS: In the pre-hospital setting 171/228 (75%) of data items handed over by paramedics to the trauma team were documented and in the in-hospital handover 335/498 (67%) of information was documented. Information least likely to be documented by trauma team members (1) in the pre-hospital setting related to treatment provided and (2) in the in-hospital setting related to signs and symptoms. While 79% of information was subsequently documented by paramedics, 9% (n=59) of information was not documented either by trauma team members or paramedics and constitutes information loss. Information handed over was not congruent with documentation on seven occasions. Discrepancies included a patient's allergy status and sites of injury (n=2). Demographic details were most likely to be documented but not handed over by paramedics. CONCLUSION: By documenting where deficits in handover occur we can identify points of vulnerability and strategies to capture this information.

Shame as a prospective predictor of self-inflicted injury in borderline personality disorder: a multi-modal analysis.

The primary aim of this study was to examine the prospective association of shame with self-inflicted injury (SII), including suicide attempts and nonsuicidal self-injury, among women with borderline personality disorder (BPD) who were enrolled in a clinical trial (N = 77). A multi-method approach was used to assess self-reported shame, nonverbal shame behaviors, and assessor ratings of shame during an interview regarding antecedents for a recent episode of SII. Higher levels of nonverbal shame behaviors predicted a higher likelihood of subsequent SII, and shorter time to SII, after controlling for past SII as well as other emotions associated with SII. Self-reported state shame and assessor ratings of shame were associated with prospective SII, but not after controlling for other emotions. These findings underscore the important role of shame in SII, particularly shame in the presence of contextual prompts for events that surround episodes of SII.

Treating co-occurring Axis I disorders in recurrently suicidal women with borderline personality disorder: a 2-year randomized trial of dialectical behavior therapy versus community treatment by experts.

This study evaluated whether dialectical behavior therapy (DBT) was more efficacious than treatment by nonbehavioral psychotherapy experts in reducing co-occurring Axis I disorders among suicidal individuals with borderline personality disorder (BPD). Women with BPD and recent and repeated suicidal and/or self-injurious behavior (n = 101) were randomly assigned to 1 year of DBT or community treatment by experts (CTBE), plus 1 year of follow-up assessment. For substance dependence disorders (SDD), DBT patients were more likely to achieve full remission, spent more time in partial remission, spent less time meeting full criteria, and reported more drug- and alcohol-abstinent days than did CTBE patients. These findings suggest that improvements in co-occurring SDD among suicidal BPD patients are specific to DBT and cannot be attributed to general factors associated with nonbehavioral expert psychotherapy. Further, group differences in SDD remission were not explained by either psychotropic medication usage or changes in BPD criterion behaviors. DBT and CTBE did not significantly differ in the reduction of anxiety disorders, eating disorders, or major depressive disorder.

Two-year randomized controlled trial and follow-up of dialectical behavior therapy vs therapy by experts for suicidal behaviors and borderline personality disorder.

CONTEXT: Dialectical behavior therapy (DBT) is a treatment for suicidal behavior and borderline personality disorder with well-documented efficacy. OBJECTIVE: To evaluate the hypothesis that unique aspects of DBT are more efficacious compared with treatment offered by non-behavioral psychotherapy experts. DESIGN: One-year randomized controlled trial, plus 1 year of posttreatment follow-up. SETTING: University outpatient clinic and community practice. PARTICIPANTS: One hundred one clinically referred women with recent suicidal and self-injurious behaviors meeting DSM-IV criteria, matched to condition on age, suicide attempt history, negative prognostic indication, and number of lifetime intentional self-injuries and psychiatric hospitalizations. INTERVENTION: One year of DBT or 1 year of community treatment by experts (developed to maximize internal validity by controlling for therapist sex, availability, expertise, allegiance, training and experience, consultation availability, and institutional prestige). MAIN OUTCOME MEASURES: Trimester assessments of suicidal behaviors, emergency services use, and general psychological functioning. Measures were selected based on previous outcome studies of DBT. Outcome variables were evaluated by blinded assessors. RESULTS: Dialectical behavior therapy was associated with better outcomes in the intent-to-treat analysis than community treatment by experts in most target areas during the 2-year treatment and follow-up period. Subjects receiving DBT were half as likely to make a suicide attempt (hazard ratio, 2.66; P = .005), required less hospitalization for suicide ideation (F(1,92) = 7.3; P = .004), and had lower medical risk (F(1,50) = 3.2; P = .04) across all suicide attempts and self-injurious acts combined. Subjects receiving DBT were less likely to drop out of treatment (hazard ratio, 3.2; P < .001) and had fewer psychiatric hospitalizations (F(1,92) = 6.0; P = .007) and psychiatric emergency department visits (F(1,92) = 2.9; P = .04). CONCLUSIONS: Our findings replicate those of previous studies of DBT and suggest that the effectiveness of DBT cannot reasonably be attributed to general factors associated with expert psychotherapy. Dialectical behavior therapy appears to be uniquely effective in reducing suicide attempts.

Risky assessments: participant suicidality and distress associated with research assessments in a treatment study of suicidal behavior.

The purpose of this study was to examine patterns of self-reported suicidality and distress during research assessments in a sample of 63 women meeting criteria for borderline personality disorder and current and chronic suicidality. The risk management protocol we used during the two-year study period (University of Washington Risk Assessment Protocol; UWRAP) is described. Results indicated that changes in suicidality following assessments were small and relatively infrequent, and were just as likely to reflect decreases in suicidality as increases (17.5% versus 16.4% of sessions, respectively). Further, longitudinal analyses indicated that changes in suicidality became increasingly rare over the course of the 2-year study. Ratings of distress were more changeable than suicidality, underscoring the need for separate measurement of these constructs when assessing risk. With the aid of the UWRAP, our assessors judged 15 participants as high-risk status in 28 assessment sessions (3.7% of all sessions). In comparison to the rest of the sample, these individuals were of significantly greater clinical severity as measured by the HRSD 17-item, GAF scores, number and severity of previous suicide attempts, and number of previous psychiatric hospitalizations. Low-intensity risk intervention strategies (e.g., validating participant's feelings) were typically sufficient to reduce risk in these participants. Overall, our findings indicate that research with highly suicidal individuals can be done safely with the use of well-trained assessors and an appropriate crisis management protocol.