Clinician Perspectives on Specifications for Metrics to Inform Pediatric Alarm Management.

Background: Ongoing management of monitor alarms is important for reducing alarm fatigue among clinicians (e.g., nurses, physicians). Strategies to enhance clinician engagement in active alarm management in pediatric acute care have not been well explored. Access to alarm summary metrics may enhance clinician engagement. Objective: To lay the foundation for intervention development, we sought to identify functional specifications for formulating, packaging, and delivering alarm metrics to clinicians. Methods: Our team of clinician scientists and human factors engineers conducted focus groups with clinicians from medical-surgical inpatient units in a children's hospital. We inductively coded transcripts, developed codes into themes, and grouped themes into "current state" and "future state." Results: We conducted five focus groups with 13 clinicians (eight registered nurses and five doctors of medicine). In the current state, information exchanged among team members about alarm burden is initiated by nurses on an ad hoc basis. For a future state, clinicians identified ways in which alarm metrics could help them manage alarms and described specific information, such as alarm trends, benchmarks, and contextual data, that would support decision-making. Conclusion: We developed four recommendations for future strategies to enhance clinicians' active management of patient alarms: (1) formulate alarm metrics for clinicians by categorizing alarm rates by type and summarizing alarm trends over time, (2) package alarm metrics with contextual patient data to facilitate clinicians' sensemaking, (3) deliver alarm metrics in a forum that facilitates interprofessional discussion, and (4) provide clinician education to establish a shared mental model about alarm fatigue and evidence-based alarm-reduction strategies.

Contribution of MicroRNA-27b-3p to Synovial Fibrotic Responses in Knee Osteoarthritis.

OBJECTIVE: Synovial fibrosis contributes to osteoarthritis (OA) pathology, but the underlying mechanisms remain unknown. We have observed increased microRNA-27b-3p (miR-27b-3p) levels in synovial fluid of patients with late-stage radiographic knee OA. Here, we investigated the contribution of miR-27b-3p to synovial fibrosis in patients with severe knee OA and in a mouse model of knee OA. METHODS: We stained synovium sections obtained from patients with radiographic knee OA scored according to the Kellgren/Lawrence scale and mice that underwent destabilization of the medial meniscus (DMM) for miR-27b-3p using in situ hybridization. We examined the effects of intraarticular injection of miR-27b-3p mimic into naive mouse knee joints and intraarticular injection of a miR-27b-3p inhibitor into mouse knee joints after DMM. We performed transfection with miR-27b-3p mimic and miR-27b-3p inhibitor in human OA fibroblast-like synoviocytes (FLS) using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) array, RNA sequencing, RT-qPCR, Western blotting, immunofluorescence, and migration assays. RESULTS: We observed increased miR-27b-3p expression in the synovium from patients with knee OA and in mice with DMM-induced arthritis. Injection of the miR-27b-3p mimic in mouse knee joints induced a synovial fibrosis-like phenotype, increased synovitis scores, and increased COL1A1 and α-smooth muscle actin (α-SMA) expression. In the mouse model of DMM-induced arthritis, injection of the miR-27b-3p inhibitor decreased α-SMA but did not change COL1A1 expression levels or synovitis scores. Transfection with the miR-27b-3p mimic in human OA FLS induced profibrotic responses, including increased migration and expression of key extracellular matrix (ECM) genes, but transfection with the miR-27b-3p inhibitor had the opposite effects. RNA sequencing identified a PPARG/ADAMTS8 signaling axis regulated by miR-27b-3p in OA FLS. Human OA FLS transfected with miR-27b-3p mimic and then treated with the PPARG agonist rosiglitazone or with ADAMTS8 small interfering RNA exhibited altered expression of select ECM genes. CONCLUSION: Our findings demonstrate that miR-27b-3p has a key role in ECM regulation associated with synovial fibrosis during OA.

Effect of Colonic Absorption on the Pharmacokinetic Properties of Delayed-Release and Extended-Release Methylphenidate: In Vivo, In Vitro, and Modeling Evaluations.

Most stimulants used to treat attention-deficit/hyperactivity disorder are administered in the morning and absorbed in the upper gastrointestinal tract. DR/ER-MPH (formerly HLD200), an evening-dosed delayed-release and extended-release methylphenidate, is predicted to be absorbed in the proximal colon. The pharmacokinetic (PK) profile of DR/ER-MPH is characterized by an 8- to 10-hour delay in initial methylphenidate absorption and a subsequent gradual increase in plasma concentration, followed by a slow decline. To examine the relationship of absorption site to pharmacokinetics, the DR/ER-MPH formulation was altered to release methylphenidate in the small intestine and distal colon. The 3 formulations were administered in an open-label, 3-way, crossover study in healthy adults (N = 18). Compared with the small intestine formulation, the PK profile of the proximal colon (DR/ER-MPH) formulation exhibited a longer delay before initial methylphenidate absorption, decreased peak methylphenidate concentration, increased time to peak concentration, and decreased bioavailability; these characteristics were amplified in the distal colon formulation. Safety profiles fell within the expectations for methylphenidate products. Modeled PK profiles were similar between the small intestine formulation and a morning-dosed extended-release methylphenidate (both predicted to release methylphenidate in the upper gastrointestinal tract), providing additional evidence that the PK profile of DR/ER-MPH is shaped by colonic absorption.

Biosimilar Infliximab in Inflammatory Bowel Disease: Outcomes of a Managed Switching Programme.

BACKGROUND AND AIMS: Biosimilar infliximab CT-P13 offers the potential for large drug acquisition cost savings. However, there are limited published data regarding its efficacy, safety, and immunogenicity in inflammatory bowel disease [IBD], particularly in switching IBD patients from originator to biosimilar infliximab. We present the outcomes of a service evaluation of switching IBD patients established on originator infliximab to biosimilar, using a managed switching programme funded via a gain share agreement in a UK teaching hospital. METHODS: Evaluation outcomes included drug persistence, changes in drug acquisition costs, patient-reported side effects, adverse events, patient outcomes assessed using the IBD-control Patient-Reported Outcome Measures [PROM] questionnaire, serum drug and antibody levels, and routinely collected biochemical markers. RESULTS: A total of 143 patients with IBD [118 Crohn's disease, 23 ulcerative colitis, 2 IBD unclassified] were switched from originator infliximab to CT-P13. Patients reported a similar incidence of side effects before and after switch. No clinically significant differences were observed in mean C-reactive protein [CRP], albumin, haemoglobin levels, or platelet and white cell counts after the switch to CT-P13, whereas mean IBD-control-8 score improved from 10.4 to 11.2 [p = 0.041]. There was no significant difference in drug persistence between biosimilar and originator infliximab [p = 0.94] and no increase in immunogenicity was found. Drug acquisition costs decreased by £40,000-60,000 per month. CONCLUSIONS: A managed switching programme from originator infliximab to biosimilar CT-P13 in IBD, using a gain-share agreement, delivers significant cost savings and investment in clinical services while maintaining similar patient-reported outcomes, biochemical response, drug persistence, and adverse event profile.

The impact of an inflammatory bowel disease nurse-led biologics service.

INTRODUCTION: Southampton General Hospital provides inflammatory bowel disease (IBD) services for a population of 650 000. Biological agents have impacted hugely on IBD but are costly drugs requiring careful supervision. These challenges led us to develop a specialist nurse-led biologics service to improve patient care. METHOD: A 2010 case note audit highlighted areas for improvement in monitoring biologics and follow-up. A business case was developed to establish an IBD nurse to ensure identification and appropriate screening, education and review of biologics patients. A gain share was agreed with the local Care Commissioning Group (CCG) and £60 000 invested. Outcomes were reaudited in 2014. RESULTS: Biologic use has grown rapidly from 90 patients in 2011 to 330 in 2014. All records are now kept in a centralised database. Infection screening improved from 79% to 100%. In 2014, 96% of patients had follow-up ≤4 months post-induction to assess response, but two patients were seen at 7 months. 80% were followed up again at 9-12 months (100% at 9-14 months), all with treatment decisions. The initial investment was recouped via commissioners funding 368 additional outpatient appointments and 35 colonoscopies. Savings represented 15% total yearly biologic costs. CONCLUSIONS: The introduction of the IBD biologics nurse-led service resulted in significant gains in care quality and costs. The need for improved follow-up of patients on biologics reflects increased pressures on clinic resources across the country. With continued biologics expansion, the introduction of a biologics nurse has provided invaluable support to patients and the IBD team at Southampton General Hospital.

Comparison of the pharmacokinetics of apricitabine in the presence and absence of ritonavir-boosted tipranavir: a phase I, open-label, controlled, single-centre study.

BACKGROUND AND OBJECTIVE: Apricitabine is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. The aim of this phase I study was to investigate whether administration of apricitabine with the HIV protease inhibitor tipranavir (ritonavir-boosted) affects the pharmacokinetic profile of apricitabine. METHODS: This phase I study was conducted in 18 healthy adult male subjects. Subjects received a single dose of apricitabine 800 mg on the morning of day 1 followed by tipranavir 500 mg plus ritonavir 200 mg every 12 hours from day 2 to day 9 to achieve steady-state concentrations of tipranavir/ritonavir. On day 10, subjects received a single morning dose of apricitabine 800 mg and a single dose of tipranavir 500 mg plus ritonavir 200 mg. Following dosing on days 1, 9 and 10, pharmacokinetic sampling was undertaken over 12 hours post-dosing to determine the plasma concentrations of apricitabine and tipranavir. RESULTS: The administration of a single dose of apricitabine 800 mg in the presence of steady-state tipranavir/ritonavir concentrations resulted in an increase in the apricitabine area under the plasma concentration-time curve of approximately 40% and in the apricitabine maximum plasma concentration of approximately 25% relative to apricitabine 800 mg administered alone. Apricitabine was well tolerated when administered with tipranavir/ritonavir. CONCLUSION: A moderate increase in apricitabine exposure was seen after co-administration with ritonavir-boosted tipranavir but this increase was not of clinical significance. No adjustment of apricitabine dosing is required when administered with ritonavir-boosted tipranavir.

Genome shuffling of Lactobacillus for improved acid tolerance.

Fermentation-based bioprocesses rely extensively on strain improvement for commercialization. Whole-cell biocatalysts are commonly limited by low tolerance of extreme process conditions such as temperature, pH, and solute concentration. Rational approaches to improving such complex phenotypes lack good models and are especially difficult to implement without genetic tools. Here we describe the use of genome shuffling to improve the acid tolerance of a poorly characterized industrial strain of Lactobacillus. We used classical strain-improvement methods to generate populations with subtle improvements in pH tolerance, and then shuffled these populations by recursive pool-wise protoplast fusion. We identified new shuffled lactobacilli that grow at substantially lower pH than does the wild-type strain on both liquid and solid media. In addition, we identified shuffled strains that produced threefold more lactic acid than the wild type at pH 4.0. Genome shuffling seems broadly useful for the rapid evolution of tolerance and other complex phenotypes in industrial microorganisms.

Genome shuffling leads to rapid phenotypic improvement in bacteria.

For millennia, selective breeding, on the basis of biparental mating, has led to the successful improvement of plants and animals to meet societal needs. At a molecular level, DNA shuffling mimics, yet accelerates, evolutionary processes, and allows the breeding and improvement of individual genes and subgenomic DNA fragments. We describe here whole-genome shuffling; a process that combines the advantage of multi-parental crossing allowed by DNA shuffling with the recombination of entire genomes normally associated with conventional breeding. We show that recursive genomic recombination within a population of bacteria can efficiently generate combinatorial libraries of new strains. When applied to a population of phenotypically selected bacteria, many of these new strains show marked improvements in the selected phenotype. We demonstrate the use of this approach through the rapid improvement of tylosin production from Streptomyces fradiae. This approach has the potential to facilitate cell and metabolic engineering and provide a non-recombinant alternative to the rapid production of improved organisms.