Is there a role for biogenic amine receptors in mediating ß-phenylethylamine and RO5256390-induced vascular contraction?

BACKGROUND: Substantial evidence indicates trace amines can induce vasoconstriction independently of noradrenaline release. However, the mechanism underlying noradrenaline-independent vasoconstrictor responses to trace amines has not yet been established. This study evaluates the role of trace amine-associated receptor 1 (TAAR1) and other biogenic amine receptors in mediating ß-phenylethylamine and the TAAR-1 selective agonist RO5256390-induced vasoconstriction. METHODS: Vasoconstrictor responses to ß-PEA and the TAAR1-selective agonist, RO5256390 were assessed in vitro in endothelium-denuded aortic rings and third-order mesenteric arteries of male Sprague Dawley rats. RESULTS: ß-PEA and RO5256390 induced concentration-dependent vasoconstriction of aortic rings but not third-order mesenteric arteries. Vasoconstrictor responses in aortic rings were insensitive to antagonists of 5-HT and dopamine. The murine-selective TAAR1 antagonist, EPPTB, had no effect on either ß-PEA or RO5256390-induced vasoconstriction. The α1-adrenoceptor antagonist, prazosin, and the α2-adrenoceptor antagonist, yohimbine, induced a shift of the ß-PEA concentration response curve too small to be ascribed to antagonism of α1- or α2-adrenoceptors, respectively. The α2-adrenoceptor antagonist atipamezole had no effect on ß-PEA or RO5256390-induced vasoconstriction. CONCLUSION: Vasoconstrictor responses to trace amines are not mediated by classical biogenic amine neurotransmitter receptors. Insensitivity of ß-PEA vasoconstrictor responses to EPPTB, may be explained by its low affinity for rat rather than murine TAAR1. Therefore, TAAR1 remains the most likely candidate receptor mediating vasoconstrictor responses to trace amines and that prazosin and yohimbine have low affinity for TAAR1.

Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system.

Short-interfering RNA (siRNA) has gained significant interest for treatment of neurological diseases by providing the capacity to achieve sustained inhibition of nearly any gene target. Yet, achieving efficacious drug delivery throughout deep brain structures of the CNS remains a considerable hurdle. We herein describe a lipid-siRNA conjugate that, following delivery into the cerebrospinal fluid (CSF), is transported effectively through perivascular spaces, enabling broad dispersion within CSF compartments and through the CNS parenchyma. We provide a detailed examination of the temporal kinetics of gene silencing, highlighting potent knockdown for up to five months from a single injection without detectable toxicity. Single-cell RNA sequencing further demonstrates gene silencing activity across diverse cell populations in the parenchyma and at brain borders, which may provide new avenues for neurological disease-modifying therapies.

Assessing Inhaler Techniques of Asthma Patients Using Aerosol Inhalation Monitors (AIM): A Cross-Sectional Study.

A high percentage of asthma patients have symptoms that are not well controlled, despite effective drugs being available. One potential reason for this may be that poor inhaler technique limits the dose delivered to the lungs, thereby reducing the therapeutic efficacy. The aim of this study was to assess the prevalence of poor inhaler technique in an asthma patient population and to probe the impact of various demographic parameters on technique quality. This study was conducted at community pharmacies across Wales, UK. Patients diagnosed with asthma and 12 years or older were invited to participate. An aerosol inhalation monitor (AIM, Vitalograph®) was used to measure the quality of patient inhaler technique. A total of 295 AIM assessments were carried out. There were significant differences in the quality of inhaler technique across the different inhaler types (p < 0.001, Chi squared). The best technique was associated with dry-powder inhalers (DPI devices, 58% of 72 having good technique), compared with pressurized metered-dose inhalers (pMDI) or pMDIs with a spacer device (18% of 174 and 47% of 49 AIM assessments, respectively). There were some significant associations between gender, age, and quality of inhaler technique, as determined with adjusted odds ratios. It seems that the majority of asthmatic patients were not using their inhalers appropriately. We recommend that healthcare professionals place more emphasis on assessing and correcting inhaler technique, as poor inhaler technique might be responsible for the observed lack of symptom control in the asthma patient population.

The 5'UTR of HCoV-OC43 adopts a topologically constrained structure to intrinsically repress translation.

The emergence of SARS-CoV-2, which is responsible for the COVID-19 pandemic, has highlighted the need for rapid characterization of viral mechanisms associated with cellular pathogenesis. Viral UTRs represent conserved genomic elements that contribute to such mechanisms. Structural details of most CoV UTRs are not available, however. Experimental approaches are needed to allow for the facile generation of high-quality viral RNA tertiary structural models, which can facilitate comparative mechanistic efforts. By integrating experimental and computational techniques, we herein report the efficient characterization of conserved RNA structures within the 5'UTR of the HCoV-OC43 genome, a lab-tractable model coronavirus. We provide evidence that the 5'UTR folds into a structure with well-defined stem-loops (SLs) as determined by chemical probing and direct detection of hydrogen bonds by NMR. We combine experimental base-pair restraints with global structural information from SAXS to generate a 3D model that reveals that SL1-4 adopts a topologically constrained structure wherein SLs 3 and 4 coaxially stack. Coaxial stacking is mediated by short linker nucleotides and allows SLs 1 to 2 to sample different cojoint orientations by pivoting about the SL3,4 helical axis. To evaluate the functional relevance of the SL3,4 coaxial helix, we engineered luciferase reporter constructs harboring the HCoV-OC43 5'UTR with mutations designed to abrogate coaxial stacking. Our results reveal that the SL3,4 helix intrinsically represses translation efficiency since the destabilizing mutations correlate with increased luciferase expression relative to wildtype without affecting reporter mRNA levels, thus highlighting how the 5'UTR structure contributes to the viral mechanism.

Encoded Conformational Dynamics of the HIV Splice Site A3 Regulatory Locus: Implications for Differential Binding of hnRNP Splicing Auxiliary Factors.

Alternative splicing of the HIV transcriptome is controlled through cis regulatory elements functioning as enhancers or silencers depending on their context and the type of host RNA binding proteins they recruit. Splice site acceptor A3 (ssA3) is one of the least used acceptor sites in the HIV transcriptome and its activity determines the levels of tat mRNA. Splice acceptor 3 is regulated by a combination of cis regulatory sequences, auxiliary splicing factors, and presumably RNA structure. The mechanisms by which these multiple regulatory components coordinate to determine the frequency in which ssA3 is utilized is poorly understood. By NMR spectroscopy and phylogenetic analysis, we show that the ssA3 regulatory locus is conformationally heterogeneous and that the sequences that encompass the locus are conserved across most HIV isolates. Despite the conformational heterogeneity, the major stem loop (A3SL1) observed in vitro folds to base pair the Polypyrimdine Tract (PPyT) to the Exon Splicing Silencer 2p (ESS2p) element and to a conserved downstream linker. The 3D structure as determined by NMR spectroscopy further reveals that the A3 consensus cleavage site is embedded within a unique stereochemical environment within the apical loop, where it is surrounded by alternating base-base interactions. Despite being described as a receptor for hnRNP H, the ESS2p element is sequestered by base pairing to the 3' end of the PPyT and within this context it cannot form a stable complex with hnRNP H. By comparison, hnRNP A1 directly binds to the A3 consensus cleavage site located within the apical loop, suggesting that it can directly modulate U2AF assembly. Sequence mutations designed to destabilize the PPyT:ESS2p helix results in an increase usage of ssA3 within HIV-infected cells, consistent with the PPyT becoming more accessible for U2AF recognition. Additional mutations introduced into the downstream ESS2 element synergize with ESS2p to cause further increases in ssA3 usage. When taken together, our work provides a unifying picture by which cis regulatory sequences, splicing auxiliary factors and RNA structure cooperate to provide stringent control over ssA3. We describe this as the pair-and-lock mechanism to restrict access of the PPyT, and posit that it operates to regulate a subset of the heterogenous structures encompassing the ssA3 regulatory locus.

Stakeholders' Views about the Management of Stable Chronic Conditions in Community Pharmacies.

The role of the community pharmacist has evolved to include the provision of more clinical services for patients. Those people who have stable chronic conditions will be managed in community pharmacies. This qualitative study used semi-structured in-depth interviews to understand the potential of providing additional patient-centred care for patients with stable chronic conditions in community pharmacies and identify potential limitations of this approach. Participants were recruited from Welsh Government, Local Health Boards (LHBS), Community Pharmacy Wales (CPW) and the Royal Pharmaceutical Society Wales (RPSW). The interviews were audio-recorded, transcribed verbatim, and analysed thematically. Eight interviews were conducted. The identified themes were as follows: (1) inconsistency and bureaucracy in commissioning pharmacy services; (2) availability of funding and resources; (3) disagreement and uncertainty about the contribution of the community pharmacy sector; (4) continuity of patient medical information and fragmented care; (5) accessibility, capacity and facilities in community pharmacy; (6) pharmacy education and clinical expertise, and (7) patient acceptability. It was clear that the potential benefit of managing stable chronic diseases in community pharmacies was recognised; however, several limitations expressed by stakeholders of pharmacy services need to be considered prior to moving forward.

The Effect of Optic Nerve Sheath Fenestration on Intraocular Pressure in Patients With Idiopathic Intracranial Hypertension.

BACKGROUND: To evaluate the change in intraocular pressure (IOP) in patients with idiopathic intracranial hypertension (IIH) who underwent optic nerve sheath fenestration (ONSF) and to determine if radiographic evidence of posterior scleral or globe indentation influenced IOP. METHODS: This is a retrospective analysis of IOP in IIH patients who underwent ONSF. The study included all patients from September 2010 to March 2018 operated on by a single surgeon (R.M.). IOPs preoperatively and postoperatively were recorded along with the acetazolamide dosage and whether there was evidence of posterior scleral or globe indentation on preoperative MRI. RESULTS: A total of 29 patients (35 eyes) with IIH underwent ONSF. The average reduction in IOP among all patients was 1.24 mm Hg (P = 0.0218), but this increased to 2.69 mm Hg (P = 0.004) in patients who were maintained on the same dosage of acetazolamide in the preoperative and postoperative period. Furthermore, the reduction in IOP in those with posterior scleral or globe indentation was 2.5 mm Hg (P = 0.0095). When the perioperative period was evaluated, the mean decrease in IOP was 1.83 mm Hg (P = 0.0217). CONCLUSIONS: Reducing the cerebral spinal fluid pressure (CSFP) at the level of the intraorbital optic nerve through an ONSF can slightly reduce the IOP. In those with evidence of posterior globe or scleral indentation/flattening, the reduction in IOP was higher, which supports the theory that CSF pressure indents the globe and leads to an increase in IOP. Although these changes in IOP are small, this study provides further evidence for a connection between IOP and CSFP.

Complex decay dynamics of HIV virions, intact and defective proviruses, and 2LTR circles following initiation of antiretroviral therapy.

In persons living with HIV-1 (PLWH) who start antiretroviral therapy (ART), plasma virus decays in a biphasic fashion to below the detection limit. The first phase reflects the short half-life (<1 d) of cells that produce most of the plasma virus. The second phase represents the slower turnover (t1/2 = 14 d) of another infected cell population, whose identity is unclear. Using the intact proviral DNA assay (IPDA) to distinguish intact and defective proviruses, we analyzed viral decay in 17 PLWH initiating ART. Circulating CD4+ T cells with intact proviruses include few of the rapidly decaying first-phase cells. Instead, this population initially decays more slowly (t1/2 = 12.9 d) in a process that largely represents death or exit from the circulation rather than transition to latency. This more protracted decay potentially allows for immune selection. After ∼3 mo, the decay slope changes, and CD4+ T cells with intact proviruses decay with a half-life of 19 mo, which is still shorter than that of the latently infected cells that persist on long-term ART. Two-long-terminal repeat (2LTR) circles decay with fast and slow phases paralleling intact proviruses, a finding that precludes their use as a simple marker of ongoing viral replication. Proviruses with defects at the 5' or 3' end of the genome show equivalent monophasic decay at rates that vary among individuals. Understanding these complex early decay processes is important for correct use of reservoir assays and may provide insights into properties of surviving cells that can constitute the stable latent reservoir.

Considerations on the use of carbon and nitrogen isotopic ratios for sediment fingerprinting.

Carbon and nitrogen stable isotopic ratios are increasingly used in sediment fingerprinting studies. However, questions remain regarding tracer conservativeness during sediment transport and other error considerations. We investigate conservativeness processes, including carbon oxidation and nitrogen mineralization, using experiments. We also test how other considerations impact the isotopic ratios including algae accrual into temporary sediment deposits in the river, the physical loss of organic matter via disaggregation, concentration dependent mixing, and time-varying isotopic ratios of sediment sources. Results show all processes and considerations can change isotope abundance, however, significance varied. Carbon oxidation, nitrogen mineralization and upland seasonality of sediment sources did not significantly change isotopic ratios. Algae accrual, concentration dependency mixing, physical loss of organic matter during transport, and seasonality of the in-stream sediment source significantly changed the isotopic ratios for the conditions tested. Fertilization significantly impacted the stable carbon isotopic ratio in one case considered. Results from sediment fingerprinting simulations and testing how well the virtual mixture fits the mass balance equation agreed with significance results for tracer changes, and some uncertainty considerations changed fractional contribution of sources by as much as 50%. A noteworthy recommendation is the mean isotopic ratios of sediment sources should be separated by at least 1‰ to lessen tracer conservativeness concerns in fingerprinting simulation. We recommend concentration dependent mixing becomes the accepted practice when using isotopic ratios, however, we warn against using particle size corrections. We recommend the loss of organic matter during disaggregation be accounted for in fingerprinting estimates. We recommend algae accrual in in-stream sediment deposits should either be accounted for or in-stream sediment should be treated as a time-varying source in sediment fingerprinting simulations. Finally, we recommend both the carbon and nitrogen isotopic ratio should be tested as potential tracers because the two tracers performed similarly when testing how well the virtual mixture fits the mass balance equations.

Pediatric surgical site infection (SSI) following ambulatory surgery: Incidence, risk factors and patient outcomes.

BACKGROUND: Inpatient surgical site infections (SSIs) cause morbidity in children. The SSI rate among pediatric ambulatory surgery patients is less clear. To fill this gap, we conducted a multiple-institution, retrospective epidemiologic study to identify incidence, risk factors, and outcomes. METHODS: We identified patients aged <22 years with ambulatory visits between October 2010 and September 2015 via electronic queries at 3 medical centers. We performed sample chart reviews to confirm ambulatory surgery and adjudicate SSIs. Weighted Poisson incidence rates were calculated. Separately, we used case-control methodology using multivariate backward logistical regression to assess risk-factor association with SSI. RESULTS: In total, 65,056 patients were identified by queries, and we performed complete chart reviews for 13,795 patients; we identified 45 SSIs following ambulatory surgery. The weighted SSI incidence following pediatric ambulatory surgery was 2.00 SSI per 1,000 ambulatory surgeries (95% confidence interval [CI], 1.37-3.00). Integumentary surgeries had the highest weighted SSI incidence, 3.24 per 1,000 ambulatory surgeries (95% CI, 0.32-12). The following variables carried significantly increased odds of infection: clean contaminated or contaminated wound class compared to clean (odds ratio [OR], 9.8; 95% CI, 2.0-48), other insurance type compared to private (OR, 4.0; 95% CI, 1.6-9.8), and surgery on weekend day compared to weekday (OR, 30; 95% CI, 2.9-315). Of the 45 instances of SSI following pediatric ambulatory surgery, 40% of patients were admitted to the hospital and 36% required a new operative procedure or bedside incision and drainage. CONCLUSIONS: Our findings suggest that morbidity is associated with SSI following ambulatory surgery in children, and we also identified possible targets for intervention.

Simulation-Based Mastery Learning Improves Ultrasound-Guided Peripheral Intravenous Catheter Insertion Skills of Practicing Nurses.

INTRODUCTION: Difficult intravenous (IV) access (DIVA) is frequently encountered in the hospital setting. Ultrasound-guided peripheral IV catheter (USGPIV) insertion has emerged as an effective procedure to establish access in patients with DIVA. Despite the increased use of USGPIV, little is known about the optimal training paradigms for bedside nurses. Therefore, we developed and evaluated a novel, sustainable, USGPIV simulation-based mastery learning (SBML) curriculum for nurses. METHODS: This is a prospective cohort study of an USGPIV SBML training program for bedside nurses over a 12-month period. We evaluated skills and self-confidence before and after training and measured the proportion of the nurses achieving independent, proctor, and instructor status. Procedure logs and surveys were used to explore the nurse experience and utilization of USGPIV on real patients with DIVA 3 months after the intervention. RESULTS: Two hundred thirty-eight nurses enrolled in the study. The USGPIV skill checklist scores increased from median of 6.0 [interquartile range = 4.0-9.0 (pretest) to 29.0, interquartile range = 28-30 (posttest), P < 0.001]. The USGPIV confidence improved from before (mean = 2.32, SD = 1.17) to after (mean = 3.85, SD = 0.73, P < 0.001) training (5-point Likert scale). Sixty-two percent of the nurses enrolled achieved independent status, 47.5% became proctors, and 11.3% course trainers. At 3-month posttraining, the nurses had attempted a mean of 35.6 USGPIV insertions with an 89.5% success rate. CONCLUSIONS: This novel USGPIV SBML curriculum improves nurses' insertion skills, self-confidence, and progresses patient care through USGPIV insertions on hospitalized patients with DIVA.

Central Venous Catheter Salvage in Ambulatory Central Line-Associated Bloodstream Infections.

BACKGROUND: Guidelines for treatment of central line-associated bloodstream infection (CLABSI) recommend removing central venous catheters (CVCs) in many cases. Clinicians must balance these recommendations with the difficulty of obtaining alternate access and subjecting patients to additional procedures. In this study, we evaluated CVC salvage in pediatric patients with ambulatory CLABSI and associated risk factors for treatment failure. METHODS: This study was a secondary analysis of 466 ambulatory CLABSIs in patients <22 years old who presented to 5 pediatric medical centers from 2010 to 2015. We defined attempted CVC salvage as a CVC left in place ≥3 days after a positive blood culture result. Salvage failure was removal of the CVC ≥3 days after CLABSI. Successful salvage was treatment of CLABSI without removal of the CVC. Bivariate and multivariable logistic regression analyses were used to test associations between risk factors and attempted and successful salvage. RESULTS: A total of 460 ambulatory CLABSIs were included in our analysis. CVC salvage was attempted in 379 (82.3%) cases. Underlying diagnosis, CVC type, number of lumens, and absence of candidemia were associated with attempted salvage. Salvage was successful in 287 (75.7%) attempted cases. Underlying diagnosis, CVC type, number of lumens, and absence of candidemia were associated with successful salvage. In patients with malignancy, neutropenia within 30 days before CLABSI was significantly associated with both attempted salvage and successful salvage. CONCLUSIONS: CVC salvage was often attempted and was frequently successful in ambulatory pediatric patients presenting with CLABSI.

Pediatric Ambulatory Central Line-Associated Bloodstream Infections.

BACKGROUND: Inpatient pediatric central line-associated bloodstream infections (CLABSIs) cause morbidity and increased health care use. Minimal information exists for ambulatory CLABSIs despite ambulatory central line (CL) use in children. In this study, we identified ambulatory pediatric CLABSI incidence density, risk factors, and outcomes. METHODS: Retrospective cohort with nested case-control study at 5 sites from 2010 through 2015. Electronic queries were used to identify potential cases on the basis of administrative and laboratory data. Chart review was used to confirm ambulatory CL use and adjudicated CLABSIs. Bivariate followed by multivariable backward logistic regression was used to identify ambulatory CLABSI risk factors. RESULTS: Queries identified 4600 potentially at-risk children; 1658 (36%) had ambulatory CLs. In total, 247 (15%) patients experienced 466 ambulatory CLABSIs with an incidence density of 0.97 CLABSIs per 1000 CL days. Incidence density was highest among patients with tunneled externalized catheters versus peripherally inserted central catheters and totally implanted devices: 2.58 CLABSIs per 1000 CL days versus 1.46 vs 0.23, respectively (P < .001). In a multivariable model, clinic visit (odds ratio [OR] 2.8; 95% confidence interval [CI]: 1.4-5.5) and low albumin (OR 2.3; 95% CI: 1.2-4.3) were positively associated with CLABSI, and prophylactic antimicrobial agents for underlying conditions within the preceding 30 days (OR 0.22; 95% CI: 0.12-0.40) and operating room CL placement (OR 0.36; 95% CI: 0.16-0.79) were inversely associated with CLABSI. A total of 396 patients (85%) were hospitalized because of ambulatory CLABSI with an 8-day median length of stay (interquartile range 5-13). CONCLUSIONS: Ambulatory pediatric CLABSI incidence density is appreciable and associated with health care use. CL type, patients with low albumin, prophylactic antimicrobial agents, and placement setting may be targets for reduction efforts.

Characterization of Negative Allosteric Modulators of the Calcium-Sensing Receptor for Repurposing as a Treatment of Asthma.

Asthma is still an incurable disease, and there is a recognized need for novel small-molecule therapies for people with asthma, especially those poorly controlled by current treatments. We previously demonstrated that calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs), calcilytics, uniquely suppress both airway hyperresponsiveness (AHR) and inflammation in human cells and murine asthma surrogates. Here we assess the feasibility of repurposing four CaSR NAMs, which were originally developed for oral therapy for osteoporosis and previously tested in the clinic as a novel, single, and comprehensive topical antiasthma therapy. We address the hypotheses, using murine asthma surrogates, that topically delivered CaSR NAMs 1) abolish AHR; 2) are unlikely to cause unwanted systemic effects; 3) are suitable for topical application; and 4) inhibit airway inflammation to the same degree as the current standard of care, inhaled corticosteroids, and, furthermore, inhibit airway remodeling. All four CaSR NAMs inhibited poly-L-arginine-induced AHR in naïve mice and suppressed both AHR and airway inflammation in a murine surrogate of acute asthma, confirming class specificity. Repeated exposure to inhaled CaSR NAMs did not alter blood pressure, heart rate, or serum calcium concentrations. Optimal candidates for repurposing were identified based on anti-AHR/inflammatory activities, pharmacokinetics/pharmacodynamics, formulation, and micronization studies. Whereas both inhaled CaSR NAMs and inhaled corticosteroids reduced airways inflammation, only the former prevented goblet cell hyperplasia in a chronic asthma model. We conclude that inhaled CaSR NAMs are likely a single, safe, and effective topical therapy for human asthma, abolishing AHR, suppressing airways inflammation, and abrogating some features of airway remodeling. SIGNIFICANCE STATEMENT: Calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs) reduce airway smooth muscle hyperresponsiveness, reverse airway inflammation as efficiently as topical corticosteroids, and suppress airway remodeling in asthma surrogates. CaSR NAMs, which were initially developed for oral therapy of osteoporosis proved inefficacious for this indication despite being safe and well tolerated. Here we show that structurally unrelated CaSR NAMs are suitable for inhaled delivery and represent a one-stop, steroid-free approach to asthma control and prophylaxis.

Use of Physician-Estimated and Patient Self-Reported Weights to Guide Initial Fluid Resuscitation in Emergency Department Patients With Suspected Sepsis.

BACKGROUND: Knowledge of patient weight is required to guide initial intravenous fluid therapy for patients with sepsis-associated hypotension or elevated lactate. Previous studies have shown patients are better estimators of their weight than medical providers are; critically ill patients, however, may be unable to provide this information. OBJECTIVES: This study compares the accuracy of physician-estimated and patient self-reported weights to subsequent inpatient bed/stretcher scale weights for guiding initial protocol-based intravenous fluid therapy in the treatment of emergency department patients with suspected sepsis. METHODS: Adult patients presenting with a suspected diagnosis of severe sepsis to a large, urban, academic emergency department had either physician-estimated or patient self-reported weights recorded on presentation. All patients had subsequent inpatient bed/stretcher scale weights recorded on the first day of hospitalization. RESULTS: Physician-estimated and patient self-reported weights linearly correlated (P < .001) with inpatient bed/stretcher scale weights. Median accuracy error for physicians (5.4% [2.0-10.1]) and patients (3.9% [1.6-6.4]) was not significantly different (P = .28). Physician-estimated and patient self-reported weights accuracy was determined at multiple levels: within 5% (46%, 57%, respectively), 10% (75%, 90%), 15% (90%, 95%), and 20% (100%, 95%) error tolerances, as well accurate estimates within 5 kg (69.2%, 70.0%). CONCLUSIONS: Both physician-estimated and patient self-reported weights are reliable when calculating initial protocol-based intravenous fluid resuscitation for emergency department patients with sepsis.

Difficult intravenous access in the emergency department: Performance and impact of ultrasound-guided IV insertion performed by nurses.

BACKGROUND: Difficult intravenous access (DIVA) is a common problem in Emergency Departments (EDs), yet the prevalence and clinical impact of this condition is poorly understood. Ultrasound-guided peripheral intravenous catheter (USGPIV) insertion is a successful modality for obtaining intravenous (IV) access in patients with DIVA. OBJECTIVES: We aimed to describe the prevalence of DIVA, explore how DIVA affects delivery of care, and determine if nurse insertion of USGPIV improves care delays among patients with DIVA. METHODS: We retrospectively queried the electronic medical record for all ED patients who had a peripheral IV (PIV) inserted at a tertiary academic medical center from 2015 to 2017. We categorized patients as having DIVA if they required ≥3 PIV attempts or an USGPIV. We compared metrics for care delivery including time-to-IV-access, time-to-laboratory-results, time-to-IV-analgesia, and ED length of stay (LOS) between patients with and without DIVA. We also compared these metrics in patients with DIVA with a physician-inserted USGPIV versus those with a nurse-inserted USGPIV. RESULTS: A total of 147,260 patients were evaluated during the study period. Of these, 13,192 (8.9%) met criteria for DIVA. Patients with DIVA encountered statistically significant delays in time-to-IV-access, time-to-laboratory-results, time-to-IV-analgesia, and ED LOS compared to patients without DIVA (all p < 0.001). Patients with nurse-inserted USGPIVs also had statistically significant improvements in time-to-IV-access, time-to-laboratory-results, time-to-IV-analgesia, and ED LOS compared to patients with physician-inserted USGPIVs (all p < 0.001). CONCLUSION: DIVA affects many ED patients and leads to delays in PIV access-related care. Nurse insertion of USGPIVs improves care in patients with DIVA.

Critical Evaluation of Biomechanical Principles and Radiographic Indicators for Fusion Assessment in a Novel Conformable Porous Mesh Implant.

INTRODUCTION: The objectives of this paper were to identify and explain specific design factors for lumbar interbody fusion (IBF) devices that can influence bone exchange and stability at the vertebral endplate interface and to provide supporting evidence of these factors through both laboratory and clinical data. The laboratory study (Part 1) compared the pressure profiles and contact areas for a minimally invasive, expandable, and conformable porous mesh (CPM) IBF device and a rigid monolithic lateral PEEK cage (LPC). Furthermore, to demonstrate how these laboratory results translate clinically, a quantitative and qualitative assessment of subject x-rays and computed tomography (CT) scans from a US Food and Drug Administration (FDA) investigational device exemption (IDE) trial of the CPM was performed (Part 2). METHODS: Part 1: Load profile testing. Either CPM or LPC was sandwiched between 2 flat or shaped Grade 15 foam blocks. Each implant type was compressed at a rate of 0.1 mm/s for 3 loads (1100, 2000, or 3000 N). Device and bone graft contact area were analyzed for each test condition, and corresponding load profiles were quantified and mapped using pressure film. Part 2: Radiographic fusion assessment. Two independent radiologists analyzed 12- and 24-month motion studies and CTs for fusion, defined as bridging bone across the intervertebral space. The same CTs were assessed for qualitative biomechanical signs of bone healing. RESULTS: CPM demonstrated significant direct loading on the bone graft across all tested loading conditions, while the LPC graft registered a negligible amount of pressure at only the extreme load of 3000 N. Contact area was in turn statistically greater (P < .05) for CPM. CPM fusion rates were 97.9% and 99% at 12 and 24 months, respectively. Radiographic signs of bone healing are described in terms of radiating bone struts and regions of greater intensity. CONCLUSIONS: CPM allows for an optimized contact area for bone exchange and graft incorporation. The load profiles demonstrate widespread load sharing across the device. The expandable, compliant, porous mesh provides a unique area for bone exchange, contributing to qualitative biomechanical radiographic evidence of bone healing that ultimately leads to clinically acceptable fusion rates as observed in the FDA IDE trial.

Impacts of preferential flow and agroecosystem management on subsurface particulate phosphorus loadings in tile-drained landscapes.

Recent research on tile-drainage has placed emphasis on dissolved reactive phosphorus (DRP) delivery and transport pathways but less emphasis on particulate P (PP), resulting in its exclusion from agricultural water management models. In this study, we quantified the fluxes, mechanisms, and factors driving PP delivery into tiles through statistical analysis of a long-term hydrologic and water quality dataset. The dataset includes 5 yr of surface and tile discharge, total P (TP), DRP, total nitrogen (TN), and dissolved inorganic N concentrations from two edge-of-field study sites with contrasting soil and management practices. Hydrograph recession techniques were coupled with multiple linear regression for understanding hydrologic flow pathways, and empirical mode decomposition (EMD) time-series analysis was used to determine the significance of PP seasonality processes and the effect of management practices. The analysis of hydrologic flow pathways demonstrated that quickflow contributed 66 and 36% of subsurface discharge in the clay and loam sites, respectively. Phosphorus loading analysis showed that macropore flow plays a significant role in PP delivery to subsurface P loading and that PP significantly contributed to TP and DRP delivery; however, greater PP loadings were observed at the clay site despite greater subsurface discharge and soil test P levels at the loam site. Furthermore, PP delivery was significantly affected by environmental conditions and management practices. We highlight the efficacy of hydrograph recession analysis for identifying macropore and diffuse drainage, of P/N ratios to characterize sediment delivery mechanisms in tiles, and of EMD to detect management impacts on TP and DRP at the field scale.

Costs of ambulatory pediatric healthcare-associated infections: Central-line-associated bloodstream infection (CLABSIs), catheter-associated urinary tract infection (CAUTIs), and surgical site infections (SSIs).

OBJECTIVE: Ambulatory healthcare-associated infections (HAIs) occur frequently in children and are associated with morbidity. Less is known about ambulatory HAI costs. This study estimated additional costs associated with pediatric ambulatory central-line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTI), and surgical site infections (SSIs) following ambulatory surgery. DESIGN: Retrospective case-control study. SETTING: Four academic medical centers. PATIENTS: Children aged 0-22 years seen between 2010 and 2015 and at risk for HAI as identified by electronic queries. METHODS: Chart review adjudicated HAIs. Charges were obtained for patients with HAIs and matched controls 30 days before HAI, on the day of, and 30 days after HAI. Charges were converted to costs and 2015 USD. Mixed-effects linear regression was used to estimate the difference-in-differences of HAI case versus control costs in 2 models: unrecorded charge values considered missing and a sensitivity analysis with unrecorded charge considered $0. RESULTS: Our search identified 177 patients with ambulatory CLABSIs, 53 with ambulatory CAUTIs, and 26 with SSIs following ambulatory surgery who were matched with 382, 110, and 75 controls, respectively. Additional cost associated with an ambulatory CLABSI was $5,684 (95% confidence interval [CI], $1,005-$10,362) and $6,502 (95% CI, $2,261-$10,744) in the 2 models; cost associated with a CAUTI was $6,660 (95% CI, $1,055, $12,145) and $2,661 (95% CI, -$431 to $5,753); cost associated with an SSI following ambulatory surgery at 1 institution only was $6,370 (95% CI, $4,022-$8,719). CONCLUSIONS: Ambulatory HAI in pediatric patients are associated with significant additional costs. Further work is needed to reduce ambulatory HAIs.

Pediatric ambulatory catheter-associated urinary tract infections (CAUTIs): Incidence, risk factors, and patient outcomes.

OBJECTIVE: Catheter-associated urinary tract infections (CAUTIs) occur frequently in pediatric inpatients, and they are associated with increased morbidity and cost. Few studies have investigated ambulatory CAUTIs, despite at-risk children utilizing home urinary catheterization. This retrospective cohort and case-control study determined incidence, risk factors, and outcomes of pediatric patients with ambulatory CAUTI. DESIGN: Broad electronic queries identified potential patients with ambulatory urinary catheters, and direct chart review confirmed catheters and adjudicated whether ambulatory CAUTI occurred. CAUTI definitions included clean intermittent catheterization (CIC). Our matched case-control analysis assessed risk factors. SETTING: Five urban, academic medical centers, part of the New York City Clinical Data Research Network. PATIENTS: Potential patients were age <22 years who were seen between October 2010 and September 2015. RESULTS: In total, 3,598 eligible patients were identified; 359 of these used ambulatory catheterization (representing186,616 ambulatory catheter days). Of these, 63 patients (18%) experienced 95 ambulatory CAUTIs. The overall ambulatory CAUTI incidence was 0.51 infections per 1,000 catheter days (1.35 for indwelling catheters and 0.47 for CIC; incidence rate ratio, 2.88). Patients with nonprivate medical insurance (odds ratio, 2.5; 95% confidence interval, 1.1-6.3) were significantly more likely to have ambulatory CAUTIs in bivariate models but not multivariable models. Also, 45% of ambulatory CAUTI resulted in hospitalization (median duration, 3 days); 5% resulted in intensive care admission; 47% underwent imaging; and 88% were treated with antibiotics. CONCLUSIONS: Pediatric ambulatory CAUTIs occur in 18% of patients with catheters; they are associated with morbidity and healthcare utilization. Ambulatory indwelling catheter CAUTI incidence exceeded national inpatient incidence. Future quality improvement research to reduce these harmful infections is warranted.