Machine Learning Differentiates Extracorporeal Membrane Oxygenation Mortality Risk Profiles Among Trauma Patients.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is resource intensive with high mortality. Identifying trauma patients most likely to derive a survival benefit remains elusive despite current ECMO guidelines. Our objective was to identify unique patient risk profiles using the largest database of trauma patients available. METHODS: ECMO patients ≥16 years were identified using Trauma Quality Improvement Program data (2010-2019). Machine learning K-median clustering (ML) utilized 101 variables including injury severity, demographics, comorbidities, and hospital stay information to generate unique patient risk profiles. Mortality and patient and center characteristics were evaluated across profiles. RESULTS: A total of 1037 patients were included with 33% overall mortality, mean age 32 years, and median ISS = 26. The ML identified 3 unique patient risk profile groups. Although mortality rates were equivalent across the 3 groups, groups were distinguished by (Group 1) young (median 25 years), severely injured (ISS = 34) patients with thoracic and head injuries (99%) via blunt mechanism (93%), and a high prevalence of ARDS (77%); (Group 2) relatively young (median 30 years) and moderately injured (ISS = 22) patients with exposure-related injuries (11%); and (Group 3) older (median 46 years) patients with a high proportion of comorbidities (69%) and extremity injuries (100%). There were no differences based on center ECMO volume, teaching status, or ACS-Level across all 3 groups. CONCLUSION: Machine learning compliments traditional analyses by identifying unique mortality risk profiles for trauma patients receiving ECMO. These details can further inform treatment guidelines, clinical decision making, and institutional criteria for ECMO usage.

To the point: Utility of laparoscopy for operative management of stabbing abdominal trauma.

BACKGROUND: Algorithms for managing penetrating abdominal trauma are conflicting or vague regarding the role of laparoscopy. We hypothesized that laparoscopy is underutilized among hemodynamically stable patients with abdominal stab wounds. METHODS: Trauma Quality Improvement Program data (2016-2019) were used to identify stable (SBP ≥110 and GCS ≥13) patients ≥16yrs with stab wounds and an abdominal procedure within 24hr of admission. Patients with a non-abdominal AIS ≥3 or missing outcome information were excluded. Patients were analyzed based on index procedure approach: open, therapeutic laparoscopy (LAP), or LAP-conversion to open (LCO). Center, clinical characteristics and outcomes were compared according to surgical approach and abdominal AIS using non-parametric analysis. RESULTS: 5984 patients met inclusion criteria with 7 â€‹% and 8 â€‹% receiving therapeutic LAP and LCO, respectively. The conversion rate for patients initially treated with LAP was 54 â€‹%. Compared to conversion or open, therapeutic LAP patients had better outcomes including shorter ICU and hospital stays and less infection complications, but were younger and less injured. Assessing by abdominal AIS eliminated ISS differences, meanwhile LAP patients still had shorter hospital stays. At time of admission, 45 â€‹% of open patients met criteria for initial LAP opportunity as indicated by comparable clinical presentation as therapeutic laparoscopy patients. CONCLUSIONS: In hemodynamically stable patients, laparoscopy remains infrequently utilized despite its increasing inclusion in current guidelines. Additional opportunity exists for therapeutic laparoscopy in trauma, which appears to be a viable alternative to open surgery for select injuries from abdominal stab wounds. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Developing a user-friendly report for electronically assisted surveillance of catheter-associated urinary tract infection.

Catheter-associated urinary tract infection (CAUTI) surveillance is labor intensive, generally involving manual medical record review. We developed a prototype automated report through iterative design. Surveys and qualitative interviews were administered to key stakeholders to assess the report design. We found that different provider types expressed different needs regarding report content and format. Therefore, determining the primary audience for reporting data on CAUTI a priori is critical to developing useful reports, particularly as this process becomes standardized and automated.

User-centered design of discharge warnings tool for colorectal surgery patients.

OBJECTIVES: Readmission following colorectal surgery, typically due to surgery-related complications, is common. Patient-centered discharge warnings may guide recognition of early complication signs after colorectal surgery. MATERIALS AND METHODS: User-centered design of a discharge warnings tool consisted of iterative health literacy review and a heuristic evaluation with human factors and clinical experts as well as patient end users to establish content validity and usability. RESULTS: Literacy evaluation of the prototype suggested >12th-grade reading level. Subsequent revisions reduced reading level to 8th grade or below. Contents were formatted during heuristic evaluation into 3 action-oriented zones (green, yellow, and red) with relevant warning lexicons. Usability testing demonstrated comprehension of this 3-level lexicon and recognition of appropriate patient actions to take for each level. DISCUSSION: We developed a discharge warnings tool for colorectal surgery using staged user-centered design. The lexicon of surgical discharge warnings could structure communication among patients, caregivers, and clinicians to improve post-discharge care.

Theory-based and evidence-based design of audit and feedback programmes: examples from two clinical intervention studies.

BACKGROUND: Audit and feedback (A&F) is a common intervention used to change healthcare provider behaviour and, thus, improve healthcare quality. Although A&F can be effective its effectiveness varies, often due to the details of how A&F interventions are implemented. Some have suggested that a suitable conceptual framework is needed to organise the elements of A&F and also explain any observed differences in effectiveness. Through two examples from applied research studies, this article demonstrates how a suitable explanatory theory (in this case Kluger & DeNisi's Feedback Intervention Theory (FIT)) can be systematically applied to design better feedback interventions in healthcare settings. METHODS: Case 1: this study's objective was to reduce inappropriate diagnosis of catheter-associated urinary tract infections (CAUTI) in inpatient wards. Learning to identify the correct clinical course of action from the case details was central to this study; consequently, the feedback intervention featured feedback elements that FIT predicts would best activate learning processes (framing feedback in terms of group performance and providing of correct solution information). We designed a highly personalised, interactive, one-on-one intervention with healthcare providers to improve their capacity to distinguish between CAUTI and asymptomatic bacteruria (ASB) and treat ASB appropriately. Case 2: Simplicity and scalability drove this study's intervention design, employing elements that FIT predicted positively impacted effectiveness yet still facilitated deployment and scalability (eg, delivered via computer, delivered in writing). We designed a web-based, report-style feedback intervention to help primary care physicians improve their care of patients with hypertension. RESULTS: Both studies exhibited significant improvements in their desired outcome and in both cases interventions were received positively by feedback recipients. SUMMARY: A&F has been a popular, yet inconsistently implemented and variably effective tool for changing healthcare provider behaviour and, improving healthcare quality. Through the systematic use of theory such as FIT, robust feedback interventions can be designed that yield greater effectiveness. Future work should look to comparative effectiveness of specific design elements and contextual factors that identify A&F as the optimal intervention to effectuate healthcare provider behaviour change. TRIAL REGISTRATION NUMBER: NCT01052545, NCT00302718; post-results.

Toward more usable electronic voting: testing the usability of a smartphone voting system.

OBJECTIVE: The goal of this research was to assess the usability of a voting system designed for smart-phones. BACKGROUND: Smartphones offer remote participation in elections through the use of pervasive technology. Voting on these devices could, among other benefits, increase voter participation while allowing voters to use familiar technology. However, the usability of these systems has not been assessed. METHOD: A mobile voting system optimized for use on a smartphone was designed and tested against traditional voting platforms for usability. RESULTS: There were no reliable differences between the smartphone-based system and other voting methods in efficiency and perceived usability. More important, though, smartphone owners committed fewer errors on the mobile voting system than on the traditional voting systems. CONCLUSION: Even with the known limitations of small mobile platforms in both displays and controls, a carefully designed system can provide a usable voting method. Much of the concern about mobile voting is in the area of security; therefore, although these results are promising, security concerns and usability issues arising from mitigating them must be strongly considered. APPLICATION: The results of this experiment may help to inform current and future election and public policy officials about the benefits of allowing voters to vote with familiar hardware.

A Q-like transcription factor regulates biofilm development in Escherichia coli by controlling expression of the DLP12 lysis cassette.

The DLP12 lysis cassette (essD, ybcT, rzpD/rzoD) is required in certain Escherichia coli strains for normal curli expression and biofilm development. Tightly controlled regulation of the lysis cassette is of particular importance, since its overexpression causes host cell lysis. In silico analysis revealed a putative intrinsic transcriptional terminator 100 bp upstream of essD and within 2000 bp of ybcQ (Q(DLP12)), a putative lambda (λ) Q-like antiterminator. We hypothesized that Q(DLP12) may be required for effective expression of the lysis cassette. In this work we report on the role of Q(DLP12) as a positive regulator of DLP12 lysis cassette expression. Mutants lacking Q(DLP12) exhibited a biofilm-defective phenotype analogous to that of the lysis cassette knockouts. This defect occurred through the downregulation of curli transcription, which is also consistent with that seen in the lysis cassette mutants and was restored by complementation by ectopic expression of Q(DLP12). In addition, Q(DLP12) overexpression caused cell lysis, as demonstrated by leakage of ß-galactosidase activity from cells. This was accompanied by upregulation of the DLP12 lysis cassette as demonstrated by increased essD transcription, which was documented with gfp-reporter assays, RT-PCR and chromatin immunoprecipitation (ChIP). We provide evidence that this Q-mediated effect resulted from direct interaction of Q(DLP12) with the lysis cassette promoter (essDp), as demonstrated by electrophoretic gel mobility shift assay (EMSA). We propose that Q(DLP12) encodes a functional transcriptional regulator, which promotes expression of the DLP12 lysis cassette. This work provides evidence of a regulator from a defective prophage affecting host cell physiology.

Earthworm bioassays and seedling emergence for monitoring toxicity, aging and bioaccumulation of anthropogenic waste indicator compounds in biosolids-amended soil.

Land application of biosolids (treated sewage sludge) can be an important route for introducing xenobiotic compounds into terrestrial environments. There is a paucity of available information on the effects of biosolids amendment on terrestrial organisms. In this study, the influence of biosolids and biosolids aging on earthworm (Eisenia fetida) reproduction and survival and lettuce (Lactuca sativa) seedling emergence was investigated. Earthworms were exposed to soils amended with varying quantities of biosolids (0, 1, 2, 3, or 4% dry mass). To investigate the influence of biosolids aging, the biosolids used in the study were aged for differing lengths of time (2 or 8 weeks) prior to exposure. All of the adult earthworms survived in the biosolids-amended soils at all concentrations that were aged for 2 weeks; however, only 20% of the adults survived in the soil amended with the highest concentration of biosolids and aged for 8 weeks. Reproduction as measured by mean number of juveniles and unhatched cocoons produced per treatment correlated inversely with biosolids concentration, although the effects were generally more pronounced in the 8-week aged biosolids-soil samples. Latent seedling emergence and reduced seedling fitness correlated inversely with biosolids concentration, but these effects were tempered in the 8-week aged versus the 2-week aged soil-biosolids mixtures. Anthropogenic waste indicator compounds (AWIs) were measured in the biosolids, biosolids-soil mixtures, and earthworm samples. Where possible, bioaccumulation factors (BAFs) were calculated or estimated. A wide variety of AWIs were detected in the biosolids (51 AWIs) and earthworm samples (≤19 AWI). The earthworms exposed to the 8-week aged biosolids-soil mixtures tended to accumulate greater quantities of AWIs compared to the 2-week aged mixture, suggesting that the bioavailability of some AWIs was enhanced with aging. The BAFs for a given AWI varied with treatment. Notably large BAFs were determined for some AWIs. For example, the maximum BAF determined for para-cresol, methyl salicylate, bisphenol-A, and cholesterol was greater than 100 in some treatments.

Role of DLP12 lysis genes in Escherichia coli biofilm formation.

Phages have recently been implicated as important in biofilm development, although the mechanisms whereby phages impact biofilms remain unclear. One defective lambdoid phage carried by Escherichia coli K-12 is DLP12. Among the genes found in DLP12 are essD, ybcS and rzpD/rzoD, which are homologues of the Lambda phage genes encoding cell-lysis proteins (S, R and Rz/Rz(1)). The role that these DLP12 lysis genes play in biofilm formation was examined in deletion mutants of E. coli PHL628, a curli-overproducing, biofilm-forming K-12 derivative. Strains lacking essD, ybcS and rzpD/rzoD were unable to form wild-type biofilms. While all mutants were compromised in attachment to abiotic surfaces and aggregated less well than the wild-type, the effect of the essD knockout on biofilm formation was less dramatic than that of deleting ybcS or rzpD/rzoD. These results were consistent with electron micrographs of the mutants, which showed a decreased number of curli fibres on cell surfaces. Also consistent with this finding, we observed that expression from the promoter of csgB, which encodes the curli subunits, was downregulated in the mutants. As curli production is transcriptionally downregulated in response to cell wall stress, we challenged the mutants with SDS and found them to be more sensitive to the detergent than the wild-type. We also examined the release of (14)C-labelled peptidoglycan from the mutants and found that they did not lose labelled peptidoglycan to the same extent as the wild-type. Given that curli production is known to be suppressed by N-acetylglucosamine 6-phosphate (NAG-6P), a metabolite produced during peptidoglycan recycling, we deleted nagK, the N-acetylglucosamine kinase gene, from the lysis mutants and found that this restored curli production. This suggested that deletion of the lysis genes affected cell wall status, which was transduced to the curli operon by NAG-6P via an as yet unknown mechanism. These observations provide evidence that the S, R and Rz/Rz(1) gene homologues encoded by DLP12 are not merely genetic junk, but rather play an important, though undefined, role in cell wall maintenance.

Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale.

OBJECTIVE: Spontaneous reports of sexual side effects were infrequent during placebo-controlled clinical trials of selegiline transdermal system (STS). The objective of this study was to examine the impact of STS 6 mg/24 hours on various domains of sexual function in patients with major depressive disorder (MDD), using a patient-rated questionnaire. METHOD: Data from 4 short-term (6 to 8 weeks), randomized, double-blind, placebo-controlled trials of STS in patients with MDD (DSM-IV criteria) were included in the meta-analysis (STS, N = 389; placebo, N = 400). The Medex Sexual Dysfunction Subscale was used to assess sexual interest, arousal, maintenance of interest, orgasm, and satisfaction. Estimates of the average effect of study drug on each item of sexual function and 95% confidence intervals were calculated using a fixed-effects model due to homogeneity of study means. The direct effect of STS versus placebo was estimated using multivariate regression models, with baseline item score as a covariate and controlling for improvement in depression. Analyses were performed on the total population and by gender. Data were collected between January 1997 and April 2000. RESULTS: Estimates of difference between STS and placebo demonstrated a nonsignificant trend toward a positive treatment effect of STS on most sexual function items and significant improvement in sexual satisfaction. For women, there was a significant positive effect on interest, maintaining interest during sex, and satisfaction. The direct effect of STS on changes in individual item scores was minimal in men and showed a trend for improvement in women. CONCLUSION: This meta-analysis suggests that short-term therapy with STS 6 mg/24 hours does not impair any aspect of sexual function in MDD patients as measured using a patient-rated questionnaire.

Treatment effects of selegiline transdermal system on symptoms of major depressive disorder: a meta-analysis of short-term, placebo-controlled, efficacy trials.

OBJECTIVE: Selegiline transdermal system (STS) is efficacious for the treatment of major depressive disorder (MDD). This meta-analysis explores treatment effects of STS for individual symptoms of MDD derived from line-item analyses of the 28-item Hamilton Rating Scale for Depression (HAM-D28) and the Montgomery-Asberg Depression Rating Scale (MADRS). METHODS: Change in score from baseline to end of treatment for each item of the HAM-D28 and MADRS was assessed using a multilevel model for meta-analysis of continuous outcome data from all five short-term, randomized, placebo-controlled efficacy trials conducted during preapproval clinical development of STS for MDD. Utilizing a random-effects model with trial effects fixed and adjusting for baseline scores, confidence intervals (95%) were computed for treatment differences between STS and placebo. RESULTS: STS exhibited significant treatment effects on core depression symptoms (HAM-D Bech-6 items: depressed mood, guilt, work and activities, retardation, psychic anxiety, general somatic symptoms), reverse vegetative symptoms (oversleeping, overeating), motoric retardation, suicide, and genital symptoms (libido). Significant STS treatment effects were also noted for each MADRS item except for reduced sleep and appetite. The most prominent MADRS effects were improvement in sadness, lassitude, and poor concentration. CONCLUSIONS: STS, an monoamine oxidase inhibitor antidepressant that potentiates the three major monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), has beneficial therapeutic effects for a spectrum of individual symptoms rated by the HAM-D28 and MADRS. Analyses of specific symptoms assessed by depression rating scales can offer guidance to clinicians in individualizing drug therapy based on presenting symptoms.

Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules.

The selegiline transdermal system is a monoamine oxidase inhibitor that was recently approved by the US Food and Drug Administration for the treatment of major depressive disorder. The current study was conducted during the selegiline transdermal system development program to characterize the single-dose pharmacokinetics and absolute bioavailability of selegiline administered by the 6-mg/24-h selegiline transdermal system in healthy volunteers. Selegiline transdermal system results were compared with those obtained after a single 10-mg oral dose of selegiline HCl. The selegiline pharmacokinetics differed greatly between the 2 routes of administration. Transdermal selegiline administration reduced metabolism and produced a high, sustained plasma selegiline concentration over the dosing period, with an absolute bioavailability of 73%. By contrast, oral dosing produced a sharp plasma selegiline peak that occurred within 1 hour and declined rapidly, with an absolute bioavailability of 4%. The data provide the basis for therapeutic advantages of the selegiline transdermal system in administering antidepressant doses of selegiline.

Evaluation of the potential for pharmacodynamic and pharmacokinetic drug interactions between selegiline transdermal system and two sympathomimetic agents (pseudoephedrine and phenylpropanolamine) in healthy volunteers.

Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug-drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine. Two studies were conducted with 25 healthy volunteers to assess changes in blood pressure and heart rate during administration of pseudoephedrine or phenylpropanolamine alone or together with selegiline transdermal system. No significant differences in mean maximum changes in vital signs occurred with pseudoephedrine. No significant differences were found in mean maximum changes in systolic heart rate with phenylpropanolamine; however, 4 of 12 subjects each experienced 1 isolated protocol-defined minimal pressor response without concurrent adverse effects (1 with phenylpropanolamine alone; 3 with phenylpropanolamine + selegiline transdermal system). Pharmacokinetic parameters obtained following selegiline transdermal system and pseudoephedrine or phenylpropanolamine were unremarkable. The results suggest that selegiline transdermal system 6 mg/24 h does not significantly alter the pharmacodynamics or pharmacokinetics of either pseudoephedrine or phenylpropanolamine when administered to healthy volunteers; however, it is prudent to avoid coadministration of selegiline transdermal system and sympathomimetics.

Selegiline transdermal system: an examination of the potential for CYP450-dependent pharmacokinetic interactions with 3 psychotropic medications.

Selegiline transdermal system (STS) is a recently approved monoamine oxidase inhibitor antidepressant. This article reports results from 3 studies examining the potential for cytochrome P450-dependent pharmacokinetic interactions between STS and 3 psychotropic medications that might be coadministered. Three open-label, randomized, Latin square, 3-sequence crossover design studies were conducted with healthy volunteers to determine the pharmacokinetic parameters of STS 6 mg/24 h and test drug (alprazolam, olanzapine, or risperidone) when administered alone and concomitantly. All pharmacokinetic parameters of interest were unaltered following selegiline or test drug monotherapy when compared to concomitant therapy. This was confirmed by least squares mean ratios and their 90% confidence intervals of log(e)-transformed C(max) and AUC(tau) values, using either standard bioequivalence criteria of 80% to 125% or study-defined 70% to 143% boundary criteria. These results demonstrate that STS 6 mg/24 h may provide an antidepressant option that is unlikely to result in CYP450-mediated pharmacokinetic drug-drug interactions.

Effects of a tyramine-enriched meal on blood pressure response in healthy male volunteers treated with selegiline transdermal system 6 mg/24 hour.

BACKGROUND: Monoamine oxidase inhibitors are well recognized as effective antidepressant agents but are rarely used due, in part, to the risk of hypertensive crisis following the ingestion of foods high in tyramine ("cheese reaction"). A selegiline transdermal system (STS) was developed to provide antidepressant concentrations of selegiline in the brain, while preserving the gastrointestinal monoamine oxidase A (MAO-A) barrier. The present study was conducted to determine the effect of the STS 6 mg/24 hour on cardiovascular safety following the ingestion of approximately 400 mg of tyramine consumed as a component of aged cheeses. METHODS: In this open-label, single-center phase I study, cardiovascular vital signs were recorded following tyramine challenges during placebo and STS 6 mg/24 hr treatment. Subjects were observed for clinical signs and symptoms of a pressor response and/or potential hypertensive crisis during and following the challenges. RESULTS: Ingestion of tyramine-enriched meals following 13 consecutive days of treatment with the STS 6 mg/24 hr (pharmacokinetic steady-state) produced no clinically significant changes in cardiovascular vital signs in 12 healthy adult male subjects. No evidence of a tyramine pressor effect on systolic blood pressure or evidence of hypertensive crisis occurred during the STS treatment. CONCLUSION: These results suggest that STS 6 mg/24 hr may be administered without concern for dietary tyramine consumption.

Tyramine pressor sensitivity during treatment with the selegiline transdermal system 6 mg/24 h in healthy subjects.

The oral tyramine pressor test was administered to healthy males during treatment with a selegiline transdermal system (STS; 6 mg/24 h). The tyramine sensitivity factor (TSF) was calculated from the ratio of baseline and on-treatment tyramine pressor doses. The tyramine sensitivity factor value following 9 days of treatment with the selegiline transdermal system was 1.85 +/- 0.10. Extended treatment, 33 days, produced a small, clinically non-meaningful increase in this value. The tyramine sensitivity factor for the selegiline transdermal system was similar to that following treatment with 10 mg/d of oral selegiline capsules but more than 20 times less than observed during tranylcypromine treatment. A larger increase in the tyramine sensitivity factor was observed following extended selegiline transdermal system treatment at a higher dose (12 mg/24 h), which was significantly decreased following coadministration of tyramine capsules with a meal. These results suggest a wide tyramine safety margin for the selegiline transdermal system and provide evidence that the 6-mg/24-h selegiline transdermal system can be administered safely without dietary tyramine restrictions.

Systemic absorption of topical lidocaine in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster.

Topical lidocaine has been recently marketed as a new treatment for post-herpetic neuralgia. The aim of our study was to characterize the absorption profile of and systemic exposure to lidocaine from patch and gel formulations in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. The bioavailability of lidocaine from the patch formulation averaged 3%, and was similar after single and repeated doses. Systemic exposure to lidocaine and monoethylglycinexylidide (MEGX), the primary active metabolite of lidocaine, after application of lidocaine gel or patches was minimal in normal volunteers, patients with post-herpetic neuralgia, and patients with acute herpes zoster. Considering the benefit versus risk of topical lidocaine, systemic absorption and toxicity of lidocaine seems not to be a significant risk.