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This prospective study examined whether the integration of acute care nurse practitioners (ACNP) in a 'semiclosed' surgical intensive care unit (SICU) model increased compliance with clinical practice guidelines (CPG). Patients were admitted to critical care services with a (a) 'semiclosed'/ACNP team or (b) 'mandatory consultation'/non-ACNP team. CPG compliance was significantly higher (P < .05) on the 'semiclosed'/ACNP team for all 3 CPGs examined in the study. [ABSTRACT FROM AUTHOR]

Importance: Despite guidelines recommending avoidance of benzodiazepine administration to older patients, many of them now receive benzodiazepines as a part of anesthesia care. The effectiveness of clinician- and patient-facing interventions to discourage such use remains insufficiently characterized., Objective: To evaluate the effect of clinician peer comparison, patient informational mail, or a combination of these interventions compared with usual care on the rate of perioperative benzodiazepine administration to older patients., Design, Setting, and Participants: This 2 × 2 factorial, stepped-wedge, cluster randomized clinical trial of a corporate quality improvement initiative was conducted between August 8, 2022, and May 28, 2023, across 415 hospitals, surgery centers, and physician offices in 8 US states served by anesthesia clinicians from a national anesthesia practice. Participants were adults aged 65 years or older who underwent an elective surgical or endoscopic procedure with general anesthesia. Data analyses followed the intention-to-treat principle., Intervention: Patients were randomly assigned to 1 of 4 groups-clinician peer comparison (wherein clinicians received feedback regarding their performance compared with other clinicians in the practice), patient informational mail (wherein patients received an informational letter encouraging them to have a discussion regarding medication selection with their clinician on the day of surgery), both interventions, or usual care (no intervention)., Main Outcomes and Measures: Rate of benzodiazepine administration during anesthesia care and patient satisfaction with anesthesia care (measured by the Anesthesia Patient Satisfaction Questionnaire, version 2)., Results: Among the 509 269 enrolled participants (255 871 females [50.2%]; mean [SD] age, 74 [7] years), 81 363 (16.0%) were assigned to clinician peer comparison, 98 520 (19.3%) to patient informational mail, 169 712 (33.3%) to both interventions, and 159 674 (31.4%) to usual care. Among patients who received benzodiazepine during anesthesia care, 24.5% were in the usual care group compared with 19.7% in the clinician peer comparison group, 20.0% in the patient informational mail group, and 19.7% in the combination group. After adjustment for time, none of the study interventions were associated with lower odds of benzodiazepine administration compared with usual care (odds ratio [OR], 1.02 [95% CI, 0.98-1.07]; P = .35 for clinician peer comparison; OR, 1.01 [95% CI, 0.96-1.05]; P = .81 for patient informational mail; and OR, 1.11 [95% CI, 1.05-1.16]; P < .001 for combined interventions). Satisfaction scores were high in all groups and did not vary by treatment assignment., Conclusions and Relevance: This randomized clinical trial found that clinician peer comparison, patient informational mail, or a combination of both interventions did not reduce benzodiazepine administration to older patients compared with usual care; patient satisfaction remained high throughout the study. Overall, the findings suggest a need to explore other patient-targeted interventions to improve anesthesia care., Trial Registration: Clinicaltrials.gov Identifier: NCT05436392.

Background: The effects of spinal versus general anesthesia on long-term outcomes have not been well studied. This study tested the hypothesis that spinal anesthesia is associated with better long-term survival and functional recovery than general anesthesia., Methods: A prespecified analysis was conducted of long-term outcomes of a completed randomized superiority trial that compared spinal anesthesia versus general anesthesia for hip fracture repair. Participants included previously ambulatory patients 50 yr of age or older at 46 U.S. and Canadian hospitals. Patients were randomized 1:1 to spinal or general anesthesia, stratified by sex, fracture type, and study site. Outcome assessors and investigators involved in the data analysis were masked to the treatment arm. Outcomes included survival at up to 365 days after randomization (primary); recovery of ambulation among 365-day survivors; and composite endpoints for death or new inability to ambulate and death or new nursing home residence at 365 days. Patients were included in the analysis as randomized., Results: A total of 1,600 patients were enrolled between February 12, 2016, and February 18, 2021; 795 were assigned to spinal anesthesia, and 805 were assigned to general anesthesia. Among 1,599 patients who underwent surgery, vital status information at or beyond the final study interview (conducted at approximately 365 days after randomization) was available for 1,427 (89.2%). Survival did not differ by treatment arm; at 365 days after randomization, there were 98 deaths in patients assigned to spinal anesthesia versus 92 deaths in patients assigned to general anesthesia (hazard ratio, 1.08; 95% CI, 0.81 to 1.44, P = 0.59). Recovery of ambulation among patients who survived a year did not differ by type of anesthesia (adjusted odds ratio for spinal vs. general, 0.87; 95% CI, 0.67 to 1.14; P = 0.31). Other outcomes did not differ by treatment arm., Conclusions: Long-term outcomes were similar with spinal versus general anesthesia., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Objective: To identify the most important health-related quality of life (HRQOL) domains and patient-reported outcomes after upper extremity transplantation (UET) in individuals with upper extremity amputation., Design: Verbatim audio-recordings of individual interviews and focus groups were analyzed using qualitative, grounded theory-based methods to identify important domains of HRQOL and provide guidance for outcomes measurement after UET., Setting: Individual interviews were conducted by phone. Focus groups were conducted at 5 upper extremity vascularized composite allotransplantation (VCA) centers in the US and at an international conference of VCA experts., Participants: Individual phone interviews were conducted with 5 individuals with lived experience of UET. Thirteen focus groups were conducted with a total of 59 clinical professionals involved in UET., Interventions: Not applicable., Main Outcome Measures: Not applicable., Results: Twenty-eight key HRQOL domains were identified, including physical functioning and medical complications, positive and negative emotional functioning, and social participation, relations, and independence. We identified key constructs for use in evaluation of the potentially substantial physical, medical, social, and emotional effects of UET., Conclusions: This study provides an overview of the most important issues affecting HRQOL after UET, including several topics that are unique to individuals with UET. This information will be used to establish systematic, comprehensive, and longitudinal measurement of post-UET HRQOL outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The REGAIN (Regional versus General Anesthesia for Promoting Independence after Hip Fracture) trial found similar ambulation and survival at 60 days with spinal versus general anesthesia for hip fracture surgery. Trial outcomes evaluating pain, prescription analgesic use, and patient satisfaction have not yet been reported., Objective: To compare pain, analgesic use, and satisfaction after hip fracture surgery with spinal versus general anesthesia., Design: Preplanned secondary analysis of a pragmatic randomized trial. (ClinicalTrials.gov: NCT02507505)., Setting: 46 U.S. and Canadian hospitals., Participants: Patients aged 50 years or older undergoing hip fracture surgery., Intervention: Spinal or general anesthesia., Measurements: Pain on postoperative days 1 through 3; 60-, 180-, and 365-day pain and prescription analgesic use; and satisfaction with care., Results: A total of 1600 patients were enrolled. The average age was 78 years, and 77% were women. A total of 73.5% (1050 of 1428) of patients reported severe pain during the first 24 hours after surgery. Worst pain over the first 24 hours after surgery was greater with spinal anesthesia (rated from 0 [no pain] to 10 [worst pain imaginable]; mean difference, 0.40 [95% CI, 0.12 to 0.68]). Pain did not differ across groups at other time points. Prescription analgesic use at 60 days occurred in 25% (141 of 563) and 18.8% (108 of 574) of patients assigned to spinal and general anesthesia, respectively (relative risk, 1.33 [CI, 1.06 to 1.65]). Satisfaction was similar across groups., Limitation: Missing outcome data and multiple outcomes assessed., Conclusion: Severe pain is common after hip fracture. Spinal anesthesia was associated with more pain in the first 24 hours after surgery and more prescription analgesic use at 60 days compared with general anesthesia., Primary Funding Source: Patient-Centered Outcomes Research Institute .

Background: Controversy continues regarding appropriate indications for posterior malleolus fracture fixation in unstable rotational trimalleolar ankle injuries, with limited data comparing gait in operatively treated trimalleolar ankle fractures vs control populations. The purpose of this study was to evaluate the effect of trimalleolar ankle fracture fixation on gait parameters in the early postoperative period as compared to a healthy control population., Methods: Adult patients having undergone operative treatment of isolated trimalleolar ankle fractures were eligible for inclusion. A total of 10 patients met the inclusion criteria and participated in the analysis. Patients were evaluated using standard parameters of human gait 6 months after their index procedures, with gait values compared to a population of 17 non-age-matched healthy control subjects in addition to literature values of healthy populations of younger and older subjects., Results: Significant differences were noted between the spatiotemporal gait parameters of healthy control subjects and patients who had undergone operative treatment of trimalleolar ankle fractures. However, within the fracture group itself, no differences were found between patients with or without posterior malleolar fixation for any of the tested gait parameters. When patients were compared to literature values of younger and older healthy control populations, they were found to have gait patterns more similar to older rather than younger individuals., Conclusion: Operative fixation of trimalleolar ankle fracture does not restore normal gait function in the early postoperative period. Fixation of the posterior malleolus in particular also does not appear to improve gait characteristics. Patients who undergo surgery for these injuries demonstrate gait patterns similar to those of healthy older adults., Level of Evidence: Level II, Therapeutic (prospective cohort study)., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online., (© The Author(s) 2020.)

Precision medicine offers potential for improved outcomes by tailoring interventions based on patient-specific demographics and disease-specific data. Precision methods are relatively unexplored in trauma patients. New research is being looked at for precision methods to treat patients with large extremity wounds, nonunions, and fractures associated with polytrauma. Precision-based clinical decision tools are being validated to optimize timing for open wound definitive closure. Early patient-specific biomarkers to stratify nonunion risk within 1 week of fracture are being explored. Patient-specific data to stage timing of major fracture interventions in multiply injured patients are being interrogated.

Open fractures are characterized by disruption of the skin and soft tissue, which allows for microbial contamination and colonization. Preventing infection-related complications of open fractures and other acute wounds remains an evolving challenge due to an incomplete understanding of how microbial colonization and contamination influence healing and outcomes. Culture-independent molecular methods are now widely used to study human-associated microbial communities without introducing culture biases. Using such approaches, the objectives of this study were to (1) define the long-term temporal microbial community dynamics of open fracture wounds and (2) examine microbial community dynamics with respect to clinical and demographic factors. Fifty-two subjects with traumatic open fracture wounds (32 blunt and 20 penetrating injuries) were enrolled prospectively and sampled longitudinally from presentation to the emergency department (ED) and at each subsequent inpatient or outpatient encounter. Specimens were collected from both the wound center and adjacent skin. Culture-independent sequencing of the 16S ribosomal RNA gene was employed to identify and characterize microbiota. Upon presentation to the ED and time points immediately following, sample collection site (wound or adjacent skin) was the most defining feature discriminating microbial profiles. Microbial composition of adjacent skin and wound center converged over time. Mechanism of injury most strongly defined the microbiota after initial convergence. Further analysis controlling for race, gender, and age revealed that mechanism of injury remained a significant discriminating feature throughout the continuum of care. We conclude that the microbial communities associated with open fracture wounds are dynamic in nature until eventual convergence with the adjacent skin community during healing, with mechanism of injury as an important feature affecting both diversity and composition of the microbiota. A more complete understanding of the factors influencing microbial contamination and/or colonization in open fractures is a critical foundation for identifying markers indicative of outcome and deciphering their respective contributions to healing and/or complication., (© 2018 by the Wound Healing Society.)

The ability to profile expression levels of a large number of mRNAs and microRNAs (miRNAs) within the same sample, using a single assay method, would facilitate investigations of miRNA effects on mRNA abundance and streamline biomarker screening across multiple RNA classes. A protocol is described for reverse transcription of long RNA and miRNA targets, followed by preassay amplification of the pooled cDNAs and quantitative PCR (qPCR) detection for a mixed panel of candidate RNA biomarkers. The method provides flexibility for designing custom target panels, is robust over a range of input RNA amounts, and demonstrated a high assay success rate.

Precise identification of bacteria associated with post-injury infection, co-morbidities, and outcomes could have a tremendous impact in the management and treatment of open fractures. We characterized microbiota colonizing open fractures using culture-independent, high-throughput DNA sequencing of bacterial 16S ribosomal RNA genes, and analyzed those communities with respect to injury mechanism, severity, anatomical site, and infectious complications. Thirty subjects presenting to the Hospital of the University of Pennsylvania for acute care of open fractures were enrolled in a prospective cohort study. Microbiota was collected from wound center and adjacent skin upon presentation to the emergency department, intraoperatively, and at two outpatient follow-up visits at approximately 25 and 50 days following initial presentation. Bacterial community composition and diversity colonizing open fracture wounds became increasingly similar to adjacent skin microbiota with healing. Mechanism of injury, severity, complication, and location were all associated with various aspects of microbiota diversity and composition. The results of this pilot study demonstrate the diversity and dynamism of the open fracture microbiota, and their relationship to clinical variables. Validation of these preliminary findings in larger cohorts may lead to the identification of microbiome-based biomarkers of complication risk and/or to aid in management and treatment of open fractures., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Objective: Patients, family members and ICU nurses have a higher level of satisfaction with the semiclosed ICU model. Whether or not resident physicians have this same reaction has not yet been investigated. We hypothesized that surgical residents would have improved job satisfaction with the transition from a mandatory consultation SICU to a semiclosed SICU model., Design: Prospective, longitudinal survey., Setting: Tertiary-care University Hospital., Participants: Categorical general surgery residents., Interventions: Change from mandatory consultation SICU to semiclosed SICU., Measurements and Main Results: Categorical surgery residents at a tertiary-care university hospital were surveyed at 3 time points during and after the transition from a mandatory consultation SICU to a semiclosed SICU. The survey consisted of 12 questions designed to gauge the residents' overall job satisfaction as related to the SICU. All questions were on a 5-point Likert scale. Analysis of variance for trend and Fisher exact test were performed to compare the responses. 97 surveys were received. The response rates for the 3 periods were 66, 62 and 72%. Residents were less likely to feel "out of the loop" regarding the care of their ICU patients in the later periods (p = 0.046). There was significant improvement over time in scores for the statement "there is often confusion about placing orders for the care of my patients in the ICU" (p = 0.001). The critical care team's management of all orders in the SICU significantly improved resident job satisfaction over the 3-year period (p = 0.027). There were no significant differences between the responses of junior and senior residents., Conclusions: Resident satisfaction improved significantly over time with the transition from a mandatory consultation SICU to a semiclosed SICU.

Breast cancers expressing estrogen receptor-alpha (ERalpha) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ERalpha, other pathways of estrogen response have been identified including ERbeta and GPR30, a membrane receptor for estrogen, and the key mechanisms regulating expression of ERs and hormone response remain controversial. Herein, we show that TFAP2C is the key regulator of hormone responsiveness in breast carcinoma cells through the control of multiple pathways of estrogen signaling. TFAP2C regulates the expression of ERalpha directly by binding to the ERalpha promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ERalpha target genes, including pS2, MYB, and RERG. Furthermore, TFAP2C controlled the expression of GPR30. In distinct contrast, TFAP2A, a related factor expressed in breast cancer, was not involved in estrogen-mediated pathways but regulated expression of genes controlling cell cycle arrest and apoptosis including p21(CIP1) and IGFBP-3. Knockdown of TFAP2C abrogated the mitogenic response to estrogen exposure and decreased hormone-responsive tumor growth of breast cancer xenografts. We conclude that TFAP2C is a central control gene of hormone response and is a novel therapeutic target in the design of new drug treatments for breast cancer.

Background: Estimation of volume status in the high-acuity surgical population can be challenging. The use of intensivist bedside ultrasound (INBU) to rapidly assess volume status in the surgical intensive care unit (SICU) was hypothesized to be feasible and as accurate as invasive measures., Methods: Clinician sonographers (CSs) were trained to perform basic cardiac ultrasound and sonographic assessment of the inferior vena cava (IVC). A convenience sample of general surgery and trauma patients was enrolled in the SICU. The CS interpreted IVC and cardiac parameters and then categorized the subject as hypovolemic or not hypovolemic. Intensivists caring for the patients were blinded to the INBU findings and made a real-time expert clinical judgment (ECJ) of the patient's volume status (hypovolemic vs. not hypovolemic) using all available traditional data., Results: A total of nine CSs performed 70 studies; three of the CSs performed the majority of the studies (86%). Adequate ultrasound (US) views for cardiac and IVC assessment were obtained in 96% and 89% of studies, respectively. The ECJ was considered to be the standard to which comparisons were made. The concordance rate between ECJ and central venous pressure was 62%. ECJ concordance with sonographic measures were similar (cardiac US = 75%, IVC US = 67%, and IVC collapse index = 65%). All pairwise comparisons against the ECJ/CVP agreement were not significantly different., Conclusions: INBU is feasible in the SICU and is equivalent to central venous pressure in assessing volume status. Noninvasive methods to assess volume status may decrease the need for invasive procedures.

Background: The pulmonary artery catheter (PAC) has been fraught with controversy over issues of safety and impact on outcomes variables for many years. Multiple attempts to quantify the utility of this diagnostic instrument have failed to resolve the matter. Previous investigations have focused on either quantifying inter-rater variability of waveform output interpretation from PACs or on clinical outcomes when PACs are used in care. We tested the hypothesis that the true link between a diagnostic tool and outcomes is treatment selection, and an instrument that minimizes or eliminates the need for data interpretation would also minimize the variability of treatment selections., Study Design: We performed a prospective, single institutional, single blinded survey study., Results: The inter-rater variability of waveform interpretation among all raters was notable (p < 0.01); for continuous end diastolic volume index interpretation, there was no notable inter-rater variability (p=1.0). Inter-rater variability of treatment selections based on waveform interpretation was notable for all raters (p < 0.01). Continuous end diastolic volume index data presentation of hemodynamic status did not result in notable inter-rater variability in treatment selections (p=0.10). Treatment choices based on continuous end diastolic volume index among raters with 5 or more years of experience are not different from clinical practice guideline-directed choices (p > 0.05), independent of patient ventilator status., Conclusions: Digital output volumetric PACs eliminate inter-rater variability of data interpretation, decrease inter-rater variability of data-driven treatment selections, and improve rater agreement with clinical practice guidelines when compared with traditional waveform output PACs.

We studied the role of cysteine as an intracellular radiation protector under conditions in which both oxygen and thiols were monitored at 37 degrees C. In HCT-116 human colon cancer cells, the intracellular cysteine content affects the radiation survival dramatically at intermediate oxygen levels, but not at zero or high oxygen levels. Using a spin-through-oil method with a dual radioactive label detection system, we measured intracellular cysteine and glutathione (GSH) levels for cells in suspension culture. A comparison of the cysteine levels of monolayer cells lysed in situ and of trypsinized monolayer cells in suspension (Horan et al., Cytometry 29, 76-82, 1997) revealed that, upon trypsinization from monolayer culture and transfer to a spinner apparatus at 37 degrees C, HCT-116 cells lose most of their intracellular cysteine. Over the 60-min time course of control experiments, these cells do not recover intracellular cysteine despite the availability of cystine (the disulfide of cysteine) in the medium. When cells in spinner culture are provided with exogenous cysteine, they initially concentrate it to 10-fold the extracellular concentration, with the concentration factor decreasing to about 5-fold over the course of an hour. The intracellular GSH concentration changes little throughout this period, regardless of the changes in cysteine levels. The same apparatus was used to assess the survival of HCT-116 cells irradiated at 37 degrees C under conditions of constant pO(2) monitoring. For cells without added cysteine, the oxygen concentration for half-maximal radiation sensitivity was about 7.5 mmHg (intermediate hypoxia), more than twice the commonly accepted value (3 mmHg). At 7.5 mmHg, cells with added cysteine (intracellular concentration 3.5 mM) were almost as radioresistant as severely hypoxic cells (approximately 0.005% oxygen). Cells in parallel experiments in which the cells were grown in monolayers on glass Petri dishes had intermediate cysteine values and also intermediate radiosensitivity. We conclude that the radiation response of cells at intermediate oxygen levels is controlled predominantly by intracellular cysteine levels and that the cysteine levels commonly found in tumors may increase the K(m) for radiosensitivity to values much higher than suggested previously.

Photodynamic therapy is a technique for killing cells with visible light after pretreatment with a photosensitizing agent. We demonstrated significant in vitro fungicidal activity against Aspergillus fumigatus of the photosensitizer Green 2W, activated with 630 nm light. This effect was both inoculum- and light dose-dependent. At a Green 2W concentration of 31.5 mg/L, there was complete killing of 2.7 x 10(1) cfu/mL with a light dose of 110 J/cm(2) and up to 2.7 x 10(6) cfu/mL with a light dose of 385 J/cm(2).

In intact mammalian cells, ionizing radiation causes substantially less damage to DNA in the absence of oxygen than in the presence of oxygen. In contrast, when DNA is isolated (usually from viruses) and irradiated in solution, the absence of oxygen does not lead to a decrease in damage unless low-molecular-weight thiols are also present. We investigated an intermediate condition: that of DNA irradiated in isolated nuclei. Using an HPLC-based assay of thiols with electrochemical detection, we have determined that the nuclear isolation procedure leads to the elimination of virtually all low-molecular-weight thiols (predominantly glutathione and cysteine). Thus it was our expectation that the thiol-depleted state would concurrently eliminate the OER, and thereby mimic the isolated DNA system, while retaining structural characteristics of chromosomal DNA. We evaluated radiation-induced DNA damage in isolated nuclei by measuring single-strand breaks using alkaline elution and by measuring double-strand breaks using neutral elution and pulsed-field gel electrophoresis. Despite the removal of low-molecular-weight thiol compounds, the oxygen dependence of radiation-induced damage more closely paralleled that of whole cells than that of DNA in solution. Thus damage of DNA irradiated in isolated nuclei is dependent on oxygen.

The importance of glutathione (GSH) in contributing to cancer therapy resistance is well established. Various advantages may accrue from the ability to determine the distribution of GSH content in individual tumor cells disaggregated from solid tumors using flow cytometric techniques compared with biochemical or chemical measurements of the average GSH level in bulk tissue samples. The flow cytometric technique requires a thiol-reactive fluorescent adduct which is stable and which can differentiate cellular GSH from protein thiols. Thiol-reactive compounds specific for GSH require facilitated conjugation by endogenous cellular enzymes, but such compounds have not been found to accurately monitor GSH in human cells. Compounds which react generally with all thiols require a GSH-depleted calibration control to assess GSH vs. non-GSH components of fluorescent-adduct formation. Our report addresses this question, and compares three different thiol assays in several cell lines. We have found a simple way to control for non-GSH adduct formation. This involves a selective permeabilization process to release low molecular weight adducts (dominated by GSH and cysteine). In application to the desired goal of assessing the distribution of GSH in cells disaggregated from tumors, we have identified a problem with cell-line-specific thiol loss during the tumor cell disaggregation process.