A nurse-driven penicillin allergy risk score in the preoperative setting was associated with increased cefazolin use perioperatively.

STUDY OBJECTIVE: To characterize and assess the effects of a preoperative, nurse-driven penicillin allergy risk stratification tool on rates of perioperative cefazolin and second-line antibiotic use. DESIGN: Quasi-experimental quality improvement study of penicillin-allergic surgical patients undergoing procedures for which cefazolin is indicated. SETTING: Outpatient Perioperative Care Clinic (PCC) for preoperative surgical patients at a tertiary care center. PATIENTS: 670 and 1371 adult penicillin-allergic PCC attendants and non-attendants, respectively. INTERVENTION: A paper penicillin allergy risk stratification questionnaire was administered during the PCC visit. Nurses were educated on its use. MEASUREMENTS: Antibiotic (cefazolin, clindamycin, vancomycin) use rates in the 24 months before and 17 months after intervention implementation in November 2020 (November 2018 - April 2022) were assessed in penicillin-allergic PCC attendants with statistical process control charts. Multivariable logistic regression assessed antibiotic use rates pre- and post-intervention adjusting for age, sex, surgical specialty and penicillin allergy history severity. Similar analyses were done in penicillin-allergic PCC non-attendants. MAIN RESULTS: Of 670 penicillin-allergic PCC attendants, 451 (median [IQR] age, 66 (Sousa-Pinto et al., 2021 [14])) were analyzed pre-intervention and 219 (median [IQR] age, 66 (Mine et al., 1970 [13])) post-intervention. One month after implementation, process measures demonstrated an upward shift in cefazolin use for PCC attendants versus no shift or other special cause variation for PCC non-attendants. There were increased odds of cefazolin use (aOR 1.67, 95% CI [1.09-2.57], P = 0.019), decreased odds of clindamycin use (aOR 0.61, 95% CI [0.42-0.89], P = 0.010) and decreased odds of vancomycin use (aOR 0.56, 95% CI [0.35-0.88], P = 0.013) in PCC attendants post-intervention. This effect did not occur in PCC non-attendants. There was no increase in perioperative anaphylaxis post-intervention. CONCLUSIONS: A simple penicillin allergy risk stratification tool implemented in the preoperative setting was associated with increased use of cefazolin and decreased rates of second-line agents post implementation.

Association of neurocognitive disorders with morbidity and mortality in older adults undergoing major surgery in the USA: a retrospective, population-based, cohort study.

BACKGROUND: Neurocognitive disorders become increasingly common as patients age, and increasing numbers of surgical interventions are done on older patients. The aim of this study was to understand the clinical characteristics and outcomes of surgical patients with neurocognitive disorders in the USA in order to guide future targeted interventions for better care. METHODS: This retrospective cohort study used claims data for US Medicare beneficiaries aged 65 years and older with a record of inpatient admission for a major diagnostic or therapeutic surgical procedure between Jan 1, 2017, and Dec 31, 2018. Data were retrieved through a data use agreement between Dartmouth Hitchcock Medical Center and US Centers for Medicare and Medicaid Services via the Research Data Assistance Center. The exposure of interest was the presence of a pre-existing neurocognitive disorder as defined by diagnostic code within 3 years of index hospital admission. The primary outcome was mortality at 30 days, 90 days, and 365 days from date of surgery among all patients with available data. FINDINGS: Among 5 263 264 Medicare patients who underwent a major surgical procedure, 767 830 (14·59%) had a pre-existing neurocognitive disorder and 4 495 434 (85·41%) had no pre-existing neurocognitive disorder. Adjusting for demographic factors and comorbidities, patients with a neurocognitive disorder had higher 30-day (hazard ratio 1·24 [95% CI 1·23-1·25]; p<0·0001), 90-day (1·25 [1·24-1·26]; p<0·0001), and 365-day mortality (1·25 [1·25-1·26]; p<0·0001) compared with patients without a neurocognitive disorder. INTERPRETATION: Our findings suggest that the presence of a neurocognitive disorder is independently associated with an increased risk of mortality. Identification of a neurocognitive disorder before surgery can help clinicians to better disclose risks and plan for patient care after hospital discharge. FUNDING: Department of Anesthesiology and Perioperative Medicine at Dartmouth Hitchcock Medical Center.

Postoperative rehospitalization in older surgical patients: an age-stratified analysis.

BACKGROUND: Older adults comprise 40% of surgical inpatients and are at increased risk of postoperative rehospitalization. A decade ago, 30-day rehospitalizations for Medicare patients were reported as 15%, and more than 70% was attributed to medical causes. In the interim, there have been several large-scale efforts to establish best practice for older patients through surgical quality programs and national initiatives by Medicare and the National Health Service. To understand the current state of rehospitalization in the USA, we sought to report the incidence and cause of 30-day rehospitalization across surgical types by age. STUDY DESIGN: We performed a retrospective study utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) dataset from 2015 to 2019. Our primary exposure of interest was age. Patients were categorized into four groups: 18-49, 50-64, 65-74, and 75 + years old. Reasons for rehospitalization were evaluated using NSQIP defined causes and reported International Classification of Disease (ICD)-9 and ICD-10 codes. Our primary outcome was the incidence of unplanned 30-day rehospitalization and secondary outcome the cause for rehospitalization. Variables were summarized by age group through relative (%) and absolute (n) frequencies; chi-square tests were used to compare proportions. Since rehospitalization is a time-to-event outcome in which death is a competing event, the cumulative incidence of rehospitalization at 30 days was estimated using the procedure proposed by Gray. The same strategy was used for estimating the cumulative incidence for unplanned rehospitalizations. RESULTS: A total of 2,798,486 patients met inclusion criteria; 198,542 had unplanned rehospitalization (overall 7.09%). Rehospitalization by age category was 6.12, 6.99, 7.50, and 9.50% for ages 18-49, 50-64, 65-74, and 75 + , respectively. Complications related to the digestive system were the single most common cause of rehospitalization across age groups. Surgical site infection was the second most common cause, with the relative frequency decreasing with age as follows: 21.74%, 19.08%, 15.09%, and 9.44% (p < .0001). Medical causes such as circulatory or respiratory complications were more common with increasing age (2.10%, 4.43%, 6.27%, 8.86% and 3.27, 4.51, 6.07, 8.11%, respectively). CONCLUSION: We observed a decrease in overall rehospitalization for older surgical patients compared to studies a decade ago. The oldest (≥ 75) surgical patients had the highest 30-day rehospitalization rates (9.50%). The single most common reason for rehospitalization was the same across age groups and likely attributed to surgery (ileus). However, the aggregate of medical causes of rehospitalization was more common in older patients; surgical and respiratory reasons were twice as common in this group. Rehospitalization increased by age for some surgery types, e.g., lower extremity bypass, more than others, e.g., ventral hernia repair. Future investigations should focus on interventions to reduce medical complications and further decrease postoperative rehospitalization for older surgical patients undergoing high-risk procedures.

Point-Of-Care Ultrasound Screening for Proximal Lower Extremity Deep Venous Thrombosis.

Acute lower extremity deep venous thrombosis (DVT) is a serious vascular disorder that requires accurate and early diagnosis to prevent life-threatening sequelae. While whole leg compression ultrasound with color and spectral Doppler is commonly performed in radiology and vascular labs, point-of-care ultrasound (POCUS) is becoming more common in the acute care setting. Providers appropriately trained in focused POCUS can perform a rapid bedside examination with high sensitivity and specificity in critically ill patients. This paper describes a simplified yet validated approach to POCUS by describing a three-zone protocol for lower extremity DVT POCUS image acquisition. The protocol explains the steps in obtaining vascular images at six compression points in the lower extremity. Beginning at the level of the proximal thigh and moving distally to the popliteal space, the protocol guides the user through each of the compression points in a stepwise manner: from the common femoral vein to the femoral and deep femoral vein bifurcation, and, finally, to the popliteal vein. Further, a visual aid is provided that may assist providers during real-time image acquisition. The goal in presenting this protocol is to help make proximal lower extremity DVT exams more accessible and efficient for POCUS users at the patient's bedside.

Cognitive impairment and frailty screening in older surgical patients: a rural tertiary care centre experience.

INTRODUCTION: Despite a clear association between cognitive impairment and physical frailty and poor postoperative outcomes in older adults, preoperative rates are rarely assessed. We sought to implement a preoperative cognitive impairment and frailty screening programme to meet the unique needs of our rural academic centre. METHODS: Through stakeholder interviews, we identified five primary drivers underlying screening implementation: staff education, technology infrastructure, workload impact, screening value and patient-provider communication. Based on these findings, we implemented cognitive dysfunction (AD8, Mini-Cog) and frailty (Clinical Frailty Scale) screening in our preoperative care clinic and select surgical clinics. RESULTS: In the preoperative care clinic, many of our patients scored positive for clinical frailty (428 of 1231, 35%) and for cognitive impairment (264 of 1781, 14.8%). In our surgical clinics, 27% (35 of 131) and 9% (12 of 131) scored positive for clinical frailty and cognitive impairment, respectively. Compliance to screening improved from 48% to 86% 1 year later. CONCLUSION: We qualitatively analysed stakeholder feedback to drive the successful implementation of a preoperative cognitive impairment and frailty screening programme in our rural tertiary care centre. Preliminary data suggest that a clinically significant proportion of older adults screen positive for preoperative cognitive impairment and frailty and would benefit from tailored inpatient care.

Intensive Care Clinicians' Views on the Role of Chaplains.

There is evidence that addressing the religious and spiritual needs of patients has positive effects on patient satisfaction and health care utilization. However, in the intensive care unit (ICU), chaplains are often consulted only at the very end of life, thereby leaving patients' spiritual needs unmet. This study looked at the views of 219 ICU clinicians on the role of chaplains. We found that all clinicians find chaplains helpful when a patient is dying or when the chaplain brings up religious or spiritual topics. Physicians find chaplains less helpful in other clinical scenarios such as challenging family meetings or when patients are recovering. Nurses are more likely to consult chaplains for a difficult family meeting or when patients are recovering from critical illness. Communication between clinicians and chaplains, both directly and indirectly through electronic health record notes, remains infrequent, highlighting the need for interventions aimed at improving multidisciplinary spiritual care.

Training Community Clergy in Serious Illness: Balancing Faith and Medicine.

Community-based clergy are highly engaged in helping seriously ill patients address spiritual concerns at the end of life (EOL). While they desire EOL training, no data exist in guiding how to conceptualize a clergy-training program. The objective of this study was used to identify best practices in an EOL training program for community clergy. As part of the National Clergy Project on End-of-Life Care, the project conducted key informant interviews and focus groups with active clergy in five US states (California, Illinois, Massachusetts, New York, and Texas). A diverse purposive sample of 35 active clergy representing pre-identified racial, educational, theological, and denominational categories hypothesized to be associated with more intensive utilization of medical care at the EOL. We assessed suggested curriculum structure and content for clergy EOL training through interviews and focus groups for the purpose of qualitative analysis. Thematic analysis identified key themes around curriculum structure, curriculum content, and issues of tension. Curriculum structure included ideas for targeting clergy as well as lay congregational leaders and found that clergy were open to combining resources from both religious and health-based institutions. Curriculum content included clergy desires for educational topics such as increasing their medical literacy and reviewing pastoral counseling approaches. Finally, clergy identified challenging barriers to EOL training needing to be openly discussed, including difficulties in collaborating with medical teams, surrounding issues of trust, the role of miracles, and caution of prognostication. Future EOL training is desired and needed for community-based clergy. In partnering together, religious-medical training programs should consider curricula sensitive toward structure, desired content, and perceived clergy tensions.

Utility of Angle Correction for Hemodynamic Measurements with Doppler Echocardiography.

OBJECTIVES: The routine application angle correction (AnC) in hemodynamic measurements with transesophageal echocardiography currently is not recommended but potentially could be beneficial. The authors hypothesized that AnC can be applied reliably and may change grading of aortic stenosis (AS). DESIGN: Retrospective analysis. SETTING: Single institution, university hospital. PARTICIPANTS: During phase I, use of AnC was assessed in 60 consecutive patients with intraoperative transesophageal echocardiography. During phase II, 129 images from a retrospective cohort of 117 cases were used to quantify AS by mean pressure gradient. INTERVENTIONS: A panel of observers used custom-written software in Java to measure intra-individual and inter-individual correlation in AnC application, correlation with preoperative transthoracic echocardiography gradients, and regrading of AS after AnC. MEASUREMENTS AND MAIN RESULTS: For phase I, the median AnC was 21 (16-35) degrees, and 17% of patients required no AnC. For phase II, the median AnC was 7 (0-15) degrees, and 37% of assessed images required no AnC. The mean inter-individual and intra-individual correlation for AnC was 0.50 (95% confidence interval [CI] 0.49-0.52) and 0.87 (95% CI 0.82-0.92), respectively. AnC did not improve agreement with the transthoracic echocardiography mean pressure gradient. The mean inter-rater and intra-rater agreement for grading AS severity was 0.82 (95% CI 0.81-0.83) and 0.95 (95% CI 0.91-0.95), respectively. A total of 241 (7%) AS gradings were reclassified after AnC was applied, mostly when the uncorrected mean gradient was within 5 mmHg of the severity classification cutoff. CONCLUSIONS: AnC can be performed with a modest inter-rater and intra-rater correlation and high degree of inter-rater and intra-rater agreement for AS severity grading.

Palliative Care Planner: A Pilot Study to Evaluate Acceptability and Usability of an Electronic Health Records System-integrated, Needs-targeted App Platform.

RATIONALE: The quality and patient-centeredness of intensive care unit (ICU)-based palliative care delivery is highly variable. OBJECTIVE: To develop and pilot an app platform for clinicians and ICU patients and their family members that enhances the delivery of needs-targeted palliative care. METHODS: In the development phase of the study, we developed an electronic health record (EHR) system-integrated mobile web app system prototype, PCplanner (Palliative Care Planner). PCplanner screens the EHR for ICU patients meeting any of five prompts (triggers) for palliative care consultation, allows families to report their unmet palliative care needs, and alerts clinicians to these needs. The evaluation phase included a prospective before/after study conducted at a large academic medical center. Two control populations were enrolled in the before period to serve as context for the intervention. First, 25 ICU patients who received palliative care consults served as patient-level controls. Second, 49 family members of ICU patients who received mechanical ventilation for at least 48 hours served as family-level controls. Afterward, 14 patients, 18 family members, and 10 clinicians participated in the intervention evaluation period. Family member outcomes measured at baseline and 4 days later included acceptability (Client Satisfaction Questionnaire [CSQ]), usability (Systems Usability Scale [SUS]), and palliative care needs, assessed with the adapted needs of social nature, existential concerns, symptoms, and therapeutic interaction (NEST) scale; the Patient-Centeredness of Care Scale (PCCS); and the Perceived Stress Scale (PSS). Patient outcomes included frequency of goal concordant treatment, hospital length of stay, and discharge disposition. RESULTS: Family members reported high PCplanner acceptability (mean CSQ, 14.1 [SD, 1.4]) and usability (mean SUS, 21.1 [SD, 1.7]). PCplanner family member recipients experienced a 12.7-unit reduction in NEST score compared with a 3.4-unit increase among controls (P = 0.002), as well as improved mean scores on the PCCS (6.6 [SD, 5.8]) and the PSS (-0.8 [SD, 1.9]). The frequency of goal-concordant treatment increased over the course of the intervention (n = 14 [SD, 79%] vs. n = 18 [SD, 100%]). Compared with palliative care controls, intervention patients received palliative care consultation sooner (3.9 [SD, 2.7] vs. 6.9 [SD, 7.1] mean days), had a shorter mean hospital length of stay (20.5 [SD, 9.1] vs. 22.3 [SD, 16.0] patient number), and received hospice care more frequently (5 [36%] vs. 5 [20%]), although these differences were not statistically significant. CONCLUSIONS: PCplanner represents an acceptable, usable, and clinically promising systems-based approach to delivering EHR-triggered, needs-targeted ICU-based palliative care within a standard clinical workflow. A clinical trial in a larger population is needed to evaluate its efficacy.

Seeking and Accepting: U.S. Clergy Theological and Moral Perspectives Informing Decision Making at the End of Life.

BACKGROUND: People with serious illness frequently rely on religion/spirituality to cope with their diagnosis, with potentially positive and negative consequences. Clergy are uniquely positioned to help patients consider medical decisions at or near the end of life within a religious/spiritual framework. OBJECTIVE: We aimed to examine clergy knowledge of end-of-life (EOL) care and beliefs about the role of faith in EOL decision making for patients with serious illness. DESIGN: Key informant interviews, focus groups, and survey. SETTING/SUBJECTS: A purposive sample of 35 active clergy in five U.S. states as part of the National Clergy End-of-Life Project. MEASUREMENT: We assessed participant knowledge of and desire for further education about EOL care. We transcribed interviews and focus groups for the purpose of qualitative analysis. RESULTS: Clergy had poor knowledge of EOL care; 75% desired more EOL training. Qualitative analysis revealed a theological framework for decision making in serious illness that balances seeking life and accepting death. Clergy viewed comfort-focused treatments as consistent with their faith traditions' views of a good death. They employed a moral framework to determine the appropriateness of EOL decisions, which weighs the impact of multiple factors and upholds the importance of God-given free will. They viewed EOL care choices to be the primary prerogative of patients and families. Clergy described ambivalence about and a passive approach to counseling congregants about decision making despite having defined beliefs regarding EOL care. CONCLUSIONS: Poor knowledge of EOL care may lead clergy to passively enable congregants with serious illness to pursue potentially nonbeneficial treatments that are associated with increased suffering.

Electronic Care Coordination From the Preoperative Clinic.

Fragmented and variable perioperative care exposes patients to unnecessary risks and handoff errors. The perioperative surgical home aims to optimize quality, value-based care. We performed a retrospective evaluation of how a preoperative assessment center could coordinate care through e-mails sent to a patient's healthcare team that initiate discussion on critical clinical information. During 100 clinic days on which 8122 patients were evaluated, 606 triggered e-mails, with a potential impact on 19 elements across the perioperative care spectrum. Four cases were canceled, and 42 cases were rescheduled. By fostering information exchange, these communications could advance patient-centered, value-enhanced quality and safety outcomes.

Clergy Views on a Good Versus a Poor Death: Ministry to the Terminally Ill.

BACKGROUND: Clergy are often important sources of guidance for patients and family members making medical decisions at the end-of-life (EOL). Previous research revealed spiritual support by religious communities led to more aggressive care at the EOL, particularly among minority patients. Understanding this phenomenon is important to help address disparities in EOL care. OBJECTIVE: The study objective was to explore and describe clergy perspectives regarding "good" versus "poor" death within the participant's spiritual tradition. METHODS: This was a qualitative, descriptive study. Community clergy from various spiritual backgrounds, geographical locations within the United States, and races/ethnicities were recruited. Participants included 35 clergy who participated in one-on-one interviews (N = 14) and two focus groups (N = 21). Semistructured interviews explored clergy viewpoints on factors related to a "good death." Principles of grounded theory were used to identify a final set of themes and subthemes. RESULTS: A good death was characterized by wholeness and certainty and emphasized being in relationship with God. Conversely, a "poor death" was characterized by separation, doubt, and isolation. Clergy identified four primary determinants of good versus poor death: dignity, preparedness, physical suffering, and community. Participants expressed appreciation for contextual factors that affect the death experience; some described a "middle death," or one that integrates both positive and negative elements. Location of death was not viewed as a significant contributing factor. CONCLUSIONS: Understanding clergy perspectives regarding quality of death can provide important insights to help improve EOL care, particularly for patients highly engaged with faith communities. These findings can inform initiatives to foster productive relationships between clergy, clinicians, and congregants and reduce health disparities.

Association of presence and timing of invasive airway placement with outcomes after pediatric in-hospital cardiac arrest.

BACKGROUND: Little data exist regarding the association of presence of an invasive airway before cardiac arrest or early placement of an invasive airway after cardiac arrest with outcomes in children who experience in-hospital cardiac arrest. METHODS: We conducted a retrospective review of patients aged 1 day to 18 years who received cardiopulmonary resuscitation (CPR) for ≥ 1 min in any of the three intensive care units (ICUs) at a tertiary care, academic children's hospital between 2002 and 2010. Specific outcomes evaluated included survival to hospital discharge, return of spontaneous circulation (ROSC), 24-h survival, and good neurological status at hospital discharge. We fitted multivariable logistic regression models to evaluate the association between the presence of an invasive airway prior to cardiac arrest and timing of placement of an invasive airway with these outcomes. RESULTS: Three hundred and ninety-one patients were included. Of these, 197 (51%) patients were already tracheally intubated before the occurrence of cardiac arrest. Median time to intubation was 6 min [interquartile range (IQR): 2, 12] among the 194 patients tracheally intubated following cardiac arrest. We found lower survival to hospital discharge among patients intubated prior to cardiac arrest (intubated vs. non-intubated group, 43% vs. 61%, p < 0.001). After adjusting for patient and event characteristics, presence of an invasive airway prior to cardiac arrest was not associated with a significant improvement in survival to hospital discharge [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.42-1.16, p = 0.17], or good neurological outcomes (OR: 0.60, 95% CI: 0.34-1.05, p = 0.07). Similarly, early placement of an invasive airway after cardiac arrest was also not associated with an improvement in survival to hospital discharge (OR: 1.05, 95% CI: 0.78-1.42, p = 0.73), or good neurological outcomes (OR: 1.08, 95% CI: 0.77-1.53, p = 0.65). CONCLUSIONS: Our study demonstrates that presence of an invasive airway prior to cardiac arrest or early placement of an invasive airway after cardiac arrest is not associated with an improvement in survival to hospital discharge or good neurological outcomes. Further study of the relationship between invasive airway management and survival following cardiac arrest is warranted.

Incidence, predictors, and outcomes of extubation failure in children after orthotopic heart transplantation: a single-center experience.

The objective of this study is to describe the incidence, etiologies, predictors, and outcomes of extubation failure in children undergoing orthotopic heart transplantation (OHT). A Retrospective, observational study was designed to evaluate clinical outcomes. . The study was conducted in a cardiovascular intensive care unit (CVICU) setting at a single, tertiary care, academic children's hospital. We collected demographic, pre-operative, intra-operative, post-operative and peri-extubation data in a retrospective, observational format from patients who underwent OHT at our institution. Clinical outcomes evaluated included the success or failure of extubation, CVICU length of stay (LOS), hospital LOS, and in-hospital mortality. We utilized descriptive and univariate statistics to compare the group with extubation failure to the group with extubation success. There were no interventions in this study. During the study period, 127 patients qualified for inclusion. The median age of patients was 108 months [interquartile range (IQR): 25-169] and median weight was 23 kg (IQR: 10.6-48). Extubation failure occurred in 12.5 % (16/127) of the patients. Median duration of mechanical ventilation was 2 days (IQR: 1-4.5), median CVICU LOS was 7 days (IQR: 5-13), and the median hospital LOS was 36 days (IQR: 20-74). Overall in-hospital mortality was 2 % (2/127). There was a significant improvement in blood pressure (p < 0.001) with a decrease in inotropic score (p < 0.001) after removal of positive pressure ventilation among the patients with extubation success. Independent factors associated with extubation failure included lower body weight, need for mechanical ventilation prior to heart transplantation, renal failure prior to extubation attempt, and right ventricular diastolic dysfunction prior to extubation attempt. Our study demonstrates that extubation failure in patients after OHT is infrequent and the causes are diverse. Extubation success in children after OHT is associated with improvement in mean arterial blood pressure, decrease in inotropic support, and decrease in supplemental oxygen requirement.

Variability of characteristics and outcomes following cardiopulmonary resuscitation events in diverse ICU settings in a single, tertiary care children's hospital*.

OBJECTIVE: The primary objective of this study was to compare and contrast the characteristics and survival outcomes of cardiopulmonary resuscitation for "monitored" events in pediatric patients treated with chest compressions more than or equal to 1 minute in varied ICU settings. DESIGN: Retrospective observational study. SETTING: Three different specialized ICUs in a single, tertiary care, academic children's hospital. PATIENTS: We collected demographic information, preexisting conditions, preevent characteristics, event characteristics, and outcome data. The primary outcome measure was survival to hospital discharge. Secondary outcome measures included return of spontaneous circulation, 24-hour survival, and survival with good neurologic outcome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four hundred eleven patients treated with chest compressions for more than or equal to 1 minute were included in the analysis: 170 patients were located in the cardiovascular ICU, 157 patients in the neonatal ICU, and 84 patients in the PICU. Arrest durations were longer in the cardiovascular ICU than other ICUs. Use of extracorporeal cardiopulmonary resuscitation was more prevalent in the cardiovascular ICU (cardiovascular ICU, 17%; neonatal ICU, 3%; PICU, 4%). Return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and good neurologic outcome were highest among neonatal ICU patients (survival to discharge, 53%) followed by cardiovascular ICU patients (survival to discharge, 46%) and PICU patients (survival to discharge, 36%). In a multivariable model controlling for patient and event characteristics, using cardiovascular ICU as reference, adjusted odds of survival in PICU were 0.33 (95% CI, 0.14-0.76; p = 0.009) and odds of survival in neonatal ICU were 0.80 (95% CI, 0.31-2.11; p = 0.65). CONCLUSIONS: Comparative analysis of pediatric patients undergoing cardiopulmonary resuscitation in three different ICU settings demonstrated a significant variation in baseline, preevent, and event characteristics. Although outcomes vary significantly among the three different ICUs, it was difficult to ascertain if this difference was due to variation in the disease process or variation in the location of the patient.

A titratable two-step transcriptional amplification strategy for targeted gene therapy based on ligand-induced intramolecular folding of a mutant human estrogen receptor.

PURPOSE: The efficacy and safety of cardiac gene therapy depend critically on the level and the distribution of therapeutic gene expression following vector administration. We aimed to develop a titratable two-step transcriptional amplification (tTSTA) vector strategy, which allows modulation of transcriptionally targeted gene expression in the myocardium. PROCEDURES: We constructed a tTSTA plasmid vector (pcTnT-tTSTA-fluc), which uses the cardiac troponin T (cTnT) promoter to drive the expression of the recombinant transcriptional activator GAL4-mER(LBD)-VP2, whose ability to transactivate the downstream firefly luciferase reporter gene (fluc) depends on the binding of its mutant estrogen receptor (ER(G521T)) ligand binding domain (LBD) to an ER ligand such as raloxifene. Mice underwent either intramyocardial or hydrodynamic tail vein (HTV) injection of pcTnT-tTSTA-fluc, followed by differential modulation of fluc expression with varying doses of intraperitoneal raloxifene prior to bioluminescence imaging to assess the kinetics of myocardial or hepatic fluc expression. RESULTS: Intramyocardial injection of pcTnT-tTSTA-fluc followed by titration with intraperitoneal raloxifene led to up to tenfold induction of myocardial fluc expression. HTV injection of pcTnT-tTSTA-fluc led to negligible long-term hepatic fluc expression, regardless of the raloxifene dose given. CONCLUSIONS: The tTSTA vector strategy can effectively modulate transgene expression in a tissue-specific manner. Further refinement of this strategy should help maximize the benefit-to-risk ratio of cardiac gene therapy.

Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms.

BACKGROUND: Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease. METHODOLOGY/PRINCIPAL FINDINGS: AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE(-/-) mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE(-/-) mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion. CONCLUSION/SIGNIFICANCE: Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.

Heparin-induced thrombocytopenia after total knee arthroplasty, with subsequent adrenal hemorrhage.

Heparin-induced thrombocytopenia (HIT) is a life-threatening immune-mediated adverse effect of chemoprophylaxis for venous thromboembolic events. We present the case of a 44-year-old man who developed bilateral adrenal hemorrhage (BAH) as a sequela of HIT after bilateral total knee arthroplasty. In our review of clinical management of HIT-induced BAH, we discuss the 21 published cases of this phenomenon, 14 of which occurred after orthopedic surgery. Given the potentially fatal consequences and the importance of early intervention, physicians should be on the alert for recognizing HIT-induced BAH in patients experiencing shock unresponsive to fluid resuscitation. In addition, chemoprophylaxis with alternative agents such as a synthetic pentasaccharide factor Xa inhibitor and oral direct thrombin inhibitors that are associated with lower risks of HIT in orthopedic patients merits exploration.

Choice of biological source material supersedes oxidative stress in its influence on DJ-1 in vivo interactions with Hsp90.

DJ-1 is a small but relatively abundant protein of unknown function that may undergo stress-dependent cellular translocation and has been implicated in both neurodegenerative diseases and cancer. As such, DJ-1 may be an excellent study object to elucidate the relative influence of the cellular context on its interactome and for exploring whether acute exposure to oxidative stressors alters its molecular environment. Using quantitative mass spectrometry, we conducted comparative DJ-1 interactome analyses from in vivo cross-linked brains or livers and from hydrogen peroxide-treated or naïve embryonic stem cells. The analysis identified a subset of glycolytic enzymes, heat shock proteins 70 and 90, and peroxiredoxins as interactors of DJ-1. Consistent with a role of DJ-1 in Hsp90 chaperone biology, we document destabilization of Hsp90 clients in DJ-1 knockout cells. We further demonstrate the existence of a C106 sulfinic acid modification within DJ-1 and thereby establish that this previously inferred modification also exists in vivo. Our data suggest that caution has to be exerted in interpreting interactome data obtained from a single biological source material and identify a role of DJ-1 as an oxidative stress sensor and partner of a molecular machinery notorious for its involvement in cell fate decisions.