Risk Factors for Trochanteric Bursitis Following Total Hip Arthroplasty: A Radiographic Analysis.

BACKGROUND: Trochanteric bursitis (TB) is a prevalent complication following total hip arthroplasty (THA), with increased offset hypothesized as a potential risk factor. This study investigated potential TB predictors in THA patients, including radiographic measurements of offset and leg length, comorbidities, and patient characteristics. METHODS: In this retrospective cohort study, all THA patients from a single academic tertiary care center between 2005 and 2021 were reviewed. Exclusion criteria included less than one-year follow-up, osteonecrosis, or fracture. Manual radiographic measurements of offset (acetabular, femoral, and total) and leg length from preoperative and postoperative antero-posterior pelvis X-rays were taken, with scaling using femoral cortical diameter. Univariable and multivariable Cox proportional hazard models were employed to estimate TB risk. RESULTS: Of 1,094 patients, 103 (9.4%) developed TB, with a median (Q1, Q3) time to presentation of 41.8 weeks (25.5, 66.9). In univariable models, only sex was associated with increased TB risk, with women exhibiting a 1.79 times increased risk (hazard ratio: 1.79 (1.16, 2.76), P = .009). Changes in acetabular offset, femoral offset, total offset, and leg length between preoperative and postoperative radiographs were not associated with an increased risk of developing TB in the univariate or multivariate models. Furthermore, various offset thresholds were evaluated, with no amount of increased offset showing increased TB risk. CONCLUSIONS: This study found no relationship between femoral, acetabular, or total offset and TB following THA. These findings suggest that surgeons may consider adding offset for increased prosthetic stability in high-risk cases. However, given that this is a retrospective study, the authors are not advocating for the routine use of increased offset. The study identified women as a risk factor with a 1.79 times higher TB risk, highlighting the importance of counseling women patients on this heightened risk.

Decreasing Radiation Exposure in Pediatric Clavicle and Metatarsal Fractures: A QI Initiative.

BACKGROUND: Protecting the pediatric population from unnecessary medical radiation is an important public health initiative. Efforts have been made to reduce radiation exposure in the treatment of pediatric fractures without compromising quality of care. Using a standardized protocol for imaging of pediatric clavicle and metatarsal fractures is a reliable method for reducing pediatric radiation exposure in the management of these fractures. METHODS: In the year 2015, the senior author altered follow-up imaging practices for 2 common pediatric fractures: metatarsal and clavicular. Initial radiographic evaluation included the standard 3 views for metatarsal fractures and 2 views for clavicle fractures. This standard diagnostic procedure remained constant throughout the study. Follow-up x-rays from 2009 to 2014 routinely included 3 views of the foot and 2 views of the clavicle. The protocol was changed and from 2016 to 2019, follow-up x-rays for fractures routinely included 2 views of the foot and 1 view of the clavicle, thereby decreasing the number of x-rays utilized to manage these fractures. RESULTS: There was a significant reduction in the number of clavicle x-rays (P<0.001) and metatarsal x-rays (P=0.004) taken in follow-up between the time-periods. Median values for metatarsal views decreased by 1, matching the adjustment in protocol. In addition, the vast majority of clavicle fractures (90.80%) were managed with 1 follow-up view in 2016 to 2019 compared with 2 views (72.48%) from 2009 to 2014. CONCLUSIONS: This study achieved a reduction in radiation exposure in pediatric patients with nonoperatively managed clavicle and metatarsal fractures. Improving the quality of care of patients through decreasing the number of x-rays taken protects individuals from adverse side effects, as well as offers various public health benefits in terms of reduction in expenditures. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Angioarchitectural features amongst patients with unruptured brain arteriovenous malformations presenting with headache: findings from a single center retrospective review of 76 patients.

BACKGROUND: Brain arteriovenous malformations (AVMs) consist of abnormal connections between arteries and veins via an interposing nidus. While hemorrhage is the most common presentation, unruptured AVMs can present with headaches, seizures, neurological deficits, or be found incidentally. It remains unclear as to what AVM characteristics contribute to pain generation amongst unruptured AVM patients with headaches. METHODS: To assess this relationship, the current study evaluates angiographic and clinical features amongst patients with unruptured brain AVMs presenting with headache. Loyola University Medical Center medical records were queried for diagnostic codes corresponding to AVMs. In patients with unruptured AVMs, we analyzed the correlation between the presenting symptom of headache and various demographic and angiographic features. RESULTS: Of the 144 AVMs treated at our institution between 1980 and 2017, 76 were unruptured and had sufficient clinical data available. Twenty-three presented with headaches, while 53 patients had other presenting symptoms. Patients presenting with headache were less likely to have venous stenosis compared to those with a non-headache presentation (13 % vs. 36 %, p = 0.044). CONCLUSIONS: Our study suggests that the absence of venous stenosis may contribute to headache symptomatology. This serves as a basis for further study of correlations between AVM angioarchitecture and symptomatology to direct headache management in AVM patients.

Factors associated with missed assessments in a 2-year longitudinal study of acute respiratory distress syndrome survivors.

BACKGROUND: To evaluate participant-related variables associated with missing assessment(s) at follow-up visits during a longitudinal research study. METHODS: This is a prospective, longitudinal, multi-site study of 196 acute respiratory distress syndrome (ARDS) survivors. More than 30 relevant sociodemographic, physical status, and mental health variables (representing participant characteristics prior to ARDS, at hospital discharge, and at the immediately preceding follow-up visit) were evaluated for association with missed assessments at 3, 6, 12, and 24-month follow-up visits (89-95% retention rates), using binomial logistic regression. RESULTS: Most participants were male (56%), white (58%), and ≤ high school education (64%). Sociodemographic characteristics were not associated with missed assessments at the initial 3-month visit or subsequent visits. The number of dependencies in Activities of Daily Living (ADLs) at hospital discharge was associated with higher odds of missed assessments at the initial visit (OR: 1.26, 95% CI: 1.12, 1.43). At subsequent 6-, 12-, and 24 months visits, post-hospital discharge physical and psychological status were not associated with subsequent missed assessments. Instead, the following were associated with lower odds of missed assessments: indicators of poorer health prior to hospital admission (inability to walk 5 min (OR: 0.46; 0.23, 0.91), unemployment due to health (OR: 0.47; 0.23, 0.96), and alcohol abuse (OR: 0.53; 0.28, 0.97)) and having the preceding visit at the research clinic rather than at home/facility, or by phone/mail (OR: 0.54; 0.31, 0.96). Inversely, variables associated with higher odds of missed assessments at subsequent visits include: functional dependency prior to hospital admission (i.e. dependency with > = 2 Instrumental Activities of Daily Living (IADLs) (OR: 1.96; 1.08, 3.52), and missing assessments at preceding visit (OR: 2.26; 1.35, 3.79). CONCLUSIONS: During the recovery process after hospital discharge, dependencies in physical functioning (e.g. ADLs, IADLs) prior to hospitalization and at hospital discharge were associated with higher odds of missed assessments. Conversely, other indicators of poorer health at baseline were associated with lower odds of missed assessments after the initial post-discharge visit. To reduce missing assessments, longitudinal clinical research studies may benefit from focusing additional resources on participants with dependencies in physical functioning prior to hospitalization and at hospital discharge.

One-year outcomes of rosuvastatin versus placebo in sepsis-associated acute respiratory distress syndrome: prospective follow-up of SAILS randomised trial.

BACKGROUND: Prior randomised trials have evaluated statins in patients with sepsis and acute respiratory distress syndrome (ARDS), but there has been no comprehensive evaluation of long-term effects, despite potential neuromuscular and mental health adverse effects of these drugs. AIM: To evaluate the effect of rosuvastatin versus placebo on survival, physical function and performance, and mental health outcomes in patients with sepsis-associated ARDS. METHODS: Prospective follow-up evaluation of the ARDS Clinical Trials Network Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo in 568 mechanically ventilated patients with sepsis-associated ARDS, with blinded 6-month outcome assessment performed in the 272 eligible survivors for age-adjusted and sex-adjusted 36-Item Short Form Health Survey (SF-36) physical function and mental health domains, and in 84 eligible survivors for the 6 min walk test, along with secondary outcomes evaluations of survival, and additional patient-reported and performance-based measures at 6-month and 12-month follow-up. RESULTS: Over 1-year follow-up, there was no significant difference in cumulative survival in the rosuvastatin versus placebo groups (58% vs 61%; p=0.377), with survivors demonstrating substantial impairments in physical function and mental health. Rosuvastatin versus placebo had no effect (mean treatment effect (95% CI)) on SF-36 physical function (0 (-7 to 8), p=0.939) or mental health (-6 (-12 to 1) p=0.085) domains, 6 min walk distance (per cent predicted: 2 (-9 to 14), p=0.679) or the vast majority of secondary outcomes. CONCLUSIONS: Over 1-year follow-up, patients with sepsis-associated ARDS had high cumulative mortality, with survivors commonly experiencing impairments in physical functioning and performance, and mental health. Randomisation to rosuvastatin had no effect on these outcomes. TRIAL REGISTRATION NUMBER: NCT00979121 and NCT00719446.

Infarct volume predicts critical care needs in stroke patients treated with intravenous thrombolysis.

INTRODUCTION: Patients receiving intravenous thrombolysis with recombinant tissue plasminogen activator (IVT) for ischemic stroke are monitored in an intensive care unit (ICU) or a comparable unit capable of ICU interventions due to the high frequency of standardized neurological exams and vital sign checks. The present study evaluates quantitative infarct volume on early post-IVT MRI as a predictor of critical care needs and aims to identify patients who may not require resource intense monitoring. METHODS: We identified 46 patients who underwent MRI within 6 h of IVT. Infarct volume was measured using semiautomated software. Logistic regression and receiver operating characteristics (ROC) analysis were used to determine factors associated with ICU needs. RESULTS: Infarct volume was an independent predictor of ICU need after adjusting for age, sex, race, systolic blood pressure, NIH Stroke Scale (NIHSS), and coronary artery disease (odds ratio 1.031 per cm(3) increase in volume, 95% confidence interval [CI] 1.004-1.058, p = 0.024). The ROC curve with infarct volume alone achieved an area under the curve (AUC) of 0.766 (95% CI 0.605-0.927), while the AUC was 0.906 (95% CI 0.814-0.998) after adjusting for race, systolic blood pressure, and NIHSS. Maximum Youden index calculations identified an optimal infarct volume cut point of 6.8 cm(3) (sensitivity 75.0%, specificity 76.7%). Infarct volume greater than 3 cm(3) predicted need for critical care interventions with 81.3% sensitivity and 66.7% specificity. CONCLUSION: Infarct volume may predict needs for ICU monitoring and interventions in stroke patients treated with IVT.

Risk factors for physical impairment after acute lung injury in a national, multicenter study.

RATIONALE: Existing studies of risk factors for physical impairments in acute lung injury (ALI) survivors were potentially limited by single-center design or relatively small sample size. OBJECTIVES: To evaluate risk factors for three measures of physical impairments commonly experienced by survivors of ALI in the first year after hospitalization. METHODS: A prospective, longitudinal study of 6- and 12-month physical outcomes (muscle strength, 6-minute-walk distance, and Short Form [SF]-36 Physical Function score) for 203 survivors of ALI enrolled from 12 hospitals participating in the ARDS Network randomized trials. Multivariable regression analyses evaluated the independent association of critical illness-related variables and intensive care interventions with impairments in each physical outcome measure, after adjusting for patient demographics, comorbidities, and baseline functional status. MEASUREMENTS AND MAIN RESULTS: At 6 and 12 months, respectively, mean (± SD) values for strength (presented as proportion of maximum strength score evaluated using manual muscle testing) was 92% (± 8%) and 93% (± 9%), 6-minute-walk distance (as percent-predicted) was 64% (± 22%) and 67% (± 26%), and SF-36 Physical Function score (as percent-predicted) was 61% (± 36%) and 67% (± 37%). After accounting for patient baseline status, there was significant association and statistical interaction of mean daily dose of corticosteroids and intensive care unit length of stay with impairments in physical outcomes. CONCLUSIONS: Patients had substantial impairments, from predicted values, for 6-minute-walk distance and SF-36 Physical Function outcome measures. Minimizing corticosteroid dose and implementing existing evidence-based methods to reduce duration of intensive care unit stay and associated patient immobilization may be important interventions for improving ALI survivors' physical outcomes.

Physical and cognitive performance of patients with acute lung injury 1 year after initial trophic versus full enteral feeding. EDEN trial follow-up.

RATIONALE: We hypothesized that providing patients with acute lung injury two different protein/calorie nutritional strategies in the intensive care unit may affect longer-term physical and cognitive performance. OBJECTIVES: To assess physical and cognitive performance 6 and 12 months after acute lung injury, and to evaluate the effect of trophic versus full enteral feeding, provided for the first 6 days of mechanical ventilation, on 6-minute-walk distance, cognitive impairment, and secondary outcomes. METHODS: A prospective, longitudinal ancillary study of the ARDS Network EDEN trial evaluating 174 consecutive survivors from 5 of 12 centers. Blinded assessments of patients' arm anthropometrics, strength, pulmonary function, 6-minute-walk distance, and cognitive status (executive function, language, memory, verbal reasoning/concept formation, and attention) were performed. MEASUREMENTS AND MAIN RESULTS: At 6 and 12 months, respectively, the mean (SD) percent predicted for 6-minute-walk distance was 64% (22%) and 66% (25%) (P = 0.011 for difference between assessments), and 36 and 25% of survivors had cognitive impairment (P = 0.001). Patients performed below predicted values for secondary physical tests with small improvement from 6 to 12 months. There was no significant effect of initial trophic versus full feeding for the first 6 days after randomization on survivors' percent predicted for 6-minute-walk distance, cognitive impairment status, and all secondary outcomes. CONCLUSIONS: EDEN trial survivors performed below predicted values for physical and cognitive performance at 6 and 12 months, with some improvement over time. Initial trophic versus full enteral feeding for the first 6 days after randomization did not affect physical and cognitive performance.

Evaluation of Antibiotic Allergy in the Ambulatory Setting Using a Standardized Questionnaire.

Patients are sometimes mislabeled as having an immune-mediated antibiotic allergy in their medical records. Therefore, the aim of this study was to investigate the prevalence of subjects with non-immune mediated reactions to antibiotics using a standardized questionnaire. Subjects aged 18 years and older with a documented antibiotic allergy were identified and recruited from 2 outpatient clinics in the greater Chicago area. Subjects completed a standardized questionnaire during a single visit regarding their previous adverse reaction to an antibiotic. For subjects with multiple documented antibiotic allergies, 1 questionnaire was filled out for each antibiotic allergy. Investigators subsequently evaluated the questionnaire responses to determine whether the adverse reaction was a true immune-mediated allergic reaction or an adverse drug reaction. A total of 98 subjects were recruited with completion of 159 questionnaires. Eighteen subjects (18.37%, 95% CI: 10.7%, 26.3%) had antibiotic allergy labels with no corresponding immune-mediated reaction history. There were 35 allergy labels (22.0%, 95% CI: 14.7%, 29.4%) that were unlikely to be immune-mediated. Antibiotics with the highest percentage of clinical histories that were unlikely to be immune-mediated were macrolides (8 of 11 subjects), nitrofurantoin (1 of 2 subjects), and amoxicillin/clavulanate (2 of 8 subjects). The most common antibiotic allergy labels were penicillin (43 of 159 subjects), sulfonamides (25 of 159 subjects), and fluoroquinolones (21 of 159 subjects). Identification of adverse reactions to antibiotics that are unlikely to be immune-mediated can be accomplished using a standardized questionnaire in the outpatient setting. Improved identification of low-risk antibiotic allergy labels can guide de-labeling initiatives to improve antibiotic prescribing.

Standardized Management of Sickle Cell Disease Patients and the Effects on Care Utilization and Costs.

An individualized management program for patients with sickle cell disease (SCD) was created to reduce health care utilization and cost. The program was implemented to standardize the management of patients with SCD. SCD encounters from January 2010 to December 2020 were reviewed for analysis. Preintervention utilization of inpatient, emergency room, and outpatient settings was compared to postintervention. There were 7114 encounters analyzed. Outpatient encounters increased from 36.5% to 70.9%; inpatient encounters decreased from 38.6% to 20.3%; and emergency department visits decreased from 20.3% to 8.8%. The number of high inpatient utilizers decreased 8.4% and the number of individuals who received any emergency care decreased 11.9%. When comparing average charges per time period, the median charge per encounter decreased by $1838 postintervention compared to preintervention. This newly implemented SCD program demonstrated success through shifting the care of the SCD patient to the outpatient setting rather than the emergency department or inpatient hospitalizations.

Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital experience.

BACKGROUND: Chemotherapy has improved the outcome of patients with newly diagnosed osteosarcoma, but its role in relapsed disease is unclear. METHODS: We reviewed the records of all patients who were treated for relapsed high-grade osteosarcoma at our institution between 1970 and 2004. Postrelapse event-free survival (PREFS) and postrelapse survival (PRS) were estimated, and outcome comparisons were made using an exact log-rank test. RESULTS: The 10-year PREFS and PRS of the 110 patients were 11.8% ± 3.5% and 17.0% ± 4.3%, respectively. Metastasis at initial diagnosis (14%), and relapse in lung only (75%) were not significantly associated with PREFS or PRS. Time from initial diagnosis to first relapse (RL1) ≥18 months (43%), surgery at RL1 (76%), and ability to achieve second complete remission (CR2, 56%) were favorably associated with PREFS and PRS (P ≤ 0.0002). In patients without CR2, chemotherapy at RL1 was favorably associated with PREFS (P = 0.01) but not with PRS. In patients with lung relapse only, unilateral relapse and number of nodules ( ≤ 3) were associated with better PREFS and PRS (P ≤ 0.0005); no patients with bilateral relapse survived 10 years. The median PREFS after treatment with cisplatin, doxorubicin, methotrexate, and ifosfamide was 3.5 months (95% confidence interval, 2.1-5.2), and the median PRS was 8.2 months (95% confidence interval, 5.2-15.1). CONCLUSIONS: Late relapse, surgical resection, and unilateral involvement (in lung relapse only) favorably impact outcome after relapse. Surgery is essential for survival; chemotherapy may slow disease progression in patients without CR2. These data are useful for designing clinical trials that evaluate novel agents.

Assessing Leg Length and Offset in Anterior Total Hip Arthroplasty: Overlay Versus AP Pelvis Intraoperative Radiographic Techniques: A Retrospective Cohort Study.

INTRODUCTION: Two intraoperative radiographic techniques to determine leg length and offset during anterior total hip arthroplasty (THA) are the AP pelvis and overlay techniques. The AP pelvis method measures LLDs and offset using AP fluoroscopic images, whereas the overlay method uses printed images of the native and replaced hips. The purpose of this study was to compare these techniques regarding clinical and radiographic LLD and offset discrepancies. METHODS: Patients of a single surgeon at two hospitals from September 2017 to January 2021 were retrospectively reviewed. Clinically detectable LLD was recorded. Radiographic measurements were obtained from preoperative and postoperative radiographs. LLD was determined based on the vertical distance between the lesser trochanters and the ischial tuberosities. Total offset was measured using a combination of femoral and medial offset. The Student t-test, Fisher exact test, and Wilcoxon rank sum tests were used for statistical analysis. RESULTS: Seventy-one procedures were done using the overlay technique and 61 used for the AP pelvis technique. No significant differences were observed in mean postoperative LLD (2.66 versus 2.88 mm, P = 0.66) and mean postoperative offset discrepancy (5.37 versus 4.21 mm, P = 0.143) between the overlay versus AP pelvis groups. The mean preoperative to postoperative absolute difference in offset was less than 5 mm in both groups. Clinically detectable LLD was noted in six of 71 patients in the overlay group and one of 61 in the AP pelvis group (P = 0.123). CONCLUSION: No notable differences were observed in intraoperative leg length and offset discrepancies during direct anterior THA between the AP pelvis and overlay techniques, suggesting they are equally effective in determining LLD and offset intraoperatively. The choice of technique to use anterior THA should be based primarily on the surgeon's preference, comfort, and available resources.

Initial testing of the CENP-E inhibitor GSK923295A by the pediatric preclinical testing program.

BACKGROUND: The centromere kinesin motor protein CENP-E plays a crucial role in mitosis, and is an appealing molecular target in cancer. GSK923295A is an allosteric inhibitor of CENP-E that is undergoing clinical evaluation. PROCEDURES: GSK923295A was evaluated against the 23 cell lines in the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposures to concentrations ranging from 1.0 nM to 10.0 µM. GSK923295A was also tested in vivo against the PPTP acute lymphoblastic leukemia (ALL) and solid tumor xenograft panels using a days 1-3 and 8-10 schedule that was repeated at day 21. The agent was administered via the intraperitoneal (i.p.) route at a daily dose of 125 mg/kg. RESULTS: The median IC(50) for all PPTP cell lines was 27 nM, with the median IC(50) for the ALL panel being the lowest (18 nM) and for the neuroblastoma panel the highest (39 nM). Excessive toxicity was observed for each of the 8 xenografts of the ALL panel in NOD/SCID mice. Thirty-five solid tumor xenograft models were considered evaluable. GSK923295A induced significant differences in event-free survival distribution compared to controls in 32 of 35 evaluable solid tumor xenografts tested. Objective responses were noted in 13 of 35 solid tumor xenografts, including 9 with maintained complete responses, and 3 with complete response (CR). CONCLUSIONS: GSK923295A demonstrated significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts. These results suggest that CENP-E may be a valuable therapeutic target in pediatric cancer.

Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program.

BACKGROUND: IMC-A12, a fully human antibody that blocks ligand binding to the Type 1 insulin-like growth factor receptor, and rapamycin, a selective inhibitor of mTORC1 signaling, have both demonstrated significant antitumor activity against PPTP solid tumor models. Here we have evaluated antitumor activity of each agent individually and in combination against nine tumor models. PROCEDURES: IMC-A12 was administered twice weekly and rapamycin was administered daily for 5 days per week for a planned 4 weeks. The impact of combining IMC-A12 with rapamycin was evaluated using two measures: (1) the "therapeutic enhancement" measure, and (2) a linear regression model for time-to-event to formally evaluate for sub- and supra-additivity for the combination compared to the agents used alone. RESULTS: Two osteosarcomas, and one Ewing sarcoma of the nine xenografts tested showed therapeutic enhancement. The combination effect was most dramatic for EW-5 for which PD2 responses of short duration were observed for both single agents and a prolonged PR response was observed for the combination. Both OS-2 and OS-9 showed significantly longer times to progression with the combination compared to either of the single agents, although objective response criteria were not met. CONCLUSIONS: The combination of IMC-A12 with rapamycin was well tolerated, and induced tumor responses that were superior to either single agent alone in several models. These studies confirm reports using other antibodies that inhibit IGF-1 receptor-mediated signaling that indicate enhanced therapeutic effect for this combination, and extend the range of histotypes to encompass additional tumors expressing IGF-1R where this approach may be effective.

Initial testing of the hypoxia-activated prodrug PR-104 by the pediatric preclinical testing program.

BACKGROUND: PR-104 is rapidly hydrolyzed to PR-104A in vivo, which is activated by reduction to the corresponding 5-hydroxylamine (PR-104H) and amine (PR-104M) to produce DNA interstrand cross-links. PR-104 activation can occur via hypoxia-dependent reductases and also independently of hypoxia by aldo-keto reductase (AKR) 1C3. PROCEDURES: PR-104A was tested against the PPTP in vitro panel (10 nM to 100 µM), and PR-104 in vivo using a weekly × 6 schedule at its maximum tolerated dose (MTD) of 550 mg/kg. Subsequently PR-104 was tested at 270 and 110 mg/kg. Pharmacokinetics for PR-104 and its metabolites were determined, as were levels of AKR1C3 RNA and protein in xenografts. RESULTS: In vitro, the leukemia models were most sensitive to PR-104A. In vivo, PR-104 induced objective responses at its MTD in 21/34 solid tumor models and maintained complete responses against 7/7 acute lymphoblastic leukemia (ALL) models. At 270 mg/kg and lower dose levels, PR-104 did not induce solid tumor regressions, suggesting a steep dose-response relationship. Pharmacokinetic analysis suggests higher systemic exposures to PR-104A and its metabolites in mice compared to those achievable in patients. Levels of AKR1C3 protein did not correlate with tumor responsiveness. CONCLUSIONS: As monotherapy, PR-104 demonstrated a high level of activity against both solid tumor and ALL models at its MTD, but the activity was almost completely lost at half the MTD dose for solid tumors. Pharmacokinetic data at the PR-104 MTD from human trials suggest that PR-104 metabolites may not reach the plasma exposures in children that were associated with high-level preclinical activity.

TBSA and length of stay impact quality of life following burn injury.

INTRODUCTION: Burn injuries create physiologic, physical, and emotional effects acutely and long-lasting. Recovery is extensive and requires long-term care. Impaired function related to pain, deconditioning, weakness, and contracture formation are common. We sought to determine factors that impact quality of life (QOL) post recovery. Specifically, to assess whether Health Related QOL (HRQOL) decreases with increasing percent total body surface area (TBSA) and length of stay (LOS). We also explored QOL as a function of burn mechanism. METHODS: Patients >18 years of age with >9.5% TBSA between 1 and 6 years post-burn injury were contacted by mail and asked if they were willing to participate. Those who agreed responded by returning their completed Burn Specific Health Scale-Brief (BSHS-B). Medical records were accessed to determine demographic and treatment information. RESULTS: Statistical analysis revealed a strong correlation between total QOL (total score of BSHS-B) and LOS and TBSA. All domains were negatively correlated with increasing LOS and TBSA. LOS was most strongly correlated with decreasing work function and social function. There were no differences in QOL between burn mechanism. CONCLUSIONS: QOL is greatly impacted by TBSA and LOS.More attention to body image and returning to work should be given, regardless of the type of burn mechanism.

Hospital Readmission and Subsequent Decline in Long-Term Survivors of Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome is associated with long-term physical impairments. Although readmission is common, little is known about the impact of readmissions on the physical status of this population. The purpose of this study was to evaluate the association between hospital readmission, with or without an intensive care unit stay, and physical status in survivors of acute respiratory distress syndrome. The exposure was hospital readmission, categorized as (1) no readmission, (2) readmitted 1 or more times without an intensive care unit stay, or (3) readmitted 1 or more times with an intensive care unit stay. The incidence of readmission was assessed during years 3, 4, and 5 of the study. The outcome was physical decline or death. Decline was evaluated via 3 separate measures: muscle strength, exercise capacity, and self-reported physical function. Of the 132 survivors, 64% (n = 84) had 1 or more readmissions and 27% (n = 35) of them had 1 or more intensive care unit stays. Rates of decline in the year prior were similar regardless of readmission status in the current year. Multivariable logistic regression models indicated that readmission without an intensive care unit stay versus no readmission was not significantly associated with decline. Readmission with an intensive care unit stay versus no readmission was associated with physical decline. Clinicians and researchers should consider the effect of a readmission to an intensive care unit, distinct from hospital readmission, on acute respiratory distress syndrome survivors' physical status.

Physical declines occurring after hospital discharge in ARDS survivors: a 5-year longitudinal study.

PURPOSE: Survivors of acute respiratory distress syndrome (ARDS) are at high risk for new or ongoing physical declines after hospital discharge. The objective of our study was to evaluate the epidemiology of physical declines over 5-year follow-up and identify patients at risk for decline. METHODS: This multi-site prospective cohort study evaluated ARDS survivors who completed a physical status assessment at 3 or 6 months post-discharge. Three measures were evaluated: muscle strength (Medical Resource Council sumscore); exercise capacity [6-min walk test (6MWT)]; physical functioning [36-Item Short Form Health Survey (SF-36 survey)]. Patients were defined as "declined" if a comparison of their current and prior score showed a decrease that was greater than the Reliable Change Index-or if the patient died. Risk factors [pre-ARDS baseline status, intensive care unit (ICU) illness severity, and other intensive care variables] were evaluated using longitudinal, generalized linear regression models for each measure. RESULTS: During the follow-up of 193 ARDS survivors (55 % male; median age 49 years), 166 (86 %) experienced decline in ≥1 physical measure (including death) and 133 (69 %) experienced a physical decline (excluding death). For all measures, age was a significant risk factor [odds ratios (OR) 1.34-1.69 per decade; p < 0.001]. Pre-ARDS comorbidity (Charlson Index) was independently associated with declines in strength and exercise capacity (OR 1.10 and 1.18, respectively; p < 0.02), and organ failure [maximum daily Sequential Organ Failure Assessment (SOFA) score in ICU] was associated with declines in strength (OR 1.06 per 1 point of SOFA score; p = 0.02). CONCLUSIONS: Over the follow-up period, the majority of ARDS survivors experienced a physical decline, with older age and pre-ICU comorbidity being important risk factors for this decline.

Rosuvastatin versus placebo for delirium in intensive care and subsequent cognitive impairment in patients with sepsis-associated acute respiratory distress syndrome: an ancillary study to a randomised controlled trial.

BACKGROUND: Delirium is common in mechanically ventilated patients and is associated with cognitive impairment lasting at least 1 year after hospital discharge. Preclinical and observational studies suggest that the use of statins might reduce delirium in intensive care. We assessed whether the pleiotropic effects of statins can reduce delirium in intensive care and decrease subsequent cognitive impairment in a randomised controlled trial. METHODS: We did this ancillary study within the SAILS trial, a randomised controlled trial assessing mortality and ventilator-free days for rosuvastatin versus placebo for patients with sepsis-associated acute respiratory distress syndrome. This study was done at 35 hospitals in the USA. Patients were randomly assigned in permuted blocks of eight and stratified by hospital to receive either rosuvastatin (40 mg loading dose and then 20 mg daily until the earliest of 3 days after discharge from intensive care, study day 28, or death) or placebo. Patients and investigators were masked to treatment assignment. Delirium was assessed with the validated Confusion Assessment Method for intensive care. Cognitive function was assessed with tests for executive function, language, verbal reasoning and concept formation, and working, immediate, and delayed memory. We defined cognitive impairment as having one of these domains at least two SDs below population norms or at least two domains at least 1·5 SDs below norms. The primary endpoint was daily delirium status in intensive care up to 28 days in the intention-to-treat population and secondary endpoints were cognitive function at 6 months and 12 months. This trial is registered with ClinicalTrials.gov (NCT00979121 and NCT00719446). FINDINGS: 272 patients were assessed for delirium daily in intensive care. The mean proportion of days with delirium was 34% (SD 30%) in the rosuvastatin group versus 31% (29%) in the placebo group; hazard ratio 1·14, 95% CI 0·92-1·41, p=0·22. At 6 months, 19 (36%) of 53 patients in the rosuvastatin group versus 29 (38%) of 77 in the placebo group had cognitive impairment, with no significant difference between groups (treatment effect 0·93, 95% CI 0·39-2·22; p=0·87). At 12 months, 20 (30%) of 67 patients versus 23 (28%) of 81 patients had cognitive impairment, with no significant difference between groups (treatment effect 1·1, 95% CI 0·5-2·6; p=0·82). INTERPRETATION: Most patients had delirium, with around a third of survivors having cognitive impairment over 1 year of follow-up. Despite encouraging preclinical and observational studies, this trial shows no benefit of rosuvastatin in reducing delirium in intensive care or cognitive impairment during 12 months of follow-up although the study was not powered for superiority. Thus, there is continued need to evaluate interventions aimed at attenuating intensive care and post-intensive-care cognitive impairments commonly observed in this population. FUNDING: National Heart, Lung and Blood Institute; Johns Hopkins Institute for Clinical and Translational Research; the SAILS trial was also supported by AstraZeneca.