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Minimally invasive hysterectomy is a commonly performed gynecologic procedure with associated postoperative pain managed with opioid medications. Uncontrolled postoperative pain leads to increased opioid use/abuse, longer hospital stays, increase in healthcare visits, and may negatively affect patient satisfaction. Current data suggests that reduced pneumoperitoneum insufflation pressure during laparoscopic surgery may impact postoperative pain. Given the current opioid epidemic, surgeons are proactively finding ways to reduce postoperative pain. It is unclear how reduced pneumoperitoneum pressure impacts the surgeon. We investigated the impact of reduced pneumoperitoneum insufflation pressure on surgeon satisfaction.This was a pilot, double-blinded, randomized controlled trial from March 2020 to July 2021 comparing pneumoperitoneum pressure of 15 mmHg to reduced pressures of 12 mmHg and 10 mmHg during laparoscopic hysterectomy.A total of 40 patients were randomized (13 - 15 mmHg, 13 - 12 mmHg, and 14 - 10 mmHg). The primary outcome was surgeon satisfaction. Secondary outcomes included patient satisfaction, operative time, blood loss, postoperative pain, opioid usage, and discharge timing. There were no differences in baseline demographics or perioperative characteristics. Surgeon satisfaction was negatively impacted with lower pneumoperitoneum pressures greatest with 10 mmHg, including overall satisfaction (p =.01), overall effect of the pneumoperitoneum (p =.04), and quality of visualization (p =.01). There was an apparent although not statistically significant difference in operative time (p =.06) and blood loss (p =.054). There was no difference in patient satisfaction, postoperative pain scores, opioid usage, or time to discharge.Reduced pneumoperitoneum insufflation pressure during laparoscopic hysterectomy negatively impacted surgeon satisfaction with a trend towards longer operative times and greater blood loss, and did not positively impact patient satisfaction, postoperative pain, opioid demand, or discharge timing.

BackgroundThe biological consequences of stress from the social environment pattern health outcomes. This study investigated whether social stress is prospectively associated with fracture incidence among racially and ethnically diverse, postmenopausal women.MethodsData from 160 709 postmenopausal women in the Women’s Health Initiative was analysed using Cox proportional hazards regression models to examine prospective associations of social stress with time to total and hip fracture incidence. Self-reported questionnaires measuring social strain, social functioning and social support were used to assess social stress.ResultsAge and race/ethnicity modified associations between social stress and total and hip fractures. HRs for the associations between higher social support (indicating lower social stress) and total fractures among those age 50–59 years were 0.92 (95% CI: 0.90 to 0.94); HR=0.94 (95% CI: 0.93 to 0.95) for those age 60–69 years and HR=0.96 (95% CI: 0.95 to 0.98) for those age 70–79 years. Higher social strain was associated with greater hip fracture incidence among Native American women (HR=1.84, 95% CI: 1.10 to 3.10), Asian women (HR=1.37, 95% CI: 1.01 to 1.86) and white women (HR=1.04, 95% CI: 1.01 to 1.08).ConclusionIdentifying population patterns of fracture incidence as biological expressions of social environments reveals how race/ethnic specific social environmental factors influence disparities in fractures.

Higher chest compression release velocity (CCRV) has been associated with better outcomes after out-of-hospital cardiac arrest (OHCA), and patient factors have been associated with variations in chest wall compliance and compressibility. We evaluated whether patient sex, age, weight, and time in resuscitation were associated with CCRV during pre-hospital resuscitation from OHCA.Observational study of prospectively collected OHCA quality improvement data in two suburban EMS agencies in Arizona between 10/1/2008 and 12/31/2016. Subject-level mean CCRV during the first 10 min of compressions was correlated with categorical variables by the Wilcoxon rank-sum test and with continuous variables by the Spearman's rank correlation coefficient. Generalized estimating equation and linear mixed-effect models were used to study the trend of CCRV over time.During the study period, 2535 adult OHCA cases were treated. After exclusion criteria, 1140 cases remained for analysis. Median duration of recorded compressions was 8.70 min during the first 10 min of CPR. An overall decline in CCRV was observed even after adjusting for compression depth. The subject-level mean CCRV was higher for minutes 0-5 than for minutes 5-10 (mean 347.9 mm/s vs. 339.0 mm/s, 95% CI of the difference -12.4 to -5.4, p 0.0001). Males exhibited a greater mean CCRV compared to females [344.4 mm/s (IQR 307.3-384.6) vs. 331.5 mm/s (IQR 285.3-385.5), p = 0.013]. Mean CCRV was negatively correlated with age and positively correlated with patient weight.CCRV declines significantly over the course of resuscitation. Patient characteristics including male sex, younger age, and increased weight were associated with a higher CCRV.

BackgroundBone loss is a major public health concern with large proportions of older women experiencing osteoporotic fractures. Previous research has established a relationship between psychosocial stressors and fractures. However, few studies have investigated bone loss as an intermediary in this relationship. This study investigates whether social stress is associated with bone loss during a 6-year period in postmenopausal women.MethodsData from 11 020 postmenopausal women from the USA was used to examine self-reported psychosocial stress in relation to change in bone mineral density (BMD) measured at the femoral neck, lumbar spine and total hip. Linear regression models were used to examine associations between social measures of psychosocial stress (social strain, social functioning and social support) and per cent change in BMD over 6 years.ResultsHigh social stress was associated with decreased BMD over 6 years. After adjustment for confounders, each point higher in social strain was associated with 0.082% greater loss of femoral neck BMD, 0.108% greater loss of total hip BMD and 0.069% greater loss of lumbar spine BMD (pConclusionThe findings provide evidence for an association between high social stress and greater bone loss over 6 years of follow-up. In agreement with the prior literature, the findings for social strain and social functioning suggest that poor quality of social relationships may be associated with bone loss in postmenopausal women.

BACKGROUND Exosomes isolated from plasma of lung transplant recipients (LTxRs) with bronchiolitis obliterans syndrome (BOS) contain human leukocyte antigens and lung self-antigens (SAgs), K-alpha 1 tubulin (Kα1T) and collagen type V (Col-V). The aim was to determine the use of circulating exosomes with lung SAgs as a biomarker for BOS. METHODS Circulating exosomes were isolated retrospectively from plasma from LTxRs at diagnosis of BOS and at 6 and 12 months before the diagnosis (n = 41) and from stable time-matched controls (n = 30) at 2 transplant centers by ultracentrifugation. Exosomes were validated using Nanosight, and lung SAgs (Kα1T and Col-V) were detected by immunoblot and semiquantitated using ImageJ software. RESULTS Circulating exosomes from BOS and stable LTxRs demonstrated 61- to 181-nm vesicles with markers Alix and CD9. Exosomes from LTxRs with BOS (n = 21) showed increased levels of lung SAgs compared with stable (n = 10). A validation study using 2 separate cohorts of LTxRs with BOS and stable time-matched controls from 2 centers also demonstrated significantly increased lung SAgs–containing exosomes at 6 and 12 months before BOS. CONCLUSIONS Circulating exosomes isolated from LTxRs with BOS demonstrated increased levels of lung SAgs (Kα1T and Col-V) 12 months before the diagnosis (100% specificity and 90% sensitivity), indicating that circulating exosomes with lung SAgs can be used as a non-invasive biomarker for identifying LTxRs at risk for BOS.

Study Objective To investigate the impact of retained cystoscopy fluid after laparoscopic hysterectomy on time to spontaneous void, time to discharge, urinary retention, bladder discomfort, and patient satisfaction. Design Single-blind randomized controlled trial. Setting An academic medical center. Patients One hundred and twenty patients who underwent laparoscopic hysterectomy with universal cystoscopy for benign indications, excluding pelvic organ prolapse and urinary incontinence indications. Interventions From October 10, 2018, to October 17, 2019, we compared 200 mL retained cystoscopy fluid and complete bladder emptying after laparoscopic hysterectomy with universal cystoscopy. Measurements and Main Results A total of 120 patients were enrolled and randomized (59 in the retained cystoscopy fluid group and 61 in the emptied fluid group). The primary outcome was time to first spontaneous void. The secondary outcomes were time to discharge, urinary retention rates, bladder discomfort, and patient satisfaction. A sample size of 120 was calculated to detect a 57-minute difference in time to spontaneous void. There were minimal differences in baseline demographics and surgical characteristics between the groups. There was an apparent, although not significant, difference in time to void of 25 minutes (143 minutes vs 168 minutes, p = .20). Time to discharge and urinary retention rates did not differ (199 minutes vs 214 minutes, p = .40, and 13.6% vs 8.2%, p = .51, respectively). There was no difference in postoperative bladder discomfort and patient satisfaction. Conclusion Retained cystoscopy fluid after laparoscopic hysterectomy did not significantly affect time to first spontaneous void, time to discharge, urinary retention, bladder discomfort, or patient satisfaction.

Study objective We evaluate the effect of implementing the out-of-hospital pediatric traumatic brain injury guidelines on outcomes in children with major traumatic brain injury. Methods The Excellence in Prehospital Injury Care for Children study is the preplanned secondary analysis of the Excellence in Prehospital Injury Care study, a multisystem, intention-to-treat study using a before-after controlled design. This subanalysis included children younger than 18 years who were transported to Level I trauma centers by participating out-of-hospital agencies between January 1, 2007, and June 30, 2015, throughout Arizona. The primary and secondary outcomes were survival to hospital discharge or admission for children with major traumatic brain injury and in 3 subgroups, defined a priori as those with moderate, severe, and critical traumatic brain injury. Outcomes in the preimplementation and postimplementation cohorts were compared with logistic regression, adjusting for risk factors and confounders. Results There were 2,801 subjects, 2,041 in preimplementation and 760 in postimplementation. The primary analysis (postimplementation versus preimplementation) yielded an adjusted odds ratio of 1.16 (95% confidence interval 0.70 to 1.92) for survival to hospital discharge and 2.41 (95% confidence interval 1.17 to 5.21) for survival to hospital admission. In the severe traumatic brain injury cohort (Regional Severity Score–Head 3 or 4), but not the moderate or critical subgroups, survival to discharge significantly improved after guideline implementation (adjusted odds ratio = 8.42; 95% confidence interval 1.01 to 100+). The improvement in survival to discharge among patients with severe traumatic brain injury who received positive-pressure ventilation did not reach significance (adjusted odds ratio = 9.13; 95% confidence interval 0.79 to 100+). Conclusion Implementation of the pediatric out-of-hospital traumatic brain injury guidelines was not associated with improved survival when the entire spectrum of severity was analyzed as a whole (moderate, severe, and critical). However, both adjusted survival to hospital admission and discharge improved in children with severe traumatic brain injury, indicating a potential severity-based interventional opportunity for guideline effectiveness. These findings support the widespread implementation of the out-of-hospital pediatric traumatic brain injury guidelines.

Objective High grade serous ovarian cancer (HGSC) remains one of the most lethal malignancies in females. We previously reported that γ-glutamyl cyclotransferase (GGCT) was significantly upregulated in serous ovarian cancer. The current study was aimed to explore the function and underlying mechanism of GGCT in HGSC. Methods GGCT expression was assessed by immunohistochemistry in 128 HGSC patients. Stable cell lines with GGCT gene overexpression or knockdown were established to investigate the function of GGCT in HGSC in vitro and in vivo . Results GGCT is highly upregulated in HGSC tissues and associated with FIGO stage, lymph node metastasis and ascitic fluid volume. High expression of GGCT is associated with poor survival in HGSC patients. The Harrell's c-indexes of the prognostic models for overall survival and progression-free survival prediction were 0.758 and 0.726, respectively. GGCT knockdown suppresses proliferation, clone formation, migration, and invasion of tumor cells in vitro while forced GGCT overexpression presents opposite results. Furthermore, GGCT silencing inhibits tumor growth and spread in vivo . Epithelial-mesenchymal transition (EMT) and PI3K/AKT/mTOR signaling pathway are suppressed in GGCT silenced cells and enhanced in GGCT overexpressed cells. Inactivation of PI3K/AKT/mTOR signaling pathway in GGCT overexpressed cells induces EMT inhibition. Conclusions Our data reveals an important role of GGCT in regulating EMT and progression of HGSC, providing a valuable prognostic marker and potential target for treatment of HGSC patients.

Aim of study This study aims to quantify the relative impact of Dispatcher-Initiated Telephone cardiopulmonary resuscitation (TCPR) on survival and survival with favorable functional outcome after out-of-hospital cardiac arrest (OHCA) in a population of patients served by multiple emergency dispatch centers and more than 130 emergency medical services (EMS) agencies. Methods We conducted a retrospective, observational study of EMS-treated adult (≥18 years) patients with OHCA of presumed cardiac origin in Arizona, between January 1, 2011, and December 31, 2014. We compared survival and functional outcome among three distinct groups of OHCA patients: those who received no CPR before EMS arrival (no CPR group); those who received BCPR before EMS arrival and prior to or without telephone CPR instructions (BCPR group); and those who received TCPR (TCPR group). Results In this study, 2310 of 4391 patients met the study criteria (median age, 62 years; IQR 50, 74; 1540 male). 32.8% received no CPR, 23.8% received Bystander-Initiated CPR and 43.4% received TCPR. Overall survival was 11.5%. Using no CPR as the reference group, the multivariate adjusted odds ratio for survival at hospital discharge was 1.51 (95% confidence interval [CI], 1.04, 2.18) for BCPR and 1.64 (95% CI, 1.16, 2.30) for TCPR. The multivariate adjusted odds ratio of favorable functional outcome at discharge was 1.58 (95% CI 1.05, 2.39) for BCPR and 1.56 (95% CI, 1.06, 2.31) for TCPR. Conclusion TCPR is independently associated with improved survival and improved functional outcome after OHCA.

Objectives To determine whether the relationship between anthropometric measurements of obesity and mortality varies according to age, race, and ethnicity in older women. Design Prospective cohort study of multiethnic postmenopausal women. Setting Women's Health Initiative (WHI) observational study and clinical trials in 40 clinics. Participants Postmenopausal women aged 50–79 participating in WHI (N = 161,808). Measurements Baseline height, weight, and waist circumference (WC) were measured, and body mass index (BMI) was calculated based on height and weight. Demographic, health, and lifestyle data from a baseline questionnaire were used as covariates. The outcome was adjudicated death (n = 18,320) during a mean follow-up of 11.4 ± 3.2 years. Results Hazard ratios (HRs) and 95% confidence intervals (95% CIs) indicated that ethnicity and age modified (P < .01) the relationship between obesity and mortality. Underweight was associated with higher mortality, but overweight or slight obesity was not a risk factor for mortality in most ethnic groups except for Hispanic women in the obesity I category (HR = 1.42, 95% CI = 1.04–1.95). BMI was not or was only weakly associated with mortality in individuals aged 70–79 (HR = 0.90, 95% CI = 0.85–0.95 for overweight; HR = 0.98, 95 CI = 0.92–1.06 for obese I; HR = 1.11, 95% CI = 1.00–1.23 for obese II; HR = 1.08, 95% CI = 0.92–1.26 for obese III). In contrast, higher central obesity measured using WC was consistently associated with higher mortality in all groups. Conclusion Underweight is a significant risk factor for mortality in older women, and healthy BMI ranges may need to be specific for age, race, and ethnicity. The findings support a consistent relationship between central obesity and mortality.

Emergency medical telecommunicators can play a key role in improving outcomes from out-of-hospital cardiac arrest (OHCA) by providing instructions for cardiopulmonary resuscitation (CPR) to callers. Telecommunicators, however, frequently encounter barriers that obstruct the Telephone CPR (TCPR) process. The nature and frequency of these barriers in public and residential locations have not been well investigated. The aim of this study is to identify the barriers to TCPR in public and residential locations.We conducted a retrospective study of audio recordings of EMS-confirmed OHCAs from eight regional 9-1-1 dispatch centers between January 2012 and December 2013.We reviewed 1850 eligible cases (public location OHCAs: N=223 and residential location OHCAs: N=1627). Telecommunicators less frequently encountered barriers such as inability to calm callers in public than in residential locations (2.1% vs 8.5%, p=0.002) or inability to place victims on a hard flat surface (13.9% vs 25.4%, p0.001). However, the barrier where callers were not with patients was more frequently observed in public than in residential locations (11.8% vs 2.7%, p0.001).This study revealed that barriers to TCPR are distributed differently across public and residential locations. Understanding these differences can aid in the development of strategies to enhance bystander CPR and improve overall patient outcomes.

To compare obstetric and surgical outcomes of transabdominal cerclage (TAC) via laparotomy (TAC-LAP) versus robotic-assisted (TAC-RA) approaches.Retrospective cohort study.An academic medical center.Sixty-nine women with acquired or congenital cervical insufficiency.All women underwent TAC either by laparotomy or robotic-assisted approaches by 2 primary surgeons between January 2003 and July 2018. Women with a preconceptional TAC without a subsequent pregnancy were excluded.A total of 69 women met inclusion criteria in the 15-year study period with 40 in the historical TAC-LAP group and 29 in the TAC-RA group. Gestational age at delivery was similar in the 2 groups (36 weeks 3 days vs 37 weeks; median difference -1 day, 95% confidence interval [CI] -6 to 2, p = .36). There were no differences in birth weight, Apgar scores, neonatal intensive care unit admission, or neonatal survival. Estimated blood loss and length of stay were significantly greater in the TAC-LAP group (50 mL vs 20 mL; median difference 25, 95% CI 5-40, p = .007 and 76 hours vs 3 hours; median difference 71, 95% CI 65-75, p.001, respectively). Operative time was significantly shorter in the TAC-LAP group (65 minutes vs 132 minutes; median difference -64.7, 95% CI -79 to -49, p.001). There was one intra-operative complication and 4 minor postoperative complications in the TAC-LAP group and none observed in the TAC-RA group. All outcomes were similar when comparing postconceptional TAC alone, except there was no longer a difference in blood loss. When comparing pre- versus postconceptional robotic TAC, there were no differences in surgical outcomes.Robotic TAC has similar favorable obstetric outcomes to traditional laparotomy and is associated with reduced blood loss and shorter hospital stays. Despite longer operative times, the robotic group did not experience any intra-operative or postoperative complications, which speaks to the benefits of this minimally invasive approach to TAC.

Introduction: Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait. Methods: In this study, we selected 1493 single-nucleotide polymorphisms (SNP) in 155 candidate genes involved in anabolic, catabolic, growth hormone, and other related pathways and examined their association with LM, assessed by dual-energy x-ray absorptiometry, in a sample of 2760 non-Hispanic and Hispanic white postmenopausal women from the Women’s Health Initiative (WHI) Observational Study. We assessed the replication of our top findings in a meta-analysis of 20 genome-wide association studies (n = 38,292) conducted by the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Musculoskeletal Working Group. Results: We identified 32 SNPs that had nominally significant associations with LM in the WHI cohort. In the replication stage, we find that SNP rs2276541 in the activin A receptor, type IIB (ACVR2B), was significantly associated with LM (β = 0.15, P = 2.17 × 10−5). ACVR2B codes for a receptor for a negative regulator of skeletal muscle, myostatin, and has previously been identified in a candidate gene study as a determinant of skeletal muscle mass. Conclusions: Our findings support a previously proposed role of ACVR2B allelic variation as a determinant of muscle mass and extend prior findings in men and women. Additional large-scale studies will be needed to confirm our findings in different populations.

T cell-mediated immunity has the ability to produce durable anti-melanoma responses resulting in improved survival of patients with advanced melanoma. Antigen presentation is a key determinant of T cell responses. Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma antigens to CD4+ T cells. However, GILT expression in melanoma has not been defined. We evaluated GILT and MHC class II expression in human primary and metastatic melanomas and nevi using immunohistochemistry. GILT staining in melanocytes was observed in 70% of primary and 58% of metastatic melanomas versus 0% of nevi. When present, the GILT staining intensity in melanocytes was typically faint. Both GILT and MHC class II expression were increased in melanocytes of primary and metastatic melanomas compared with nevi. GILT staining in antigen presenting cells was detected in 100% of primary and metastatic melanomas versus 31% of nevi and was typically intense. GILT expression was increased in antigen presenting cells of primary and metastatic melanomas compared to nevi, whereas MHC class II had equivalent high expression in antigen presenting cells of all melanocytic lesions. GILT staining in keratinocytes was detected in 67% of primary melanomas versus 14% of nevi and 6% of metastatic melanomas. GILT, but not MHC class II, expression was increased in keratinocytes of primary melanomas compared to nevi and metastases. GILT expression is anticipated to result in improved presentation of melanoma antigens and more effective anti-melanoma T cell responses. GILT expression may be a biomarker of immune recognition of melanoma.

International Guidelines recommend measurement of end-tidal carbon dioxide (EtCO2) to enhance cardiopulmonary resuscitation (CPR) quality and optimize blood flow during CPR. Numerous factors impact EtCO2 (e.g., ventilation, metabolism, cardiac output), yet few clinical studies have correlated CPR quality and EtCO2 during actual out-of-hospital cardiac arrest (OHCA) resuscitations. The purpose of this study was to describe the association between EtCO2 and CPR quality variables during OHCA.This is an observational study of prospectively collected CPR quality and capnography data from two EMS agencies participating in a statewide resuscitation quality improvement program. CPR quality and capnography data from adult (≥18 years) cardiac resuscitation attempts (10/2008-06/2013) were collected and analyzed on a minute-by-minute basis using RescueNet™ Code Review. Linear mixed effect models were used to evaluate the association between (log-transformed) EtCO2 level and CPR variables: chest compression (CC) depth, CC rate, CC release velocity (CCRV), ventilation rate.Among the 1217 adult OHCA cases of presumed cardiac etiology, 925 (76.0%) had a monitor-defibrillator file with CPR quality data, of which 296 (32.0%) cases had1 minute of capnography data during CPR. After capnography quality review, 66 of these cases (22.3%) were excluded due to uninterpretable capnography, resulting in a final study sample of 230 subjects (mean age 68 years; 69.1% male), with a total of 1581 minutes of data. After adjustment for other CPR variables, a 10 mm increase in CC depth was associated with a 4.0% increase in EtCO2 (p0.0001), a 10 compression/minute increase in CC rate with a 1.7% increase in EtCO2 (p = 0.02), a 10 mm/second increase in CCRV with a 2.8% increase in EtCO2 (p = 0.03), and a 10 breath/minute increase in ventilation rate with a 17.4% decrease in EtCO2 (p0.0001).When controlling for known CPR quality variables, increases in CC depth, CC rate and CCRV were each associated with a statistically significant but clinically modest increase in EtCO2. Given the small effect sizes, the clinical utility of using EtCO2 to guide CPR performance is unclear. Further research is needed to determine the practicality and impact of using real-time EtCO2 to guide CPR delivery in the prehospital environment.

Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventive efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of the three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared with single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventive effects. More significant effects may be observed in subjects with greater baseline cutaneous damage. Cancer Prev Res; 9(2); 128–34. ©2015 AACR. See related article by Tsai and Hawk, p. 125

Background Firefighting is a hazardous profession and firefighters suffer workplace injury at a higher rate than most US workers. Decreased physical fitness is associated with injury in firefighters. A physical fitness intervention was implemented among Tucson Fire Department recruit firefighters with the goals of decreasing injury and compensation claims frequency and costs during the recruit academy, and over the subsequent probationary year. Methods Department injury records were analysed and described by body part, injury type and mechanism of injury. Injury and workers’ compensation claims outcomes from the recruit academy initiation through the 12-month probationary period for the intervention recruit class were compared with controls from three historical classes. Results The majority of injuries were sprains and strains (65.4%), the most common mechanism of injury was acute overexertion (67.9%) and the lower extremity was the most commonly affected body region (61.7%). The intervention class experienced significantly fewer injuries overall and during the probationary year (p=0.009), filed fewer claims (p=0.028) and experienced claims cost savings of approximately US$33 000 (2013) from avoided injury and reduced claims costs. The estimated costs for programme implementation were $32 192 leading to a 1-year return on investment of 2.4%. Conclusions We observed reductions in injury occurrence and compensation costs among Probationary Firefighter Fitness (PFF-Fit) programme participants compared with historical controls. The initiation of the PFF-Fit programme has demonstrated promise in reducing injury and claims costs; however, continued research is needed to better understand the programme's potential effectiveness with additional recruit classes and carryover effects into the recruit's career injury potential.

The aim of our study was to assess the impact of coronary angiography (CAG) after out-of-hospital cardiac arrest (OHCA) without ST-elevation (STE).Prospective observational study of adult (age ≥ 18) OHCA of presumed cardiac etiology from 1/01/2010-12/31/2014 admitted to one of 40 recognized cardiac receiving centers within a statewide resuscitation network.Among 11,976 cases, 1881 remained for analysis after exclusions. Of the 1230 non-STE cases, 524 (43%) underwent CAG with resultant PCI in 157 (30%). Survival in non-STE cases was: 56% in cases without CAG; 82% in cases with CAG but without PCI; and 78% in those with PCI (p 0.0001). In cases without STE the aOR for survival with CAG alone was 2.34 (95% CI 1.69-3.24) and for CAG plus PCI was 1.98 (95% CI 1.26-3.09). The aOR for CPC 1/2 with CAG alone was 6.89 (95% CI 3.99-11.91) and for CAG plus PCI was 2.95 (95% CI 1.59-5.47). After propensity matching, CAG was associated with an aOR for survival of 2.10 (95% CI 1.30-3.55) and for CPC 1/2 it was 5.06 (95% CI 2.29-11.19).In OHCA without STE, CAG was strongly and independently associated with survival regardless of whether PCI was performed. The association between CAG and positive outcomes remained after propensity matching.

The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers. Cancer Prev Res; 8(8); 720–8. ©2015 AACR.

Supplemental Digital Content is Available in the Text., Objective: To investigate the comparative acute health effects associated with exposures to diesel and 75% biodiesel/25% diesel (B75) blend fuel emissions. Methods: We analyzed multiple health endpoints in 48 healthy adults before and after exposures to diesel and B75 emissions in an underground mine setting—lung function, lung and systemic inflammation, novel biomarkers of exposure, and oxidative stress were assessed. Results: B75 reduced respirable diesel particulate matter by 20%. Lung function declined significantly more after exposure to diesel emissions. Lung inflammatory cells along with sputum and plasma inflammatory mediators increased significantly to similar levels with both exposures. Urinary 8-hydroxydeoxyguanosine, a marker of oxidative stress, was not significantly changed after either exposure. Conclusions: Use of B75 lowered respirable diesel particulate matter exposure and some associated acute health effects, although lung and systemic inflammation were not reduced compared with diesel use.

Limonene is a lipophilic monoterpene found in high levels in citrus peel. Limonene demonstrates anticancer properties in preclinical models with effects on multiple cellular targets at varying potency. While of interest as a cancer chemopreventive, the biologic activity of limonene in humans is poorly understood. We conducted metabolite profiling in 39 paired (pre/postintervention) plasma samples from early-stage breast cancer patients receiving limonene treatment (2 g QD) before surgical resection of their tumor. Metabolite profiling was conducted using ultra-performance liquid chromatography coupled to a linear trap quadrupole system and gas chromatography-mass spectrometry. Metabolites were identified by comparison of ion features in samples to a standard reference library. Pathway-based interpretation was conducted using the human metabolome database and the MetaCyc database. Of the 397 named metabolites identified, 72 changed significantly with limonene intervention. Class-based changes included significant decreases in adrenal steroids (P < 0.01), and significant increases in bile acids (P ≤ 0.05) and multiple collagen breakdown products (P < 0.001). The pattern of changes also suggested alterations in glucose metabolism. There were 47 metabolites whose change with intervention was significantly correlated to a decrease in cyclin D1, a cell-cycle regulatory protein, in patient tumor tissues (P ≤ 0.05). Here, oral administration of limonene resulted in significant changes in several metabolic pathways. Furthermore, pathway-based changes were related to the change in tissue level cyclin D1 expression. Future controlled clinical trials with limonene are necessary to determine the potential role and mechanisms of limonene in the breast cancer prevention setting. Cancer Prev Res; 8(1); 86–93. ©2014 AACR.

Background Emergency 9‐1‐1 callers use a wide range of terms to describe abnormal breathing in persons with out‐of‐hospital cardiac arrest ( OHCA ). These breathing descriptors can obstruct the telephone cardiopulmonary resuscitation ( CPR ) process. Methods and Results We conducted an observational study of emergency call audio recordings linked to confirmed OHCA s in a statewide Utstein‐style database. Breathing descriptors fell into 1 of 8 groups (eg, gasping, snoring). We divided the study population into groups with and without descriptors for abnormal breathing to investigate the impact of these descriptors on patient outcomes and telephone CPR process. Callers used descriptors in 459 of 2411 cases (19.0%) between October 1, 2010, and December 31, 2014. Survival outcome was better when the caller used a breathing descriptor (19.6% versus 8.8%, P OHCA recognition, CPR instruction, and telephone CPR were lower than when callers did not use a breathing descriptor (79.7% versus 93.0%, P P =0.0078; and 60.2% versus 66.9%, P =0.0123, respectively). The time interval between call receipt and OHCA recognition was longer when the caller used a breathing descriptor (118.5 versus 73.5 seconds, P Conclusions Descriptors of abnormal breathing are associated with improved outcomes but also with delays in the identification of OHCA . Familiarizing telecommunicators with these descriptors may improve the telephone CPR process including OHCA recognition for patients with increased probability of survival.

Thymic cellularity is influenced by a variety of biological and environmental factors, such as age and stress; however, little is known about the molecular genetic mechanisms that regulate this process. Immediate early genes of the Early growth response (Egr) family have critical roles in immune function and response to environmental stress. The transcription factors, Egr1, Egr2 and Egr3, play roles in the thymus and in peripheral T-cell activation. Nab2, which binds Egrs 1, 2, and 3 as a co-regulator of transcription, also regulates peripheral T-cell activation. However, a role for Nab2 in the thymus has not been reported. Using Nab2-deficient (KO) mice we found that male Nab2KO mice have reduced thymus size and decreased numbers of thymocytes, compared with age-matched wildtype (WT) mice. Furthermore, the number of thymocytes in Nab2KO males decreases more rapidly with age. This effect is sex-dependent as female Nab2KO mice show neither reduced thymocyte numbers nor accelerated thymocyte loss with age, compared to female WT littermates. Since stress induces expression of Nab2 and the Egrs, we examined whether loss of Nab2 alters stress-induced decrease in thymic cellularity. Restraint stress induced a significant decrease in thymic cellularity in Nab2KO and WT mice, with significant changes in the thymocyte subset populations only in the Nab2KO mice. Stress reduced the percentage of DP cells by half and increased the percentage of CD4SP and CD8SP cells by roughly three-fold in Nab2KO mice. These findings indicate a requirement for Nab2 in maintaining thymocyte number in male mice with age and in response to stress.

Objective Previous research has linked complex or formed visual hallucinations (VH) to Lewy-type alpha-synucleinopathy (LTS) in neocortical and limbic areas. As Alzheimer's disease pathology often co-occurs with LTS, we questioned whether this pathology – amyloid plaques and neurofibrillary tangles – might also be linked to VH. Methods We performed a semi-quantitative neuropathological study across brainstem, limbic, and cortical structures in subjects with a documented clinical history of VH and a clinicopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), or dementia with Lewy bodies (DLB). 173 subjects – including 50 with VH and 123 without VH – were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical variables examined included the Mini-mental State Exam, Hoehn & Yahr stage, and total dopaminergic medication dose. Neuropathological variables examined included total and regional LTS and plaque and tangle densities. Results A significant relationship was found between the density of LTS and the presence of VH in PD, AD, and DLB. Plaque and tangle densities also were associated with VH in PD (p = .003 for plaque and p = .004 for tangles) but not in AD, where densities were high regardless of the presence of hallucinations. Furthermore, with DLB cases excluded, comorbidity of PD and AD was significantly more prevalent among subjects + VH than subjects −VH (p Conclusion These findings suggest that both AD and PD neuropathology contribute to the pathogenesis of VH. Incident VH could be predictive of concomitant AD/PD pathology even when criteria are not met for a second diagnosis.

Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption.To characterize FM symptoms and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms.A longitudinal, observational study of 51 subjects with FM (range 55-95 years) and 81 control subjects (58-95 years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment.Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80 % or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin.In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated.Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.

IMPORTANCE: Traumatic brain injury (TBI) is a massive public health problem. While evidence-based guidelines directing the prehospital treatment of TBI have been promulgated, to our knowledge, no studies have assessed their association with survival. OBJECTIVE: To evaluate the association of implementing the nationally vetted, evidence-based, prehospital treatment guidelines with outcomes in moderate, severe, and critical TBI. DESIGN, SETTING, AND PARTICIPANTS: The Excellence in Prehospital Injury Care (EPIC) Study included more than 130 emergency medical services systems/agencies throughout Arizona. This was a statewide, multisystem, intention-to-treat study using a before/after controlled design with patients with moderate to critically severe TBI (US Centers for Disease Control and Prevention Barell Matrix-Type 1 and/or Abbreviated Injury Scale Head region severity ≥3) transported to trauma centers between January 1, 2007, and June 30, 2015. Data were analyzed between October 25, 2017, and February 22, 2019. INTERVENTIONS: Implementation of the prehospital TBI guidelines emphasizing avoidance/treatment of hypoxia, prevention/correction of hyperventilation, and avoidance/treatment of hypotension. MAIN OUTCOMES AND MEASURES: Primary: survival to hospital discharge; secondary: survival to hospital admission. RESULTS: Of the included patients, the median age was 45 years, 14 666 (67.1%) were men, 7181 (32.9%) were women; 16 408 (75.1% ) were white, 1400 (6.4%) were Native American, 743 (3.4% ) were Black, 237 (1.1%) were Asian, and 2791 (12.8%) were other race/ethnicity. Of the included patients, 21 852 met inclusion criteria for analysis (preimplementation phase [P1]: 15 228; postimplementation [P3]: 6624). The primary analysis (P3 vs P1) revealed an adjusted odds ratio (aOR) of 1.06 (95% CI, 0.93-1.21; P = .40) for survival to hospital discharge. The aOR was 1.70 (95% CI, 1.38-2.09; P

GOALS We intended to identify the factors associated with missed appointments at a gastroenterology (GI) clinic in an academic setting. BACKGROUND Missed clinic appointments reduce clinic efficiency, waste resources, and increase costs. Limited data exist on subspecialty clinic attendance. STUDY We performed a case-control study using data from the electronic health record of patients scheduled for an appointment at the adult GI clinic at the Banner University Medical Center between March and October of 2014. Patients who missed their appointment during the study period served as cases. Controls were randomly selected from patients who completed their appointment during the study period. Analysis included univariate and multivariate logistic regression analysis. RESULTS Of 2331 scheduled clinic appointments, 195 (8.4%) were missed appointments. Longer waiting time from referral to scheduled appointment was significantly associated with missed appointment (AOR=1.014; 95% CI, 1.01-1.02; P

Bystander cardiopulmonary resuscitation (CPR) significantly improves survival from out-of-hospital cardiac arrest but is provided in less than half of events on average. Telephone CPR (TCPR) can significantly increase bystander CPR rates and improve clinical outcomes.To investigate the effect of a TCPR bundle of care on TCPR process measures and outcomes.A prospective, before-after, observational study of adult patients with out-of-hospital cardiac arrest not receiving bystander CPR before the 9-1-1 call between October 1, 2010, and September 30, 2013.A TCPR program, including guideline-based protocols, telecommunicator training, data collection, and feedback, in 2 regional dispatch centers servicing metropolitan Phoenix, Arizona. Audio recordings of out-of-hospital cardiac arrest calls were audited and linked with emergency medical services and hospital outcome data.Survival to hospital discharge and functional outcome at hospital discharge.There were 2334 out-of-hospital cardiac arrests (798 phase 1 [P1] and 1536 phase 2 [P2]) in the study group; 64% (1499) were male, and the median age was 63 years (age range, 9-101 years; interquartile range, 51-75 years). Provision of TCPR increased from 43.5% in P1 to 52.8% in P2 (P .001), yielding an increase of 9.3% (95% CI, 4.9%-13.8%). The median time to first chest compression decreased from 256 seconds in P1 to 212 seconds in P2 (P .001). All rhythm survival was significantly higher in P2 (184 of 1536 [12.0%]) compared with P1 (73 of 798 [9.1%]), with an adjusted odds ratio (aOR) of 1.47 (95% CI, 1.08-2.02; P = .02) in a logistic regression model and an adjusted difference in absolute survival rates (adjusted rate difference) of 3.1% (95% CI, 1.5%-4.9%). Survival for patients with a shockable initial rhythm significantly improved in P2 (107 of 306 [35.0%]) compared with P1 (42 of 170 [24.7%]), with an aOR of 1.70 (95% CI, 1.09-2.65; P = .02) and an adjusted rate difference of 9.6% (95% CI, 4.8%-14.4%). The rate of favorable functional outcome was significantly higher in P2 (127 of 1536 [8.3%]; 95% CI, 6.9%-9.8%) than in P1 (45 of 798 [5.6%]; 95% CI, 4.1%-7.5%), with an aOR of 1.68 (95% CI, 1.13-2.48; P = .01) and an adjusted rate difference of 2.7% (95% CI, 1.3%-4.4%).Implementation of a guideline-based TCPR bundle of care was independently associated with significant improvements in the provision and timeliness of TCPR, survival to hospital discharge, and survival with favorable functional outcome.

Insulin and insulin-like growth factor (IGF) genes are implicated in colorectal carcinogenesis. Gene-by-gene interactions that influence the insulin/IGF pathways were hypothesized as modifiers of colorectal neoplasia risk. We built a classification tree to detect interactions in 18 IGF and insulin pathway-related genes and metachronous colorectal neoplasia among 1,439 subjects pooled from two chemoprevention trials. The probability of colorectal neoplasia was greatest (71.8%) among carriers of any A allele for rs7166348 (IGF1R) and AA genotype for rs1823023 (PIK3R1). In contrast, carriers of any A at rs7166348 (IGF1R), any G for the PIK3R1 variant, and AA for rs10426094 (INSR) had the lowest probability (14.3%). Logistic regression modeling showed that any A at rs7166348 (IGF1R) with the AA genotype at rs1823023 (PIK3R1) conferred the highest odds of colorectal neoplasia (OR 3.7; 95% CI 2.2-6.5), compared with carriage of GG at rs7166348 (IGF1R). Conversely, any A at rs7166348 (IGFR1), any G allele at rs1823023 (PIK3R1), and the AA genotype at rs10426094 (INSR) conferred the lowest odds (OR 0.22; 95% CI 0.07-0.66). Stratifying the analysis by parent study and intervention arm showed highly consistent trends in direction and magnitude of associations, with preliminary evidence of genotype effects on measured IGF-1 levels in a subgroup of subjects. These results were compared to those from multifactor dimensionality reduction, which identified different single nucleotide polymorphisms in the same genes (INSR and IGF1R) as effect modifiers for colorectal neoplasia. These results support a role for genetic interactions in the insulin/IGF pathway genes in colorectal neoplasia risk.

Adherence to medications is critical to optimizing HIV care and is a major challenge in youth. The utility of directly observed therapy (DOT) to improve adherence in youth with HIV remains undefined and prompted this pilot study. Four U.S. sites were selected for this 24-week cooperative group study to assess feasibility and to identify the logistics of providing DOT to HIV-infected youth with demonstrated adherence problems. Once-a-day DOT was provided by DOT facilitators at the participant's choice of a community-based location and DOT tapered over 12 weeks to self-administered therapy based on ongoing adherence assessments. Twenty participants, median age 21 years and median CD4 227 cells/μl, were enrolled. Participants chose their homes for 82% of DOT visits. Compliance with recommended DOT visits was (median) 91%, 91%, and 83% at weeks 4, 8, and 12, respectively. Six participants completed >90% of the study-specified DOT visits and successfully progressed to self-administered therapy (DOT success); only half sustained >90% medication adherence 12 weeks after discontinuing DOT. Participants considered DOT successes were more likely to have higher baseline depression scores (p = 0.046). Via exit surveys participants reported that meeting with the facilitator was easy, DOT increased their motivation to take medications, they felt sad when DOT ended, and 100% would recommend DOT to a friend. In conclusion, this study shows that while community-based DOT is safe, feasible, and as per participant feedback, acceptable to youth, DOT is not for all and the benefits appear short-lived. Depressed youth appear to be one subgroup that would benefit from this intervention. Study findings should help inform the design of larger community-based DOT intervention studies in youth.

Out-of-hospital hypotension has been associated with increased mortality in traumatic brain injury. The association of traumatic brain injury mortality with the depth or duration of out-of-hospital hypotension is unknown. We evaluated the relationship between the depth and duration of out-of-hospital hypotension and mortality in major traumatic brain injury.We evaluated adults and older children with moderate or severe traumatic brain injury in the preimplementation cohort of Arizona's statewide Excellence in Prehospital Injury Care study. We used logistic regression to determine the association between the depth-duration dose of hypotension (depth of systolic blood pressure90 mm Hg integrated over duration [minutes] of hypotension) and odds of inhospital death, controlling for significant confounders.There were 7,521 traumatic brain injury cases included (70.6% male patients; median age 40 years [interquartile range 24 to 58]). Mortality was 7.8% (95% confidence interval [CI] 7.2% to 8.5%) among the 6,982 patients without hypotension (systolic blood pressure ≥90 mm Hg) and 33.4% (95% CI 29.4% to 37.6%) among the 539 hypotensive patients (systolic blood pressure90 mm Hg). Mortality was higher with increased hypotension dose: 0.01 to 14.99 mm Hg-minutes 16.3%; 15 to 49.99 mm Hg-minutes 28.1%; 50 to 141.99 mm Hg-minutes 38.8%; and greater than or equal to 142 mm Hg-minutes 50.4%. LogIn this study, the depth and duration of out-of-hospital hypotension were associated with increased traumatic brain injury mortality. Assessments linking out-of-hospital blood pressure with traumatic brain injury outcomes should consider both depth and duration of hypotension.

Use of standard adult lopinavir/ritonavir (LPV/RTV) dosing (400/100 mg) during the third trimester of pregnancy results in reduced LPV exposure. The goal of this study was to determine LPV exposure during the third trimester of pregnancy and 2 weeks postpartum with a higher LPV/RTV dose.The Pediatric AIDS Clinical Trials Group Protocol 1026s is an ongoing, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving LPV/RTV 400/100 mg twice daily during the second trimester and 533/133 mg twice daily during the third trimester through 2 weeks postpartum. Intensive steady state 12-hour pharmacokinetic profiles were performed during the third trimester and at 2 weeks postpartum and were optional during the second trimester. LPV and RTV were measured by reverse-phase high-performance liquid chromatography with a detection limit of 0.09 microg/mL.Twenty-six HIV-infected pregnant women were studied. Median LPV area under the plasma concentration-time curve (AUCs) for the second trimester, third trimester, and postpartum were 57, 88, and 152 microg.h.mL, respectively. Median minimum LPV concentrations were 1.9, 4.1, and 8.3 microg/mL.The higher LPV/RTV dose (533/133 mg) provided LPV exposure during the third trimester similar to the median AUC (80 microg.h.mL) in nonpregnant adults taking standard doses. However, the AUC on this increased dose at 2 weeks postpartum was considerably higher. These data suggest that the higher LPV/RTV dose should be used in third trimester pregnant women; that it should be considered in second trimester pregnant women, especially those who are protease inhibitor experienced; and that postpartum LPV/RTV dosing can be reduced to standard dosing by 2 weeks after delivery.

The goal of HAART is to promote reconstitution of CD4+ T cells and other immune responses. We evaluated the extent and the kinetics of immune reconstitution in HIV-infected children over 144 weeks of successful HAART.Thirty-seven children receiving their first HAART regimen had plasma HIV RNA; T cells and subpopulations; T-cell rearrangement excision circles (TREC) DNA; candida, HIVCD4 and HIVCD8 enzyme-linked immunospot measured at regular intervals.Plasma HIV RNA became undetectable in 81% of patients at 24 weeks and remained undetectable in 77% at 144 weeks. In contrast, CD4+% continuously increased. Distribution of T-cell subpopulations changed rapidly during the first 48 weeks of HAART and more slowly thereafter. At 144 weeks, total, naive and activated CD4+% and naive CD8+% of HIV-infected children were not significantly different from those of healthy age-matched controls, whereas total and activated CD8+% remained elevated. CD4 and CD8 TREC content increased only during the first 48 weeks of HAART. They positively correlated with each other and with total CD4+%, naive CD4+% and naive CD8+%. Candida and HIVCD4 enzyme-linked immunospot increased over time reaching peak values at 48 weeks and 144 weeks, respectively. HIVCD8 enzyme-linked immunospot decreased in magnitude over 144 weeks of HAART but retained its breadth. Baseline CD4+% positively correlated with CD4+% and with functional immune reconstitution at week 144, whereas baseline TREC correlated with TREC at week 144.HIV-infected children acquired normal distribution of CD4 T cells and other subpopulations and recovered CD4-mediated HIV immunity after 144 weeks of HAART.

BACKGROUND. Compliance with complex antiretroviral therapy regimens is a problem for HIV-1–infected children and their families. Simple, safe, and effective regimens are important for long-term therapeutic success. METHODS. A novel, once-daily dosing regimen of 3 antiretroviral drugs, emtricitabine, didanosine, and efavirenz, was tested in 37 therapy-naive HIV-infected children and adolescents between 3 and 21 years of age (inclusive). Subjects were followed for ≥96 weeks on an intention-to-treat basis. Signs, symptoms, plasma HIV-1 RNA viral load, CD4 counts, and safety laboratories were followed regularly. End points were the proportion of subjects with plasma HIV RESULTS. Thirty-seven subjects enrolled at 16 sites. Two subjects with rashes during the first 2 weeks of therapy were the only adverse events leading to study-drug discontinuation. Other early (before protocol-scheduled conclusion) study discontinuations included 3 viral failures on treatment and 5 patients who stopped therapy for apparently nonmedical reasons. Possible drug-related adverse events included 1 grade 4 low-glucose and 5 varied grade 3 events. There were no deaths. Virologic outcomes demonstrated that 32 (85%) of 37 subjects achieved viral suppression to CONCLUSIONS. A once-daily regimen of emtricitabine, didanosine, and efavirenz proved to be safe and tolerable and demonstrated good immunologic and virologic efficacy in this 2-year study.

Obesity, often defined as a body mass index (BMI; weight (kg)/height (m)(2)) of 30 or higher, has been associated with mortality, but age-related body composition changes can be masked by stable BMI. A subset of Women's Health Initiative participants (postmenopausal women aged 50-79 years) enrolled between 1993 and 1998 who had received dual-energy x-ray absorptiometry scans for estimation of total body fat (TBF) and lean body mass (LBM) (n = 10,525) were followed for 13.6 (standard deviation, 4.6) years to test associations between BMI, body composition, and incident mortality. Overall, BMI ≥35 was associated with increased mortality (adjusted hazard ratio (HR) = 1.45, 95% confidence interval (CI): 1.16, 1.82), while TBF and LBM were not. However, an interaction between age and body composition (P < 0.001) necessitated age stratification. Among women aged 50-59 years, higher %TBF increased risk of death (HR = 2.44, 95% CI: 1.38, 4.34) and higher %LBM decreased risk of death (HR = 0.41, 95% CI: 0.23, 0.74), despite broad-ranging BMIs (16.4-69.1). However, the relationships were reversed among women aged 70-79 years (P < 0.05). BMI did not adequately capture mortality risk in this sample of postmenopausal women. Our data suggest the clinical utility of evaluating body composition by age group to more robustly assess mortality risk among postmenopausal women.

Atherosclerosis and diabetes are closely associated and both involve extensive degradation of the aortic elastin. Increased elastase activity has been detected in diabetic animal aortae. We have demonstrated enhanced elastolytic cathepsin S in human atherosclerotic lesions but insufficient amounts of its endogenous inhibitor cystatin C, suggesting alterations of serum cathepsin S and/or cystatin C in patients with atherosclerosis or diabetes. In this study, we measured levels of both cathepsin S and cystatin C in sera from 240 patients by ELISA. Among these patients, 107 had a diagnosis of atherosclerotic stenosis, 103 were diabetic, and 30 had neither condition. Multiple linear regression analysis demonstrated that significantly higher serum levels of cathepsin S in patients with either atherosclerotic stenosis (p

Objective: To describe abacavir pharmacokinetics during pregnancy and postpartum; physiological changes during pregnancy are known to affect antiretroviral drug disposition. Design: The Pediatric AIDS Clinical Trials Group P1026s study is an on-going, prospective, non-blinded pharmacokinetic study of pregnant women receiving one or more antiretroviral drugs for routine clinical care, including a cohort receiving abacavir 300 mg twice daily. Methods: Serial plasma samples (predose, 1, 2, 4, and 6 h postdose) obtained antepartum (30–36 weeks of gestation) and again postpartum (6–12 weeks after delivery) were assayed for abacavir concentration by reversed-phase high-performance liquid chromatography. Results: Antepartum evaluations were available for 25 women [mean age, 28.6 years (SD, 6); mean third-trimester weight 92 kg (SD, 35.4); and race/ethnicity 52% black, 28% Hispanic, 16% white, 4% Asian], with geometric mean abacavir area under the concentration–time curve (AUC) of 5.9 mg·h/l [90% confidence interval (CI), 5.2–6.8] and maximum plasma concentration (Cmax) of 1.9 mg/l (90% CI, 1.6–2.2). Seventeen women completed postpartum sampling, and the ratios of antepartum to postpartum AUC and Cmax were 1.04 (90% CI, 0.91–1.18) and 0.79 (90% CI, 0.65–0.98), respectively. Conclusions: Abacavir AUC during pregnancy was similar to that at 6–12 weeks postpartum and to that for non-pregnant historical controls (5.8 mg·h/l). Consequently, pregnancy does not appear to affect overall abacavir exposure significantly or to necessitate dose adjustments.

Saliva, a biological fluid, is a promising candidate for novel approaches to prognosis, clinical diagnosis, monitoring and management of patients with both oral and systemic diseases. However, to date, saliva has not been widely investigated as a biomarker for radiation exposure. Since white blood cells are also present in saliva, it should theoretically be possible to investigate the transcriptional biomarkers of radiation exposure classically studied in whole blood. Therefore, we collected whole blood and saliva samples from eight head and neck cancer patients before the start of radiation treatment, at mid-treatment and after treatment. We then used a panel of five genes: BAX, BBC3, CDKN1A, DDB2 and MDM2, designated for assessing radiation dose in whole blood to evaluate gene expression changes that can occur during radiotherapy. The results revealed that the expression of the five genes did not change in whole blood. However, in saliva, CDKN1A and DDB2 were significantly overexpressed at the end, compared to the start, of radiotherapy, and MDM2 was significantly underexpressed between mid-treatment and at the end of treatment. Interestingly, CDKN1A and DDB2 expressions also showed an increasing monotonic relationship with total radiation dose received during radiotherapy. To our knowledge, these results show for the first time the ability to detect gene expression changes in saliva after head and neck cancer radiotherapy, and pave the way for further promising studies validating saliva as a minimally invasive means of biofluid collection to directly measure radiation dose escalation during treatment.

Colonoscopy is the preferred method for colon cancer screening, but can miss polyps and flat neoplasms with low color contrast. The objective was to develop a new autofluorescence method that improves image contrast of colonic neoplasms.We selected the three strongest native fluorescence signals and developed a novel method where fluorescence images are processed in a ratiometric formula to represent the likely cellular and structural changes associated with neoplasia. Native fluorescence images of fresh surgical specimens of the colon containing normal mucosa, polypoid and flat adenomas as well as adenocarcinoma were recorded using a prototype multi-spectral imager. Sixteen patients, with a mean age of 62 years (range 28-81) undergoing elective resection for colonic neoplasms were enrolled. High contrast images were seen with fluorescence from tryptophan (Tryp), flavin adenine dinucleotide (FAD) and collagen.When the image intensity of Tryp was divided pixel by pixel, by the intensities of FAD and collagen, the resulting formulaic ratio (FR) images were of exceptionally high contrast. The FR images of adenomas and adenocarcinomas had increased Weber contrast.FR imaging is a novel imaging process that represents the likely metabolic and structural changes in colonic neoplasia that produces images with remarkably high contrast.

OBJECTIVES To determine the cardiovascular and hemostatic effects of fire suppression and postexposure active cooling. METHODS Forty-four firefighters were evaluated before and after a 12-minute live-fire drill. Next, 50 firefighters performing the same drill were randomized to undergo postfire forearm immersion in 10 °C water or standard rehabilitation. RESULTS In the first study, heart rate and core body temperature increased and serum C-reactive protein decreased but there were no significant changes in fibrinogen, sE-selectin, or sL-selectin. The second study demonstrated an increase in blood coagulability, leukocyte count, factors VIII and X, cortisol, and glucose, and a decrease in plasminogen and sP-selectin. Active cooling reduced mean core temperature, heart rate, and leukocyte count. CONCLUSIONS Live-fire exposure increased core temperature, heart rate, coagulability, and leukocyte count; all except coagulability were reduced by active cooling.

Background: Vitamin D levels and calcium intake have been associated with risk of colorectal neoplasia, and genetic variation in vitamin D pathway genes may affect circulating vitamin D metabolite concentrations and/or risk for colorectal lesions. This study evaluated associations between polymorphic variation in the Gc-globulin (GC) and calcium-sensing receptor (CASR) and odds for metachronous colorectal neoplasia and vitamin D metabolite concentrations. Methods: Participants from the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) trials (n = 1,439) were analyzed using a single-nucleotide polymorphism (SNP) tagging approach, with a subset (n = 404) of UDCA trial participants for whom vitamin D metabolite concentrations were also available. A total of 25 GC and 35 CASR tagSNPs were evaluated using multiple statistical methods. Results: Principal components analyses did not reveal gene-level associations between GC or CASR and colorectal neoplasia; however, a significant gene-level association between GC and 25(OH)D concentrations (P < 0.01) was observed. At the individual SNP level and following multiple comparisons adjustments, significant associations were observed between seven GC (rs7041, rs222035, rs842999, rs1155563, rs12512631, rs16846876, and rs1746825) polymorphisms and circulating measures of 25(OH)D (adjusted P < 0.01) and CASR SNP rs1042636 and proximal colorectal neoplasia (adjusted P = 0.01). Conclusions: These results show a possible association between variation in CASR and odds of colorectal neoplasia as well as the potential role of variation in GC with circulating 25(OH)D concentrations. Impact: Additional research is warranted to determine the mechanism of GC genotype in influencing 25(OH)D concentrations and to further elucidate the role of CASR in colorectal neoplasia. Cancer Epidemiol Biomarkers Prev; 21(2); 368–75. ©2011 AACR.

BACKGROUND Few data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure. DESIGN International Maternal Pediatric Adolescent AIDS Clinical Trials 1026 s is an ongoing, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included 2 cohorts receiving atazanavir/ritonavir 300 mg/100 mg once daily, either with or without tenofovir. METHODS Intensive steady-state 24-hour pharmacokinetic profiles were performed during the third trimester and at 6-12 weeks postpartum. Atazanavir was measured by reverse-phase high-performance liquid chromatography (detection limit 0.047 mcg/mL). Pharmacokinetic targets were the estimated 10th percentile atazanavir area under the concentration versus time curve [(AUC): 29.4 mcg · hr · mL-1] in nonpregnant historical controls (mean AUC = 57 mcg · hr · mL-1) and a trough concentration of 0.15 mcg/mL, the concentration target used in therapeutic drug monitoring programs. RESULTS Median atazanavir AUC was reduced during the third trimester compared with postpartum for subjects not receiving tenofovir (41.9 vs. 57.9 mcg · hr · mL-1, P = 0.02) and for subjects receiving tenofovir (28.8 vs. 39.6 mcg · hr · mL-1, P = 0.04). During the third trimester, AUC was below the target in 33% (6 of 18) of women not receiving tenofovir and 55% (11 of 20) of women receiving tenofovir. Trough concentration was below the target in 6% (1 of 18) of women not receiving tenofovir and 15% (3 of 20) of women receiving tenofovir. The median (range) ratio of cord blood/maternal atazanavir concentration in 29-paired samples was 0.18 (0-0.45). CONCLUSIONS Atazanavir exposure is reduced by pregnancy and by concomitant tenofovir use. A dose increase of atazanavir/ritonavir to 400 mg/100 mg may be necessary in pregnant women to ensure atazanavir exposure equivalent to that seen in nonpregnant adults.

Background: Interest in biomarker patterns and disease has led to the development of immunoassays that evaluate multiple analytes in parallel while using little sample. However, there are no current standards for multiplex configuration, validation, and quality. Thus, validation by platform, population, and question of interest is recommended. We sought to determine the best blood fraction for multiplex evaluation of circulating biomarkers in post-menopausal women, and to explore body composition phenotype discrimination by biomarkers. Methods: Archived serum and plasma samples from a sample of healthy post-menopausal women with the highest (n=9) and lowest (n=11) percent lean mass, as determined by dual-energy X-ray absorptiometry, were used to measure 90 analytes using bead-based, suspension multiplex assays. Replicates of serum and plasma were analyzed in a random selection of four of these individuals. Results: Ninety percent of the analytes were detectable for ≥50% of samples; when limited to these well detected analytes, mean replicate correlations for serum and plasma were 0.87 and 0.85, respectively. Serum had lower error rates discriminating phenotypes; seven serum vs. two plasma analytes discriminated extreme body phenotypes. Conclusions: Serum and plasma performed similarly for the majority of the analytes. Serum showed a slight advantage in predicting extreme body composition phenotypes in postmenopausal women using parallel evaluation of analytes.

OBJECTIVE Reduced lopinavir concentrations have been demonstrated with use of the capsule formulation during the third trimester of pregnancy. This study determined lopinavir exposure with an increased dose of the new tablet formulation during the third trimester. DESIGN International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is a prospective nonblinded pharmacokinetic study in HIV-infected pregnant women, including a cohort receiving 2 lopinavir/ritonavir tablets (400 mg/100 mg) twice daily during the second trimester, 3 tablets (600 mg/150 mg) twice daily during the third trimester, and 2 tablets (400 mg/100 mg) twice daily post delivery through 2 weeks postpartum. METHODS Steady-state 12-hour pharmacokinetic profiles were performed during pregnancy and at 2 weeks postpartum. Lopinavir and ritonavir were measured by reverse-phase high-performance liquid chromatography (detection limit, 0.09 mcg/mL). RESULTS Thirty-three women were studied. Median lopinavir AUC for the second trimester (n = 11), third trimester (n = 33), and postpartum (n = 27) were 72, 96, and 133 mcg x hr/mL, respectively. Median minimum lopinavir concentrations were 3.4, 4.9, and 6.9 mcg/mL. CONCLUSIONS The higher lopinavir/ritonavir tablet dose (600 mg/150 mg) provided exposure during the third trimester similar to the average AUC (98 mcg x hr x mL(-1) in nonpregnant adults taking 400 mg/100 mg twice daily. The higher dose should be used during the second and third trimesters of pregnancy. Postpartum dosing can be reduced to standard dosing before 2 weeks postpartum.

Objectives Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum. Methods The participants were HIV-1-infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady-state 12-h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration–time curve (AUC0–12) was ≥10th percentile NFV AUC0–12 in non-pregnant historical controls (18.5 μg h/mL). Results Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (Cmax), 12-h post-dose concentration (C12) and AUC0–12 were significantly lower during the third trimester compared to postpartum (P≤0.03). The metabolite hydroxyl-tert-butylamide (M8) AUC0–12 and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (P

Objectives To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. Methods Twenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante- and postpartum comparisons were made using paired t-tests and using a ‘bioequivalence’ approach to determine confidence interval (CI). Results The average NVP Area Under the Curve (AUC) was 56 ± 13 mcg*h/mL antepartum and 61 ± 15 mcg*h/mL postpartum. The typical parameters ± standard error were apparent clearance (CL/F)=3.51 ± 0.18 L/h and apparent volume of distribution (Vd/F)=121 ± 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80–1.02. The median (± standard deviation) cord blood to maternal NVP concentration ratio was 0.91 ± 0.90. Conclusions Pregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.

The risk of breast cancer transiently increases immediately following pregnancy; peaking between 3-7 years. The biology that underlies this risk window and the effect on the natural history of the disease is unknown. MicroRNAs (miRNAs) are small non-coding RNAs that have been shown to be dysregulated in breast cancer. We conducted miRNA profiling of 56 tumors from a case series of multiparous Hispanic women and assessed the pattern of expression by time since last full-term pregnancy. A data-driven splitting analysis on the pattern of 355 miRNAs separated the case series into two groups: a) an early group representing women diagnosed with breast cancer ≤ 5.2 years postpartum (n = 12), and b) a late group representing women diagnosed with breast cancer ≥ 5.3 years postpartum (n = 44). We identified 15 miRNAs with significant differential expression between the early and late postpartum groups; 60% of these miRNAs are encoded on the X chromosome. Ten miRNAs had a two-fold or higher difference in expression with miR-138, miR-660, miR-31, miR-135b, miR-17, miR-454, and miR-934 overexpressed in the early versus the late group; while miR-892a, miR-199a-5p, and miR-542-5p were underexpressed in the early versus the late postpartum group. The DNA methylation of three out of five tested miRNAs (miR-31, miR-135b, and miR-138) was lower in the early versus late postpartum group, and negatively correlated with miRNA expression. Here we show that miRNAs are differentially expressed and differentially methylated between tumors of the early versus late postpartum, suggesting that potential differences in epigenetic dysfunction may be operative in postpartum breast cancers.

Background Optimal antiretroviral exposure during pregnancy is critical for prevention of mother-to-child HIV transmission and for maternal health. Pregnancy can alter antiretroviral pharmacokinetics. Our objective was to describe lopinavir/ritonavir (LPV/r) pharmacokinetics during pregnancy. Methods We performed intensive steady-state 12-h pharmacokinetic profiles of lopinavir and ritonavir (three capsules: LPV 400 mg/r 100 mg) at 30-36 weeks gestation and 6-12 weeks postpartum. Maternal and umbilical cord blood samples were obtained at delivery. We measured LPV and ritonavir by reverse-phase high-performance liquid chromatography. Target LPV area under concentration versus time curve (AUC) was > or = 52 microg h/ml, the estimated 10th percentile LPV AUC in non-pregnant historical controls (mean AUC = 83 microg h/ml). Results Seventeen women completed antepartum evaluations; average gestational age was 35 weeks. Geometric mean antepartum LPV AUC was 44.4 microg h/ml [90% confidence interval (CI), 38.7-50.9] and 12-h post-dose concentration (C12h) was 1.6 microg/ml (90% CI, 1.1-2.5). Twelve women completed postpartum evaluations; geometric mean LPV AUC was 65.2 microg h/ml (90% CI, 49.7-85.4) and C12h was 4.6 microg/ml (90% CI, 3.7-5.7). The geometric mean ratio of antepartum/postpartum LPV AUC was 0.72 (90% CI, 0.54-0.96). Fourteen of 17 (82%) pregnant and three of 12 (25%) postpartum women did not meet our target LPV AUC. The ratio of cord blood/maternal LPV concentration in ten paired detectable samples was 0.2 +/- 0.13. Conclusions LPV/r exposure during late pregnancy was lower compared to postpartum and compared to non-pregnant historical controls. Small amounts of lopinavir cross the placenta. The pharmacokinetics, safety, and effectiveness of increased LPV/r dosing during the third trimester of pregnancy should be investigated.

To develop a photographic sun damage assessment scale for forearm skin and test its feasibility and utility for consistent classification of sun damage.For a blinded comparison, 96 standardized 8 × 10 digital photographs of participants' forearms were taken. Photographs were graded by an expert dermatologist using an existing 9-category dermatologic assessment scoring scale until all categories contained photographs representative of each of 4 clinical signs. Triplicate photographs were provided in identical image sets to 5 community dermatologists for blinded rating using the dermatologic assessment scoring scale.Academic skin cancer prevention clinic with high-level experience in assessment of sun-damaged skin.Volunteer sample including participants from screenings, chemoprevention, and/or biomarker studies.Reproducibility and agreement of grading among dermatologists by Spearman correlation coefficient to assess the correlation of scores given for the same photograph, κ statistics for ordinal data, and variability of scoring among dermatologists, using analysis of variance models with evaluating physician and photographs as main effects and interaction effect variables to account for the difference in scoring among dermatologists.Correlations (73% to90%) between dermatologists were all statistically significant (P.001). Scores showed good to substantial agreement but were significantly different (P.001) for each of 4 clinical signs and the difference varied significantly (P.001) among photographs.With good to substantial agreement, we found the development of a photographic forearm sun damage assessment scale highly feasible. In view of significantly different rating scores, a photographic reference for assessment of sun damage is also necessary.