Acute downregulation of emerin alters actomyosin cytoskeleton connectivity and function.

Fetal lung fibroblasts contribute dynamic infrastructure for the developing lung. These cells undergo dynamic mechanical transitions, including cyclic stretch and spreading, which are integral to lung growth in utero. We investigated the role of the nuclear envelope protein emerin in cellular responses to these dynamic mechanical transitions. In contrast to control cells, which briskly realigned their nuclei, actin cytoskeleton, and extracellular matrices in response to cyclic stretch, fibroblasts that were acutely downregulated for emerin showed incomplete reorientation of both nuclei and actin cytoskeleton. Emerin-downregulated fibroblasts were also aberrantly circular in contrast to the spindle-shaped controls and exhibited an altered pattern of filamentous actin organization that was disconnected from the nucleus. Emerin knockdown was also associated with reduced myosin light chain phosphorylation during cell spreading. Interestingly, emerin-downregulated fibroblasts also demonstrated reduced fibronectin fibrillogenesis and production. These findings indicate that nuclear-cytoskeletal coupling serves a role in the dynamic regulation of cytoskeletal structure and function and may also impact the transmission of traction force to the extracellular matrix microenvironment.

CSF and serum inflammatory response and association with outcomes in spontaneous intracerebral hemorrhage with intraventricular extension: an analysis of the CLEAR-III Trial.

BACKGROUND: Intracerebral hemorrhage (ICH) results in a cascade of inflammatory cell activation with recruitment of peripheral leukocytes to the brain parenchyma and surrounding the hematoma. We hypothesized that in patients with ICH and intraventricular hemorrhage (IVH), a robust cerebrospinal fluid (CSF) inflammatory response occurs with leukocyte subtypes being affected by alteplase treatment and contributing to outcomes. METHODS: Serum and CSF cell counts from patients in the phase 3 Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) trial were analyzed. CSF leukocytes were corrected for the presence of red blood cells. Trends in cell counts were plotted chronologically. Associations were evaluated between serum and CSF leukocyte subtypes and adjudicated functional outcome (modified Rankin Scale; mRS) at 30 and 180 days and bacterial infection according to treatment with intraventricular alteplase versus saline. RESULTS: A total of 279 and 292 patients had ≥3 differential cell counts from serum and CSF, respectively. CSF leukocyte subtypes evolved during IVH resolution with a significantly augmented inflammatory response for all subtypes in alteplase- compared to saline-treated patients. CSF leukocyte subtypes were not associated with detrimental effect on functional outcomes in the full cohort, but all were associated with poor 30-day outcome in saline-treated patients with IVH volume ≥20 mL. Higher serum lymphocytes were associated with good functional outcomes (mRS 0-3) in the entire cohort and saline-treated but not alteplase-treated group. Conversely, increased serum neutrophil-to-lymphocyte ratio (NLR) in the entire cohort and saline group was associated with worse functional outcomes. Higher median serum lymphocytes were associated with the absence of infection at 7 days. CONCLUSIONS: Aseptic CSF inflammation after IVH involves all leukocyte subtypes. Serum lymphocytes may be associated with better outcomes by mitigating infection. Alteplase augments the inflammatory response without affecting outcomes.

Intracranial Hypertension and Cerebral Perfusion Pressure Insults in Adult Hypertensive Intraventricular Hemorrhage: Occurrence and Associations With Outcome.

OBJECTIVES: Elevated intracranial pressure and inadequate cerebral perfusion pressure may contribute to poor outcomes in hypertensive intraventricular hemorrhage. We characterized the occurrence of elevated intracranial pressure and low cerebral perfusion pressure in obstructive intraventricular hemorrhage requiring extraventricular drainage. DESIGN: Prospective observational cohort. SETTING: ICUs of 73 academic hospitals. PATIENTS: Four hundred ninety-nine patients enrolled in the CLEAR III trial, a multicenter, randomized study to determine if extraventricular drainage plus intraventricular alteplase improved outcome versus extraventricular drainage plus saline. INTERVENTIONS: Intracranial pressure and cerebral perfusion pressure were recorded every 4 hours, analyzed over a range of thresholds, as single readings or spans (≥ 2) of readings after adjustment for intracerebral hemorrhage severity. Impact on 30- and 180-days modified Rankin Scale scores was assessed, and receiver operating curves were analyzed to identify optimal thresholds. MEASUREMENTS AND MAIN RESULTS: Of 21,954 intracranial pressure readings, median interquartile range 12 mm Hg (8-16), 9.7% were greater than 20 mm Hg and 1.8% were greater than 30 mm Hg. Proportion of intracranial pressure readings from greater than 18 to greater than 30 mm Hg and combined intracranial pressure greater than 20 plus cerebral perfusion pressure less than 70 mm Hg were associated with day-30 mortality and partially mitigated by intraventricular alteplase. Proportion of cerebral perfusion pressure readings from less than 65 to less than 90 mm Hg and intracranial pressure greater than 20 mm Hg in spans were associated with both 30-day mortality and 180-day mortality. Proportion of cerebral perfusion pressure readings from less than 65 to less than 90 mm Hg and combined intracranial pressure greater than 20 plus cerebral perfusion pressure less than 60 mm Hg were associated with poor day-30 modified Rankin Scale, whereas cerebral perfusion pressure less than 65 and less than 75 mm Hg were associated with poor day-180 modified Rankin Scale. CONCLUSIONS: Elevated intracranial pressure and inadequate cerebral perfusion pressure are not infrequent during extraventricular drainage for severe intraventricular hemorrhage, and level and duration predict higher short-term mortality and long-term mortality. Burden of low cerebral perfusion pressure was also associated with poor short- and long-term outcomes and may be more significant than intracranial pressure. Adverse consequences of intracranial pressure-time burden and cerebral perfusion pressure-time burden should be tested prospectively as potential thresholds for therapeutic intervention.

Alcohol Use Patterns and Subsequent Sexual Behaviors Among Women, Men who have Sex with Men and Men who have Sex with Women Engaged in Routine HIV Care in the United States.

Among people with HIV, alcohol use is associated with increased prevalence of sexual transmission behaviors. We examined associations between alcohol use in the prior year and sexual behaviors approximately six months later among 1857 women, 6752 men who have sex with men (MSM) and 2685 men who have sex with women (MSW). Any alcohol use was associated with increased risk of unsafe vaginal sex among women; anal sex and =>2 anal sex partners among MSM; and anal sex, =>2 anal or vaginal sex partners, and unsafe vaginal sex among MSW. In particular, among women >7 alcoholic drinks/week and among MSW =>5 alcoholic drinks/drinking day increased the likelihood of certain subsequent sexual behaviors. For all groups, especially women, the risk of sex under the influence of drugs/alcohol markedly increased with increases in quantity and frequency of alcohol consumption. These different patterns of drinking and sexual behaviors indicate the importance of tailored counseling messages to women, MSM and MSW.

Third Ventricle Obstruction by Thalamic Intracerebral Hemorrhage Predicts Poor Functional Outcome Among Patients Treated with Alteplase in the CLEAR III Trial.

INTRODUCTION: The Clot Lysis: Evaluating Accelerated Resolution of IVH trial examined whether irrigating the ventricular system with alteplase improved functional outcomes in patients with small intracerebral hemorrhage (ICH) and large intraventricular hemorrhage (IVH). Thalamic ICH location was common and was associated with poor outcome. One possible explanation is thalamic ICH-associated mass effect obstructing the third ventricle. We hypothesized that patients with thalamic ICH obstructing the third ventricle would have worse functional outcomes compared to patients without obstructing lesions. METHODS: ICH obstruction of third ventricle was defined as third ventricle compression on 1 or more axial computed tomography slices visually impeding cerebral spinal fluid flow. If the third ventricle was casted with IVH, it was scored as such. Multivariable logistic regression analyses were used to determine whether obstruction of the third ventricle predicts poor functional outcomes defined as modified Rankin score (mRS) 4-6, higher mRS, and mortality at 180 days. Models were adjusted for thalamic ICH location, ICH volume, IVH volume, age, hydrocephalus, baseline Glasgow coma scale, and percentage of low cerebral perfusion pressures during treatment. RESULTS: Among saline-treated patients, obstruction of the third ventricle by IVH was a significant predictor of higher mRS at 180 days (OR 1.87, CI 1.01-3.47) and mortality at 180 days (OR 2.73, CI 1.27-5.87) while obstruction by ICH was not. In contrast, among alteplase-treated patients, obstruction by ICH was a significant predictor of mRS 4-6 (OR 3.20, CI 1.30-7.88) and higher mRS at 180 days (OR 2.33, CI 1.24-4.35), while obstruction by IVH was not. CONCLUSIONS: Poor outcomes were associated with mass-related obstruction of the third ventricle from thalamic ICH in alteplase-treated patients and from IVH in saline-treated patients. Once the ventricular system is cleared with alteplase, obstruction of cerebral spinal fluid flow from thalamic ICH might become important in functional recovery.

Establishing a Multidisciplinary Head and Neck Clinical Pathway: An Implementation Evaluation and Audit of Dysphagia-Related Services and Outcomes.

Head and neck cancer (HNC) guidelines recommend regular multidisciplinary team (MDT) monitoring and early intervention to optimize dysphagia outcomes; however, many factors affect the ability to achieve these goals. The aims of this study were to explore the barriers/facilitators to establishing and sustaining a MDT HNC care pathway and to examine the dysphagia-related speech-language pathology (SLP) and dietetic components of the pathway. Using the Consolidated Framework for Implementation Research (CFIR), a mixed methods study design was used to evaluate an established MDT HNC pathway. Ten MDT members provided perceptions of facilitators/barriers to implementing and sustaining the pathway. Patients attending the SLP and dietetic components of the pathway who commenced treatment between 2013 and 2014 (n = 63) were audited for attendance, outcome data collected per visit, and swallowing outcomes to 24-month post-treatment. Dysphagia outcomes were compared to a published cohort who had received intensive prophylactic dysphagia management. Multiple CFIR constructs were identified as critical to implementing and sustaining the pathway. Complexity was a barrier. Patient attendance was excellent during treatment, with low rates of non-compliance (< 15%) to 24 months. Collection of clinician/patient outcome tools was good during treatment, but lower post-treatment. Dysphagia outcomes were good and comparable to prior published data. The pathway provided patients with access to regular supportive care and provided staff opportunities to provide early and ongoing dysphagia monitoring and management. However, implementing and sustaining a HNC pathway is complex, requiring significant staff resources, financial investment, and perseverance. Regular audits are necessary to monitor the quality of the pathway.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.

BACKGROUND: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING: National Institute of Neurological Disorders and Stroke.

The Johns Hopkins Fall Risk Assessment Tool: A Study of Reliability and Validity.

Patient falls and fall-related injury remain a safety concern. The Johns Hopkins Fall Risk Assessment Tool (JHFRAT) was developed to facilitate early detection of risk for anticipated physiologic falls in adult inpatients. Psychometric properties in acute care settings have not yet been fully established; this study sought to fill that gap. Results indicate that the JHFRAT is reliable, with high sensitivity and negative predictive validity. Specificity and positive predictive validity were lower than expected.

Rehabilitation and Psychosocial Determinants of Cochlear Implant Outcomes in Older Adults.

OBJECTIVE: The cochlear implant (CI) has been shown to be associated with better hearing, cognitive abilities, and functional independence. There is variability however in how much benefit each recipient derives from his or her CI. This study's primary objective is to determine the effects of individual and environmental characteristics on CI outcomes. DESIGN: Seventy-six adults who developed postlingual severe to profound hearing loss and received their first unilateral CI at 65 years and older were eligible for the study. Fifty-five patients were asked to participate and the 33 (60%) with complete data were classified as "group 1." The remaining patients were placed in "group 2." Primary outcomes included changes in quality of life and open-set speech perception scores. Independent variables included age, health status, trait emotional intelligence (EI), comfort with technology, and living arrangements. Survey outcomes and audiological measurements were collected prospectively at 12 months after surgery, whereas preoperative data were collected retrospectively. Comparisons between groups 1 and 2 were made. Wilcoxon signed rank test, Spearman correlations, Mann-Whitney tests, Chi-square tests, and linear regressions were performed only on group 1 data. RESULTS: Having a CI was associated with improved quality of life and speech perception. Familiarity with electronic tablets was associated with increased 12-month postoperative AzBio gains when adjusted for preoperative AzBio scores (adjusted p = 0.019), but only marginally significant when a family-wise error correction was applied (p = 0.057). Furthermore, patients who lived with other people scored at least 20 points higher on the AzBio sentences than those who lived alone (adjusted p = 0.046). Finally, consultation with an auditory rehabilitation therapist was associated with higher self-reported quality of life (p = 0.035). CONCLUSION: This study suggests that in a cohort of older patients cochlear implantation is associated with a meaningful increase in both quality of life and speech perception. Furthermore, it suggests the potential importance of adjunct support and services, including the tailoring of CI rehabilitation sessions depending on the patient's familiarity with technology and living situation. Investment in rehabilitation and other services is associated with improvements in quality of life and may mitigate clinical, individual and social risk factors for poor communication outcome.

Efficacy of parent-delivered behavioral therapy for primary complex motor stereotypies.

AIM: Primary complex motor stereotypies (CMS) are persistent, patterned, repetitive, rhythmic movements in young people with typical development. This study evaluated the efficacy of an instructional DVD as a home-based, parent-administered, behavioral therapy for primary CMS. METHOD: Eighty-one children with primary CMS were enrolled. Primary outcome measures included the Stereotypy Severity Scale (SSS) - Motor and Impairment scores, and Stereotypy Linear Analog Scale (SLAS). Mean CMS onset was 13.4 months (SD 13.1). Eligibility required observed CMS. Psychiatric disorders were not exclusionary and a stable medication regimen was required. Intellectual disability, neurological disorder, autism spectrum disorder, and tics were exclusionary. Initial assessments were completed via REDCap before receipt of the DVD. Fifty-four of the 81 children (34 male, 20 female; mean age 8y 2mo, SD 1.42, range 7-14y) completed assessments at 1, 2, or 3 months after receiving the DVD. RESULTS: Reductions (baseline to last assessment) in SSS Motor, SSS Impairment, and SLAS scores (all p<0.001) represented change ratios of -15%, -24%, and a -20% respectively. Greatest relative treatment benefit was observed by younger children (ages 7-8y), and by 1 month after receipt of DVD, while a parent global assessment scale showed progressive improvement throughout the study. INTERPRETATION: An instructional DVD for parent-delivered behavioral therapy was a safe, effective intervention for primary CMS.

Anesthesiologists and Disaster Medicine: A Needs Assessment for Education and Training and Reported Willingness to Respond.

BACKGROUND: Anesthesiologists provide comprehensive health care across the emergency department, operating room, and intensive care unit. To date, anesthesiologists' perspectives regarding disaster medicine and public health preparedness have not been described. METHODS: Anesthesiologists' thoughts and attitudes were assessed via a Web-based survey at 3 major academic institutions. Frequencies, percentages, and odds ratios (ORs) were used to assess self-reported perceptions of knowledge and skills, as well as attitudes and beliefs regarding education and training, employee development, professional obligation, safety, psychological readiness, efficacy, personal preparedness, and willingness to respond (WTR). Three representative disaster scenarios (natural disaster [ND], radiological event [RE], and pandemic influenza [PI]) were investigated. Results are reported as percent or OR (95% confidence interval). RESULTS: Participants included 175 anesthesiology attendings (attendings) and 95 anesthesiology residents (residents) representing a 47% and 51% response rate, respectively. A minority of attendings indicated that their hospital provides adequate pre-event preparation and training (31% [23-38] ND, 14% [9-21] RE, and 40% [31-49] PI). Few residents felt that their residency program provided them with adequate preparation and training (22% [14-33] ND, 16% [8-27] RE, and 17% [9-29] PI). Greater than 85% of attendings (89% [84-94] ND, 88% [81-92] RE, and 87% [80-92] PI) and 70% of residents (81% [71-89] ND, 71% [58-81] RE, and 82% [70-90] PI) believe that their hospital or residency program, respectively, should provide them with preparation and training. Approximately one-half of attendings and residents are confident that they would be safe at work during response to a ND or PI (55% [47-64] and 58% [49-67] of attendings; 59% [48-70] and 48% [35-61] of residents, respectively), whereas approximately one-third responded the same regarding a RE (31% [24-40] of attendings and 28% [18-41] of residents). Fewer than 40% of attendings (34% [26-43]) and residents (38% [27-51]) designated who would take care of their family obligations in the event they were called into work during a disaster. Regardless of severity, 79% (71-85) of attendings and 73% (62-82) of residents indicated WTR to a ND, whereas 81% (73-87) of attendings and 70% (58-81) of residents indicated WTR to PI. Fewer were willing to respond to a RE (63% [55-71] of attendings and 52% [39-64] of residents). In adjusted logistic regression analyses, those anesthesiologists who reported knowing one's role in response to a ND (OR, 15.8 [4.5-55.3]) or feeling psychologically prepared to respond to a ND (OR, 6.9 [2.5-19.0]) were found to be more willing to respond. Similar results were found for RE and PI constructs. Both attendings and residents were willing to respond in whatever capacity needed, not specifically to provide anesthesia. CONCLUSIONS: Few anesthesiologists reported receiving sufficient education and training in disaster medicine and public health preparedness. Providing education and training and enhancing related employee services may further bolster WTR and help to build a more capable and effective medical workforce for disaster response.

Effect of Postoperative Dressing on Excisions Performed on the Leg: A Comparison Between Zinc Oxide Compression Dressings Versus Standard Wound Care.

BACKGROUND: Wound healing on the legs may be complicated by delayed healing and other postoperative problems. Two potential postoperative wound care regimens for sutured excisions on the legs include a standard pressure dressing and zinc oxide compression dressings. Limited data exist comparing the efficacy of these 2 options. OBJECTIVE: To compare outcomes of standard postoperative wound care dressing versus postoperative use of a zinc oxide compression dressings for sutured repairs on the legs. METHODS: In this retrospective cohort study, healing time and complication rate of 44 patients treated with standard dressing and 36 patients treated with zinc oxide compression dressings were compared. RESULTS: At 19 days, 91.7% of patients receiving zinc oxide dressing were fully healed, whereas only 65.9% of patients receiving standard wound care were healed. Complications were noted in 6 of the patients receiving standard dressing (13.6%); no complications occurred in the zinc oxide dressing group. CONCLUSION: Zinc oxide compression dressings were a practical option for postoperative wound care, with decreased incidence of delayed wound healing, and fewer complications versus standard postoperative wound dressing.

Body Mass Hides the Curve: Thoracic Scoliometer Readings Vary by Body Mass Index Value.

BACKGROUND: Guidelines suggest referral for scoliosis when rib slope (scoliometer measurement, angle of trunk rotation) is ≥7 degrees. We hypothesized that overweight and obese patients would have lower scoliometer measurements compared with normal-weight and underweight patients for a given spinal curvature, causing overweight and obese patients with adolescent idiopathic scoliosis to present for treatment later and with larger curves. Our goal was to determine the association between scoliometer readings and major curve magnitudes in relation to body mass index (BMI). METHODS: This retrospective cohort study at a tertiary referral center included 483 patients (420 girls) aged 10 to 18 years (mean age, 14±1.6 y) with thoracic adolescent idiopathic scoliosis who presented to 1 orthopaedic surgeon for initial evaluation of spinal deformity from 2010 to 2015. Records were reviewed for BMI percentile for age and sex (underweight, ≤fourth percentile; normal weight, fifth to 84th percentile; overweight, 85th to 94th percentile; obese, ≥95th percentile), patient characteristics, thoracic scoliometer measurements, and thoracic major curves. RESULTS: Of the 483 patients, 23 were underweight, 372 were normal weight, 52 were overweight, and 36 were obese. Obese patients had a larger mean major curve (44 degrees) than normal-weight patients (34 degrees) (P=0.004). The odds of presenting with a major curve ≥20 degrees were 4.9 (95% confidence interval, 1.1-22; P=0.037) times higher for obese versus normal-weight patients. Receiver operating characteristic analysis of major curves (≥20 vs. <20 degrees) estimated the scoliometer values with the greatest sensitivity and specificity to be 8 degrees for underweight patients, 7 degrees for normal-weight patients, 6 degrees for overweight patients, and 5 degrees for obese patients. CONCLUSIONS: Obese patients presented with larger thoracic curves versus normal-weight patients. Differences in chest-wall thickness in patients with different BMI values may alter scoliometer measurements for a given rotational deformity. Our data suggest new referral criteria for the scoliometer test based on BMI values. Specifically, obese patients should be referred at an angle of trunk rotation of 5 degrees. LEVEL OF EVIDENCE: Level II.

Preinvasive and Invasive Cervical Adenocarcinoma: Preceding Low-Risk or Negative Pap Result Increases Time to Diagnosis.

OBJECTIVES: The aims of the study were to investigate screening histories of women with adenocarcinoma in situ (AIS) and adenocarcinoma (AdCa) of the cervix and to further evaluate screening for glandular disease. MATERIALS AND METHODS: Screening histories were retrospectively collected for patients with AIS or AdCa at a single large-volume academic institution from 2005 to 2015. Fisher exact and Wilcoxon rank sum tests were used to compare AIS with AdCa patient characteristics, distribution of preceding Pap (i.e., trigger Pap) results, and high-risk human papillomavirus testing. The association between Pap result and time to diagnosis was evaluated. RESULTS: Eighty-seven cases, 50 AIS and 37 AdCa, met study criteria; median age was 31 and 43 years, respectively. Among the AIS cohort, 52.0% had a negative or low-risk trigger Pap result versus 24.3% of those with AdCa (p = .001). The time to diagnosis of AIS ranged from 8.4 to 18.8 weeks for those with high- versus low-risk or negative trigger Pap results, respectively (p = .002). The time to diagnosis of AdCa ranged from 14.6 to 44.7 weeks for those with high- versus low-risk or negative trigger Pap results, respectively (p = .003). Among those with high-risk human papillomavirus testing, 89.7% tested positive at the time of trigger Pap with 100% positivity among those with low-risk or negative trigger Pap results. CONCLUSIONS: Cervical AIS and AdCa affect many young nulliparous women and commonly preceded by low-risk or negative Pap testing. The interval to diagnosis increases with low-risk and negative Pap results, and therefore, further investigation into optimal screening for glandular lesions is needed.

Health-related quality of life before and after head and neck squamous cell carcinoma: Analysis of the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey linkage.

BACKGROUND: Understanding health-related quality of life (HRQOL) is crucial to providing high-quality survivorship care for patients with head and neck squamous cell carcinoma (HNSCC). Trends in and prognostic significance of HRQOL before and after HNSCC have not been well described. METHODS: HRQOL for older individuals with HNSCC was examined using the linked Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey database. Surveys assessing HRQOL from 5 years prediagnosis to 10 years postdiagnosis were included. HRQOL over time was modeled using multilevel linear regression with restricted cubic splines and was reported as either total HRQOL or change in HRQOL (denoted Δ). The association of prediagnosis HRQOL with survival was examined. RESULTS: In total, 1653 individuals were included; of these, 61% completed 1 survey, and 39% completed multiple surveys. Overall HRQOL decreased progressively until 13 months postdiagnosis, then recovered toward baseline between 2 and 5 years. However, after stratification by survival group, the postdiagnosis recovery was not observed. Individuals with shorter survival had lower HRQOL prediagnosis (<2-year survivors, 87.3; > 5-year survivors, 96.4; P = .004) with a steeper decline in HRQOL during diagnosis and treatment (<2-year survivors: Δ, -16.6; 95% confidence interval [CI], -23.8, -9.4; > 5-year survivors: Δ, -0.9; 95% CI, -1.8, 0.08). Radiotherapy and advanced stage were associated with greater declines in HRQOL during diagnosis and treatment (P < .001). Higher prediagnosis HRQOL was independently associated with improved overall survival (adjusted hazard ratio for 10-point increase, 0.91; 95% CI, 0.85-0.97). CONCLUSIONS: HRQOL declines before and after HNSCC, whereas any observed posttreatment recovery is likely an artifact of shorter survival among individuals with the lowest HRQOL. The prognostic implication of prediagnosis HRQOL may inform patient counseling. Cancer 2016;122:1861-70. © 2016 American Cancer Society.

Differentiating neuromyelitis optica from other causes of longitudinally extensive transverse myelitis on spinal magnetic resonance imaging.

BACKGROUND: Although spinal magnetic resonance imaging (MRI) findings of neuromyelitis optica (NMO) have been described, there is limited data available that help differentiate NMO from other causes of longitudinally extensive transverse myelitis (LETM). OBJECTIVE: To investigate the spinal MRI findings of LETM that help differentiate NMO at the acute stage from multiple sclerosis (MS) and other causes of LETM. METHODS: We enrolled 94 patients with LETM into our study. Bright spotty lesions (BSL), the lesion distribution and location were evaluated on axial T2-weighted images. Brainstem extension, cord expansion, T1 darkness and lesion enhancement were noted. We also reviewed the brain MRI of the patients during LETM. RESULTS: Patients with NMO had a greater amount of BSL and T1 dark lesions (p < 0.001 and 0.003, respectively). The lesions in NMO patients were more likely to involve greater than one-half of the spinal cord's cross-sectional area; to enhance and be centrally-located, or both centrally- and peripherally-located in the cord. Of the 62 available brain MRIs, 14 of the 27 whom were NMO patients had findings that may be specific to NMO. CONCLUSIONS: Certain spinal cord MRI features are more commonly seen in NMO patients and so obtaining brain MRI during LETM may support diagnosis.

Effects of Obesity and Leptin Deficiency on Morphine Pharmacokinetics in a Mouse Model.

BACKGROUND: Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another. METHODS: Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant. RESULTS: DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: -4.9; 95% confidence interval [CI]: -8.8 to -0.9) as well as a decreased Cl/F (MD: -4.0; 95% CI: -8.9 to -0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1-1330.6), CMAX (MD: 6.8; 95% CI: 2.7-10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5-35.6), as well as a decreased Cl/F (MD: -7.0; 95% CI: -11.6 to -2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4-1065.4), CMAX (MD: 5.3; 95% CI: 3.2-10.3), and T1/2 (MD: 18.3; 95% CI: 2.8-33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: -779.9; 95% CI: -1229.8 to -330), CMAX (MD: -6.1; 95% CI: -11.4 to -0.9), and T1/2 (MD: -19; 95% CI: -35.1 to -2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3-10.4). CONCLUSIONS: Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism.

Development and validation of a quality-of-life questionnaire for mechanically ventilated ICU patients.

OBJECTIVE: To develop and validate a new instrument for measuring health-related quality of life in mechanically ventilated patients in the ICU. DESIGN: Expert panel consensus and a prospective longitudinal survey. SETTING: Urban, academic, tertiary care medical center. PATIENTS: One hundred fifteen awake, mechanically ventilated, ICU patients who either received a tracheostomy or remained endotracheally intubated. INTERVENTIONS: A new quality-of-life instrument was developed and validated by using pilot study data; informal interviews of patients, families, and nurses; expert panel consensus; and item analyses. The new instrument was used to measure quality of life at three time points (5 d, 10 d, and 15 d after intubation). MEASUREMENTS AND MAIN RESULTS: A new 12-item quality-of-life questionnaire for mechanically ventilated patients was developed. Patients' responses to the quality-of-life questionnaire revealed moderate-to-high correlations with EuroQol scores (r = -0.4 to -0.9) and the EuroQol Visual Analog Scale (r = 0.6-0.9) across the three times and a moderate correlation with the Sequential Organ Failure Assessment tool (r = 0.5) at 10 days after intubation. Cronbach α ranged from 0.80 to 0.94 across the three times. The quality-of-life questionnaire for mechanically ventilated patients was responsive to changes in treatment modalities (tracheostomy vs no tracheostomy and early vs late tracheostomy demarcated by 10 d of intubation). Exploratory factor analysis revealed that this instrument was unidimensional in nature. CONCLUSIONS: The new quality-of-life questionnaire for mechanically ventilated patients is valid and can reliably measure quality of life in mechanically ventilated ICU patients. It may provide clinicians with an accurate assessment of patients' quality of life and facilitate optimal decision making regarding patients' ICU plan of care.

Pharyngocutaneous fistula after total laryngectomy: a single-institution experience, 2001-2012.

PURPOSE: The purpose of this study was to determine the incidence of and risk factors for pharyngocutaneous fistula in patients undergoing total laryngectomy at a single institution. MATERIALS AND METHODS: The records of 59 patients undergoing primary or salvage total laryngectomy at our institution from 2001 to 2012 were retrospectively reviewed. Data collected included patient, tumor and treatment characteristics, and surgical technique. Risk factors were analyzed for association with pharyngocutaneous fistula formation. RESULTS: Twenty patients (34%) developed fistulas. Preoperative tracheostomy (OR 4.1; 95% CI 1.3-13 [p=0.02]) and low postoperative hemoglobin (OR 9.1; 95% CI 1.1-78 [p=0.04]) were associated with fistula development. Regarding surgical technique, primary sutured closure of the total laryngectomy defect had the lowest fistula rate (11%). In comparison, primary stapled closure and pectoralis onlay flap over primary closure had nonsignificantly increased fistula rates (43%, OR 6.0; 95% CI 1.0-37.3 [p=0.06] and 25%, OR 2.7; 95% CI 0.4-23.9 [p=0.38], respectively). Pectoralis flap incorporated into the suture line had a significantly increased fistula rate (50%, OR 7.1; 95% CI 1.4-46 [p=0.02]). After stratification for salvage status, patient comorbidities were associated with fistula in non-salvage cases whereas disease-related characteristics were associated with fistula in salvage cases. Fistula development was associated with increased length of hospital stay (p<0.001) and increased time before oral diet initiation (p<0.001). CONCLUSIONS: Pharyngocutaneous fistula is a common complication of total laryngectomy. Preoperative tracheostomy, postoperative hemoglobin, and surgical technique are important in determining the risk of fistula.

EPPM and willingness to respond: the role of risk and efficacy communication in strengthening public health emergency response systems.

This study examines the attitudinal impact of an Extended Parallel Process Model (EPPM)-based training curriculum on local public health department (LHD) workers' willingness to respond to representative public health emergency scenarios. Data are from 71 U.S. LHDs in urban and rural settings across nine states. The study explores changes in response willingness and EPPM threat and efficacy appraisals between randomly assigned control versus intervention health departments, at baseline and 1 week post curriculum, through an EPPM-based survey/resurvey design. Levels of response willingness and emergency response-related attitudes/beliefs are measured. Analyses focus on two scenario categories that have appeared on a U.S. government list of scenarios of significant concern: a weather-related emergency and a radiological "dirty" bomb event (U.S. Department of Homeland Security, 2007). The greatest impact from the training intervention on response willingness was observed among LHD workers who had low levels of EPPM-related threat and efficacy perceptions at baseline. Self-efficacy and response efficacy and response willingness increased in intervention LHDs for both scenarios, with greater response willingness increases observed for the radiological "dirty" bomb terrorism scenario. Findings indicate the importance of building efficacy versus enhancing threat perceptions as a path toward greater response willingness, and suggest the potential applicability of such curricular interventions for boosting emergency response willingness among other cadres of health providers.