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Neural wearables can enable life-saving drowsiness and health monitoring for pilots and drivers. While existing in-cabin sensors may provide alerts, wearables can enable monitoring across more environments. Current neural wearables are promising but most require wet-electrodes and bulky electronics. This work showcases in-ear, dry-electrode earpieces used to monitor drowsiness with compact hardware. The employed system integrates additive-manufacturing for dry, user-generic earpieces, existing wireless electronics, and offline classification algorithms. Thirty-five hours of electrophysiological data were recorded across nine subjects performing drowsiness-inducing tasks. Three classifier models were trained with user-specific, leave-one-trial-out, and leave-one-user-out splits. The support-vector-machine classifier achieved an accuracy of 93.2% while evaluating users it has seen before and 93.3% when evaluating a never-before-seen user. These results demonstrate wireless, dry, user-generic earpieces used to classify drowsiness with comparable accuracies to existing state-of-the-art, wet electrode in-ear and scalp systems. Further, this work illustrates the feasibility of population-trained classification in future electrophysiological applications.

In the United States (US), pressure ulcers affect ≤3 million people and costs exceed 26.8 billion US dollars in spending. To examine trends in primary pressure ulcer (PPU) hospitalization mortality, length of hospital stay (LOS), and inflation-adjusted charges (IAC) in the US from 2005 to 2014 by race/ethnicity. We secondarily examined the relationship between race/ethnicity with PPU mortality, LOS, and IAC with race/ethnicity. This cross-sectional study used Nationwide Inpatient Sample (NIS) data from 2005 to 2014. The study sample included all hospitalizations with the designated ICD-9-CM code of 707.20-25 (pressure ulcer). There was a notable decline in PPU hospitalization from 11.5% to 7.77 % between 2005 and 2014. The mean mortality decreased from 2.32% to 1.12% (P < .001), the mean LOS declined from 9.39 days (P < .001), and the mean IAC per hospitalization decreased from $30,935 to $29,432 (P < .001). Positive changes observed in mortality, LOS, and IAC trends were consistent across different racial and ethnic groups. The results of multivariable logistic and linear regression analyses revealed that Black patients (β = 0.68, 95% CI 0.36-1.01, P < .001) and patients belonging to the Other race/ethnic category (β = 0.93, 95% CI 0.18-1.69) had longer hospital stays compared to their White counterparts. Regarding IAC, Black patients (β = 2846, 95% CI 1254-4439, P < .005), Hispanic patients (β = 6527, 95% CI 4925-8130), and patients from the Other race/ethnic category (β = 3473, 95% CI 1771-5174) had higher IAC for PPU treatment compared to their White counterparts. PPU hospitalization discharges, as well as hospitalization mortality, LOS, and IAC, decreased during the study period, however, our findings revealed disparities in PPU outcomes among different racial/ethnic groups. Implications of the findings are discussed.

BACKGROUND: To report baseline characteristics, patient reported outcomes and treatment of children with Juvenile Dermatomyositis (JDM) in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. METHODS: Children newly diagnosed with JDM were enrolled in the CARRA Registry from 41 pediatric rheumatology centers. Baseline patient demographics, disease characteristics, assessments, patient reported outcome and treatments were recorded. RESULTS: In the first year, 119 JDM participants were enrolled. Most were female (63.4%), and white (72.3%) with a median diagnosis age 8.0 years (IQR 4.0-11.5), and median age of disease onset 7.0 years (IQR 3.5-7.5). They had characteristic rashes (92.4%), elevated muscle enzymes (83.2%), physician global score 4.0 (IQR 2.5-5.0) and manual muscle testing score 63.5 (IQR 51.0-75.0). Calcinosis (3.4%) and interstitial lung disease (

Numerous ethical issues surged the moment acquired immunodeficiency syndrome (AIDS) was discovered. As advocates of people living with HIV/AIDS (PLWHA), health professionals encounter many ethical dilemmas in clinical practice. However, it remains unclear how health professionals solve these issues. The descriptive qualitative research was conducted through semi-structured interviews with 22 health professionals from May to August 2018. Three themes emerged from data analyses of the interviews: (1) real ethical dilemma experienced by health professionals, (2) factors influencing ethical judgment, (3) ethical motivations. About two-thirds of participants failed to recall ethical dilemmas experienced in their clinical practice. Emotions, gender, occupation, and difficulty balancing different roles may influence the ethical judgments of health professionals. In the ethical decision-making (EDM) process, most participants took other people's interests into consideration and conformed to law and professional codes of conduct. However, the fear of medical disputes (conflicts with families and others) was experienced by many participants, influencing their ethical behaviors.

Aim and objectivesThis study aims to test the hypothesis that job satisfaction and organisational commitment might play a mediating roles between workload, quality of supervision, extra-role behaviour, pay satisfaction and intention to care of patients with COVID-19.BackgroundGiven the high incidence of coronavirus and shortage of nurses in Iranian hospitals, learning about nurses' intention to care for patients with COVID-19 is important.DesignIn this cross-sectional study, 648 Iranian nurses were surveyed during March 2020. The online questionnaire consisted of two parts. The mediating role was explored for the following: job satisfaction and commitment in the association of workload, quality of supervisor, extra-role behaviours, and pay satisfaction with the intention to care. The study adhered to STROBE checklist for cross-sectional studies.ResultsThe results of this study show that job satisfaction and organisational commitment mediated the relationship of nurses' workload, quality of supervisor, extra-role behaviours, and pay satisfaction with the intention to care for patients with COVID-19.ConclusionThe results of the study indicate the importance of job satisfaction and organisational commitment as mechanisms that help to understand the association of nurses' workload, quality of supervisor, extra-role behaviours and pay satisfaction with the intention to care during the COVID-19 pandemic.Relevance to clinical practiceHospital managers need to attend to the role of nurses' job satisfaction and other organisational factors to ensure that they can cope with the challenges of the COVID-19 pandemic.

Aim and objectivesThis study aims to test the hypothesis that job satisfaction and organisational commitment might play a mediating roles between workload, quality of supervision, extra-role behaviour, pay satisfaction and intention to care of patients with COVID-19.BackgroundGiven the high incidence of coronavirus and shortage of nurses in Iranian hospitals, learning about nurses' intention to care for patients with COVID-19 is important.DesignIn this cross-sectional study, 648 Iranian nurses were surveyed during March 2020. The online questionnaire consisted of two parts. The mediating role was explored for the following: job satisfaction and commitment in the association of workload, quality of supervisor, extra-role behaviours, and pay satisfaction with the intention to care. The study adhered to STROBE checklist for cross-sectional studies.ResultsThe results of this study show that job satisfaction and organisational commitment mediated the relationship of nurses' workload, quality of supervisor, extra-role behaviours, and pay satisfaction with the intention to care for patients with COVID-19.ConclusionThe results of the study indicate the importance of job satisfaction and organisational commitment as mechanisms that help to understand the association of nurses' workload, quality of supervisor, extra-role behaviours and pay satisfaction with the intention to care during the COVID-19 pandemic.Relevance to clinical practiceHospital managers need to attend to the role of nurses' job satisfaction and other organisational factors to ensure that they can cope with the challenges of the COVID-19 pandemic.

Background: Several studies indicate a high prevalence of depression around the world during the period of the COVID-19 pandemic. Using a valid instrument to capture the depression of an individual in this situation is both important and timely. The present study aims to evaluate the psychometric properties of the Persian version of the Center for Epidemiological Studies Depression Scale (CES-D) among the public during the COVID-19 pandemic in Iran. Method: This is a cross-sectional study that was conducted in the Iranian population (n = 600) from April to July 2020. A two-part online form was used: sociodemographic characteristics and depression items (CES-D). The construct validity and internal consistency reliability of the scale were evaluated. Result: The results of the exploratory factor analysis illustrated two factors with 43.35% of the total variance of the depression were explained. Confirmatory factor analysis indicated that this model fits well. Internal consistency reliability was evaluated, and it was acceptable. Conclusion: The findings demonstrated that, in the Iranian sample, this depression scale yielded two factors (somatic and positive affects) solutions with suitable psychometric properties.

Lung fibrosis is increasingly detected with aging and has been associated with poor outcomes in acute lung injury or infection. However, the molecular programs driving this pro-fibrotic evolution are unclear. Here we profile distal lung samples from healthy human donors across the lifespan. Gene expression profiling by bulk RNAseq reveals both increasing cellular senescence and pro-fibrotic pathway activation with age. Quantitation of telomere length shows progressive shortening with age, which is associated with DNA damage foci and cellular senescence. Cell type deconvolution analysis of the RNAseq data indicates a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts with age. Consistent with this pro-fibrotic profile, second harmonic imaging of aged lungs demonstrates increased density of interstitial collagen as well as decreased alveolar expansion and surfactant secretion. In this work, we reveal the transcriptional and structural features of fibrosis and associated functional impairment in normal lung aging.

PurposeOlder patients undergoing radiation therapy (RT) for pelvic malignancies are at increased risk for pelvic fracture, which is associated with significant morbidity and mortality. RT techniques such as brachytherapy or intensity modulated RT (IMRT) allow for more conformal dose distributions, but it is not known whether the risk for pelvic fracture varies by RT modality.Methods and materialsThis observational cohort study involved 28,354 patients ≥65 years old, treated with RT for pelvic malignancies. We evaluated the relative risk of pelvic fracture by type of RT when accounting for baseline factors. To test for nonspecific effects, we also evaluated risk of nonpelvic fractures in the same population.ResultsThe 5-year incidence of pelvic fractures was 12.7% (95% confidence interval [CI], 11.6%-13.8%), 11.8% (10.8%-12.8%), and 3.7% (3.4%-4.0%) for patients with gastrointestinal, gynecologic, and prostate cancer, respectively. On multivariable analysis, being treated with IMRT (hazard ratio, 0.85; 95% CI, 0.73-0.99) or brachytherapy therapy alone (hazard ratio, 0.43; 95% CI, 0.34-0.54) was associated with a reduced hazard for pelvic fractures compared with 3D conformal radiation therapy in female patients. In contrast, there was no association with RT modality and the hazard for nonpelvic fractures among females. There was no significant association between pelvic fractures and IMRT or brachytherapy for male patients. White race, advanced age, and higher comorbidity were associated with an increased hazard for pelvic fracture.ConclusionsIMRT and brachytherapy were associated with a reduced risk of pelvic fractures in older women undergoing RT for pelvic malignancies. Pelvic insufficiency fracture risk should be considered when treating with pelvic RT.

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak increases the importance of strategies to enhance urgent medical care delivery in long-term care (LTC) facilities that could potentially reduce transfers to emergency departments. The study objective was to model resource requirements to deliver virtual urgent medical care in LTC facilities. METHODS: We used data from all general medicine inpatient admissions at 7 hospitals in the Greater Toronto Area, Ontario, Canada, over a 7.5-year period (Apr. 1, 2010, to Oct. 31, 2017) to estimate historical patterns of hospital resource use by LTC residents. We estimated an upper bound of potentially avoidable transfers by combining data on short admissions (≤ 72 h) with historical data on the proportion of transfers from LTC facilities for which patients were discharged from the emergency department without admission. Regression models were used to extrapolate future resource requirements, and queuing models were used to estimate physician staffing requirements to perform virtual assessments. RESULTS: There were 235 375 admissions to general medicine wards, and residents of LTC facilities (age 16 yr or older) accounted for 9.3% (n = 21 948) of these admissions. Among the admissions of residents of LTC facilities, short admissions constituted 24.1% (n = 5297), and for 99.8% (n = 5284) of these admissions, the patient received laboratory testing, for 86.9% (n = 4604) the patient received plain radiography, for 41.5% (n = 2197) the patient received computed tomography and for 81.2% (n = 4300) the patient received intravenous medications. If all patients who have short admissions and are transferred from the emergency department were diverted to outpatient care, the average weekly demand for outpatient imaging per hospital would be 2.6 ultrasounds, 11.9 computed tomographic scans and 23.9 radiographs per week. The average daily volume of urgent medical virtual assessments would range from 2.0 to 5.8 per hospital. A single centralized virtual assessment centre staffed by 2 or 3 physicians would provide services similar in efficiency (measured by waiting time for physician assessment) to 7 separate centres staffed by 1 physician each. INTERPRETATION: The provision of acute medical care to LTC residents at their facility would probably require rapid access to outpatient diagnostic imaging, within-facility access to laboratory services and intravenous medication and virtual consultations with physicians. The results of this study can inform efforts to deliver urgent medical care in LTC facilities in light of a potential surge in COVID-19 cases.

PurposePrevious studies indicate that the benefit of therapy depends on patients' risk for cancer recurrence relative to noncancer mortality (ω ratio). We sought to test the hypothesis that patients with head and neck cancer (HNC) with a higher ω ratio selectively benefit from intensive therapy.Experimental designWe analyzed 2,688 patients with stage III-IVB HNC undergoing primary radiotherapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score on the basis of tumor, demographic, and health factors. Analysis was by intention to treat.ResultsDecreasing age, improved performance status, higher body mass index, node-positive status, P16-negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥0.80 were more likely to benefit from intensive treatment [5-year overall survival (OS), 70.0% vs. 56.6%; HR of 0.73, 95% confidence interval (CI): 0.57-0.94; P = 0.016] than those with ω score

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

Mutations in the microtubule-associated protein tau (MAPT) underlie multiple neurodegenerative disorders, yet the pathophysiological mechanisms are unclear. A novel variant in MAPT resulting in an alanine to threonine substitution at position 152 (A152T tau) has recently been described as a significant risk factor for both frontotemporal lobar degeneration and Alzheimer's disease. Here we use complementary computational, biochemical, molecular, genetic and imaging approaches in Caenorhabditis elegans and mouse models to interrogate the effects of the A152T variant on tau function. In silico analysis suggests that a threonine at position 152 of tau confers a new phosphorylation site. This finding is borne out by mass spectrometric survey of A152T tau phosphorylation in C. elegans and mouse. Optical pulse-chase experiments of Dendra2-tau demonstrate that A152T tau and phosphomimetic A152E tau exhibit increased diffusion kinetics and the ability to traverse across the axon initial segment more efficiently than wild-type (WT) tau. A C. elegans model of tauopathy reveals that A152T and A152E tau confer patterns of developmental toxicity distinct from WT tau, likely due to differential effects on retrograde axonal transport. These data support a role for phosphorylation of the variant threonine in A152T tau toxicity and suggest a mechanism involving impaired retrograde axonal transport contributing to human neurodegenerative disease.

China is experiencing a rapid increase in the number of HIV-infected women. In this study, we describe the development and preliminary evaluation of an intervention tailored for Chinese HIV-infected women and caregivers to improve their self- and family management, with goals of enhancing their physical quality of life (QOL) and decreasing their depressive symptomatology. Forty-one HIV-infected women and their caregivers were recruited from two premier Chinese hospitals from July 2014 through March 2016. Participants were randomized to either the control or intervention arm for the Self- and Family Management Intervention (SAFMI). Each study dyad in the intervention arm received three counseling sessions with a nurse interventionist. At baseline, immediate post-intervention (month 1) and follow-up (month 3), the participants were assessed by a self-reported survey. Generalized Hierarchical Linear Modeling was used to evaluate the efficacy of the intervention. Chinese HIV-infected women in the intervention arm had significantly higher probability of higher physical QOL at month 1 and lower probability of clinically meaningful depressive symptomatology at month 3 compared with women in the control arm. In contrast, the effects of the intervention were less salient for caregivers. This study represents one of the first in China to include family caregivers in HIV management. Feasibility and acceptability were high, in that family members were willing to join the study, learn about HIV, and practice new skills to support the HIV-infected women in their lives. A larger trial is needed to fully evaluate this intervention which shows promising preliminary effects in promoting physical QOL and decreasing depressive symptomatology among Chinese HIV-infected women.

PurposeGeneralized competing event (GCE) models improve stratification of patients according to their risk of cancer events relative to competing causes of mortality. The potential impact of such methods on clinical trial power and cost, however, is uncertain. We sought to test the hypothesis that GCE models can reduce estimated clinical trial cost in elderly patients with cancer.MethodsPatients with nonmetastatic head and neck (n = 9,677), breast (n = 22,929), or prostate cancer (n = 51,713) were sampled from the SEER-Medicare database. Using multivariable Cox proportional hazards models, we compared risk scores for all-cause mortality (ACM) and cancer-specific mortality (CSM) with GCE-based risk scores for each disease. We applied a cost function to estimate the cost and duration of clinical trials with a primary end point of overall survival in each population and in high-risk subpopulations. We conducted sensitivity analyses to examine model uncertainty.ResultsFor the purpose of enriching subpopulations, GCE models reduced estimated clinical trial cost compared with Cox models of ACM and CSM in all disease sites. The relative cost reductions with GCE models compared with ACM and CSM models, respectively, were -68.4% and -14.4% in prostate cancer, -38.8% and -18.3% in breast cancer, and -17.1% and -4.1% in head and neck cancer. Cost savings in breast and prostate cancers were on the order of millions of dollars. The GCE model also reduced relative clinical trial duration compared with CSM and ACM models for all disease sites. The optimal risk score cutoff for clinical trial enrollment occurred near the top tertile for all disease sites.ConclusionGCE models have significant potential to improve clinical trial efficiency and reduce cost, with a potentially large impact in prostate and breast cancers.

PurposeComorbidity is an independent predictor of mortality and treatment tolerance in head and neck cancer and should be considered with regard to treatment intensification. Multiple previously validated models can be used to evaluate comorbidity and propensity to benefit from intensive treatment, but they have not been directly compared.Materials and methodsAn online tool was developed and used to calculate the Charlson Comorbidity Index (CCI), Adult Comorbidity Evaluation-27 (ACE-27), Cumulative Illness Rating Scale for Geriatrics (CIRS-G), Geriatric 8 (G8), Cancer and Aging Research Group (CARG), and Generalized Competing Event (GCE) scores. To assess interrater variability, five evaluators independently calculated scores on a retrospective cohort of 20 patients. Correlation between models as well as age and performance status were calculated from a cohort of 40 patients.ResultsThe GCE and G8 models had an excellent (intraclass correlation coefficient and Fleiss' kappa ≥ 0.75) degree of interrater agreement. The CCI, ACE-27, CIRS-G, and CARG had a good (intraclass correlation coefficient and Fleiss' kappa 0.6-0.74) degree of interrater agreement. There was statistically significant correlation between models, especially with the CCI, ACE-27, and CIRS-G indices. Increased age was correlated with an increased CCI score and having moderate to severe comorbidity was correlated with the ACE-27 model. Except for the G8 model, the comorbidity indices were not associated with Eastern Cooperative Oncology Group performance status.ConclusionWe developed an online tool to calculate indices of comorbidity in patients with head and neck cancer with a high degree of reproducibility. Comorbidity is not strongly correlated with performance status and should be independently evaluated in patients.

China is experiencing a rapid increase in the number of HIV-infected women. In this study, we describe the development and preliminary evaluation of an intervention tailored for Chinese HIV-infected women and caregivers to improve their self- and family management, with goals of enhancing their physical quality of life (QOL) and decreasing their depressive symptomatology. Forty-one HIV-infected women and their caregivers were recruited from two premier Chinese hospitals from July 2014 through March 2016. Participants were randomized to either the control or intervention arm for the Self- and Family Management Intervention (SAFMI). Each study dyad in the intervention arm received three counseling sessions with a nurse interventionist. At baseline, immediate post-intervention (month 1) and follow-up (month 3), the participants were assessed by a self-reported survey. Generalized Hierarchical Linear Modeling was used to evaluate the efficacy of the intervention. Chinese HIV-infected women in the intervention arm had significantly higher probability of higher physical QOL at month 1 and lower probability of clinically meaningful depressive symptomatology at month 3 compared with women in the control arm. In contrast, the effects of the intervention were less salient for caregivers. This study represents one of the first in China to include family caregivers in HIV management. Feasibility and acceptability were high, in that family members were willing to join the study, learn about HIV, and practice new skills to support the HIV-infected women in their lives. A larger trial is needed to fully evaluate this intervention which shows promising preliminary effects in promoting physical QOL and decreasing depressive symptomatology among Chinese HIV-infected women.

BackgroundPrevious studies have reported conflicting information regarding the prognostic role of p16 in nonoropharyngeal head and neck squamous cell carcinoma (HNSCC).MethodsUsing the US Veterans Affairs database, we analyzed 1448 patients with locoregionally advanced HNSCC and known p16 status diagnosed between 2005 and 2015 and treated with surgery, radiotherapy, or chemoradiotherapy. Tumor p16 status was determined through manual review of pathology reports of primary tumor specimens. Oropharyngeal (n = 1061) or nonoropharyngeal (n = 387; hypopharyngeal, laryngeal, or oral cavity) tumor site was determined from tumor registry data and manually reviewed for accuracy. We used multivariable Cox regression to analyze the effect of p16 status on overall survival (OS), cancer-specific survival (CSS), and competing mortality (CM) for oropharyngeal or nonoropharyngeal tumor sites. All statistical tests were two-sided.ResultsIn multivariable models adjusting for treatment, stage, age, comorbidity, and body mass index, patients with p16-positive tumors had improved OS, CSS, and CM compared with patients with p16-negative tumors in both oropharyngeal (OS: hazard ratio [HR] = 0.53, 95% confidence interval [CI] = 0.40 to 0.71, P < .001; CSS: HR = 0.50, 95% CI = 0.35 to 0.73, P < .001; CM: HR = 0.59, 95% CI = 0.38 to 0.93, P = .02) and nonoropharyngeal primary sites (OS: HR = 0.41, 95% CI = 0.25 to 0.69, P < .001; CSS: HR = 0.37, 95% CI = 0.18 to 0.77, P = .008; CM: HR = 0.46, 95% CI = 0.23 to 0.95, P = .04). The prognostic impact of p16 status did not statistically significantly differ by primary tumor site for OS, CSS, or CM (Pinteraction > .05).ConclusionsOur findings support the hypothesis that p16 has a similar prognostic role in both nonoropharyngeal and oropharyngeal cancer. Consideration should be given to increased testing for p16 in laryngeal, hypopharyngeal, and oral cavity primaries.

Ultraviolet B (UVB) radiation induces mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPDs), in epidermal keratinocytes (KC). To prevent skin carcinogenesis, these DNA photoproducts must be removed by nucleotide excision repair (NER) or apoptosis. Here we report that the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of UVB-induced CPDs in human HaCaT KC and skin from SKH-1 hairless mice. Subsequent RNA interference and inhibitor studies in KC revealed that AHR specifically suppresses global genome but not transcription-coupled NER. In further experiments, we found that the accelerated repair of CPDs in AHR-compromised KC depended on a modulation of the p27 tumor suppressor protein. Accordingly, p27 protein levels were increased in AHR-silenced KC and skin biopsies from AHR-/- mice, and critical for the improvement of NER. Besides increasing NER activity, AHR inhibition was accompanied by an enhanced occurrence of DNA double-strand breaks triggering KC apoptosis at later time points after irradiation. The UVB-activated AHR thus acts as a negative regulator of both early defense systems against carcinogenesis, NER and apoptosis, implying that it exhibits tumorigenic functions in UVB-exposed skin. In fact, AHR-/- mice developed 50% less UVB-induced cutaneous squamous cell carcinomas in a chronic photocarcinogenesis study than their AHR+/+ littermates. Taken together, our data reveal that AHR influences DNA damage-dependent responses in UVB-irradiated KC and critically contributes to skin photocarcinogenesis in mice.

BackgroundPrevious studies have found that overestimating treatment effects (i.e. 'optimism bias') leads to underpowered clinical trials. The prevalence of 'optimism bias' in contemporary National Clinical Trials Network (NCTN) cancer clinical trials is unknown.MethodsWe conducted a systematic review of NCTN phase III randomized trials published from January 2007 to January 2017. We compared the hypothesized versus observed treatment effects in each trial, and examined whether trial-related factors were correlated with the study results. We also reviewed the methods of each protocol to assess whether a rationale for the hypothesized effect size was provided.ResultsWe identified 161 clinical trials, of which 130 were eligible for analysis. Original protocols could not be located for 8 trials (5.0%). Twenty-eight trials (21.5%) observed a statistically significant difference in the primary end point favoring the experimental treatment. The median ratio of observed-to-expected hazard ratios among trials that observed a statistically significant effect on the primary end point was 1.07 (range: 0.33-1.28) versus 1.32 (range: 0.86-2.02) for trials that did not, compared with 1.34 and 1.86, respectively, for National Cancer Institute (NCI) trials published between 1955 and 2006. An effect size at least as large as the one projected in the protocol trials was observed in 9.8% of trials, compared with 17% of NCI trials published from 1955 to 2006. Most trials (64.6%) provided no rationale to support the magnitude of the proposed treatment effect in the protocol.ConclusionsDespite a reduction in 'optimism bias' compared with previous eras, most contemporary NCTN phase III trials failed to establish statistically significant benefits of new cancer therapies. Better rationalization of proposed effect sizes in research protocols is needed.

Context- Colonic inertia is a debilitating form of primary chronic constipation with unknown etiology and diagnostic criteria, often requiring pancolectomy. We have occasionally observed massively enlarged submucosal ganglia containing at least 20 perikarya, in addition to previously described giant ganglia with greater than 8 perikarya, in cases of colonic inertia. These massively enlarged ganglia have yet to be formally recognized.Objective- To determine whether such "massive submucosal ganglia," defined as ganglia harboring at least 20 perikarya, characterize colonic inertia.Design- We retrospectively reviewed specimens from colectomies of patients with colonic inertia and compared the prevalence of massive submucosal ganglia occurring in this setting to the prevalence of massive submucosal ganglia occurring in a set of control specimens from patients lacking chronic constipation.Results- Seven of 8 specimens affected by colonic inertia harbored 1 to 4 massive ganglia, for a total of 11 massive ganglia. One specimen lacked massive ganglia but had limited sampling and nearly massive ganglia. Massive ganglia occupied both superficial and deep submucosal plexus. The patient with 4 massive ganglia also had 1 mitotically active giant ganglion. Only 1 massive ganglion occupied the entire set of 10 specimens from patients lacking chronic constipation.Conclusions- We performed the first, albeit distinctly small, study of massive submucosal ganglia and showed that massive ganglia may be linked to colonic inertia. Further, larger studies are necessary to determine whether massive ganglia are pathogenetic or secondary phenomena, and whether massive ganglia or mitotically active ganglia distinguish colonic inertia from other types of chronic constipation.

BackgroundThe 2016 Dar Es Salaam Call to Action on Diabetes and Other non-communicable diseases (NCDs) advocates national multi-sectoral NCD strategies and action plans based on available data and information from countries of sub-Saharan Africa and beyond. We estimated trends from 1980 to 2014 in age-standardized mean body mass index (BMI) and diabetes prevalence in these countries, in order to assess the co-progression and assist policy formulation.MethodsWe pooled data from African and worldwide population-based studies which measured height, weight and biomarkers to assess diabetes status in adults aged ≥ 18 years. A Bayesian hierarchical model was used to estimate trends by sex for 200 countries and territories including 53 countries across five African regions (central, eastern, northern, southern and western), in mean BMI and diabetes prevalence (defined as either fasting plasma glucose of ≥ 7.0 mmol/l, history of diabetes diagnosis, or use of insulin or oral glucose control agents).ResultsAfrican data came from 245 population-based surveys (1.2 million participants) for BMI and 76 surveys (182 000 participants) for diabetes prevalence estimates. Countries with the highest number of data sources for BMI were South Africa (n = 17), Nigeria (n = 15) and Egypt (n = 13); and for diabetes estimates, Tanzania (n = 8), Tunisia (n = 7), and Cameroon, Egypt and South Africa (all n = 6). The age-standardized mean BMI increased from 21.0 kg/m2 (95% credible interval: 20.3-21.7) to 23.0 kg/m2 (22.7-23.3) in men, and from 21.9 kg/m2 (21.3-22.5) to 24.9 kg/m2 (24.6-25.1) in women. The age-standardized prevalence of diabetes increased from 3.4% (1.5-6.3) to 8.5% (6.5-10.8) in men, and from 4.1% (2.0-7.5) to 8.9% (6.9-11.2) in women. Estimates in northern and southern regions were mostly higher than the global average; those in central, eastern and western regions were lower than global averages. A positive association (correlation coefficient ≃ 0.9) was observed between mean BMI and diabetes prevalence in both sexes in 1980 and 2014.ConclusionsThese estimates, based on limited data sources, confirm the rapidly increasing burden of diabetes in Africa. This rise is being driven, at least in part, by increasing adiposity, with regional variations in observed trends. African countries' efforts to prevent and control diabetes and obesity should integrate the setting up of reliable monitoring systems, consistent with the World Health Organization's Global Monitoring System Framework.

Purpose: Preclinical models have shown that the effectiveness of GL-ONC1, a modified oncolytic vaccinia virus, is enhanced by radiation and chemotherapy. The purpose of this study was to determine the safety of GL-ONC1 when delivered intravenously with chemoradiotherapy to patients with primary, nonmetastatic head and neck cancer.Experimental Design: Patients with locoregionally advanced unresected, nonmetastatic carcinoma of the head/neck, excluding stage III-IVA p16-positive oropharyngeal cancers, were treated with escalating doses and cycles of intravenous GL-ONC1, along with radiotherapy and chemotherapy. The primary aims were to define the MTD and dose-limiting toxicities, and to recommend a dose for phase II trials.Results: Between May 2012 and December 2014, 19 patients were enrolled. The most frequent adverse reactions included grade 1-2 rigors, fever, fatigue, and rash. Grade 3 adverse reactions included hypotension, mucositis, nausea, and vomiting. In 2 patients, the rash was confirmed as viral in origin by fluorescence imaging and viral plaque assay. In 4 patients, viral presence in tumor was confirmed on midtreatment biopsy by quantitative PCR. In 1 patient, live virus was confirmed in a tongue tumor 7 days after receiving the first dose of virus. The MTD was not reached. With median follow-up of 30 months, 1-year (2-year) progression-free survival and overall survival were 74.4% (64.1%) and 84.6% (69.2%), respectively.Conclusions: Delivery of GL-ONC1 is safe and feasible in patients with locoregionally advanced head/neck cancer undergoing standard chemoradiotherapy. A phase II study is warranted to further investigate this novel treatment strategy. Clin Cancer Res; 23(19); 5696-702. ©2017 AACR.

Purpose of the studyOlder homeless adults living in shelters have high rates of geriatric conditions, which may increase their risk for acute care use and nursing home placement. However, a minority of homeless adults stay in shelters and the prevalence of geriatric conditions among homeless adults living in other environments is unknown. We determined the prevalence of common geriatric conditions in a cohort of older homeless adults, and whether the prevalence of these conditions differs across living environments.Design and methodsWe interviewed 350 homeless adults, aged 50 and older, recruited via population-based sampling in Oakland, CA. We evaluated participants for common geriatric conditions. We assessed living environment using a 6-month follow-back residential calendar, and used cluster analysis to identify participants' primary living environment over the prior 6 months.ResultsParticipants stayed in 4 primary environments: unsheltered locations (n = 162), multiple locations including shelters and hotels (n = 88), intermittently with family/friends (n = 57), and, in a recently homeless group, rental housing (n = 43). Overall, 38.9% of participants reported difficulty performing 1 or more activities of daily living, 33.7% reported any falls in the past 6 months, 25.8% had cognitive impairment, 45.1% had vision impairment, and 48.0% screened positive for urinary incontinence. The prevalence of geriatric conditions did not differ significantly across living environments.ImplicationsGeriatric conditions were common among older homeless adults living in diverse environments, and the prevalence of these conditions was higher than that seen in housed adults 20 years older. Services that address geriatric conditions are needed for older homeless adults living across varied environments.

We have designed, synthesized, and applied a rhodol-based chromophore to a molecular wire-based platform for voltage sensing to achieve fast, sensitive, and bright voltage sensing using two-photon (2P) illumination. Rhodol VoltageFluor-5 (RVF5) is a voltage-sensitive dye with improved 2P cross-section for use in thick tissue or brain samples. RVF5 features a dichlororhodol core with pyrrolidyl substitution at the nitrogen center. In mammalian cells under one-photon (1P) illumination, RVF5 demonstrates high voltage sensitivity (28% ΔF/F per 100 mV) and improved photostability relative to first-generation voltage sensors. This photostability enables multisite optical recordings from neurons lacking tuberous sclerosis complex 1, Tsc1, in a mouse model of genetic epilepsy. Using RVF5, we show that Tsc1 KO neurons exhibit increased activity relative to wild-type neurons and additionally show that the proportion of active neurons in the network increases with the loss of Tsc1. The high photostability and voltage sensitivity of RVF5 is recapitulated under 2P illumination. Finally, the ability to chemically tune the 2P absorption profile through the use of rhodol scaffolds affords the unique opportunity to image neuronal voltage changes in acutely prepared mouse brain slices using 2P illumination. Stimulation of the mouse hippocampus evoked spiking activity that was readily discerned with bath-applied RVF5, demonstrating the utility of RVF5 and molecular wire-based voltage sensors with 2P-optimized fluorophores for imaging voltage in intact brain tissue.

BackgroundHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is a particularly aggressive form of the disease, and ultimately progresses in patients with metastases on standard therapies. Anthracyclines, such as doxorubicin, are an effective treatment for HER2-positive breast cancer, particularly when administered in combination with trastuzumab - however, doxorubicin-related cardiotoxicity has limited its use. Many patients are therefore never treated with anthracyclines, even upon disease progression, despite the potential for benefit. MM-302 is a novel, HER2-targeted antibody-liposomal doxorubicin conjugate that specifically targets HER2-overexpressing cells. Preclinical and Phase 1 data suggest that MM-302, as a monotherapy or in combination with trastuzumab, could be effective for managing previously treated, anthracycline-naïve, HER2-positive breast cancer, without the cardiotoxicity observed with free doxorubicin formulations.Methods/designHERMIONE is an open-label, multicenter, randomized (1:1) Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician's choice (gemcitabine, capecitabine, or vinorelbine) plus trastuzumab planned to enroll 250 anthracycline-naïve patients with locally advanced/metastatic HER2-positive breast cancer. Key inclusion criteria are: previous treatment with trastuzumab (with or without pertuzumab) in any setting; refractory or intolerant to pertuzumab (refractory to pertuzumab defined as progression in the locally advanced or metastatic setting, or disease recurrence during or within 12 months of completing pertuzumab-containing neoadjuvant and/or adjuvant therapy); and disease progression on, or intolerant to, ado-trastuzumab emtansine for locally advanced or metastatic disease. The trial is currently being conducted at sites in the USA, Canada, and Western Europe. Treatment will be administered in 21-day cycles, and will be continued until disease progression or unacceptable toxicity. The primary endpoint is independently assessed progression-free survival (PFS). Tumor response will be assessed every 6 weeks, and defined according to RECIST v1.1. Secondary endpoints include investigator-assessed PFS, overall survival (OS), OS rates at 6 months and 1 year, objective response rates, safety and tolerability, quality of life, and the pharmacokinetic profile of MM-302 plus trastuzumab.DiscussionThe HERMIONE study will evaluate the efficacy and safety of MM-302 plus trastuzumab in patients with refractory HER2-positive advanced/metastatic breast cancer for whom there are no standard of care therapies with a proven survival advantage.Trial registrationClinicaltrials.gov identifier: NCT02213744 . Registration date: 06AUG2014.

An overview of Caenorhabditis elegans as an experimental organism for studying energy balance is presented. Some of the unresolved questions that complicate the interpretation of lipid measurements from C. elegans are highlighted. We review studies that show that both lipid synthesis and lipid breakdown pathways are activated and needed for the longevity of hermaphrodites that lack their germlines. These findings illustrate the heterogeneity of triglyceride-rich lipid particles in C. elegans and reveal specific lipid signals that promote longevity. Finally, we provide a brief overview of feeding behavioral responses of C. elegans to varying nutritional conditions and highlight an unanticipated metabolic pathway that allows the incorporation of experience in feeding behavior.

PurposeTo compare a novel generalized competing event (GCE) model versus the standard Cox proportional hazards regression model for stratifying elderly patients with cancer who are at risk for competing events.MethodsWe identified 84,319 patients with nonmetastatic prostate, head and neck, and breast cancers from the SEER-Medicare database. Using demographic, tumor, and clinical characteristics, we trained risk scores on the basis of GCE versus Cox models for cancer-specific mortality and all-cause mortality. In test sets, we examined the predictive ability of the risk scores on the different causes of death, including second cancer mortality, noncancer mortality, and cause-specific mortality, using Fine-Gray regression and area under the curve. We compared how well models stratified subpopulations according to the ratio of the cumulative cause-specific hazard for cancer mortality to the cumulative hazard for overall mortality (ω) using the Akaike Information Criterion.ResultsIn each sample, increasing GCE risk scores were associated with increased cancer-specific mortality and decreased competing mortality, whereas risk scores from Cox models were associated with both increased cancer-specific mortality and competing mortality. GCE models created greater separation in the area under the curve for cancer-specific mortality versus noncancer mortality (P < .001), indicating better discriminatory ability between these events. Comparing the GCE model to Cox models of cause-specific mortality or all-cause mortality, the respective Akaike Information Criterion scores were superior (lower) in each sample: prostate cancer, 28.6 versus 35.5 versus 39.4; head and neck cancer, 21.1 versus 29.4 versus 40.2; and breast cancer, 24.6 versus 32.3 versus 50.8.ConclusionCompared with standard modeling approaches, GCE models improve stratification of elderly patients with cancer according to their risk of dying from cancer relative to overall mortality.

As genetic information becomes more readily available, there is increasing demand from both patients and providers to develop personalized approaches to cancer care. Investigators are increasingly reporting numbers of studies correlating genomic signatures and other biomarkers to survival endpoints. The extent to which cancer-specific and non-specific effects are reported in contemporary studies is unknown. In this review of 85 high-impact studies associating genetic biomarkers with cancer outcomes, 95% reported significant associations with event-free survival outcomes, yet less than half reported effects on a cancer-specific endpoint. This methodology leaves open the possibility that observed associations are unrelated to cancer.

IntroductionAcute hematologic toxicity (HT) limits optimal delivery of concurrent chemoradiotherapy (CRT) for patients with pelvic malignancies. We tested the hypothesis that pelvic bone marrow (PBM) dose-volume metrics were associated with weekly reductions in peripheral blood cell counts in cervical cancer patients undergoing CRT.MethodsWe included 102 cervical cancer patients treated with concurrent cisplatin (40 mg/m(2) /week) and pelvic radiotherapy treated at three US centres. No patient received granulocyte-monocyte colony stimulating factor (GM-CSF) or platelet transfusions. Using linear-mixed effects modelling, we analysed weekly reductions in log-transformed peripheral blood cell counts as a function of time (weeks), mean PBM dose and the PBM volume receiving ≥10 Gy (V(10)), 20 Gy (V(20)), 30 Gy (V(30)) and 40 Gy (V(40)).ResultsIncreases in mean PBM radiation dose, V(20), V(30) and V(40) were all significantly associated with a greater weekly reduction in white blood cell (WBC) and absolute neutrophil counts (ANCs). We estimated that with every 1 Gy increase in mean PBM dose, ln(ANC) was reduced by 9.6/μL per week (95% confidence interval, 1.9-17.3, P = 0.015). Subregion analysis also identified significant associations between weekly reductions in ln(WBC) and ln(ANC) within lumbosacral spine, ischium and proximal femora, as opposed to ilium.ConclusionsPBM radiation dose-volume metrics are significantly associated with weekly reductions in peripheral blood cell counts in cervical cancer patients undergoing CRT, particularly within the lower pelvis and lumbosacral spine.

BackgroundClinical trial costs may be reduced by identifying enriched subpopulations of patients with favorable risk profiles for the events of interest. However, increased selectivity affects accrual rates, with uncertain impact on clinical trial cost.MethodsWe conducted a secondary analysis of Southwest Oncology Group (SWOG) 8794 randomized trial of adjuvant radiotherapy for high-risk prostate cancer. The primary endpoint was metastasis-free survival (MFS), defined as time to metastasis or death from any cause (competing mortality). We used competing risks regression models to identify an enriched subgroup at high risk for metastasis and low risk for competing mortality. We applied a cost model to estimate the impact of enrichment on trial cost and duration.ResultsThe treatment effect on metastasis was similar in the enriched subgroup (HR, 0.42; 95% CI, 0.23-0.76) compared to the whole cohort (HR, 0.50; 95% CI, 0.30-0.81) while the effect on competing mortality was not significant in the subgroup or the whole cohort (HR 0.70; 95% CI 0.39-1.23, vs. HR 0.94; 95% CI, 0.68-1.31). Due to the higher incidence of metastasis relative to competing mortality in the enriched subgroup, the treatment effect on MFS was greater in the subgroup compared to the whole cohort (HR 0.55; 95% CI 0.36-0.82, vs. HR 0.77; 95% CI, 0.58-1.01). Trial cost was 75% less in the subgroup compared to the whole cohort ($1.7 million vs. $6.8 million), and the trial duration was 30% shorter (8.4 vs. 12.0 years).ConclusionCompeting event enrichment can reduce clinical trial cost and duration, without sacrificing generalizability.

ContextLymphoid aggregates are seen in a minority of bone marrow biopsy specimens, and when present, their neoplastic nature is often apparent by morphologic evaluation. However, the distinction between benign and malignant aggregates can be a diagnostic challenge when there are multiple aggregates with no documented history of lymphoma.ObjectiveTo aid in the distinction between benign and malignant B-cell lymphoid aggregates.DesignPreviously, we described specific distribution patterns for B and T lymphocytes within bone marrow aggregates. To statistically analyze the significance of these patterns as well as previously reported criteria, we examined 128 bone marrow specimens with benign aggregates and 78 specimens with documented malignant B-cell aggregates and calculated specific odds ratios (ORs) and 95% confidence intervals (CIs) to aid in differentiating between benign and malignant B-cell aggregates.ResultsAggregates with infiltrative edges (OR, 80.54; 95% CI, 31.76-204.21), a B-cell pattern (OR, 30.08; 95% CI, 13.28-68.10), paratrabecular location (OR, 10.17; 95% CI, 3.96-26.12), size greater than 600 μm (OR, 6.83: 95% CI, 3.61-12.93), or cytologic atypia correlated with malignancy.ConclusionsWhen taken collectively, the presence of more than 2 of these characteristic features was strongly predictive of malignancy.

BackgroundPulmonary arterial hypertension is a chronic lung disease associated with severe pulmonary vascular changes. A pathogenic role of oxidized lipids such as hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids is well established in vascular disease. Apolipoprotein A-I mimetic peptides, including 4F, have been reported to reduce levels of these oxidized lipids and improve vascular disease. However, the role of oxidized lipids in the progression of pulmonary arterial hypertension and the therapeutic action of 4F in pulmonary arterial hypertension are not well established.Methods and resultsWe studied 2 different rodent models of pulmonary hypertension (PH): a monocrotaline rat model and a hypoxia mouse model. Plasma levels of hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids were significantly elevated in PH. 4F treatment reduced these levels and rescued preexisting PH in both models. MicroRNA analysis revealed that microRNA-193-3p (miR193) was significantly downregulated in the lung tissue and serum from both patients with pulmonary arterial hypertension and rodents with PH. In vivo miR193 overexpression in the lungs rescued preexisting PH and resulted in downregulation of lipoxygenases and insulin-like growth factor-1 receptor. 4F restored PH-induced miR193 expression via transcription factor retinoid X receptor α.ConclusionsThese studies establish the importance of microRNAs as downstream effectors of an apolipoprotein A-I mimetic peptide in the rescue of PH and suggest that treatment with apolipoprotein A-I mimetic peptides or miR193 may have therapeutic value.

ObjectivesBlack patients with head and neck cancer (HNC) have poorer survival and disease control compared to non-black patients, but disparities in death from non-cancer causes (i.e., competing mortality) are less well-studied.Materials and methodsWe conducted an analysis of 538 patients (169 black, 369 non-black) with stage III-IV HNC treated on one of six multi-institutional protocols between 1993 and 2004 involving multi-agent chemoradiotherapy with or without surgery. Competing mortality was defined as death due to intercurrent comorbid disease, treatment-related morbidity, or unknown cause in the absence of disease recurrence, progression, or second malignancy. Cox proportional hazards and competing risks regression were used to estimate the effect of black race on competing mortality.ResultsBlack race was associated with increased rates of comorbidity, smoking, heavy alcohol use, advanced tumor stage, and poorer performance status (p

Phenotypic screens can identify molecules that are at once penetrant and active on the integrated circuitry of a whole cell or organism. These advantages are offset by the need to identify the targets underlying the phenotypes. Additionally, logistical considerations limit screening for certain physiological and behavioral phenotypes to organisms such as zebrafish and C. elegans. This further raises the challenge of elucidating whether compound-target relationships found in model organisms are preserved in humans. To address these challenges we searched for compounds that affect feeding behavior in C. elegans and sought to identify their molecular mechanisms of action. Here, we applied predictive chemoinformatics to small molecules previously identified in a C. elegans phenotypic screen likely to be enriched for feeding regulatory compounds. Based on the predictions, 16 of these compounds were tested in vitro against 20 mammalian targets. Of these, nine were active, with affinities ranging from 9 nM to 10 µM. Four of these nine compounds were found to alter feeding. We then verified the in vitro findings in vivo through genetic knockdowns, the use of previously characterized compounds with high affinity for the four targets, and chemical genetic epistasis, which is the effect of combined chemical and genetic perturbations on a phenotype relative to that of each perturbation in isolation. Our findings reveal four previously unrecognized pathways that regulate feeding in C. elegans with strong parallels in mammals. Together, our study addresses three inherent challenges in phenotypic screening: the identification of the molecular targets from a phenotypic screen, the confirmation of the in vivo relevance of these targets, and the evolutionary conservation and relevance of these targets to their human orthologs.

Benign lymphoid aggregates are seen in only a minority of bone marrow specimens, but their distinction from non-Hodgkin lymphoma, particularly B-cell lymphomas, can represent a diagnostic challenge. Although criteria have been proposed to help distinguish between benign and malignant aggregates, a detailed description of the distribution patterns of B and T lymphocytes within benign lymphoid aggregates has not been investigated. One hundred thirty-seven cases of bone marrow specimens containing benign aggregates were studied with a panel of immunostains. A subset of these cases was also examined for immunoglobulin gene rearrangements by polymerase chain reaction. The aggregates were categorized based on size, location (paratrabecular or random), presence of infiltrating edges, and distribution of lymphoid cell populations. In addition, we examined 40 cases of bone marrow biopsies with documented malignant lymphoid aggregates for comparison purposes. We report that the distribution of B and T lymphocytes within lymphoid aggregates may serve as a useful criterion to aid in the separation between benign and malignant aggregates. When aggregates exhibit a predominance of T cells, consist of a central core of T cells surrounded by a rim of B cells, or have a mixed distribution of B and T cells, they are more likely to be benign. On the other hand, an increased likelihood of malignancy occurs when aggregates exhibit a predominance of B cells or consist of a central core of B cells surrounded by a rim of T cells (excluding germinal center formation), and assessing other features worrisome of malignancy (large aggregate size, presence of infiltrative edges, cellular atypia, and paratrabecular location, among others) is warranted.

End-stage renal disease (ESRD) causes oxidative stress, inflammation, low-density lipoprotein (LDL) oxidation, high-density lipoprotein (HDL) deficiency and accelerated atherosclerosis. Uptake of oxidized LDL by macrophages results in foam cell and plaque formation. HDL mitigates atherosclerosis via reverse cholesterol transport and inhibition of LDL oxidation. ESRD heightens LDL inflammatory activity and suppresses HDL anti-inflammatory activity. The effect of hemodialysis on the LDL and HDL inflammatory properties is unknown. By removing the potential pro-oxidant/proinflammatory uremic toxins, dialysis may attenuate LDL inflammatory and HDL anti-inflammatory properties. Conversely, exposure to dialyzer membrane and tubing and influx of impurities from dialysate can intensify LDL and HDL inflammatory activities. This study examined the effect of hemodialysis on LDL and HDL inflammatory activities. Plasma samples were obtained from 12 normal control and 26 ESRD patients before and after hemodialysis with (16 patients) or without (10 patients) heparinization. HDL and LDL were isolated and tested for monocyte chemotactic activity in cultured endothelial cells. ESRD patients had increased LDL chemotactic activity, reduced HDL anti-inflammatory activity, paraoxonase and glutathione peroxidase levels, and elevated plasma IL-6 before dialysis. Hemodialysis partially improved LDL inflammatory and HDL anti-inflammatory activities and enhanced patients' HDL ability to suppress their LDL inflammatory activity. The salutary effect on LDL inflammatory activity was significantly greater in patients dialyzed with than those without heparin. ESRD heightens LDL inflammatory and impairs HDL anti-inflammatory activities. Hemodialysis partially improves LDL and HDL inflammatory activities. The salutary effects of hemodialysis are in part mediated by heparin, which is known to possess lipolytic and antioxidant properties.

PurposeThe purpose of this work was to gather preliminary data in normals and dry eye subjects, using a new, non-invasive imaging platform to measure the thickness of pre-corneal tear film.MethodsHuman subjects were screened for dry eye and classified as dry or normal. Tear film thickness over the inferior paracentral cornea was measured using laser illumination and a complementary metal-oxide-semiconductor (CMOS) camera. A previously developed mathematical model was used to calculate the thickness of the tear film by applying the principle of spatial auto-correlation function (ACF).ResultsMean tear film thickness values (±SD) were 3.05 μm (0.20) and 2.48 μm (0.32) on the initial visit for normals (n=18) and dry eye subjects (n=22), respectively, and were significantly different (p

ObjectivesTo image cholesteatoma using optical coherence tomography (OCT) and correlate the results with clinical findings and conventional observations obtained using binocular microscopy and histology. OCT is a high-resolution optical imaging modality that generates cross-sectional images of turbid media, such as tissue with resolution approaching that of light microscopy. OCT relies on intrinsic differences in tissue optical properties for image contrast.Study designIn vivo prospective clinical study.SettingUniversity Medical Center.PatientsPatients with cholesteatoma undergoing otologic surgery.InterventionUsing a commercial OCT imaging system, we obtained cross-sectional images (resolution, approximately 10 microm; depth penetration, approximately 1 mm) of cholesteatomas.Main outcome measuresImages are obtained by raster scanning a single mode fiber across the interior of the probe. The imaging probe is sterilized and inserted into the middle ear or mastoid under microscopic guidance, and still images of the middle ear or mastoid mucosa and cholesteatoma when present were obtained.ResultsOCT images of cholesteatomas demonstrate differences in signal intensity, which are distinct from those of normal or inflamed middle ear/mastoid mucosa. Identification of keratin in cholesteatoma, even if very thin, distinguished it from inflamed mucosa.ConclusionThis is the first study that systematically used OCT to image cholesteatoma during otologic surgery. Cholesteatomas can be distinguished from normal or inflamed adjacent mucosa.