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Appetitive traits influence food intake and weight gain throughout the life-course. Here, we investigated whether maternal attitudes to following healthy infant feeding guidelines could modify this association. Baseline data from 544 mother-infant formula-feeding dyads recruited to the Baby Milk Trial were included in this observational, cross-sectional analysis. Infant appetitive traits (food responsiveness and satiety responsiveness), maternal attitudes to following healthy infant feeding guidelines (self-efficacy, outcome-expectancy, intentions) and infant milk intakes were reported by mothers through questionnaires. Infant weight was measured using standard procedures. Associations between the maternal attitudes score or infant appetitive traits with infant milk intake and infant weight were evaluated in linear regression models adjusted for infant sex and age. To identify effect modification, the interaction term between the maternal attitudes score and infant appetitive trait was added to the model. Infants' mean age and weight were 2.3 months (SD = 0.9) and 5.5 kg (SD = 0.9), respectively. The mean daily infant milk intake reported by mothers was 895 ml/day (SD = 215). Higher maternal attitudes score was associated with lower infant milk intake (Beta = -68.4 ml/day/unit (95% CI: 96.6, -40.2)) and infant weight (Beta = -0.13 SD/unit (-0.25, -0.02)). The maternal attitudes score showed interactions with infant food responsiveness on infant milk intake (p = 0.049), and with infant satiety responsiveness on infant weight (p = 0.01). In both cases, a higher maternal attitudes score attenuated the associations between infant appetitive traits and those outcomes. This analysis provides evidence that positive maternal attitudes to following healthy infant feeding guidelines attenuate the effects of infant appetitive traits on infant milk intake and body weight. [ABSTRACT FROM AUTHOR]

This paper is a test of the urban crisis thesis, which argues that the social and economic conditions of large cities have continued to deteriorate since 1970. in addition, we examine the factors that account for differences in social distress among the cities. Finally, we investigate the regional location effect on urban social distress. In general the findings show both cross-sectionally and longitudinally that (1) the urban crisis has become worse over the years; (2) differences in social distress among cities are largely a function of economic distress, urban scale, and regional location; and (3) levels of distress have converged among cities in the old industrial North (the Rustbelt) and the South and West (the Sunbelt). In fact, the most distressed cities in the country are in the Sunbelt. [ABSTRACT FROM AUTHOR]

Two largely distinct bodies of research have demonstrated age-related alterations and disease-specific aberrations in both local gamma oscillations and patterns of cortical thickness. However, seldom has the relationship between gamma activity and cortical thickness been investigated. Herein, we combine the spatiotemporal precision of magnetoencephalography (MEG) with high-resolution magnetic resonance imaging and surface-based morphometry to characterize the relationships between somatosensory gamma oscillations and the thickness of the cortical tissue generating the oscillations in 94 healthy adults (age range: 22–72). Specifically, a series of regressions were computed to assess the relationships between thickness of the primary somatosensory cortex (S1), S1 gamma response power, peak gamma frequency, and somatosensory gating of identical stimuli. Our results indicated that increased S1 thickness significantly predicted greater S1 gamma response power, reduced peak gamma frequency, and improved somatosensory gating. Furthermore, peak gamma frequency significantly and partially mediated the relationship between S1 thickness and the magnitude of the S1 gamma response. Finally, advancing age significantly predicted reduced S1 thickness and decreased gating of redundant somatosensory stimuli. Notably, this is the first study to directly link somatosensory gamma oscillations to local cortical thickness. Our results demonstrate a multi-faceted relationship between structure and function, and have important implications for understanding age- and disease-related deficits in basic sensory processing and higher-order inhibitory function. • Possible links between local cortical thickness and gamma-band activity are unclear. • Adults underwent structural MRI and a somatosensory gating task during MEG. • Advanced oscillatory and surface-based morphometry analysis methods were combined. • Local cortical thickness predicted gamma response power, frequency, and gating. • Peak gamma frequency mediated the relationship between thickness and response power. [ABSTRACT FROM AUTHOR]

• Manipulating plant defense hormones increases the impact of fungal pathogens. • Jasmonic acid application increased the impact of CT-Rust on Cirsium arvense. • This effect was seen for belowground but not aboveground biomass. Cirsium arvense, or Canada thistle, is one of the most detrimental weeds for agricultural production. Native to south-eastern Europe, the species is now found in Many parts of Asia, North America and Australasia. In North America and New Zealand the species is considered invasive, displacing native vegetation and reducing the quality of forage in rangelands and pastures. The autoecious fungus, Puccinia punctiformis , or CT-rust, shows potential as a control agent but rarely reaches epidemic proportions in natural populations. Manipulating plant defense hormones could alter host susceptibility and allow CT-rust to have more widespread impact. To determine if applying hormones increases the infection by the fungal pathogen, Canada thistle plants were inoculated and sprayed with jasmonic acid (JA) and salicylic acid (SA). Results show that jasmonic acid application interacted with inoculation, increasing infection rates, both incidence and severity, and impact of CT-rust. We found that JA increased infection rates by nearly 20%. Infection consistently reduced root biomass and this reduction was 45% greater with the addition of JA compared to untreated control. Addition of JA at the time of inoculation could make it a more effective control agent for Canada thistle. [ABSTRACT FROM AUTHOR]

We investigated the serum concentrations of two brominated flame retardants (BFRs) – polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD) –in 59 women aged between 23 and 42 from the United Kingdom. We also collected demographic data, including age, bodyweight and height in order to test for associations with BFR levels. Temporal and global differences were also assessed using previously published data. HBCDD was detected in 68% of samples with a mean concentration of 2.2 ng/g lipid (range = <0.3–13 ng/g lipid). The dominant stereoisomer was α-HBCDD with an average contribution of 82% (0–100%) towards ΣHBCDD, was followed by γ-HBCDD (average contribution = 17%). PBDEs were detected in 95% of samples with a mean ∑PBDE (sum of BDEs −28, −47, −99, −100, −153, −154 and −183) concentration of 2.4 ng/g lipid (range = <0.4–15 ng/g lipid). BDEs −153 and −47 were the dominant congeners, contributing an average of 40% and 37% respectively, to the average ΣPBDE congener profile. Data from this study suggests that HBCDD levels decrease with age, it also suggests a positive association between bodyweight and HBCDD levels, which likewise requires a large-scale study to confirm this. The data also show that 10 years after their European ban, PBDE body burden has begun to decrease in the UK. Whilst it is too early to draw any firm conclusions for HBCDDs, they appear to be following a similar pattern to PBDEs, with levels decreasing by a factor of >2.5 since 2010. Whilst the human body burden appear to be decreasing, both PBDEs and HBCDD are still consistently detected in human serum, despite legislative action limiting their production and use. This highlights the need to continuously assess human exposure and the effectiveness of policy aimed at reducing exposure. • PBDEs (95%) and HBCDDs (68%) regularly detected in adult human serum from UK despite previous bans. • Association between HBCDD levels and bodyweight found. • UK adult PBDE body burdens are significantly lower 10 years after ban. • HBCDDs also beginning to decrease in UK adults. [ABSTRACT FROM AUTHOR]

Greater understanding of tumour immunobiology has led to a new era of cancer treatment in which immuno-oncology (IO) therapies are used to boost anti-cancer immune responses. Prominent among these therapies are immune checkpoint inhibitors (ICIs), antibody-based drugs that can unleash the power of tumour-specific CD8 + T-cells. ICIs targeting the Programmed cell death protein 1 (PD-1) cell surface receptor or its ligand PD-L1 are particularly effective, with clinical studies reporting powerful and durable therapeutic impact against many cancer types, including melanoma and non-small cell lung cancer. ICIs have the potential to transform the landscape of cancer treatment, and their development was recognised by the award of the 2018 Nobel Prize in Physiology or Medicine to James Allison and Tasuku Honjo. However, the proportion of patients responding to anti-PD-1/PD-L1 monotherapy can be low. The next major challenge involves understanding and overcoming the innate and acquired resistance that prevents most patients from responding to PD-1/PD-L1 blockade. In this review, we outline the physiological function of PD-1 and its exploitation by developing tumours. We give an overview of current FDA-approved drugs targeting PD-1 or PD-L1 and summarise clinical progress so far. We then discuss key mechanisms thought to underpin resistance to PD-1/PD-L1 blockade, describing biomarkers that could allow patient responses to be predicted before treatment, and tracked once treatment has started. We also present clinical and pre-clinical combination therapies that have been developed to overcome resistance and which have the potential to substantially extend the therapeutic reach of these revolutionary drugs. [ABSTRACT FROM AUTHOR]

PI3K-AKT pathway mutations initiate a kinase cascade that characterizes endometrial cancer (EC). As kinases seldom cause oncogenic transformation without dysregulation of antagonistic phosphatases, pivotal interactions governing this pathway were explored and correlated with clinical outcomes. After exclusion of patients with POLE mutations from The Cancer Genome Atlas EC cohort with endometrioid or serous EC, the study population was 209 patients with DNA sequencing, quantitative gene-specific RNA expression, copy number variation (CNV), and surveillance data available. Extracted data were annotated and integrated. A PIK3CA , PTEN, or PIK3R1 mutant (−mu) was present in 83% of patients; 57% harbored more than 1 mutation without adversely impacting progression-free survival (PFS) (P =.10). PIK3CA CNV of at least 1.1 (CNV high [-H]) was detected in 26% and linked to TP53 -mu and CIP2A expression (P <.001) but was not associated with PFS (P =.24). PIK3CA expression was significantly different between those with CIP2A -H and CIP2A low (−L) expression (the endogenous inhibitor of protein phosphatase 2A [PP2A]), when stratified by PIK3CA mutational status or by PIK3CA CNV-H and CNV-L (all P <.01). CIP2A -H or PPP2R1A -mu mitigates PP2A kinase dephosphorylation, and FBXW7 -mu nullifies E3 ubiquitin ligase (E3UL) oncoprotein degradation. CIP2A -H and PPP2R1A -mu (PP2A impairment) and FBXW7 -mu (E3UL impairment) were associated with compromised PFS (P <.001) and were prognostically discriminatory for PIK3CA -mu and PIK3CA CNV-H tumors (P <.001). Among documented recurrences, 84% were associated with impaired PP2A (75%) and/or E3UL (20%). PP2A and E3UL deficiencies are seminal biological drivers in EC independent of PIK3CA -mu, PTEN -mu, and PIK3R1 -mu and PIK3CA CNV. • PIK3CA mRNA expression is associated with CIP2A mRNA expression. • PIK3CA copy number variance is linked to TP53 mutations and CIP2A mRNA expression. • Imbalances in PI3K-AKT kinases and phosphatases portend oncogenic transformation. • Recurrences primarily align with CIP2A overexpression and PPP2R1A or FBXW7 mutation. • PP2A and E3 ubiquitin ligase deficiencies are associated with compromised survival. [ABSTRACT FROM AUTHOR]

To evaluate the relationship between frailty and chemotherapy delivery among women with epithelial ovarian cancer (EOC). We included women who underwent primary debulking surgery (PDS) for stage IIIC/IV EOC between 1/2/2003 and 12/30/2011, received adjuvant chemotherapy at our institution, and had data available to calculate a frailty deficit index. Frailty was defined as a frailty deficit index ≥0.15. Relative dose intensity (RDI) of chemotherapy was calculated as the percentage of the standard dose that was administered, and compared between frail and non-frail using the Wilcoxon rank-sum test. Failure to receive chemotherapy following PDS was twice as common among frail vs. non-frail women (26.7% vs 14.2%, p = 0.001). Of the 169 women who received chemotherapy at our institution, 17.2% (29/169) were frail. Frail women were older (mean, 67.9 vs 62.3 years, p = 0.01), had higher BMI (mean, 29.6 vs 25.7 kg/m2, p = 0.003), and were less likely to complete 6 cycles of chemotherapy (75.9 vs. 93.6%, p = 0.008). Using an RDI cutoff of 85%, frail women were less likely to have adequate doses of carboplatin (15.8 vs. 66.2%, p < 0.001) and paclitaxel (57.9 vs. 80.5%, p = 0.07) despite no differences in dose delays (34.5 vs. 42.1%), dose reductions (65.5 vs. 68.6%), and severe neutropenia (44.8 vs. 39.3%). After adjusting for age, frailty was associated with shorter progression-free (HR 1.58, 95% CI: 0.99–2.50) and overall survival (HR 2.14, 95% CI: 1.35–3.41). Frail women with EOC were less likely to receive chemotherapy or the optimal dose of chemotherapy after PDS despite no evidence of treatment-related toxicity. Frail EOC patients demonstrated shorter progression-free and overall survival. Further studies are needed to explore the association between frailty, chemotherapy, and survival. • Frail patients are two times less likely to receive chemotherapy after primary surgery for advanced ovarian cancer. • Frail women are less likely to complete 6 cycles of prescribed chemotherapy. • Frail women are less likely to receive >85% relative dose intensity of chemotherapy. • Suboptimal chemotherapy dosing is associated with shorter progression free and overall survival. • Frail OC patients have shorter progression free and overall survival compared to non-frail patients. [ABSTRACT FROM AUTHOR]

We previously reported an algorithm that identifies women at high risk of postoperative morbidity & mortality (M/M) as a tool to triage between neoadjuvant chemotherapy and primary surgery for epithelial ovarian cancer (EOC). We sought to independently validate its performance using multicenter data. Women who underwent surgery for stage IIIC/IV EOC between 1/1/2014 and 12/31/2017 were identified from the National Surgical Quality Improvement Program database and classified as "high risk" or "triage appropriate" using our algorithm. Outcomes were compared between triage appropriate and high-risk women using the chi-square test. 1777 women met inclusion criteria; the mean age was 62.6 years and 81.9% had stage IIIC disease. Nationally, the surgical complexity scores were low (69.8% low, 25.2% intermediate and 5.0% high). "High risk" women had 2-fold higher rate of severe 30-day complication or death (6.2% vs 3.5%; p = 0.01), a 3-fold higher rate of 30-day mortality (1.4% vs 0.5%; p = 0.08), and a higher risk of death following a severe complication (11.1% vs. 0%, p = 0.11). A sensitivity analysis excluding women with unknown albumin who didn't meet other high risk criteria showed similar results: severe 30-day complications or death (6.2% vs 3.5%; p = 0.02) and 30-day mortality (1.4% vs 0.3%; p = 0.04) for "high risk" vs "triage appropriate" women. Primary cytoreductive surgery to minimal residual disease remains the goal for EOC. We verify that our algorithm can identify women at risk of M/M using national multicenter data, despite a low complexity surgical setting and using 30-day mortality (vs. 90-day). Objective surgical risk assessment for ovarian cancer should be standard of care and can be incorporated into practice using the Mayo triage algorithm. • The Mayo triage algorithm identifies women at highest risk of morbidity & mortality (M/M) after cytoreductive surgery. • Ability of our algorithm to identify women at risk of M/M after cytoreduction is verified using national multicenter data. • Given the reproducible findings, our algorithm can be applied to ovarian cancer management in varied clinical settings. [ABSTRACT FROM AUTHOR]

To evaluate the impact of an evidence-based triage algorithm to decide between primary debulking surgery (PDS) and neoadjuvant chemotherapy followed by interval debulking surgery (NACT/IDS) for advanced epithelial ovarian cancer (EOC). Surgical morbidity and mortality (M/M) after PDS for stage IIIC-IV EOC at Mayo Clinic after implementation of the triage algorithm (contemporary cohort, 2012-July 2016) were compared to that of a historic PDS cohort (2003−2011). Mean age of the 232 women who met inclusion criteria in the contemporary cohort was 63.9 years. We observed a 71% decrease in 90-day mortality from 8.9% to 2.6% (P = 0.002) between the contemporary and historic cohorts. Accordion grade 3+ postoperative complications within 30 days after surgery decreased from 22.3% to 18.3% (P = 0.19). Among those with a grade 3+ complication, 90-day mortality rates decreased from 28.3% in the historic cohort to 2.4% in the contemporary cohort (P < 0.001) suggesting patients were better able to tolerate complex surgery. When compared to the historic PDS cohort, oncologic outcomes were also improved in the contemporary PDS cohort. Complete as well as optimal (residual disease ≤1 cm) cytoreduction rates increased (45.5% vs. 62.5% and 84.5% vs. 95.3%, respectively, P < 0.001), and the proportion of women starting chemotherapy within 42 days of surgery increased (57.4% vs. 69.8%, P = 0.001). Three-year overall survival was 53% in the historic cohort and 66% in the contemporary cohort (P < 0.001). Use of the Mayo triage algorithm for EOC was associated with reduced 90-day mortality after PDS and improved oncologic outcomes. Surgical risk assessment is a critical aspect of treatment planning in the primary management of EOC and should be incorporated into practice. • Both primary debulking (PDS) & neoadjuvant chemotherapy (NACT) are ideal approaches for different ovarian cancer patients • Choice between NACT and PDS should be based on risk of surgical morbidity and mortality • Use of our triage algorithm to choose between PDS and NACT reduces 90 day mortality after PDS • Use of our triage algorithm also improved residual disease and ability to start chemotherapy within 42 days of surgery. [ABSTRACT FROM AUTHOR]

Abstract Background Early drain removal when postoperative day (POD) one drain fluid amylase (DFA) was ≤5000 U/L reduced complications in a previous randomized controlled trial. We hypothesized that most surgeons continue to remove drains late and this is associated with inferior outcomes. Methods We assessed the practice of surgeons in a prospectively maintained pancreas surgery registry to determine the association between timing of drain removal with demographics, comorbidities, and complications. We selected patients with POD1 DFA ≤5000 U/L and excluded those without drains, and subjects without data on POD1 DFA or timing of drain removal. Early drain removal was defined as ≤ POD5. Results Two hundred and forty four patients met inclusion criteria. Only 90 (37%) had drains removed early. Estimated blood loss was greater in the late removal group (190 mL versus 100 mL, P = 0.005) and pathological findings associated with soft gland texture were more frequent (97 [63%] versus 35 [39%], P < 0.0001). Patients in the late drain removal group had more complications (84 [55%] versus 30 [33%], P = 0.001) including pancreatic fistula (55 [36%] versus 4 [4%], P < 0.0001), delayed gastric emptying (27 [18%] versus 3 [3%], P = 0.002), and longer length of stay (7 d versus 5 d, P < 0.0001). In subset analysis for procedure type, complications and pancreatic fistula remained significant for both pancreatoduodenectomy and distal pancreatectomy. Conclusions Despite level one data suggesting improved outcomes with early removal when POD1 DFA is ≤ 5000 U/L, experienced pancreas surgeons more frequently removed drains late. This practice was associated with known risk factors (estimated blood loss, soft pancreas) and may be associated with inferior outcomes suggesting potential for improvement. [ABSTRACT FROM AUTHOR]

Abstract Development of cognitive functions and the underlying neurophysiology is evident throughout childhood and adolescence, with higher order processes such as working memory (WM) being some of the last cognitive faculties to fully mature. Previous functional neuroimaging studies of the neurodevelopment of WM have largely focused on overall regional activity levels rather than the temporal dynamics of neural component recruitment. In this study, we used magnetoencephalography (MEG) to examine the neural dynamics of WM in a large cohort of children and adolescents who were performing a high-load, modified verbal Sternberg WM task. Consistent with previous studies in adults, our findings indicated left-lateralized activity throughout the task period, beginning in the occipital cortices and spreading anterior to include temporal and prefrontal cortices during later encoding and into maintenance. During maintenance, the occipital alpha increase that has been widely reported in adults was found to be relatively weak in this developmental sample, suggesting continuing development of this component of neural processing, which was supported by correlational analyses. Intriguingly, we also found sex-specific developmental effects in alpha responses in the right inferior frontal region during encoding and in parietal and occipital cortices during maintenance. These findings suggested a developmental divergence between males and females in the maturation of neural circuitry serving WM during the transition from childhood to adolescence. Highlights • A large cohort of 9–14 year-olds completed a verbal working memory task during MEG. • Behavioral performance on the working memory task improved with age. • Left-lateralized alpha responses were dynamic based on the phase of the task. • Developmental effects were sex-specific for several key oscillatory responses. [ABSTRACT FROM AUTHOR]

Abstract The higher response rates observed on ratio than on matched interval reward schedules has been attributed to the differential reinforcement of longer inter-response times (IRTs) on the interval contingency. Some data, however, seem to contradict this hypothesis, showing that the difference is still observed when the role of IRT reinforcement is neutralized by using a regulated-probability interval schedule (RPI). Given the mixed evidence for these predictions, we re-examined this hypothesis by training three groups of rats to lever press under ratio, interval and RPI schedules across two phases while matching reward rates within triads. At the end of the first phase, the master ratio and RPI groups responded at similar rates. In the second phase, an interval group yoked to the same master ratio group of the first phase responded at a lower rate than the RPI group. Post-hoc analysis showed comparable reward rates for master and yoked schedules. The experienced response-outcome rate correlations were likewise similar and approached zero as training progressed. We discuss these results in terms of a contemporary dual-system model of instrumental conditioning. [ABSTRACT FROM AUTHOR]

Highlights • The nucleus reuniens (Re) selectively supports encoding. • Suppression of the Re during encoding reduces choice accuracy to chance levels. • Performance returns to baseline, within a session, after Re suppression ceases. Abstract The nucleus reuniens (Re) of the ventral midline thalamus is known to be a critical anatomical link between the hippocampus (HPC) and the medial prefrontal cortex (mPFC). Consistent with this anatomical connectivity, the Re has been shown to be crucial for HPC-mPFC oscillatory synchrony. Moreover, Re inhibition consistently results in spatial working memory (SWM) deficits. Together, these results suggest that SWM requires HPC-mPFC synchrony via the Re. In spite of these findings, an understanding of how the Re contributes to the encoding, maintenance, and retrieval of spatial information during a SWM task is lacking. To address this issue, we trained rats to perform a SWM-dependent delayed-non-match-to-position (DNMP) task in a T-maze. Using optogenetic inhibition of Re activity, we demonstrated that Re suppression during the sample phase, but not the delay or choice phase, significantly decreased choice accuracy. We conclude that the Re contributes to the encoding of spatial information during working memory. [ABSTRACT FROM AUTHOR]

Objective Two randomized trials failed to demonstrate efficacy of platinum-based chemotherapy (PbCT) for uterine serous carcinoma (USC). Our objective was to reassess the value of PbCT for patients with microscopic residuum (R0). Methods Progression-free survival (PFS) after surgery was analyzed for 409 patients and correlated with adjuvant therapies: vaginal brachytherapy (VBRT), external beam radiotherapy (EBRT), PbCT, or combinations. Results The estimated 5-year PFS for stage I ( n = 209) USC was 65.1% for observation only; 90.7%, VBRT only; and 91.1%, PbCT ± VBRT (85% received VBRT); VBRT significantly ( P = .004) impacted PFS, but the added value of PbCT remains uncertain. Of 58 stage IIIC, PbCT-treated patients (±EBRT), 5-year PFS was 33.9%; most failures had a vascular disseminated component. Median PFS for 72 stage IV, PbCT-treated patients was 18.6 months for R0; 8.0, R1 ≤ 1 cm residual disease; and 4.6, R2 > 1 cm ( P = .008). The progression rate (PR) during 1 to 2 year follow-up for R0 was similar to PR during 0–1 year follow-up for R1 ( P = .31), suggesting recurrences in patients with R0 disease before 2 years are likely platinum resistant. PRs during follow-up were nearly identical for R0 ≥ 2 years and R1 ≥ 1 year ( P = .95), presumably showing limited numbers of platinum-sensitive tumors. Conclusions A comparison of PR for patients treated with PbCT for stage IV R0 and R1 disease suggested that a 1-year lag interval precedes clinical recognition of PbCT refractory/resistant R0 disease. Most patients treated with PbCT who had microscopic residuum had recurrences within 2 years (across stages), emphasizing the need for more effective therapy. [ABSTRACT FROM AUTHOR]

In the wild, plant sex can affect plant-herbivore interactions and higher trophic levels, including natural enemies of the herbivores. However, the possibility of manipulating plant sex to improve biological control and reduce herbivory in domesticated dioecious crops remains unexplored. The dioecious bioenergy crop, Salix viminalis , is often planted in monoclonal, and thus monosexual, fields. We investigated whether using plant clones of either sex, or mixing plants of both sexes, reduced the performance and abundance of the herbivorous pest insect Phratora vulgatissima and its main natural enemy, Anthocoris nemorum , and whether predation was affected. The herbivore laid more eggs, and the predator survived longer, on female plants in the lab. However, these effects did not translate into differences in predation rates in laboratory experiments or differential insect abundances on plants of either sex or plantation sex composition in the field. Plant genotype did have a significant effect on insect abundances, but this was due to plant traits other than sex. The results indicate that manipulating plant sex will not lead to improved biological control or reduced insect herbivory in S. viminalis energy forestry, but suggest that a focus on plant genotypic differences offers promise for improving management practices. [ABSTRACT FROM AUTHOR]

Objectives To determine surgical and pathologic variables associated with recurrence in extramammary Paget's disease (EMPD). Methods Medical records of patients seeking care for EMPD from 1/1992–9/2015 were reviewed. Follow-up was restricted to 5 years following primary surgery. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method. Risk factors were evaluated for an association with recurrence and positive margins, respectively, using Cox proportional hazards regression and logistic regression. Results Of 154 patients, 90 (58.4%) were female and 65 (41.6%) were male. Treatment consisted of wide local excision (WLE, includes WLE or radical vulvectomy, 77.3%), Mohs micrographic surgery (MMS, 19.5%), and abdominoperineal resection (3.2%). RFS at 1, 3, and 5 years was 84.5% (95% confidence interval (CI), 78.2–91.4%), 66.1% (95% CI, 57.5–75.9%), and 56.1% (95% CI, 46.9–67.1%), respectively. Positive surgical margins were univariately associated with higher risk of recurrence (HR 3.55, 95% CI 1.74, 7.24). Margin status significantly correlated with procedure type (33.3% vs. 3.4% had positive margins with WLE vs. MMS, p = 0.01). Among patients with negative margins, there was a 2.5 fold increased risk of recurrence after WLE compared to MMS (95% CI, 0.57–10.9, p = n.s.). Conclusion Inclusion of males allowed us to examine the influence of a different surgical approach (MMS) on margin status and recurrence rates in EMPD. In contrast to prior studies including solely vulvar EMPD, we observed strong association between margin status and recurrence risk. Risk of positive margins was significantly higher after WLE compared to MMS. MMS should be explored to improve outcomes in gynecologic patients with EMPD. [ABSTRACT FROM AUTHOR]

The flanker task is a test of visual selective attention that has been widely used to probe error monitoring, response conflict, and related constructs. However, to date, few studies have focused on the selective attention component of this task and imaged the underlying oscillatory dynamics serving task performance. In this study, 21 healthy adults successfully completed an arrow-based version of the Eriksen flanker task during magnetoencephalography (MEG). All MEG data were pre-processed and transformed into the time-frequency domain. Significant oscillatory brain responses were imaged using a beamforming approach, and voxel time series were extracted from the peak responses to identify the temporal dynamics. Across both congruent and incongruent flanker conditions, our results indicated robust decreases in alpha (9–12 Hz) activity in medial and lateral occipital regions, bilateral parietal cortices, and cerebellar areas during task performance. In parallel, increases in theta (3–7 Hz) oscillatory activity were detected in dorsal and ventral frontal regions, and the anterior cingulate. As per conditional effects, stronger alpha responses (i.e., greater desynchronization) were observed in parietal, occipital, and cerebellar cortices during incongruent relative to congruent trials, whereas the opposite pattern emerged for theta responses (i.e., synchronization) in the anterior cingulate, left dorsolateral prefrontal, and ventral prefrontal cortices. Interestingly, the peak latency of theta responses in these latter brain regions was significantly correlated with reaction time, and may partially explain the amplitude difference observed between congruent and incongruent trials. Lastly, whole-brain exploratory analyses implicated the frontal eye fields, right temporoparietal junction, and premotor cortices. These findings suggest that regions of both the dorsal and ventral attention networks contribute to visual selective attention processes during incongruent trials, and that such differential processes are transient and fully completed shortly after the behavioral response in most trials. [ABSTRACT FROM AUTHOR]

To evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and high-risk endometrial cancer (EC). We identified patients with stage I HIR (GOG-249 criteria) and stage II endometrioid EC, and stage I and II non-endometrioid EC who underwent surgery at Mayo Clinic and Cleveland Clinic between 1999 and 2016. Three-year RFS and CSS after observation or VB only were estimated in 16 subgroups defined by risk factors. Among 4156 ECs, we identified 447 (10.8%) stage I endometrioid HIR, 52 (1.3%) stage II endometrioid, 350 (8.4%) stage I non-endometrioid, and 17 (0.4%) stage II non-endometrioid ECs; observation or VB alone was applied in 349 (78.1%), 24 (46.2%), 187 (53.4%), and 2 (11.8%) patients, respectively. After observation or VB, stage I HIR endometrioid EC subgroups with <2 factors among grade 3, LVSI, or stage IB had a 3-year CSS >95% (lower 95% confidence intervals limit: 89.8%), whereas subgroups with ≥2 factors had poorer outcomes. No EC-related deaths after 3 years were reported in 97 stage IA non-endometrioid ECs without myometrial invasion. Stage II ECs had poor outcomes regardless of histology. Observation or VB only may be sufficient in stage I endometrioid HIR ECs with <2 factors among grade 3, LVSI, or IB and in stage IA non-endometrioid ECs without myometrial invasion. Stratification of early-stage HIR and high-risk ECs into risk subgroups potentially alleviates the overtreatment and undertreatment risk and should be considered in future research. • Some subgroups of high-intermediate-risk and high-risk endometrial cancer (EC) represent <1% of all ECs. • Three-year cause-specific survival after observation or brachytherapy only is higher than 85% in 15 of the 16 subgroups. • Observation or brachytherapy may be adequate in stage I endometrioid ECs without grade 3 or lymphovascular space invasion. • Non-endometrioid ECs without myometrial invasion have a good prognosis with only observation or vaginal brachytherapy. [ABSTRACT FROM AUTHOR]

The vertebrate peripheral nervous system (PNS) is an intricate network that conveys sensory and motor information throughout the body. During development, extracellular cues direct the migration of axons and glia through peripheral tissues. Currently, the suite of molecules that govern PNS axon-glial patterning is incompletely understood. To elucidate factors that are critical for peripheral nerve development, we characterized the novel zebrafish mutant, stl159 , that exhibits abnormalities in PNS patterning. In these mutants, motor and sensory nerves that develop adjacent to axial muscle fail to extend normally, and neuromasts in the posterior lateral line system, as well as neural crest-derived melanocytes, are incorrectly positioned. The stl159 genetic lesion lies in the basic helix-loop-helix (bHLH) transcription factor tcf15 , which has been previously implicated in proper development of axial muscles. We find that targeted loss of tcf15 via CRISPR-Cas9 genome editing results in the PNS patterning abnormalities observed in stl159 mutants. Because tcf15 is expressed in developing muscle prior to nerve extension, rather than in neurons or glia, we predict that tcf15 non-cell-autonomously promotes peripheral nerve patterning in zebrafish through regulation of extracellular patterning cues. Our work underscores the importance of muscle-derived factors in PNS development. The transcription factor tcf15 (also called paraxis) is expressed in embryonic zebrafish paraxial mesoderm, prior to peripheral nervous system (PNS) development. Expression of tcf15 is necessary for proper development of axons and glia in the posterior lateral line nerve (green), neuromasts (yellow), motor nerves (red), and neural crest-derived melanocytes (black) in larval zebrafish. In tcf15 mutants, muscle appears grossly normal, but nerves, neuromasts, and melanocytes that migrate along muscle are mispatterned. [Display omitted] • Neural crest-derived melanocytes and glia develop abnormally in stl159 zebrafish. • The stl159 lesion truncates tcf15, which is required for proper muscle development. • Sensory and motor nerves adjacent to axial muscle require tcf15 for patterning. • Early tcf15 expression in developing muscle precedes peripheral nerve patterning. [ABSTRACT FROM AUTHOR]

Objective To: a) identify prognostic factors in patients with epithelial ovarian cancer treated with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS), and b) compare post-surgical survival between patients treated with NACT/IDS for presumed unresectable disease and stage IIIC/IV patients who underwent suboptimal primary debulking surgery (PDS). Methods This was a retrospective study of consecutive stage IIIC or IV patients undergoing IDS after NACT at Mayo Clinic from January 2007 to December 2013. A subset of patients receiving NACT/IDS for the indication of unresectable disease were matched 1:1 on age and stage to a cohort of patients who underwent suboptimal PDS between 2003 and 2011. Hazard ratios and corresponding 95% confidence intervals were estimated from Cox proportional hazards models. Results We identified 87 patients treated with NACT/IDS: the median OS and PFS following surgery was 2.4 and 1.0 years, respectively. Factors associated with significantly worse OS were older age (adjusted HR 1.60 per 10-year increase in age, 95% CI 1.18, 2.16) and elevated CA-125 before IDS (adjusted HR 2.30 for CA-125 > 35 U/mL, 95% CI 1.25, 4.23). Number of adjuvant chemotherapy cycles administered did not have a significant effect on survival. In the matched cohort analysis of presumed unresectable cases undergoing NACT/IDS vs suboptimal PDS cases (n = 45 each), the NACT/IDS group had a significant OS advantage (HR 0.53; 95% CI 0.32, 0.88), and fewer patients experienced a 30-day postoperative Accordion grade 3/4 complication (11% vs 36%, P = 0.01). Conclusions Younger age and normalization of CA-125 prior to IDS are associated with improved survival with NACT/IDS. For primary EOC where resection to residual disease of 1 cm or less is unlikely, NACT/IDS is associated with improved survival and reduced perioperative morbidity compared to PDS. As these patients are likely best served by NACT/IDS, more reliable predictors of resectability would be valuable. [ABSTRACT FROM AUTHOR]

Papillomaviruses (family Papillomaviridae) are non-enveloped, circular, double-stranded DNA viruses known to infect squamous and mucosal epithelial cells. In the family Papillomaviridae there are 53 genera and 133 viral species whose members infect a variety of mammalian, avian, reptilian, and fish species. Within the Antarctic context, papillomaviruses (PVs) have been identified in Adélie penguins (Pygoscelis adeliae, 2 PVs), Weddell seals (Leptonychotes weddellii, 7 PVs), and emerald notothen (Trematomus bernacchii, 1 PV) in McMurdo Sound and Ross Island in eastern Antarctica. Here we identified 13 diverse PVs from buccal swabs of Antarctic fur seals (Arctocephalus gazella, 2 PVs) and leopard seal (Hydrurga leptonyx, 3 PVs) in western Antarctica (Antarctic Peninsula), and vaginal and nasal swabs of Weddell seals (8 PVs) in McMurdo Sound. These PV genomes group into four genera representing 11 new papillomavirus types, of which five are from two Antarctic fur seals and a leopard seal and six from Weddell seals. • 2 papillomaviruses identified in two individual Antarctic fur seals. • 3 papillomaviruses identified in a Leopard seal. • 8 papillomaviruses identified in virginal and nasal swabs of five Weddell seals. • 11 new papillomavirus types identified in 3 species of Antarctic pinnipeds. [ABSTRACT FROM AUTHOR]

Objectives Determine the predictive value of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) score, and prognostic factors for survival, in patients undergoing secondary cytoreductive surgery (SCS) for recurrent ovarian cancer in a high-volume U.S. center. Methods Medical records of women undergoing SCS between 12/1/1998 and 12/31/2013 were reviewed. Women with no gross residual disease (RD0) at primary surgery, ECOG performance status (PS) ≤ 1 at recurrence, and no ascites on CT at recurrence were classified as AGO score positive. Women with incomplete information to determine the AGO score were excluded. Overall survival (OS) and progression-free survival (PFS) following SCS, respectively, were estimated from multivariable Cox proportional hazards models. Results 192 women met inclusion criteria. Median disease-free interval (DFI) was 1.9 years (IQR, 1.0–3.5). Of the 102 (53.1%) AGO score positive cases, 84.3% (95% CI, 77.3–91.4%) achieved RD0 at SCS. However, 64.4% of AGO score negative cases also reached RD0. Patients with RD0 after SCS survived longer (median OS, 5.4 years) vs. RD ≤ 1 cm (2.4 years) vs. RD > 1 cm (1.3 years) (p < 0.001). Median PFS was also longer in patients with RD0 (1.5 years) vs. RD ≤ 1 cm (0.9 years) vs. RD > 1 cm (1.0 years) (p = 0.001). Among those with RD0 at SCS, AGO score was not associated with survival benefit, however, number of disease sites at recurrence, ECOG PS at recurrence, and DFI were associated with OS and PFS. Conclusions AGO score can identify patients with a high likelihood of complete secondary cytoreduction and improved survival. However, most AGO score negative cases were also completed resected at SCS. Additional refinement of the score is needed to exclude women from SCS. [ABSTRACT FROM AUTHOR]

In its review of the U.S. Environmental Protection Agency's toxicological review of inorganic arsenic (iAs), the National Academy of Sciences identified carcinogenic endpoints among the highest priority health effects of concern and stated the need to consider evidence that early life exposures may increase the risk of adverse health effects. Recent studies in mice suggest that in utero exposure to arsenic increases susceptibility to cancer later in life. These data are striking in light of the general lack of evidence for carcinogenicity in rodents exposed to iAs. To evaluate the transplacental carcinogenic potential of iAs, a detailed analysis of the toxicology literature evaluating the role of in utero arsenic exposure in carcinogenesis was conducted. Bladder, lung, and skin tumors, which are the tumor types most consistently reported in humans exposed to high arsenic levels, were not consistently increased in mouse studies. There was also a lack of concordance across studies for other tumor types not typically reported in humans. Therefore, we considered methodological and other critical issues that may have contributed to variable results and we suggest additional studies to address these issues. It was concluded that the available data do not provide evidence of a causal link between in utero arsenic exposure and cancer or indicate early life-stage susceptibility to arsenic-induced cancer, particularly at environmentally relevant doses. [ABSTRACT FROM AUTHOR]

Objective A growing number of studies have investigated the association between air pollution and the risk of birth defects, but results are inconsistent. The objective of this study was to examine whether maternal exposure to ambient PM 2.5 or benzene increases the risk of selected birth defects in Florida. Methods We conducted a retrospective cohort study of singleton infants born in Florida from 2000 to 2009. Isolated and non-isolated birth defect cases of critical congenital heart defects, orofacial clefts, and spina bifida were identified from the Florida Birth Defects Registry. Estimates of maternal exposures to PM 2.5 and benzene for all case and non-case pregnancies were derived by aggregation of ambient measurement data, obtained from the US Environmental Protection Agency Air Quality System, during etiologically relevant time windows. Multivariable Poisson regression was used to estimate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) for each quartile of air pollutant exposure. Results Compared to the first quartile of PM 2.5 exposure, higher levels of exposure were associated with an increased risk of non-isolated truncus arteriosus (aPR 4th Quartile , 8.80; 95% CI, 1.11–69.50), total anomalous pulmonary venous return (aPR 2nd Quartile , 5.00; 95% CI, 1.10–22.84), coarctation of the aorta (aPR 4th Quartile , 1.72; 95% CI, 1.15–2.57; aPR 3rd Quartile , 1.60; 95% CI, 1.07–2.41), interrupted aortic arch (aPR 4th Quartile , 5.50; 95% CI, 1.22–24.82), and isolated and non-isolated any critical congenital heart defect (aPR 3rd Quartile , 1.13; 95% CI, 1.02–1.25; aPR 4th Quartile , 1.33; 95% CI, 1.07–1.65). Mothers with the highest level of exposure to benzene were more likely to deliver an infant with an isolated cleft palate (aPR 4th Quartile , 1.52; 95% CI, 1.13–2.04) or any orofacial cleft (aPR 4th Quartile , 1.29; 95% CI, 1.08–1.56). An inverse association was observed between exposure to benzene and non-isolated pulmonary atresia (aPR 4th Quartile , 0.19; 95% CI, 0.04–0.84). Conclusion Our results suggest a few associations between exposure to ambient PM 2.5 or benzene and specific birth defects in Florida. However, many related comparisons showed no association. Hence, it remains unclear whether associations are clinically significant or can be causally related to air pollution exposures. [ABSTRACT FROM AUTHOR]

Acute negative and positive mood states have been linked with the development of undesirable and desirable health outcomes, respectively. Numerous factors acutely influence mood state, including exercise, caffeine ingestion, and macronutrient intake, but the influence of habitual total water intake remains unknown. The purpose of this study was to observe relationships between habitual water intake and mood. One hundred twenty healthy females (mean ± SD; age = 20 ± 2 y, BMI = 22.9 ± 3.5 kg⋅m −2 ) recorded all food and fluids consumed for 5 consecutive days. Investigators utilized dietary analysis software to determine Total Water Intake (TWI; total water content in foods and fluids), caffeine, and macronutrient consumption (i.e. protein, carbohydrate, fat). On days 3 and 4, participants completed the Profile of Mood State (POMS) questionnaire, which examined tension, depression, anger, vigor, and confusion, plus an aggregate measure of Total Mood Disturbance (TMD). For comparison of mood, data were separated into three even groups (n = 40 each) based on TWI: low (LOW; 1.51 ± 0.27 L/d), moderate (MOD; 2.25 ± 0.19 L/d), and high (HIGH; 3.13 ± 0.54 L/d). Regression analysis was performed to determine continuous relationships between measured variables. Group differences (p < 0.05) were observed for tension (MOD = 7.2 ± 5.4, HIGH = 4.4 ± 2.9), depression (LOW = 4.5 ± 5.9, HIGH = 1.7 ± 2.3), confusion (MOD = 5.9 ± 3.4, HIGH = 4.0 ± 2.1), and TMD (LOW=19.0 ± 21.8, HIGH=8.2 ± 14.2). After accounting for other mood influencers, TWI predicted TMD (r 2  = 0.104; p = 0.050). The above relationships suggest the amount of water a woman consumes is associated with mood state. [ABSTRACT FROM AUTHOR]

Objective Scant evidence exists pertaining to objectively measured sedentary time and dietary quality among adults. Therefore, we examined the relationships between sedentary time, physical activity, and dietary quality. Methods Cross-sectional analyses of a 4,910 US adults from two cycles (2003–2006) of the National Health and Nutrition Examination Survey. The primary independent variables were sedentary time and physical activity (continuous and categorical), while the outcomes were overall dietary quality (Healthy Eating Index (HEI) 2010), fruit and vegetable scores, and empty caloric intake (kcal). Results Multivariable analyses revealed that a 1 min increase in daily sedentary behavior was associated with a 0.2 kcal decrease in empty calories (− 0.18, 95% CI = − 0.34, − 0.03); however, sedentary time was not significantly related to overall dietary quality (HEI) and fruit and vegetable intake. In comparison, a 1 min increase in daily moderate-to-vigorous intensity physical activity was related to a 0.1 higher HEI score (0.08, 95% CI = 0.04, 0.11), a 0.01 higher fruit score (0.01, 95% CI = 0.01, 0.02), and conversely a 1.3 kcal decrease in empty calories (− 1.35, 95% CI = − 2.01, − 0.69). In addition, meeting physical activity guidelines was associated with a 2.8 point higher HEI score (2.82, 95% CI = 1.40, 4.25), a 0.5 point higher fruit score (0.51, 95% CI = 0.31–0.71), and 37.4 fewer empty calories (− 37.43, 95% CI = − 64.86, − 9.10). Conclusions Physical activity is significantly related to better overall dietary quality, while sedentary behavior is not. Findings suggest the need to promote physical activity and encourage adherence to dietary guidelines jointly, whereas sedentary behavior and overall dietary quality might need to be targeted independently. [ABSTRACT FROM AUTHOR]

Objective To accurately assess the benefits of tobacco control interventions and to better inform decision makers, knowledge of medical expenditures by age, gender, and smoking status is essential. Method We propose an approach to distribute smoking-attributable expenditures by age, gender, and cigarette smoking status to reflect the known risks of smoking. We distribute hospitalization days for smoking-attributable diseases according to relative risks of smoking-attributable mortality, and use the method to determine national estimates of smoking-attributable expenditures by age, sex, and cigarette smoking status. Sensitivity analyses explored assumptions of the method. Results Both current and former smokers ages 75 and over have about 12 times the smoking-attributable expenditures of their current and former smoker counterparts 35-54 years of age. Within each age group, the expenditures of formers smokers are about 70% lower than current smokers. In sensitivity analysis, these results were not robust to large changes to the relative risks of smoking-attributable mortality which were used in the calculations. Conclusion Sex- and age-group-specific smoking expenditures reflect observed disease risk differences between current and former cigarette smokers and indicate that about 70% of current smokers' excess medical care costs is preventable by quitting. [ABSTRACT FROM AUTHOR]

The survival rate for patients with oral squamous cell carcinoma (OSCC) has not seen marked improvement in recent decades despite enhanced efforts in prevention and the introduction of novel therapies. We have reported that pharmacological exacerbation of the unfolded protein response (UPR) is an effective approach to killing OSCC cells. The UPR is executed via distinct signaling cascades whereby an initial attempt to restore folding homeostasis in the endoplasmic reticulum during stress is complemented by an apoptotic response if the defect cannot be resolved. To identify novel small molecules able to overwhelm the adaptive capacity of the UPR in OSCC cells, we engineered a complementary cell-based assay to screen a broad spectrum of chemical matter. Stably transfected CHO-K1 cells that individually report (luciferase) on the PERK/eIF2α/ATF4/CHOP (apoptotic) or the IRE1/XBP1 (adaptive) UPR pathways, were engineered [1] . The triterpenoids dihydrocelastrol and celastrol were identified as potent inducers of UPR signaling and cell death in a primary screen and confirmed in a panel of OSCC cells and other cancer cell lines. Biochemical and genetic assays using OSCC cells and modified murine embryonic fibroblasts demonstrated that intact PERK-eIF2–ATF4-CHOP signaling is required for pro-apoptotic UPR and OSCC death following celastrol treatment. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study is to determine the impact of obesity on surgical and oncologic outcomes after primary debulking surgery (PDS) in advanced epithelial ovarian cancer (EOC). Methods Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/2/2003 and 12/30/2011 were included. Patient characteristics, intraoperative and postoperative outcomes, recurrence and status were abstracted. Complications were graded according to the 4-point Accordion classification. For analyses, patients were divided into three groups according to body mass index (BMI): group 1-BMI < 25.0 kg/m²; group 2-BMI 25.0-39.9 kg/m²; and group 3-BMI ≥ 40.0 kg/m². Results Of the 620 patients included in the study, 36.6%, 56.9%, and 6.5% were in weight groups 1, 2, and 3, respectively. Weight group 3 was an independent predictor of severe complications after adjusting for confounders (adjusted odds ratio (95% CI): 2.93 (1.38, 6.20) for group 3 vs. group 2). Weight group was not associated with differences in residual disease (p = 0.80). The 90-day mortality rates were 11.9%, 6.7%, and 15.7%, respectively, in weight group 1, 2, and 3 (p = 0.049 unadjusted, p = 0.01 adjusted). There was no difference in OS (p = 0.52) or PFS (p = 0.23) between weight groups. Conclusions BMI ≥ 40.0 kg/m² is an independent predictor of severe 30-day postoperative morbidity and 90-day mortality after PDS for EOC-information useful in preoperative counseling. BMI does not appear to impact long-term oncologic outcomes including residual disease at PDS, although we had limited power at the extremes of BMI. BMI may be an important factor to consider in risk-adjustment models and reimbursement strategies. [ABSTRACT FROM AUTHOR]

Highlights: [•] We model stressors and attachment security over six months following job loss. [•] We found evidence for both the stress-effects and stress-generation hypotheses. [•] More stressors were associated with prospective decreases in attachment security. [•] Lower attachment security was associated with prospective increases in stressors. [•] Adult attachment security operates in a dynamic and changing, not fixed, manner. [ABSTRACT FROM AUTHOR]

Highlights: [•] We modeled voice networks with and without auditory shifts using structural equation modeling. [•] We examined differences in connectivity between the two models. [•] We determined that STG is critical to vocalization and error detection/correction. [ABSTRACT FROM AUTHOR]

Abstract: Unlike adult mammals, adult zebrafish vigorously regenerate lost heart muscle in response to injury. The epicardium, a mesothelial cell layer enveloping the myocardium, is activated to proliferate after cardiac injury and can contribute vascular support cells or provide mitogens to regenerating muscle. Here, we applied proteomics to identify secreted proteins that are associated with heart regeneration. We found that Fibronectin, a main component of the extracellular matrix, is induced and deposited after cardiac damage. In situ hybridization and transgenic reporter analyses indicated that expression of two fibronectin paralogues, fn1 and fn1b, are induced by injury in epicardial cells, while the itgb3 receptor is induced in cardiomyocytes near the injury site. fn1, the more dynamic of these paralogs, is induced chamber-wide within one day of injury before localizing epicardial Fn1 synthesis to the injury site. fn1 loss-of-function mutations disrupted zebrafish heart regeneration, as did induced expression of a dominant-negative Fibronectin cassette, defects that were not attributable to direct inhibition of cardiomyocyte proliferation. These findings reveal a new role for the epicardium in establishing an extracellular environment that supports heart regeneration. [Copyright &y& Elsevier]

Emotional eating is a barrier to weight management. Interventions based on Acceptance and Commitment Therapy (ACT) promote the acceptance of uncomfortable feelings, which can reduce the urge to use food as a coping mechanism. We aimed to explore how participants of an ACT-based weight management intervention (WMI) experience emotional eating and relevant intervention content. We conducted semi-structured telephone interviews with participants of a digital ACT-based guided self-help WMI. Fifteen participants were purposefully selected to represent a range of demographic characteristics and emotional eating scores. We used reflexive thematic analysis to explore experiences of emotional eating. We generated five themes. Participants improved emotional eating by disconnecting emotions from behaviours though increased self-awareness (theme 1) and by implementing alternative coping strategies, including preparation, substitution, and acceptance (theme 2). Most participants maintained improvements in emotional eating over time but wished for more opportunities to re-engage with intervention content, including more immediate support in triggering situations (theme 3). Participants who struggled to engage with emotional eating related intervention content often displayed an external locus of control over emotional eating triggers (theme 4). The perceived usefulness of the intervention depended on participants' prior experiences of emotional eating, and was thought insufficient for participants with complex emotional experiences (theme 5). This ACT-based WMI helped participants with emotional eating by improving self-awareness and teaching alternative coping strategies. Intervention developers may consider adding ongoing forms of intervention that provide both real-time and long-term support. Additionally, a better understanding of how to support people with an external locus of control and people with complex experiences of emotional eating is needed. Future research may explore ways of personalising WMIs based on participants' emotional needs. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We report our experience with vulvar (Vu) and vaginal (Va) melanoma, with review of surgical and adjuvant therapy guidelines and description of our use of neoadjuvant therapy in selected cases. Methods: We reviewed patients seen at Mayo Clinic for management of Vu or Va melanoma, January 1993–February 2012. Surgical treatment, pathologic and outcome data were abstracted. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan–Meier method, and compared between subgroups using the log-rank test. Results: 50 patients underwent surgery for primary or recurrent melanoma (Vu=36, Va=14). The 5-year OS rate was 30.9%, with median OS of 3.3years. Adjuvant therapy was given to 30.6% of Vu cases with varying combinations of agents. Among Vu patients, after adjusting for node status and depth of invasion, adjuvant therapy was not associated with improved OS (p=0.39) or RFS (p=0.31). Preoperative chemotherapy was used in 2 Va cases. Despite temozolomide followed by exenteration for a 4cm multi-focal lesion, one patient died within 3months. The second patient, with a 2cm vaginal lesion, demonstrated a partial response to carboplatin and paclitaxel (CP). After local excision and lymphadenectomy she received additional CP with bevacizumab and remains disease free at 5years. CP with bevacizumab was also used in 1 Vu case with a solitary 5cm midline lesion. She underwent vulvectomy after a partial response, received additional CP and bevacizumab postoperatively, and remains without disease at 2years. Conclusion: Preoperative chemotherapy with CP and bevacizumab may improve treatment outcomes, particularly for Va and large Vu lesions. [Copyright &y& Elsevier]

Emerging technologies may enable detection of endometrial cancer with methods that are less invasive than standard biopsy methods. This study compares patient pain scores among 3 office gynecologic tract sampling methods and explores their potential determinants. A prospective study including 3 sampling methods (tampon, Tao brush (TB), endometrial biopsy (EB)) was conducted between December 2015 and August 2017 and included women ≥45 years of age presenting with abnormal uterine bleeding, postmenopausal bleeding, or thickened endometrial stripe. Patients rated pain after each sampling procedure using a 100-point visual analog scale (VAS). Of 428 enrolled, 190 (44.39%) patients underwent all 3 sampling methods and reported a VAS score for each. Nearly half were postmenopausal (n = 93, 48.9%); the majority were parous (172, 90.5%) of which 87.8% had at least one vaginal delivery. Among the 190 patients, the median (IQR) pain score was significantly lower for sampling via tampon (0 [0,2]) compared to TB (28 [12, 52]) or EB (32 [15, 60]) (both p < 0.001, Wilcoxon signed rank test). Among women who underwent tampon sampling, age and pain scores showed a weak positive correlation (Spearman rank correlation, r = 0.14; p = 0.006); EB sampling was associated with a weak inverse correlation between parity and pain scores (r = −0.14; p = 0.016). Gynecologic tract sampling using a tampon had significantly lower pain than both EB and TB. Pain with tampon sampling was positively correlated with age and pain with EB sampling was inversely correlated with parity. Pain scores for TB and EB were not significantly related to age, menopausal status, or BMI. • Gynecologic sampling using a tampon was less painful than endometrial biopsy or cytology. • Increasing age was associated with higher pain scores with tampon sampling. • Future studies of tampon-collected vaginal fluid and molecular markers of cancer are needed. [ABSTRACT FROM AUTHOR]

Abstract: Planococcus minor (Maskell) is native to South Asia, but it is also present in several Neotropical locations including the island of Trinidad in the southern Caribbean. The mealybug poses a serious threat to uninfested countries in this region as well as the mainland U.S. As part of an effort to gather much needed information on P. minor, 33 cocoa (Theobroma cacao L.) field sites on the island were surveyed in 2006 with a view to assess the occurrence and pest status of the mealybug. P. minor was identified from 20 field sites, indicating that it was well distributed across the island on this crop, which appeared to be a reliable indicator host plant. Infestation levels were generally low and populations were sparsely distributed across the field sites categorized into three habitat types. The following year, nine field sites were surveyed for natural enemies of P. minor using laboratory-infested potatoes in sentinel traps. Species from four insect orders and six families were collected and identified. The major predators belonged to the families Cecidomyiidae and Coccinellidae. Two primary parasitoids, Leptomastix dactylopii Howard (Encyrtidae) and Coccidoxenoides perminutus (Girault) (=Pauridia peregrina Timberlake, =Coccidoxenoides peregrinus (Timberlake)) (Encyrtidae), were reared from different mealybug stages, along with several hyperparasitoids. The primary parasitoids were probably introduced fortuitously. These diverse natural enemies were recovered throughout the sampling period from the different habitat types. The identification of key natural enemies associated with P. minor has important implications for the implementation of biological control in newly infested areas. [Copyright &y& Elsevier]

Abstract: The HA protein of the 2009 pandemic H1N1 viruses (H1N1pdm) is antigenically closely related to the HA of classical North American swine H1N1 influenza viruses (cH1N1). Since 1998, through mutation and reassortment of HA genes from human H3N2 and H1N1 influenza viruses, swine influenza strains are undergoing substantial antigenic drift and shift. In this report we describe the development of a novel monoclonal antibody (S-OIV-3B2) that shows high hemagglutination inhibition (HI) and neutralization titers not only against H1N1pdm, but also against representatives of the α, β, and γ clusters of swine-lineage H1 influenza viruses. Mice that received a single intranasal dose of S-OIV-3B2 were protected against lethal challenge with either H1N1pdm or cH1N1 virus. These studies highlight the potential use of S-OIV-3B2 as effective intranasal prophylactic or therapeutic antiviral treatment for swine-lineage H1 influenza virus infections. [Copyright &y& Elsevier]

Abstract: The atonal (ato) proneural gene specifies a stereotypic number of sensory organ precursors (SOP) within each body segment of the Drosophila ectoderm. Surprisingly, the broad expression of Ato within the ectoderm results in only a modest increase in SOP formation, suggesting many cells are incompetent to become SOPs. Here, we show that the SOP promoting activity of Ato can be greatly enhanced by three factors: the Senseless (Sens) zinc finger protein, the Abdominal-A (Abd-A) Hox factor, and the epidermal growth factor (EGF) pathway. First, we show that expression of either Ato alone or with Sens induces twice as many SOPs in the abdomen as in the thorax, and do so at the expense of an abdomen-specific cell fate: the larval oenocytes. Second, we demonstrate that Ato stimulates abdominal SOP formation by synergizing with Abd-A to promote EGF ligand (Spitz) secretion and secondary SOP recruitment. However, we also found that Ato and Sens selectively enhance abdominal SOP development in a Spitz-independent manner, suggesting additional genetic interactions between this proneural pathway and Abd-A. Altogether, these experiments reveal that genetic interactions between EGF-signaling, Abd-A, and Sens enhance the SOP-promoting activity of Ato to stimulate region-specific neurogenesis in the Drosophila abdomen. [Copyright &y& Elsevier]

Abstract: Influenza virus (Flu) infection and secondary complications are a leading cause of morbidity and mortality worldwide. The increasing number of annual Flu cases, coupled with the recent Flu pandemic, has amplified concerns about the impact of Flu on human and animal health. Similar to humans, Flu is problematic in pigs, not only as a primary pathogen but as an agent in polymicrobial pneumonia. Bordetella species play a role in mixed infections and often colonize the respiratory tract without overt clinical signs. Pigs serve as a valuable animal model for several respiratory pathogens, including Bordetella (Bb) and Flu. To investigate Flu/Bb coinfection pathogenesis, a study was completed in which pigs were inoculated with Flu-only, Bb-only or both agents (Flu/Bb). Results indicate that Flu clearance is not altered by Bb infection, but Flu does enhance Bb colonization. Pulmonary lesions in the Flu/Bb group were more severe when compared to Flu-only or Bb-only groups and Bb did not cause significant lesions unless pigs were coinfected with Flu. The type I interferon response was elevated in coinfected pigs, but increased expression of antiviral genes Mx and PKR did not appear to enhance Flu clearance in coinfected pigs, as viral clearance was similar between Flu/Bb and Flu-only groups. IL-1β and IL-8 were elevated in lungs of coinfected pigs, correlating to the days enhanced lesions were observed. Overall, Flu infection increased Bb colonization and enhanced production of proinflammatory mediators that likely contribute to exacerbated pulmonary lesions. [ABSTRACT FROM AUTHOR]

Abstract: The atonal (ato) proneural gene specifies different numbers of sensory organ precursor (SOP) cells within distinct regions of the Drosophila embryo in an epidermal growth factor-dependent manner through the activation of the rhomboid (rho) protease. How ato activates rho, and why it does so in only a limited number of sensory cells remains unclear. We previously identified a rho enhancer (RhoBAD) that is active within a subset of abdominal SOP cells to induce larval oenocytes and showed that RhoBAD is regulated by an Abdominal-A (Abd-A) Hox complex and the Senseless (Sens) transcription factor. Here, we show that ato is also required for proper RhoBAD activity and oenocyte formation. Transgenic reporter assays reveal RhoBAD contains two conserved regions that drive SOP gene expression: RhoD mediates low levels of expression in both thoracic and abdominal SOP cells, whereas RhoA drives strong expression within abdominal SOP cells. Ato indirectly stimulates both elements and enhances RhoA reporter activity by interfering with the ability of the Sens repressor to bind DNA. As RhoA is also directly regulated by Abd-A, we propose a model for how the Ato and Sens proneural factors are integrated with an abdominal Hox factor to regulate region-specific SOP gene expression. [ABSTRACT FROM AUTHOR]

Abstract: The serpinopathies encompass a large number of diseases caused by inappropriate conformational change and self-association (polymerization) of a serpin (serine proteinase inhibitor) molecule. The most common serpinopathy is α1-antitrypsin (α1AT) deficiency, which is associated with an increased risk for liver cirrhosis, hepatocellular carcinoma and early-onset emphysema. The Z variant of α1AT, which accounts for 95% of all cases of α1AT deficiency, polymerizes during synthesis and after secretion. Here, we show using intrinsic and extrinsic fluorescence probes that Z α1AT exists in a non-native conformation. We examined the thermodynamic stability by transverse urea gradient gel electrophoresis, thermal denaturation and equilibrium guanidine hydrochloride unfolding and found that, despite structural differences between the two proteins, wild-type α1AT and Z α1AT display similar unfolding pathways and thermodynamic stabilities. Far-UV circular dichroism and bis-ANS (4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid, dipotassium salt) fluorescence suggest that the intermediate ensembles formed during unfolding of wild-type α1AT and Z α1AT are characterized by similar structural features. Kinetic analysis of the unfolding transition showed that Z α1AT unfolds at least 1.5-fold faster than the wild type. The biological implications of these data are discussed. [Copyright &y& Elsevier]

Abstract: Objective: Comparison of perioperative results of patients undergoing radical hysterectomy by robotics, laparoscopy, and laparotomy. Study design: Prospective analysis of 27 patients undergoing robotic radical hysterectomy between April 2003 and September 2006. Comparison was made with patients operated by laparoscopy and laparotomy matched by age, BMI, site and type of malignancy, FIGO staging, and type of radical hysterectomy. Results: The mean operating times for patients undergoing robotic, laparoscopy and laparotomy radical hysterectomy were 189.6, 220.4, and 166.8 min, respectively; the mean blood loss was 133.1, 208.4, and 443.6 ml, respectively; the mean rate of blood loss was 0.7, 0.9, and 2.6 ml/min, respectively; the mean number of removed lymph nodes was 25.9, 25.9, and 27.7, respectively; and the mean length of hospital stay was 1.7, 2.4, and 3.6 days, respectively. There were no significant differences in intra- or postoperative complications among the three groups, no fistula formation in any patient and no conversions in the robotic or laparoscopic groups. At a mean follow up of 31.1 months, none of the patients with cervical cancer has experienced recurrence. Conclusion: Laparoscopy and robotics are preferable to laparotomy for patients requiring radical hysterectomy. Operating times for robotics and laparotomy were similar, and significantly shorter as compared to laparoscopy. Blood loss, rate of blood loss and length of hospital stay were similar for laparoscopy and robotics and significantly reduced as compared to laparotomy. [Copyright &y& Elsevier]

Abstract: Objective. : To determine the pattern of lymph node metastases, recurrence rate, and survival of patients with lateral T1 and T2 squamous cell cancer (SCC) of the vulva treated by radical vulvectomy or hemivulvectomy and inguinal lymphadenectomy. Methods. : An institutional review was performed to identify lateral T1 and T2 SCC of the vulva confined to the labium majus and minus. Results. : Sixty-one patients with lateral T1 and 61 patients with lateral T2 SCC of the vulva were treated from 1963 to 2003. Radical vulvectomy (RV) was performed in 60 patients, and radical hemivulvectomy (RHV) in 62 patients. Seven of 61 patients (11%) with T1 lesions had ipsilateral superficial inguinal lymph node (SIL) metastases, but none had deep inguinal lymph (DIL) node metastases. Nineteen of 61 patients (31%) with T2 lesions had ipsilateral SIL metastases, and 8 had ipsilateral DIL metastases. No patient had contralateral SIL or DIL metastases. Six patients (10%) with T1 lesions and seven patients (11%) with T2 lesions developed recurrence to the ipsilateral vulva and were treated by re-excision. All patients are alive with no evidence of disease 10–195 months after treatment. One patient with T1 and three patients with T2 SCC developed distant recurrence and died of disease (DOD) 10–15 months after surgery. Disease-free survival of patients with T1 lesions was 98% at 2 years and 98% at 5 years, and with T2 lesions was 95% at 2 years and 93% at 5 years. Local or distant recurrence was not more common in patients treated by RHV than in those treated by RV. Conclusion. : Lateral T1 and T2 squamous cell cancers of the vulva spread to the ipsilateral inguinal lymph nodes and can be treated effectively with RHV and ipsilateral SIL dissection. Deep inguinal lymphadenectomy is indicated only when the SIL are positive. [Copyright &y& Elsevier]

Abstract: The Chinese hamster dihydrofolate reductase (DHFR) DNA replication initiation region, the 5.8 kb ori-beta, can function as a DNA replicator at random ectopic chromosomal sites in hamster cells. We report a detailed genetic analysis of the DiNucleotide Repeat (DNR) element, one of several sequence elements necessary for ectopic ori-beta activity. Deletions within ori-beta identified a 132 bp core region within the DNR element, consisting mainly of dinucleotide repeats, and a downstream region that are required for ori-beta initiation activity at non-specific ectopic sites in hamster cells. Replacement of the DNR element with Xenopus or mouse transcriptional elements from rDNA genes restored full levels of initiation activity, but replacement with a nucleosome positioning element or a viral intron sequence did not. The requirement for the DNR element and three other ori-beta sequence elements was conserved when ori-beta activity was tested at either random sites or at a single specific ectopic chromosomal site in human cells. These results confirm the importance of specific cis-acting elements in directing the initiation of DNA replication in mammalian cells, and provide new evidence that transcriptional elements can functionally substitute for one of these elements in ori-beta. [Copyright &y& Elsevier]

Abstract: Huntington''s disease (HD) is an inherited progressive neurological disorder for which there is no effective therapy. It is caused by a CAG/polyglutamine repeat expansion that leads to abnormal protein aggregation and deposition in the brain. Several compounds have been shown to disrupt the aggregation process in vitro, including a number of benzothiazoles. To further explore the therapeutic potential of the benzothiazole aggregation inhibitors, we assessed PGL-135 and riluzole in hippocampal slice cultures derived from the R6/2 mouse, confirming their ability to inhibit aggregation with an EC50 of 40 μM in this system. Preliminary pharmacological work showed that PGL-135 was metabolically unstable, and therefore, we conducted a preclinical trial in the R6/2 mouse with riluzole. At the maximum tolerated dose, we achieved steady-state riluzole levels of 100 μM in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype. [Copyright &y& Elsevier]