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The main objective in this study was to determine the prevalence of Chronic Kidney Disease (CKD) in people with Type 2 Diabetes Mellitus (T2DM) in the Autonomous Community (AC) of Aragon (Spain) and to detect whether or not there is under-registration in the patient's history. As a secundary objetive, it was proposed to study the most relevant demographic and clinical characteristics of people with CKD. Observational and retrospective real world data study of the population over 18 years of age with a diagnosis of T2DM, between January 2017 and December 2021. A descriptive analysis of qualitative and quantitative variables, and a comparison using the parametric Student's t-test or the non-parametric Mann-Whitney U-test between both groups was performed. The prevalence of T2DM was 8.07 % and that of CKD 31.4 %, with an under-reporting of 47 %. The main risk factor associated with CKD was arterial hypertension (p<0.001), followed by dyslipidemia (p<0.001). The main treatment used for diabetes control was metformin, both in patients with and without CKD (p<0.001). A total of 56.81 % of people with T2DM and CKD did not undergo annual monitoring of their renal function (glomerular filtration rate) or determination of albuminuria. The prevalence of CKD increases in patients with T2DM (31.4 %), and in almost half of patients the diagnosis is not registered (47 %). This under-reporting delays the implementation of measures needed to prevent CKD progression. • We analyze the presence of CKD (chronic kidney disease) in people with diabetes. • Using big data of 90,700 diabetic patients, analyzing their CKD under-registration. • 31.4 % diabetic patients exhibit CKD, and 47 % of these cases are undiagnosed. • The primary risk factors associated with CKD are hypertension and dyslipidemia. • 56.8 % diabetic subjects with CKD did not undergo annual monitoring of their renal function. [ABSTRACT FROM AUTHOR]

The success of a multi-kilometre drive by a solar-powered rover at the lunar south pole depends upon careful planning in space and time due to highly dynamic solar illumination conditions. An additional challenge is that the rover may be subject to random faults that can temporarily delay long-range traverses. The majority of existing global spatiotemporal planners assume a deterministic rover-environment model and do not account for random faults. In this paper, we consider a random fault profile with a known, average spatial fault rate. We introduce a methodology to compute recovery policies that maximize the probability of survival of a solar-powered rover from different start states. A recovery policy defines a set of recourse actions to reach a safe location with sufficient battery energy remaining, given the local solar illumination conditions. We solve a stochastic reach-avoid problem using dynamic programming to find an optimal recovery policy. Our focus, in part, is on the implications of state space discretization, which is required in practical implementations. We propose a modified dynamic programming algorithm that conservatively accounts for approximation errors. To demonstrate the benefits of our approach, we compare against existing methods in scenarios where a solar-powered rover seeks to safely exit from permanently shadowed regions in the Cabeus area at the lunar south pole. We also highlight the relevance of our methodology for mission formulation and trade safety analysis by comparing different rover mobility models in simulated recovery drives from the LCROSS impact region. • The safety of a solar-powered rover depends on its location, energy and time of day. • Maximally safe behaviours depend on when and where delays occur during a traverse. • The probability of survival of a rover varies non-monotonically with time. • Min–max dynamic programming can conservatively account for the temporal risk ambiguity. [ABSTRACT FROM AUTHOR]

Trastuzumab emtansine (T-DM1) has demonstrated improvements in survival and neurological symptoms in patients with breast cancer with brain metastases (BCBM). This real-world study investigated the effectiveness of T-DM1 versus lapatinib plus capecitabine (LC) in patients with BCBM. This retrospective, observational study evaluated patients with HER2–positive BCBM using a real-world database. Eligible patients had initiated T-DM1 or LC with a prior diagnosis of brain metastasis and ≥1 prior metastatic breast cancer treatment. The primary endpoint was overall survival (OS); secondary endpoints were time to next relevant treatment or death (TTNT) and real-world progression-free survival (rwPFS). An inverse probability of treatment weighting (IPTW) approach was used to account for differences in potential baseline characteristics between treatment groups. Outcomes were described using the Kaplan-Meier method, and the average treatment effect of initiating T-DM1 versus LC was estimated using weighted Cox proportional hazard models and hazard ratio (HR). A total of 214 patients were available for analysis (T-DM1, n = 161; LC, n = 53). Demographics and baseline characteristics were generally well-balanced between treatment groups after weighting. After weighting, median OS was 17.7 (T-DM1) versus 9.6 (LC) months (HR, 0.55 [95% CI, 0.34–0.89]; P= 0.013). Median TTNT was 9.0 (T-DM1) versus 6.0 (LC) months (HR, 0.55 [95% CI, 0.36–0.85]; P = 0.005). After weighting, median rwPFS was 6.0 (T-DM1) versus 4.0 (LC) months (HR, 0.50 [95% CI, 0.36–0.69]; P < 0.001). These results support the superior effectiveness and clinical relevance of T-DM1 versus LC in patients with HER2-positive BCBM in the real world. • Breast cancer with brain metastases (BCBM) has been associated with lower survival. • T-DM1 improves survival vs lapatinib + capecitabine in real-world HER2+ BCBM patients. • Time to next treatment was also prolonged with T-DM1 vs lapatinib + capecitabine. • T-DM1 is an effective and clinically relevant option for patients with HER2+ BCBM. [ABSTRACT FROM AUTHOR]

• Our patient had terminal heart failure and was on a left ventricular assist device while awaiting a heart transplant. • We made the difficult decision to transplant her despite a positive crossmatch and active infection with SARS-CoV-2 in the donor, given the significant multiple complications she had experienced on a left ventricular assist device. • She did not develop any COVID-19–related complications despite major immunosuppression. • This is the first case report of a pediatric heart transplant with a COVID-19–positive donor, highlighting the need for ongoing organ donation evaluation in SARS-CoV-2 infection. We report the case of a 3-year-old who was highly sensitized and received cardiac transplantation from a donor in the acute phase of SARS-CoV-2 infection. Despite maximal immunosuppression owing to a positive cross-match and desensitization protocol, the patient's course was favorable. [ABSTRACT FROM AUTHOR]

Introduction: Forearm fractures are common pediatric injuries. Most displaced or angulated fractures can be managed via closed reduction in the operating room or in the Emergency Department (ED). Previous research has shown that emergency physicians can successfully perform closed reduction within ED; however, the fracture morphology amendable to ED physician reduction is unclear. The aim of this study is to detail the fracture characteristics associated with successful reduction by ED physicians.Methods: We conducted a retrospective study of children (aged <18 years) presenting to the ED of a tertiary care children's hospital (annual census 90,000) between January 2018 and December 2018 with closed distal and midshaft forearm fractures requiring reduction. Data collected included patient demographics, fracture morphology, management, and complications. Successful ED physician reduction was based on predefined criteria. Orthopedic referrals included those patients sent directly to the operating room, closed reductions performed by orthopedic trainees within the ED, and patients requiring orthopedic consultation after failed ED reduction.Results: A total of 340 patients with forearm fractures were included in the study. ED clinicians attempted to reduce 274 (80.6%) of these fractures and were successful in 256/274 (93.4%) cases. Of the 84 orthopedic referrals, 18 were after failed ED clinician attempt, and 66 were ab initio managed by orthopedics (37 in the operating room and 29 in ED). Compared to the fractures with successful ED reduction (n = 256), factors associated with orthopedic referral (n = 84) included: increasing age, midshaft location, higher degree of angulation, and completely displaced fractures. Angulated distal greenstick fractures were most likely to be successfully reduced by ED clinicians. There were no difference in complication rates between the two groups.Conclusion: In this series, fractures most amenable to reduction by ED clinicians include distal greenstick fractures, whereas midshaft and completely displaced fractures are more likely to need treatment by orthopedics. [ABSTRACT FROM AUTHOR]

Background: Adequate cellular thymidylate (dTMP) pools are essential for preservation of nuclear and mitochondrial genome stability. Previous studies have indicated that disruption in nuclear dTMP synthesis leads to increased uracil misincorporation into DNA, affecting genome stability. To date, the effects of impaired mitochondrial dTMP synthesis in nontransformed tissues have been understudied.Objectives: This study aimed to determine the effects of decreased serine hydroxymethyltransferase 2 (Shmt2) expression and dietary folate deficiency on mitochondrial DNA (mtDNA) integrity and mitochondrial function in mouse tissues.Methods: Liver mtDNA content, and uracil content in liver mtDNA, were measured in Shmt2+/- and Shmt2+/+ mice weaned onto either a folate-sufficient control diet (2 mg/kg folic acid; C) or a modified diet lacking folic acid (0 mg/kg folic acid) for 7 wk. Shmt2+/- and Shmt2+/+ mouse embryonic fibroblast (MEF) cells were cultured in defined culture medium containing either 0 or 25 nM folate (6S-5-formyl-tetrahydrofolate, folinate) to assess proliferative capacity and mitochondrial function. Chi-square tests, linear mixed models, and 2-factor ANOVA with Tukey post hoc analyses were used to analyze data.Results: Shmt2 +/- mice exhibited a 48%-67% reduction in SHMT2 protein concentrations in tissues. Interestingly, Shmt2+/- mice consuming the folate-sufficient C diet exhibited a 25% reduction in total folate in liver mitochondria. There was also a >20-fold increase in uracil in liver mtDNA in Shmt2+/- mice consuming the C diet, and dietary folate deficiency also increased uracil content in mouse liver mtDNA from both Shmt2+/+ and Shmt2+/- mice. Furthermore, decreased Shmt2 expression in MEF cells reduced cell proliferation, mitochondrial membrane potential, and oxygen consumption rate.Conclusions: This study demonstrates that Shmt2 heterozygosity and dietary folate deficiency impair mitochondrial dTMP synthesis in mice, as evidenced by the increased uracil in mtDNA. In addition, Shmt2 heterozygosity impairs mitochondrial function in MEF cells. These findings suggest that elevated uracil in mtDNA may impair mitochondrial function. [ABSTRACT FROM AUTHOR]

• We introduce feminist materialist disability theory to rethink body functionality. • Feminist disability theory reimagines difference through an affirmative lens. • This approach has important implications for theory, research, and practice. • We advocate for engagement with this theory base to advance functionality research. A burgeoning body of literature shows a positive relationship between body functionality and positive body image. Although still nascent, research centring experiences of people with disabilities and bodily differences develops this literature. In this article, we offer directions for this research, bringing body functionality into dialogue with feminist materialist disability theory to examine relations between people's bodily perceptions and the socio-material worlds they occupy. Feminist disability theory re-imagines difference through an affirmative lens, conceptualising body image as relational and processual, and approaching difference through four orientations: difference is basic to the world; difference is not deficiency; difference is not the problem, our inhospitable and ableist world is; and centring difference exposes the mythical norm. We apply this lens to body functionality research, and outline implications for research, practice, and theory, arguing that building a bridge between these frameworks offers a stepping off point for exciting directions for body image research. [ABSTRACT FROM AUTHOR]

Maintenance of CD4 T cells during chronic infections is vital for limiting pathogen burden and disease recrudescence. Although inhibitory receptor expression by CD4 T cells is commonly associated with immune suppression and exhaustion, such cell-intrinsic mechanisms that control activation are also associated with cell survival. Using a mouse model of visceral leishmaniasis (VL), we discovered a subset of lymphocyte activation gene 3 (LAG-3)-expressing CD4 T cells that co-express CXCR5. Although LAG3+CXCR5+ CD4 T cells are present in naive mice, they expand during VL. These cells express gene signatures associated with self-renewal capacity, suggesting progenitor-like properties. When transferred into Rag1 −/− mice, these LAG3+CXCR5+ CD4 T cells differentiated into multiple effector types upon Leishmania donovani infection. The transcriptional repressor B cell lymphoma-6 was partially required for their maintenance. Altogether, we propose that the LAG3+CXCR5+ CD4 T cell subset could play a role in maintaining CD4 T cell responses during persistent infections. [Display omitted] • LAG3+CXCR5+PD-1lo/int CD4 T cells expand during chronic visceral leishmaniasis • These cells express genes associated with self-renewal • LAG3+CXCR5+PD-1lo/int CD4 T cells give rise to multiple CD4 T cell subsets • BCL-6 is partially required for their maintenance Swaminathan et al. identify a CD4 T cell subset that expresses LAG3+CXCR5+PD-1lo/int and expands during chronic visceral leishmaniasis. These cells display progenitor-like capacity, express genes associated with self-renewal, and differentiate into effector as well as regulatory CD4 T cell subsets, conferring protection upon adoptive transfer. [ABSTRACT FROM AUTHOR]

Targeted alpha therapy (TAT) is an area of research with rapidly increasing importance as the emitted alpha particle has a significant effect on inducing cytotoxic effects on tumor cells while mitigating dose to normal tissues. Two significant isotopes of interest within the area of TAT are thorium-227 and actinium-225 due to their nuclear characteristics. Both isotopes have physical half-lives suitable for coordination with larger biomolecules, and additionally actinium-225 has potential to serve as an in vivo generator. In this review, the authors will discuss the production, purification, labeling reactions, and biological studies of actinium-225 and thorium-227 complexes and clinical studies. [ABSTRACT FROM AUTHOR]

The molecular mechanisms underlying the stress response are poorly described in crustaceans. This includes the snow crab (Chionoecetes opilio), a commercially important stenotherm species distributed throughout the northern hemisphere. A better understanding of the stress response in C. opilio is desperately needed for commercial and conservation purposes. The purpose of this study was to investigate the transcriptional and metabolomic response of C. opilio exposed to stressors. Crabs were randomly assigned to 24 or 72 h treatment groups where they were exposed to conditions simulating live transport (handling and air exposure). A control group was kept in cold (2 °C) and well‑oxygenated saltwater. The hepatopancreas of the crabs was sampled to perform RNA-sequencing and high-performance chemical isotope labeling metabolomics. Differential gene expression analyses showed that classic crustaceans' stress markers, such as crustacean hyperglycemic hormones and heat shock proteins, were overexpressed in response to stressors. Tyrosine decarboxylase was also up-regulated in stressed crabs, suggesting an implication of the catecholamines tyramine and octopamine in the stress response. Deregulated metabolites revealed that low oxygen was an important trigger in the stress response as intermediate metabolites of the tricarboxylic acid cycle (TCA) accumulated. Lactate, which accumulated unevenly between crabs could potentially be used to predict mortality. This study provides new information on how stressors affect crustaceans and provides a basis for the development of stress markers in C. opilio. [Display omitted] • Crustacean hyperglycemic hormone and HSPs are overexpressed in stressed snow crabs. • Tyramine and octopamine are likely involved in the stress response. • Amino acids might be an important energy source for crabs during stress. • This study provides a basis for the development of stress markers in snow crabs. • The simulated transport conditions generated a stress response that shares a lot with the hypoxia response. [ABSTRACT FROM AUTHOR]

The liver is the primary organ participating in the metabolism of xenobiotics and is therefore an important target in the safety assessment of drugs, chemicals and environmental toxins. Drug-induced liver injury (DILI) has recently become widely recognized in human medicine as an adverse event. The progression of DILI often involves “damage-associated molecular patterns” (DAMPs) of gene and protein expression such as high-mobility group boxes (HMGBs), S100 proteins and heat shock proteins (Hsp). DAMPs are released from injured or necrotic cells and are bound to Toll-like receptors (TLRs) and modulate inflammatory reactions. Previously, in thioacetamide (TAA; 300 mg/kg body weight, single injection)-induced rat liver, we demonstrated that the expressions of DAMPs, TLR4 and major histocompatibility complex (MHC) class II were simultaneously increased, accompanied with progression of hepatocellular injury and inflammation. Here we investigated the association of DILI and DAMPs, TLRs and MHC class II by using rat livers repeated injections with TAA (100 mg/kg body weight, once, three times). Two days after TAA single injection, centrilobular hepatocellular necrosis with infiltration of mononuclear cells was observed, being paralleled with increase in serum levels of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). However, two days after duplicate and triplicate injections, only mild degenerative change of hepatocytes and slight infiltration of mononuclear cells were seen in the affected centrilobular area. Serum levels of AST, ALT and ALP were also decreased to the same levels of control. mRNA expressions of DAMPs (HMGBs, S100A4 and Hsp 70-2), TLR4 and MHC class II tended to be increased only on single injection, although the number of MHC class II-positive cells in the centrilobular area was still increased on each examination point. The analysis of enzymes (CYP2E1 and Flavin monooxygenase (FMO) 3), which metabolize TAA in hepatocytes, showed a significant decrease in FMO3 on the duplicate and triplicate injections. Autophagy and regulatory T cells were not significantly changed for the attenuation of hepatocyte injury. Collectively, these results suggest that hepatocytes may adapt accumulation of the toxicant by changing their enzyme functions; furthermore, MHC class II cells, which still showed increased number in the duplicate and triplicate injections, may be related with protection from the toxicant. [ABSTRACT FROM AUTHOR]

Background: The one-carbon metabolism pathway is highly dependent on a number of B vitamins in order to provide one-carbon units for purine and thymidylate biosynthesis as well as homocysteine remethylation. Previous studies have examined folate and vitamin B-12 deficiency and their effects on formate metabolism; as of yet, to our knowledge, no studies on the effects of riboflavin deficiency on formate metabolism have been published.Objective: Our objective was to determine the effects of riboflavin deficiency on formate metabolism.Methods: Weanling male rats were randomly assigned either to control, riboflavin-replete (RR) or to experimental, riboflavin-deficient (RD) versions of the AIN-93G diet for 13 d, at which time a constant infusion of [13C]-formate was carried out to ascertain the effects of deficiency on formate production. Gas chromatography-mass spectrometry was used to measure plasma formate concentration and [13C]-formate enrichment. HPLC, LC-mass spectrometry (MS)/MS, and enzymatic assays were used for the measurement of one-carbon precursors and other metabolites.Results: RD rats had significantly lower rates of formate production (15%) as well as significantly reduced hepatic methylenetetrahydrofolate reductase activity (69%) and protein concentration (54%) compared with RR rats. There was no difference in plasma formate concentrations between the groups. Plasma serine, a potential one-carbon precursor, was significantly higher in RD rats (467 ± 73 μM) than in RR rats (368 ± 52 μM).Conclusions: Although deficiencies in folate and vitamin B-12 lead to major changes in plasma formate concentrations, riboflavin deficiency results in no significant difference; this disagrees with the prediction of a published mathematical model. Our observation of a lower rate of formate production is consistent with a role for flavoproteins in this process. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study is to examine the utility of positron emission tomography (PET) for staging and restaging after treatment of paranasal sinus carcinomas. Study Design: Retrospective data review was done. Subjects and Methods: Patients selected underwent PET for sinonasal neoplasms from 2003 to 2008 at a tertiary care referral center. Results: Seventy-seven scans were reviewed from 31 patients. The pathologies included olfactory neuroblastoma (n = 9), squamous cell carcinoma (n = 6), sinonasal undifferentiated carcinoma (n = 6), sinonasal melanoma (n = 6), and minor salivary gland carcinomas (n = 4). The positive predictive value of studies performed for restaging at the primary, neck, and distant sites were 56%, 54%, and 63%; negative predictive values were 93%, 100%, and 98%, respectively. During restaging, 32% of patients were accurately upstaged secondary to neck or distant site involvement. Conclusion: Positron emission tomography serves as a useful adjunct to conventional imaging in the management of sinonasal malignancies. Negative studies are effective in predicting absence of disease as seen in the consistently high-negative predictive values. Positive studies need to be viewed cautiously given the high rate of false-positive studies. When viewed in conjunction with clinical examination, endoscopic assessment, and focused biopsies, they may effectively result in a more accurate assessment of the extent of disease. [ABSTRACT FROM AUTHOR]

Summary Functional genomic analysis of gene expression in mice allowed us to identify a quantitative trait locus (QTL) linked in trans to the expression of 190 gene transcripts and in cis to the expression of only two genes, one of which was Ypel5 . Most of the trans -expression QTL genes were interferon-stimulated genes (ISGs), and their expression in mouse macrophage cell lines was stimulated in an IFNB1 -dependent manner by Ypel5 silencing. In human HEK293T cells, YPEL5 silencing enhanced the induction of IFNB1 by pattern recognition receptors and phosphorylation of TBK1/IKBKE kinases, whereas co-immunoprecipitation experiments revealed that YPEL5 interacted physically with IKBKE. We thus found that the Ypel5 gene (contained in a locus linked to a network of ISGs in mice) is a negative regulator of IFNB1 production and innate immune responses that interacts functionally and physically with TBK1/IKBKE kinases. [ABSTRACT FROM AUTHOR]

High resolution photoabsorption spectrum of gas-phase methylcyanoacetylene ( CH 3 C 3 N ) has been recorded from 44 500 to 130 000 cm −1 at room temperature with a vacuum ultraviolet Fourier-transform spectrometer on the DESIRS synchrotron beamline (SOLEIL). The absolute photoabsorption cross section in this range is reported for the first time. Valence shell transitions and Rydberg series converging to the ground state X ˜ + E 2 of the cation as well as series converging to electronically excited states ( A ˜ + A 1 2 and C ˜ + ) are observed and assigned. Time-dependent density-functional-theory calculations have been performed to support the assignment of the experimental spectrum in the low energy range. A tentative scaling of the previously measured CH 3 C 3 N + ion yield by Lamarre et al. [17] is proposed, based on the comparison of the absorption data above the first ionization potential with the observed autoionization structures. [ABSTRACT FROM AUTHOR]

Background: Road traffic injuries (RTIs) are a significant cause of paediatric morbidity and mortality worldwide, with a disproportionate number of these injuries occurring in low- and middle-income countries (LMICs). Adult data from LMICs suggest that weekends are particularly high-risk for RTIs, but whether children are at increased risk of RTI on weekends has not previously been investigated in any setting. This study sought to assess patterns in paediatric RTI presentations using hospital-based trauma surveillance data in Cape Town, South Africa.Methods: Data was analysed from Childsafe South Africa's prospectively collected trauma registry for injured children below 13 years of age presenting to a tertiary paediatric referral Trauma Department between 2004 and 2013.Results: During the 10-year study period, a total of 71,180 patients presented with traumatic injuries, of which 8,815 (12.4%) resulted from RTIs. RTI patients had a mean age of 5.2±3.6 years, and were predominantly males and pedestrians. RTIs were more common on weekends than weekdays (2.98 vs. 2.19 patients/day, p<0.001), representing a greater proportion of daily all-cause trauma (15.5% vs. 11.2%, p<0.001). Moreover, weekend RTI patients sustained more severe injuries than on weekdays, and compared to weekend all-cause trauma patients (injury score 1.66 vs. 1.46 and 1.43, both p<0.001). RTI patients were more likely to require admission to both the trauma ward (1.14 vs. 0.79 patients/day, p<0.001) and the PICU (0.10 vs. 0.07 patients/day, p<0.05) on weekends than on weekdays. Weekend RTI patients most frequently required admission to the trauma ward (p<0.001) and the PICU (p<0.05) during the last annual quarter.Conclusions: In a LMIC-setting, paediatric RTI patients are more frequently brought to medical attention, sustain more severe injuries and more frequently require hospital admission during the weekend. Weekends during the last annual quarter were particularly high-risk for paediatric RTIs. These findings highlight the importance of trauma surveillance data to inform targeted community prevention strategies for improving child road safety. [ABSTRACT FROM AUTHOR]

A method was devised to measure the fractional rate of protein synthesis in fish using a stable isotope labelled tracer (ring-D 5 -phenylalanine) instead of radioactive phenylalanine. This modified flooding dose technique utilizes gas chromatography with mass spectrometry detection (GC-MS). The technique was validated by measuring the fractional rate of protein synthesis in the liver and white muscle of Arctic charr ( Salvelinus alpinus ) and then tested by comparing the fractional rate of protein synthesis of fed and starved Arctic charr. The modified technique met the assumptions of the flooding dose technique and was successfully used to detect alterations in the rate of protein synthesis in fed and starved fish. This modified technique allows for studies on protein metabolism to be carried out in situations where the use of radioactivity is difficult, if not impossible. [ABSTRACT FROM AUTHOR]

Highlights: [•] Political campaigns’ can use Twitter to build effective relationships with democratically engaged publics. [•] Twitter use provides information to key stakeholder groups. [•] Twitter offers political public relations practitioners an effective way to mobilize support for candidates and campaigns. [•] Social media play an important role in achieving democratic aims. [ABSTRACT FROM AUTHOR]

Osteoradionecrosis (ORN) is a serious complication of radiation therapy characterized by non-healing exposed bone, and occurs in 5-35% of head and neck cancers treated with intensity-modulated radiotherapy (IMRT). High radiation dose, oral cavity subsite, and mandibular surgery are known risk factors for ORN development. However, whether mandibles reconstructed with fibular flaps carry an elevated risk of ORN compared to native mandibles in patients with IMRT-treated oral cavity squamous cell carcinoma (OCSCC) is unknown. An IRB-approved database of head and neck cancer patients treated at a tertiary care center was queried for patients with OCSCC treated with surgery and post-operative IMRT. Patients were included if they underwent free flap surgery, received IMRT ≥45 Gy in ≥20 fractions, and completed treatment at least two years prior to analysis to provide adequate follow-up time. ORN was graded according to Schwartz and Kagan classification: grade 1, superficial involvement of mandible; grade 2, exposed cortical bone and underlying medullary bone necrosis; grade 3, full diffuse involvement. Competing risk regression, with death as a competing event, was used to assess risk factors for the development of ORN. A total of 151 patients met inclusion criteria with median follow-up time of 32.6 months (range 0.2-190.6). Patient demographics included 60.3% male, 88.7% Caucasian, and median age 62.4 years (range 28.1-93.2). Of the 151 patients, 27.8% were current smokers and 45.7% were former smokers. Oral cavity subsites were grouped as lateralized tumors in 32.5% of patients (11.9% buccal mucosa, 8.6% retromolar trigone, 6.0% alveolar ridge, 4.0% gingiva, and 2.0% hard palate) and midline tumors in 67.6% of patients (21.2% floor of mouth, 46.4% mobile (oral) tongue). Reconstruction with soft-tissue free flap was performed in 74.8% of patients, and 25.2% of patients underwent fibular flap for mandibular reconstruction. Median radiation dose was 60 Gy in 30 fractions. ORN occurred in 13.9% of patients (n=21; 11 grade 1, 3 grade 2, 7 grade 3) and 42.4% of patients died without ORN. For patients who developed ORN, the median time to ORN was 23.9 months (range 2.4-71.2). On univariate analysis, no individual factors were associated with development of ORN; the 1-year (5.4%, 95%CI 2.5-9.8%) and 2-year (7.5%, 95%CI 3.9-12.5%) rates of ORN were low. Fibular flap mandibular reconstruction was not associated with increased risk of developing mandibular ORN compared to native mandibles in patients with oral cavity cancer following IMRT. The risk of ORN in patients treated with IMRT after mandible reconstruction is low, and fibular flaps can be safely performed with no excess concern for this mandibular ORN. Larger prospective studies are needed to definitively assess risk factors for development of ORN in this patient population. [ABSTRACT FROM AUTHOR]

Abstract: Testate amoebae are common proxy for water table depth in peatlands and are commonly used to reconstruct past hydroclimatic conditions. In northeastern America, previous transfer function development was mostly limited to ombrotrophic peatlands from continental and/or oceanic contexts. This study provides a greater range of modern analogues (n = 206) from ombrotrophic to poor minerotrophic peatlands along an ecoclimatic gradient from boreal to subarctic in both continental and oceanic regions. Multivariate analysis confirmed that water table depth is the dominant control on species distribution, and a new transfer function was developed for this environmental parameter. The WA.inv model has a RMSEP of 5.44 cm and R 2 of 0.80. The effect of spatial autocorrelation on the predictive power and statistical significance of this transfer function was also tested using newly developed statistical tests. We also improved modern analogues for two problematic species (Hyalophenia subflava and Difflugia pulex). This new testate amoeba transfer function will improve paleohydrological reconstructions from high-latitude peatlands (e.g. subarctic fens) and increase our ability to evaluate their sensitivity to ongoing climate change. [Copyright &y& Elsevier]

Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cocaine has long been known to increase blood pressure, but the degree and mechanism of vasoconstricting action remain poorly understood. Here we examine the interaction between cocaine and alpha-adrenoceptor agonists, with the action of reuptake inhibition minimized. Methods: Cocaine was administered to isolated rings of rat thoracic aorta, alone and in combination with three different adrenoceptor agonists: phenylephrine, methoxamine, and norepinephrine. Synergy analysis begins with the predicted additive effect of the combination of two agonists, based upon dose equivalence theory. This case where one agonist (cocaine) has no effect when administered alone requires only a t-test to demonstrate that a departure from additivity has occurred. Results: At doses where cocaine alone produced no vasoconstriction, it potentiated the vasoconstriction produced by all three alpha agonists, a clear indication of synergism between cocaine and these agents. Higher doses of cocaine in combination with alpha adrenoceptor agents gave an inverted-U shaped (hormetic) dose–effect curve, i.e., dose-related relaxation at higher doses. The hormetic dose–effect relation was analyzed using computational methodology based on dose equivalence to derive the unknown second component of action that causes relaxation. Conclusions: Cocaine exhibits both vasoconstricting and vasorelaxant effects. This relaxing component, possibly related to activation of myosin light chain phosphatase, was quantified as a dose–effect curve. Most important is the synergism between cocaine and alpha-adrenoceptor stimulation which cannot be explained as an action due to reuptake inhibition, and has not been previously described. [Copyright &y& Elsevier]

Although radioguided surgery has been used for the excision of sentinel nodes in breast cancer and melanoma, sparse literature exists describing its use in thyroid cancer. We report a 69-year-old patient with a previous total thyroidectomy and lymph node dissection for papillary carcinoma who was subsequently found to have recurrent metastatic disease. After a therapeutic dose of radioactive iodine, a hand-held gamma-probe was used to selectively dissect the neck. The patient was offered radioguided revision neck dissection to remove the disease using residual radioactivity of the original therapeutic iodine 131 dose. Our case report seeks to demonstrate a recent example of our use of the gamma-probe in radioguided surgical excision of recurrent metastatic papillary thyroid carcinoma. [ABSTRACT FROM AUTHOR]

Interferons (IFNs) have long been used as an immunomodulatory therapy for a large array of acute and chronic viral infections. However, IFN therapies have been plagued by severe side effects. The discovery of pathogen recognition receptors (PRR) rejuvenated the interest for immunomodulatory therapies. The successes obtained with Toll-like receptor (TLR) agonists in activating immune cells and as adjuvant for prophylactic vaccines against different viruses paved the way to targeted immunomodulatory therapy. Better characterization of pathogen-induced immune disorders and newly discovered regulators of innate immunity have now the potential to specifically withdraw prevailing subversion mechanisms and to transform antiviral treatments by introducing panviral therapeutics with less adverse effects than IFN therapies. [ABSTRACT FROM AUTHOR]