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Background Brachial plexopathy is a potentially serious complication from stereotactic body radiation therapy (SBRT) that has not been widely studied. Therefore, we compared datasets from two different institutions and generated a brachial plexus dose–response model, to quantify what dose constraints would be needed to minimize the effect on normal tissue while still enabling potent therapy for the tumor. Methods Two published SBRT datasets were pooled and modeled from patients at Indiana University and the Richard L. Roudebush Veterans Administration Medical Center from 1998 to 2007, as well as the Karolinska Institute from 2008 to 2013. All patients in both studies were treated with SBRT for apically located lung tumors localized superior to the aortic arch. Toxicities were graded according to Common Terminology Criteria for Adverse Events, and a probit dose response model was created with maximum likelihood parameter fitting. Results This analysis includes a total of 89 brachial plexus maximum point dose (Dmax) values from both institutions. Among the 14 patients who developed brachial plexopathy, the most common complications were grade 2, comprising 7 patients. The median follow-up was 30 months (range 6.1–72.2) in the Karolinska dataset, and the Indiana dataset had a median of 13 months (range 1–71). Both studies had a median range of 3 fractions, but in the Indiana dataset, 9 patients were treated in 4 fractions, and the paper did not differentiate between the two, so our analysis is considered to be in 3–4 fractions, one of the main limitations. The probit model showed that the risk of brachial plexopathy with Dmax of 26 Gy in 3–4 fractions is 10%, and 50% with Dmax of 70 Gy in 3–4 fractions. Conclusions This analysis is only a preliminary result because more details are needed as well as additional comprehensive datasets from a much broader cross-section of clinical practices. When more institutions join the QUANTEC and HyTEC methodology of reporting sufficient details to enable data pooling, our field will finally reach an improved understanding of human dose tolerance.

Purpose Stereotactic body radiation therapy (SBRT) and stereotactic ablative body radiation therapy is being increasingly used for pancreatic cancer (PCa), particularly in patients with locally advanced and borderline resectable disease. A wide variety of dose fractionation schemes have been reported in the literature. This HyTEC review uses tumor control probability models to evaluate the comparative effectiveness of the various SBRT treatment regimens used in the treatment of patients with localized PCa. Methods and Materials A PubMed search was performed to review the published literature on the use of hypofractionated SBRT (usually in 1-5 fractions) for PCa in various clinical scenarios (eg, preoperative [neoadjuvant], borderline resectable, and locally advanced PCa). The linear quadratic model with α/β= 10 Gy was used to address differences in fractionation. Logistic tumor control probability models were generated using maximum likelihood parameter fitting. Results After converting to 3-fraction equivalent doses, the pooled reported data and associated models suggests that 1-year local control (LC) without surgery is ≈79% to 86% after the equivalent of 30 to 36 Gy in 3 fractions, showing a dose response in the range of 25 to 36 Gy, and decreasing to less than 70% 1-year LC at doses below 24 Gy in 3 fractions. The 33 Gy in 5 fraction regimen (Alliance A021501) corresponds to 28.2 Gy in 3 fractions, for which the HyTEC pooled model had 77% 1-year LC without surgery. Above an equivalent dose of 28 Gy in 3 fractions, with margin-negative resection the 1-year LC exceeded 90%. Conclusions Pooled analyses of reported tumor control probabilities for commonly used SBRT dose-fractionation schedules for PCa suggests a dose response. These findings should be viewed with caution given the challenges and limitations of this review. Additional data are needed to better understand the dose or fractionation-response of SBRT for PCa.

This manuscript adds to the literature of endocrine regulation of adaptive thermogenesis and energy balance. It specifically describes the role of pituitary adenylate cyclase-activating polypeptide on the regulation of brown adipose tissue via the sympathetic nervous system with a focus on compensatory mechanisms of thermogenesis. We highlight sex-specific differences in energy metabolism.

New findings What is the central question of this study? Can chronic treatment of pituitary adenylate cyclase-activating polypeptide (PACAP) deficient mice with the melanocortin agonist melanotan II during cold acclimation rescue the impaired thermogenic capacity previously observed in PACAP deficient mice? What is the main finding and its importance? Using a genetic model of PACAP deficiency, this study provides evidence that PACAP acts upstream of the melanocortin system in regulating sympathetic nerve activity to brown adipose tissue in mice. Abstract Impaired adipose tissue function in obesity, including reduced thermogenic potential, has detrimental consequences for metabolic health. Hormonal regulation of adaptive thermogenesis is being explored as a potential therapeutic target for human obesity. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide expressed in nuclei of the hypothalamus known to regulate energy expenditure, and functional studies reveal a role for PACAP in the central regulation of thermogenesis, although mechanisms are not well understood. We hypothesized that PACAP acts upstream of the melanocortin system to regulate sympathetic nerve activity to stimulate thermogenesis. To assess this, female PACAP-/- and PACAP+/+ mice were given daily peripheral injections of a melanocortin receptor agonist, melanotan II (MTII), for 3 weeks during cold acclimation, and the effect of MTII on thermogenic capacity and adipose tissue remodelling was examined by physiological and histological analyses. MTII partially rescued the impaired thermogenic capacity in PACAP-/- mice as compared to PACAP+/+ mice as determined by measuring noradrenaline-induced metabolic rate. In addition, MTII treatment during cold acclimation corrected the previously identified deficit in lipid utilization in response to adrenergic stimulation in PACAP-/- null mice, suggesting impaired lipid mobilization may contribute to the impaired thermogenic capacity of PACAP-/- mice. Results presented here provide physiological evidence to suggest that PACAP acts upstream of melanocortin receptors to facilitate sympathetically induced mechanisms of adaptive thermogenesis in response to cold acclimation.

Purpose: Tumor treating fields (TTFields) is a novel antimitotic treatment that was first proven effective for glioblastoma multiforme, now with trials for several extracranial indications underway. Several studies focused on concurrent TTFields therapy with radiation in the same time period, but were not given simultaneously. This study evaluates the targeting accuracy of simultaneous radiation therapy while TTFields arrays are in place and powered on, ensuring that radiation does not interfere with TTFields and TTFields does not interfere with radiation. This is one of several options to enable TTFields to begin several weeks sooner, and opens potential for synergistic effects of combined therapy. Methods: TTFields arrays were attached to a warm saline water bath and salt was added until the TTFields generator reached the maximal 2000 mA peak-to-peak current. A ball cube phantom containing 2 orthogonal films surrounded by fiducials was placed in the water phantom, CT scanned, and a radiation treatment plan with 58 isocentric beams was created using a 3 cm circular collimator. Fiducial tracking was used to deliver radiation, the films were scanned, and end-to-end targeting error was measured with vendor-supplied software. In addition, radiation effects on electric fields generated by the TTFields system were assessed by examining logfiles generated from the field generator. Results: With TTFields arrays in place and powered on, the robotic radiosurgery system achieved a final targeting result of 0.47 mm, which was well within the submillimeter specification. No discernible effects on TTFields current output beyond 0.3% were observed in the logfiles when the radiation beam pulsed on and off. Conclusion: A robotic radiosurgery system was used to verify that radiation targeting was not adversely affected when the TTFields arrays were in place and the TTFields delivery device was powered on. In addition, this study verified that radiation delivered simultaneously with TTFields did not interfere with the generation of the electric fields.

INTRODUCTION: The Federal Aviation Administration Office of Aerospace Medicine (AAM) is required by law to identify pilots who have driving under the influence (DUI) convictions. It is the responsibility of AAM to determine, based on the DUI, if the pilot has a drinking problem and needs follow-up treatment. Pilots with alcohol problems are at risk to themselves and the public and need to have treatment to reduce the extent of the risk. It has been suggested by some that a blood alcohol concentration (BAC) of 0.15 g · dL-1 is evidence of tolerance and the pilot should be placed in an alcohol treatment program.METHOD: The National Institute on Alcohol Abuse and Alcoholism (NIAAA) Clinician's Guide considers a person at risk for a drinking problem when a man drinks 5 or more drinks or a woman drinks 4 or more drinks in a day and reaches a 0.08 g · dL-1 of ethanol in the blood. It is possible to estimate from a BAC or breath alcohol concentration (BrAC) the number of drinks consumed using the volume of distribution for ethanol and the weight of the individual. A spread sheet tool was developed to estimate the number of drinks consumed.RESULTS: It was determined that DUI/DWI concentrations could be used to determine the minimum number of drinks consumed. Overweight people reach binge drinking levels and higher Hingson levels at lower DUI/DWI concentrations than people with an average weight or lower.DISCUSSION: Using this tool there is a high probability (99.7%) of identifying a true binge drinker.Canfield DV, Forster EM, Cheong Z-I, Cowan JM. Breath/blood alcohol concentration as an indicator of alcohol use problems. Aerosp Med Hum Perform. 2019; 90(5):488-491.

Background: Cancer patients are at increased risk of developing severe COVID-19 disease. Possible side effects of systemic therapy and the lack of clinical data on safety and efficacy of COVID-19 vaccination in cancer patients cause uncertainty regarding the vaccination. Here, we evaluated attitude towards and effects of COVID-19 vaccination in patients with breast or gynecological cancer. The aim was to improve counseling of our patients in clinical routine. Methods: Since March 15th 2021, patients who received one of the approved COVID-19 vaccines were routinely interviewed about immediate (0-2 days) and late side effects (within two weeks after vaccination). Clinical parameters such as current therapy, time interval between therapy administration and vaccination, and changes in the therapy schedule due to the vaccination were documented. Furthermore, the willingness of non-vaccinated patients to be vaccinated was assessed. The collected data were anonymously analyzed as a part of routine quality assurance. Results: By May 10th 2021, 111 out of 217 (51.1%) interviewed patients had received at least one shot of COVID-19 vaccine and 21 patients both shots. More than half of the vaccinated patients were >55y (60.2%;mean: 60.7y, range 30-92y);69% with UICC/ FIGO stage III/IV cancer. 74.6% received Conmirnaty (BioNTech/ Pfizer), 18.9% Vaxzevria (AstraZeneca) and 6.5% Covid-19 Vaccine Moderna. After the first shot, 33.3% of the patients described no side effects, 49.1% reported a local reaction (swelling or pain), 23.4% flu-like symptoms, 10.8% headache and 3.6% nausea. 11 patients had symptoms that lasted longer than two days. In 11 cases, COVID-19 vaccination had an impact on delivery of the systemic therapy (n=10 postponements of therapy and n=1 dose reduction). 61.3% of the non-vaccinated patients (in total n=118) were already registered to get vaccinated;32.8% chose to postpone vaccination for personal reasons;5% refused vaccination. Conclusions: Breast and gynecological cancer patients appear to tolerate COVID-19 vaccination well under systemic therapy and only in few cases the vaccination interfered with the treatment schedule. Updated results will be presented at the ESMO Congress. Legal entity responsible for the study: LMU University Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

ObjectiveTo determine the long-term normal tissue complication probability with stereotactic body radiation therapy (SBRT) treatments for targets that move with respiration and its relation with the type of respiratory motion management (tracking vs. compression or gating).MethodsA PubMed search was performed for identifying literature regarding dose, volume, fractionation, and toxicity (grade 3 or higher) for SBRT treatments for tumors which move with respiration. From the identified papers logistic or probit dose-response models were fitted to the data using the maximum-likelihood technique and confidence intervals were based on the profile-likelihood method in the dose-volume histogram (DVH) Evaluator.ResultsPooled logistic and probit models for grade 3 or higher toxicity for aorta, chest wall, duodenum, and small bowel suggest a significant difference when live motion tracking was used for targeting tumors with move with respiration which was on the average 10 times lower, in the high dose range.ConclusionLive respiratory motion management appears to have a better toxicity outcome when treating targets which move with respiration with very steep peripheral dose gradients. This analysis is however limited by sparsity of rigorous data due to poor reporting in the literature.

BACKGROUND: FSGS is a heterogeneic glomerular disease. Risk factors for kidney disease ESKD and the effect of immunosuppression treatment (IST) has varied in previously published cohorts. These cohorts were limited by relatively small case numbers, short follow-up, lack of racial/ethnic diversity, a mix of adult and pediatric patients, lack of renin-angiotensin-aldosterone system (RAAS) inhibition, or lack of subgroup analysis of IST. METHODS: We compared demographics, clinical characteristics, histopathology, and IST to long-term renal survival in a large, ethnically diverse, adult cohort of 338 patients with biopsy-proven FSGS with long-term follow-up in the era of RAAS inhibition using data from the US Department of Defense health care network. RESULTS: Multivariate analysis showed that nephrotic-range proteinuria (NRP), eGFR

Background Non-renal extravasation of phosphate from the circulation and transient accumulation into tissues and extracellular fluid is a regulated process of acute phosphate homeostasis that is not well understood. Following oral consumption of phosphate, circulating levels normalize long before urinary excretion has been completed. This process is particularly critical in the setting of chronic kidney disease (CKD), where phosphate exposure is prolonged due to inefficient kidney excretion. Furthermore, CKD-associated dysregulation of mineral metabolism exacerbates pathological accumulation of phosphate causing vascular calcification (VC). In the present study, the objective was to determine whether the processes involved in the development and progression of VC are also normally involved in the systemic acute response to oral phosphate. Methods Acute circulating and physiological phosphate movement and tissue deposition was assessed in two experimental rat models of VC using radio-labelled phosphate challenge. In an adenine-induced model of CKD, VC was induced with high dietary phosphate. Animals were euthanized 2 and 6 hours after oral consumption of radiolabelled phosphate. A non-CKD model of VC was induced with 0.5ug/kg calcitriol and then withdrawn, and radiolabelled phosphate was then given to assess for vascular preference for phosphate uptake with and without the presence of an active calcification stimulus. Samples of 50 different tissues were collected to assess tissue accumulation of de novo phosphate in response the challenges. Results Animals with CKD and VC have a blunted elevation of circulating 33PO4 following oral phosphate administration and the discordant deposition can be traced to the calcifying vasculature. Deposition of de novo phosphate is present until at least 6 hours, which after active gut absorption. The accrual is stimulated by a phosphate challenge, and not present in the same degree during passive disposition of circulating phosphate. The extent of new transport to the calcifying vasculature correlates to the pre-existing burden of calcification, and can be substantially attenuated by removing the stimulus for calcification. Conclusions Our data indicate that calcifying arteries alter the systemic disposition of a phosphate challenge and acutely deposit substantial phosphate. This study supports the importance of diet as it relates to acute fluctuations of circulating phosphate and the importance of bioavailability and meal-to-meal management in CKD patients as a mediator of cardiovascular risk.

Background: The Wnt/β-catenin pathway has been implicated in the development of adynamic bone disease in early-stage chronic kidney disease (CKD). Dickkopf-related protein 1 (DKK1) and sclerostin are antagonists of the Wnt/β-catenin pathway yet have not been widely used as clinical indicators of bone disease. This study characterized levels of DKK1, sclerostin, and other biomarkers of mineral metabolism in participants across a spectrum of inulin-measured glomerular filtration rate (GFR). Methods: GFR was measured by urinary inulin clearance (mGFR) in 90 participants. Blood samples were obtained for measurement of circulating DKK1, sclerostin, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphate, α-klotho, and vitamin D metabolites including 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3. Spearman correlations and linear regressions were used where appropriate to examine the associations between measured values. Results: The median [IQR] age was 64 years [53.0–71.0], and the median [IQR] mGFR was 32.6 [21.7–60.6] mL/min. DKK1 decreased (r = 0.6, p < 0.001) and sclerostin increased (r = −0.4, p < 0.001) as kidney function declined, and both were associated with phosphate, PTH, FGF-23, and 1,25-dihydroxyvitamin D3 in the unadjusted analysis. After adjustment for age and mGFR, DKK1 remained significantly associated with PTH. Conclusion: The results of this study demonstrate opposing trends in Wnt/β-catenin pathway inhibitors, DKK1 and sclerostin, as mGFR declines. Unlike sclerostin, DKK1 levels decreased significantly as mGFR declined and was independently associated with PTH. Future studies should determine whether measurement of Wnt signaling inhibitors may be useful in predicting bone histomorphometric findings and important clinical outcomes in patients with CKD.

The South American social spider Parawixia bistriata produces a venom containing complex organic compounds with intriguing biological activities. The crude venom leads to paralysis in termites and stimulates l-glutamate uptake and inhibits GABA uptake in rat brain synaptosomes. Glutamate is the major neurotransmitter at the insect neuromuscular junction and at the mammalian central nervous system, suggesting a modulation of the glutamatergic system by the venom. Parawixin1, 2, and 10 (Pwx1, 2 and 10) are HPLC fractions that demonstrate this bioactivity. Pwx1 stimulates l-glutamate uptake through the main transporter in the brain, EAAT2, and is neuroprotective in in vivo glaucoma models. Pxw2 inhibits GABA and glycine uptake in synaptosomes and inhibits seizures and neurodegeneration, and Pwx10 increases l-glutamate uptake in synaptosomes and is neuroprotective and anticonvulsant, shown in in vivo epilepsy models. Herein, we investigated the low molecular mass compounds in this venom and have found over 20 small compounds and 36 unique acylpolyamines with and without amino acid linkers. The active substances in fractions Pwx1 and Pwx2 require further investigation. We elucidated and confirmed the structure of the active acylpolyamine in Pwx10. Both fraction Pwx10 and the synthesized component enhance the activity of transporters EAAT1 and EAAT2, and, importantly, offer in vitro neuroprotection against excitotoxicity in primary cultures. These data suggest that compounds with this mechanism could be developed into therapies for disorders in which l-glutamate excitotoxicity is involved.

Pituitary Adenylate Cyclase Activating Polypetptide (PACAP) is a peptide hormone known to regulate energy homeostasis1. Mice lacking PACAP are cold sensitive and have impaired adrenergic-induced thermogenesis2-4. Interestingly, Pacap null mice can survive cold housing if acclimated slowly, similar to what was observed in UCP1 deficient mice4,5. We hypothesized that Pacap-/- mice employ alternate thermogenic pathways to compensate for impaired adaptive thermogenesis and assessed shivering thermogenesis and UCP1-dependent and UCP1-independent adaptive thermogenesis in male and female Pacap-/- and Pacap+/+ with cold acclimation (4°C). Assessment of oxidative fibres in skeletal muscles and behavioural observations did not show evidence of prolonged shivering in male or female Pacap-/- mice during cold acclimation compared to Pacap+/+ mice. We did however observe morphological and molecular differences in adipose tissues of Pacap-/- mice compared to Pacap+/+ mice that were distinct in males and females. Cold-acclimated, female Pacap-/- mice had decreased induction of UCP1 protein in intrascapular brown fat (iBAT), yet had a significantly higher beiging and UCP1 immunoreactivity (ir) in gonadal white fat (gWAT) compared to female Pacap+/+ mice. Furthermore, beiging was observed in inguinal white fat (ingWAT) and gWAT of female Pacap-/- mice housed at thermoneutrality (30°C), a finding not observed in Pacap+/+ control mice. Unlike female mice, we did not observe impaired UCP1 induction in iBAT of male Pacap-/- mice compared to Pacap+/+ mice, and this was associated with negligible UCP1-ir in male gWAT similar to wildtype controls. Despite previous work that has established impaired adaptive thermogenesis in Pacap-/- mice4, we show here that UCP1 protein can be induced in adipose tissues of Pacap-/- mice during cold acclimation, although to a lesser degree or in a different pattern compared to Pacap+/+ control mice. Taken together, this work suggests that while PACAP is clearly involved in regulating thermoregulation, it is not required for cold-induced UCP1 expression. In addition, this work highlights sexual dimorphism in adipose tissue remodeling and induction of thermogenesis with cold acclimation. References: (1) Rudecki AP, et al. Trends Endocrinol Metab. 2016;27(9), 620–632. (2) Gray SL, et al. J Mol Endocrinol. 2001;15(10), 1739–1747. (3) Gray SL, et al. J Endocrinol. 2002;143(10), 3946–3954. (4) Diané A, et al. J Endocrinol. 2014;222, 327–339. (5) Golozoubova V, et al. FASEB J. 2001;15, 2048–2050.

The aim of this study was to compare fecal microbiome, plasma, fecal and urine metabolomes, and serum biochemistry of adult companion dogs according to body condition scores. Blood, serum/plasma, urine, and fecal samples were collected from 66 clinically healthy, adult companion dogs of either normal weight (NW), overweight (OW), or obese dogs (OB). analyses included fecal microbiome analyses via 16S ribosomal RNA gene amplicon; sequencing, nontargeted plasma, fecal, and urine metabolomics using liquid chromatography/gas chromatography-mass; spectrometry, and serum biochemistry for each dog. Few significant differences in serum biochemistry and fecal microbiome Operational Taxonomic Unit (OTU) were found between weight groups and there was high OTU variation between individual dogs. NW dogs had higher relative abundance of the genus Eubacterium (log-fold change 4.3, adjusted P value = .003) and lower relative abundance of the family Bifidobacteriaceae (log-fold change −3.6, adjusted P value = .02) compared to OB dogs. The microbiome of NW dogs had higher OTU richness compared with OB dogs. Metabolome analysis showed 185 plasma, 37 fecal, and 45 urine metabolites that significantly differed between NW and OW or OB dogs. There were notable significant differences in relative abundance of several plasma phospholipid moieties and fecal volatile fatty acids between weight phenotypes. The combinations of host and gut microbiota and metabolic shifts suggest a pattern that could help detection of early metabolic changes in overweight dogs before the development of obesity related disease. The results of this study support the need for continued investigation into sensitive measures of metabolic aberrancies in overweight dogs.

Obesity arises from disrupted energy balance and is caused by chronically higher energy intake compared to expenditure via basal metabolic rate, exercise, and thermogenesis. The brown adipose tissue (BAT), the primary thermogenic organ, has received considerable attention as a potential therapeutic target due to its ability to burn lipids in the production of heat. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been identified as a key regulator of the physiological stress response both centrally and peripherally. While PACAP has been shown to increase thermogenesis by acting at the hypothalamus to increase sympathetic output to BAT, a peripheral role for PACAP-activated thermogenesis has not been studied. We identified PACAP receptor (PAC1, VPAC1/2) expression for the first time in murine BAT and confirmed their expression in white adipose tissues. PAC1 receptor expression was significantly altered in all three adipose tissues studied in response to 3.5-week cold acclimation, with expression patterns differing by depot type. In primary cell culture, VPAC1 was increased in differentiated compared to non-differentiated brown adipocytes, and the same trend was observed for the PACAP-specific receptor PAC1 in gonadal white fat primary cultures. The primary PAC1R mRNA splice variant in interscapular BAT was determined as isoform 2 by RNA-Seq. These results show that PACAP receptors are present in adipose tissues and may have important functional roles in adipocyte differentiation, lipid metabolism, or adipose sensitization to sympathetic signaling in response to thermogenic stimuli.

Introduction: This study compared beta-blockers reported by pilots with the medications found by postmortem toxicology analysis of specimens received from fatal aviation accidents between 1999 and 2015. Several studies have compared drugs using the standard approach: Compare the drug found by toxicology analysis with the drug reported by the pilot. This study uniquely examined first the pilot-reported medication and then compared it to that detected by toxicology analysis. This study will serve two purposes: (1) determine the capability of a toxicology laboratory to detect reported medications, and (2) identify pilots with medications below detectable limits. Method: All information required for this study was extracted from the Toxicology Data Base system and was searched using ToxFlo or SQL Server Management Studio. The following information was collected and analyzed: pilot-reported trade and/or generic drug, date specimens received, time of accident, type of aviation operations (CFR), state, pilot level, age, class of medical, specimen type, specimen concentration, dose reported, frequency reported associated with the accident, quantity reported, National Transportation Safety Board (NTSB) accident event number, and all NTSB reports. Results: There were 319 pilots that either reported taking a beta-blocker or were found to be taking a beta-blocker by postmortem toxicology analysis. Metoprolol and Atenolol were the most commonly found beta-blockers (81%) in this study. Discussion: Time of death, therapeutic concentration, and specimen type were found to be factors in the ability of the laboratory to detect beta-blockers. Dose did not correlate with the ability of the toxicology laboratory to detect the beta-blocker. Conclusions: Beta-blockers taken by pilots will, in most cases, be found by a competent postmortem forensic toxicology laboratory at therapeutic concentrations. The dose taken by the pilot was not found to be a factor in the ability of the laboratory to identify beta-blockers. Time of dose, route of administration, specimen tested, and therapeutic concentration of the drug were found to be factors in the ability of the laboratory to identify beta-blockers in postmortem specimens taken from pilots that died in aviation accidents.

Background Academic health centers are facing a potential reduction in Medicare financing for graduate medical education (GME). Both the Medicare Payment Advisory Commission and the National Commission on Fiscal Responsibility and Reform (Deficit Commission) have suggested cutting approximately half the funding that teaching hospitals receive for indirect medical education. Because of the effort that goes into teaching trainees, who are only transient employees, hospital executives often see teaching programs as a drain on resources. Objective In light of the possibility of a Medicare cut to GME programs, we undertook an analysis to assess the financial risk of training programs to our institution and the possibility of saving money by reducing resident positions. Methods The chief administrative officer, in collaboration with the hospital chief financial officer, performed a financial analysis to examine the possibility of decreasing costs by reducing residency programs at the University of Massachusetts Memorial Medical Center. Results Despite the real costs of our training programs, the analysis demonstrated that GME programs have a positive impact on hospital finances. Conclusions Reducing or eliminating GME programs would have a negative impact on our hospital's bottom line.

Background and Purpose A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu2/3) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu2/3 receptor agonist prodrug were investigated. Experimental Approach After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent and subtype-selective mGlu2/3 receptor agonist LY2934747. Behavioural assessments of allodynia, hyperalgesia and nocifensive behaviours were determined in preclinical pain models after administration of LY2969822 0.3–10 mg·kg−1. In addition, the ability of i.v. LY2934747 to modulate dorsal horn spinal cord wide dynamic range (WDR) neurons in spinal nerve ligated (SNL) rats was assessed. Key Results Following treatment with LY2934747, the spontaneous activity and electrically-evoked wind-up of WDR neurons in rats that had undergone spinal nerve ligation and developed mechanical allodynia were suppressed. In a model of sensitization, orally administered LY2969822 prevented the nociceptive behaviours induced by an intraplantar injection of formalin. The on-target nature of this effect was confirmed by blockade with an mGlu2/3 receptor antagonist. LY2969822 prevented capsaicin-induced tactile hypersensitivity, reversed the SNL-induced tactile hypersensitivity and reversed complete Freund's adjuvant – induced mechanical hyperalgesia. The mGlu2/3 receptor agonist prodrug demonstrated efficacy in visceral pain models, including a colorectal distension model and partially prevented the nocifensive behaviours in the mouse acetic acid writhing model. Conclusions and implications Following oral administration of the prodrug LY2969822, the mGlu2/3 receptor agonist LY2934747 was formed and this attenuated pain behaviours across a broad range of preclinical pain models.

PURPOSE RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non–small-cell lung cancer (NSCLC). METHODS The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). RESULTS Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively ( P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months ( P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% ( P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. CONCLUSION A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.

Global warming due to greenhouse gases and atmospheric aerosols alter precipitation rates, but the influence on extreme precipitation by aerosols relative to greenhouse gases is still not well known. Here we use the simulations from the Precipitation Driver and Response Model Intercomparison Project that enable us to compare changes in mean and extreme precipitation due to greenhouse gases with those due to black carbon and sulfate aerosols, using indicators for dry extremes as well as for moderate and very extreme precipitation. Generally, we find that the more extreme a precipitation event is, the more pronounced is its response relative to global mean surface temperature change, both for aerosol and greenhouse gas changes. Black carbon (BC) stands out with distinct behavior and large differences between individual models. Dry days become more frequent with BC-induced warming compared to greenhouse gases, but so does the intensity and frequency of extreme precipitation. An increase in sulfate aerosols cools the surface and thereby the atmosphere, and thus induces a reduction in precipitation with a stronger effect on extreme than on mean precipitation. A better understanding and representation of these processes in models will provide knowledge for developing strategies for both climate change and air pollution mitigation. Black carbon and sulfate aerosols have conflicting effects on global extreme dry and precipitation events. An international team of researchers led by Jana Sillmann at the Center for International Climate Research, Oslo use model simulations to examine the effect of sulfate aerosols and black carbon compared to greenhouse gases on global mean precipitation and extreme precipitation events. Sulfate aerosols, which cool the Earth’s surface, decrease mean precipitation and in particular strongly reduce extreme precipitation events. Conversely, black carbon, which warms the Earth’s surface, may increase the intensity and frequency of extreme precipitation events, but also reduces mean precipitation leading to more extreme dry drought-like conditions. This demonstrates the need to incorporate aerosols into future climate modeling effects on global precipitation trends.

The Arctic is experiencing rapid climate change in response to changes in greenhouse gases, aerosols, and other climate drivers. Emission changes in general, as well as geographical shifts in emissions and transport pathways of short-lived climate forcers, make it necessary to understand the influence of each climate driver on the Arctic. In the Precipitation Driver Response Model Intercomparison Project, 10 global climate models perturbed five different climate drivers separately (CO2, CH4, the solar constant, black carbon, and SO4). We show that the annual mean Arctic amplification (defined as the ratio between Arctic and the global mean temperature change) at the surface is similar between climate drivers, ranging from 1.9 (± an intermodel standard deviation of 0.4) for the solar to 2.3 (±0.6) for the SO4 perturbations, with minimum amplification in the summer for all drivers. The vertical and seasonal temperature response patterns indicate that the Arctic is warmed through similar mechanisms for all climate drivers except black carbon. For all drivers, the precipitation change per degree global temperature change is positive in the Arctic, with a seasonality following that of the Arctic amplification. We find indications that SO4 perturbations produce a slightly stronger precipitation response than the other drivers, particularly compared to CO2. ©2019. The Authors.

Aims To provide an overview of cataract data in Suriname and to describe and evaluate a programme to control cataract blindness in a developing country. Design Evaluation of hospital data and findings from a population-based cross-sectional survey. Methods The implementation of a new cataract surgical intervention programme was described and retrospectively evaluated by analysing the number of cataract operations and other related indicators at the Suriname Eye Centre (SEC) in the period 2006-2014. Findings of the recent Rapid Assessment of Avoidable Blindness (2013-2014) survey were used to evaluate the national cataract situation in Suriname in people aged ≥50 years (n=2998), including prevalence of cataract blindness, outcome and cataract surgical rate (CSR). Results Since the implementation of a new cataract intervention programme, the number of cataract operations at the SEC has increased from 1150 in 2006 to 4538 in 2014, leading to an estimated national CSR of 9103 per one million inhabitants. The prevalence of bilateral cataract blindness in Suriname was 0.8% (95% CI 0.2% to 1.3%) in individuals aged ≥50 years. The proportion of eyes with a postoperative visual acuity 5%.

Background/Aims Population-based surveys on diabetes and diabetic retinopathy (DR) are necessary to increase awareness and develop screening and therapeutic programmes. The aim was to estimate the prevalence of DR in older adults of different ethnic backgrounds in Suriname. Methods Fifty clusters of 60 people aged ≥50 years were randomly selected with a probability proportional to the size of the population unit. Eligible people were randomly selected through compact segment sampling and examined using the Rapid Assessment of Avoidable Blindness plus Diabetic Retinopathy (RAAB + DR) protocol. Participants were classified as having diabetes if they: were previously diagnosed with diabetes; were receiving treatment for glucose control; had a random blood glucose level >200 mg/dL. These participants were dilated for funduscopy, assessed for DR following the Scottish DR grading protocol and evaluated for ethnicity and DR ophthalmic screening frequencies. Results A total of 2806 individuals was examined (response 93.6%). The prevalence of diabetes was 24.6%. In these patients any type of DR and/or maculopathy occurred in 21.6% and sight-threatening DR in 8.0%. Of the known diabetics, 34.2% never had an eye examination for DR and in 13.0% the last examination was >24 months ago. The prevalence of diabetes was significantly higher in Hindustani people compared with other major ethnic groups. Conclusions The prevalence of diabetes and diabetics without regular DR control in people aged ≥50 years in Suriname was higher than expected. The uptake for special services for DR has to be expanded to decrease patient delay and DR-induced blindness.

Background Emergency Department (ED) boarding threatens patient safety. It is unclear whether boarding differentially affects patients admitted to intensive care units (ICUs) versus non-ICU settings. Research design and subjects We performed a 2-hospital, 18-month, cross-sectional, observational, descriptive study of adult patients admitted from the ED. We used Kaplan-Meier estimation and Cox Proportional Hazards regression to describe differences in boarding time among patients who died during hospitalization versus those who survived, controlling for covariates that could affect mortality risk or boarding exposure, and separately evaluating patients admitted to ICUs versus non-ICU settings. Measures We extracted age, race, sex, time variables, admission unit, hospital disposition, and Elixhauser comorbidity measures and calculated boarding time for each admitted patient. Results Among 39,781 admissions from the EDs (21.3% to ICUs), non-ICU patients who died in-hospital had a 1.2-fold risk (95% confidence interval, 1.03-1.36; P=0.016) of having experienced longer boarding times than survivors, accounting for covariates. We did not observe a difference among patients admitted to ICUs. Conclusions Among non-ICU patients, those who died during hospitalization were more likely to have had incrementally longer boarding exposure than those who survived. This difference was not observed for ICU patients. Boarding risk mitigation strategies focused on ICU patients may have accounted for this difference, but we caution against interpreting that boarding can be safe. Segmentation by patients admitted to ICU versus non-ICU settings in boarding research may be valuable in ensuring that the safety of both groups is considered in hospital flow and boarding care improvements.

We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer.In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949.Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p0.0001).74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients.National Cancer Institute and Bristol-Myers Squibb.

Purpose To examine choroidal thickness in open-angle glaucoma. Methods The hospital-based case series study included a study group with patients with open-angle glaucoma and a control group. Choroidal thickness was measured by enhanced depth imaging by spectral domain optical coherence tomography. Results The study group included 39 patients (71 eyes) and the control group consisted of 189 patients (228 eyes) with no significant difference between both groups in age (P=0.16) and refractive error (P=0.07). Choroidal thickness in the foveal region (P=0.18), at a distance of 1000 μm from the fovea (P=0.39), 2000 μm from the fovea (P=0.46), and 2500 μm from the fovea (P=0.53) did not vary significantly between both groups. In multivariable analysis with adjustment for age and refractive error, choroidal thickness at the fovea [P=0.12; regression coefficient B: minus-8.60; 95% confidence interval (CI): -19.3, 2.1], at a horizontal distance of 1000 μm from the fovea (P=0.30; regression coefficient B: -4.98; 95% CI: -14.3, 4.4), 2000 μm from the fovea (P=0.20; regression coefficient B: -20.9; 95% CI: -53.2, 11.3), and 2500 μm from the fovea (P=0.45; regression coefficient B: -2.70; 95% CI: -9.67, 4.27) was not significantly associated with the diagnosis of glaucoma. In binary regression analysis with adjustment for age and refractive error, presence of glaucoma was significantly associated neither with subfoveal choroidal thickness [P=0.12; odds ratio (OR): 0.997; 95% CI: 0.993, 1.001] nor with choroidal thickness at a horizontal distance of 1000 μm from the fovea (P=0.47; OR: 0.998; 95% CI: 0.993, 1.002), 2000 μm from the fovea (P=0.23; OR: 0.997; 95% CI: 0.993, 1.002), or 2500 μm from the fovea (P=0.46; OR: 0.998; 95% CI: 0.992, 1.004). Conclusions After adjusting for age and refractive error, open-angle glaucoma was not significantly associated with a marked thinning or a thickening of the choroid in the foveal and parafoveal region.

The first clinically observable sign of an unconsciousness episode (UNCE) serves as the temporal sequence (kinetics) onset point for neurological events occurring during the loss of consciousness, unconsciousness and recovery of consciousness phases of the UNCE. The initial neurologic signs of 212 individuals exposed to gradual (N=114) and rapid (N=98) onset +Gz acceleration stress, inducing the ischemic LOC phase in 83.3±18.6s and 8.89±1.52s; p0.001 respectively, were determined. The duration of the unconscious phase (considered absolute incapacitation) was 10.42±5.3s and 9.36±3.99s; p0.1 for gradual and rapid onset +Gz-stress, respectively. Cerebral autoregulation may play a role in determination of ischemic UNCE induction and recovery. Five signs: loss of muscle control, eyelid closure, eye fixation, upward eye deviation, and muscular twitching occurred at LOC phase onset. The most frequent initial sign of LOC phase onset was loss of muscle control (84% of the episodes), followed by eye fixation (8.5%), and upward eye deviation (6.1%). Signs play a key role in differential diagnosis of syncopal, epileptic, psychogenic and other causes of UNCEs. Sign kinetics may provide insight into localization of the essential components and networks within the cephalic nervous system associated with UNCEs.

Merrillite [Ca9NaMg(PO4)7] occurs as a dominant primary Ca-phosphate mineral in martian meteorites and therefore presumably also on Mars. The mineral is an important phase in exploring differences in geologic processes between Earth and Mars, and also has astrobiological implications due to its potential role as a significant source of the bio-essential nutrient phosphate. Merrillite does not occur terrestrially as a discrete mineral phase, making it difficult to obtain for Mars-relevant studies. It can, however, be synthesized from a similar terrestrial mineral, whitlockite (natural or synthetic), through dehydrogenation. Here we present methods for synthesizing relatively large quantities (0.5 g or greater per batch) of coarse crystalline (75 μm+) Mg-whitlockite, Fe-whitlockite, mixed Fe/Mg-whitlockites, and from these synthesized minerals produce Mg-merrillite, ferrous and ferric Fe-merrillite, and ferrous and ferric mixed Fe/Mg-merrillite. Chemistry and atomic structures of synthesized Fe- and mixed Fe/Mg-whitlockite and ferrous and ferric Fe- and mixed Fe/Mg- merrillite resulting from single-crystal X-ray diffraction, infrared spectroscopy, and electron microprobe analyses are presented. We also present a mechanism for maintaining charge balance during the formation of merrillite from whitlockite. Our results shed light on these mineral structures for future martian studies, and provide methods for creating coarse crystalline merrillite for use in Mars-relevant thermodynamic, kinetic, soil/dust simulant, crystallographic, astrobiological, and other studies.

Pollinators are known to exert natural selection on floral traits, but the extent to which combinations of floral traits are subject to correlational selection (nonadditive effects of two traits on fitness) is not well understood. Over two years, we used phenotypic manipulations of plant traits to test for effects of flower colour, flower shape and their interaction on rates of pollinator visitation to Polemonium foliosissimum. We also tested for correlational selection based on weighting visitation by the amount of conspecific pollen delivered per visit by each category of insect visitor. Although bumblebees were the presumed pollinators, solitary bees and flies contributed substantially (42%) to pollination. In manipulations of one trait at a time, insects visited flowers presenting the natural colour and shape over flowers manipulated to present artificial mutants with either paler colour or a more open or more tubular flower. When both colour and shape were manipulated in combination, selection on both traits arose, with bumblebees responding mainly to colour and flies responding mainly to shape. Despite selection on both floral traits, in a year with many bumblebees, we saw no evidence for correlational selection of these traits. In a year when flies predominated, fly visitation showed a pattern of correlational selection, but not favouring the natural phenotype, and correlational selection was still not detected for expected pollen receipt. These results show that flower colour and shape are subject to pollinator-mediated selection and that correlational selection can be generated based on pollinator visitation alone, but provide no evidence for correlational selection specifically for the current phenotype.

Rice bran chemical profiles differ across rice varieties and have not yet been analysed for differential chemopreventive bioactivity. A diverse panel of seven rice bran varieties was analysed for growth inhibition of human colorectal cancer (CRC) cells. Inhibition varied from 0% to 99%, depending on the variety of bran used. Across varieties, total lipid content ranged 5-16%, individual fatty acids had 1.4- to 1.9-fold differences, vitamin E isoforms (α-, γ-, δ-tocotrienols, and tocopherols) showed 1.3- to 15.2-fold differences, and differences in γ-oryzanol and total phenolics ranged between 100-275ng/mg and 57-146ngGAE/mg, respectively. Spearman correlation analysis was used to identify bioactive compounds implicated in CRC cell growth inhibitory activity. Total phenolics and γ-tocotrienol were positively correlated with reduced CRC cell growth (p

Over the past few decades, the geographical distribution of emissions of substances that alter the atmospheric energy balance has changed due to economic growth and air pollution regulations. Here, we show the resulting changes to aerosol and ozone abundances and their radiative forcing using recently updated emission data for the period 1990–2015, as simulated by seven global atmospheric composition models. The models broadly reproduce large-scale changes in surface aerosol and ozone based on observations (e.g. −1 to −3 % yr−1 in aerosols over the USA and Europe). The global mean radiative forcing due to ozone and aerosol changes over the 1990–2015 period increased by +0.17 ± 0.08 W m−2, with approximately one-third due to ozone. This increase is more strongly positive than that reported in IPCC AR5. The main reasons for the increased positive radiative forcing of aerosols over this period are the substantial reduction of global mean SO2 emissions, which is stronger in the new emission inventory compared to that used in the IPCC analysis, and higher black carbon emissions.

In the present paper, we announce new draft genomes of four Leptospira interrogans strains named Acegua, RCA, Prea, and Capivara. These strains were isolated in the state of Rio Grande do Sul, Brazil, from cattle, dog, Brazilian guinea pig, and capybara, respectively.

Purpose In current clinical practice, single isotopes, such as 125 I or 103 Pd, are used as single sources in prostate seed implants. A mixture of two radionuclides in the seeds has been proposed for prostate cancer treatment. This study investigates a method for determining the prescription dose for these new seeds using the biological effective dose (BED). Methods Ten prostate cancer cases previously treated using single radionuclide seeds were selected for this study. The BED distribution for these cases was calculated. Plans using other radionuclides were then calculated based on this BED distribution. Prescription values could then be obtained for the calculated plans. The method was verified by calculating the prescription dose for 103 Pd and 125 I and comparing to clinical values. The method was then applied to a hybrid seed that consisted of a mixture of 125 I and 103 Pd radionuclides, which deliver equal dose to 1 cm from the source in water (50/50D@1 cm). A prescription BED value was also calculated. Results A prescription BED of 110 Gy was found to correlate to a prescription dose of 145, 120, and 137 Gy for 125 I, 103 Pd, and 50/50D@1 cm hybrid seeds, respectively. Conclusion The method introduced in this article allows one to calculate the prescription dose for new and novel sources in brachytherapy. The method was verified by calculating a prescription dose for 125 I and 103 Pd radionuclides that coincides with values used clinically.

Quantitative imaging using computed tomography, magnetic resonance imaging and positron emission tomography modalities will play an increasingly important role in the design of oncology trials addressing molecularly targeted, personalized therapies. The advent of molecularly targeted therapies, exemplified by antiangiogenic drugs, creates new complexities in the assessment of response. The Quantitative Imaging Network addresses the need for imaging modalities which can accurately and reproducibly measure not just change in tumor size but changes in relevant metabolic parameters, modulation of relevant signaling pathways, drug delivery to tumor and differentiation of apoptotic cell death from other changes in tumor volume. This article provides an overview of the applications of quantitative imaging to phase 0 through phase 3 oncology trials. We describe the use of a range of quantitative imaging modalities in specific tumor types including malignant gliomas, lung cancer, head and neck cancer, lymphoma, breast cancer, prostate cancer and sarcoma. In the concluding section, we discuss potential constraints on clinical trials using quantitative imaging, including complexity of trial conduct, impact on subject recruitment, incremental costs and institutional barriers. Strategies for overcoming these constraints are presented.

Optimization of permanent seed implant brachytherapy plans for treatment of prostate cancer should be based on biological effective dose (BED) distributions, since dose does not accurately represent biological effects between different types of sources. Currently, biological optimization for these plans is not feasible due to the amount of time necessary to calculate the BED distribution. This study provides a fast calculation method, based on the total dose, to calculate the BED distribution. Distributions of various numbers of hybrid seeds were used to calculate total dose distributions, as well as BED distributions. Hybrid seeds are a mixture of different isotopes (in this study 125I and 103Pd). Three ratios of hybrid seeds were investigated: 25/75, 50/50, and 75/25. The total dose and BED value from each voxel were coupled together to produce graphs of total dose vs. BED. Equations were then derived from these graphs. The study investigated four types of tissue: bladder, rectum, prostate, and other normal tissue. Equations were derived from the total dose – BED correspondence. Accuracy of conversion from total dose to BED was within 2 Gy; however, accuracy of conversion was found to be better for high total dose regions as compared to lower dose regions. The method introduced in this paper allows one to perform fast conversion of total dose to BED for brachytherapy using hybrid seeds, which makes the BED‐based plan optimization practical. The method defined here can be extended to other ratios, as well as other tissues that are affected by permanent seed implant brachytherapy (i.e., breast). PACS number: 87.55.de

In monoderm (single-membrane) Gram-positive bacteria, the majority of secreted proteins are first translocated across the cytoplasmic membrane into the inner wall zone. For a subset of these proteins, final destination is within the cell envelope as either membrane-anchored or cell wall-anchored proteins, whereas another subset of proteins is destined to be transported across the cell wall into the extracellular milieu. Although the cell wall is a porous structure, there is evidence that, for some proteins, transport is a regulated process. This review aims at describing what is known about the mechanisms that regulate the transport of proteins across the cell wall of monoderm Gram-positive bacteria.

Transgenic models of human disease can be used to understand pathology and to discover biomarkers of disease presence, progression and response to therapy. Here we report a study of longitudinal metabolic differences between TASTPM transgenic Alzheimer's disease (AD) mice and their wild type counterparts using (1)H magnetic resonance spectroscopy (MRS) to look for potential biomarkers for use in AD research and drug discovery. Chloroform methanol extractions were performed on the brains of mice aged between 3 and 18 months. (1)H MR spectra were recorded from the aqueous fractions. Absolute metabolite concentrations, determined from resonance integrals relative to an internal standard, were analysed by 2-way ANOVA (genotype x age). Significant effects of age alone were identified for creatine, glutamine and total choline-containing compounds. There was a marked increase in creatine in the oldest (15-18 mo) TASTPM mice. The increase in creatine was unexpected and may be caused by osmotic stress in older animals as plaque load increases. Care should be taken when using creatine as a reference metabolite during scans of these animals in vivo. A significant effect of genotype alone was identified for myo-inositol (MI), which was higher in TASTPM mice at all ages. Succinate, glycerophosphocholine and choline all showed significant effects of age and genotype. No significant effects were detected in N-acetylaspartate (NAA) levels. Increased MI could be a marker of gliosis or microglial activation in TASTPM mice, but the absence of an age dependence for MI levels means it may be a biomarker of disease, but not of disease progression. Decreased succinate is indicative of disrupted neuronal energy metabolism, an effect that has been seen in human AD.

Angst und mogliche Schmerzen spielen bei vielen Patienten im Vorausblick auf einen rhinochirurgischen Eingriff und im Kontext mit einer Nasentamponade eine grose Rolle. Dieser Sachverhalt wird in einer prospektiven Studie objektiviert. Prospektive, kontrollierte, randomisierte Studie mit Vergleich von 3 verschiedenen Nasentamponaden im Hinblick auf Angst und Schmerz. Die Patienten litten an einer polyposen chronischen Pansinusitis und wurden einer Pansinus-Operation unterzogen. Sie wurden taglich uber einen Zeitraum von 5 Tagen mit standardisierten Fragebogen (u. a. FPI-R, KASA, STAI) untersucht, erganzt durch Vorlage visuell-analoger Skalen. Die Tamponaden wurden am 2. postoperativen Tag entfernt. Es konnten die Daten von 73 Patienten ausgewertet werden (Polyvinyl-acetat-Tamponade N=14; Fingerling-Tamponade N=37, Fingerling-Tamponade mit Atemhilfsrohrchen N=22). Weibliches Geschlecht, eine grundsatzlich eingeschrankte Stimmungslage, fehlende praoperative Schmerzen sowie ein erweiterter Informations-Austausch mit Laien vor dem Eingriff waren mit einem hoheren praoperativen Angstzustand verbunden. Patienten hatten signifikant weniger Angst, wenn eine Nasentamponade mit Atemhilfsrohrchen in Aussicht gestellt wurde. Ein hoheres Risiko fur vermehrte perioperative Angste haben Patientinnen, die sich Rat uber die bevorstehende Operation im Familien- oder Bekanntenkreis einholen oder Patientinnen mit praoperativ ungunstiger Gemutslage. Das Angebot auf eine zumindest teilweise erhaltene Nasenatmung nach dem Eingriff vermag diesen Zustand zu bessern.

During aviation accident investigations, vitreous fluid and urine samples from pilot fatalities are analyzed for glucose and blood for hemoglobin A(1c) (HbA(1c)) to monitor diabetic pilots and to discover other pilots with undiagnosed/unreported diabetes. The prevalence of elevated glucose concentrations in fatally injured pilots was evaluated by searching the Civil Aerospace Medical Institute's Toxicology Database for the period 1998-2005. Out of 1335 pilots involving 363 vitreous fluid, 365 urine, and 607 vitreous fluid and urine analyses, 43 pilots had elevated glucose in vitreous fluid (>125 mg/dL) and/or in urine (>100 mg/dL). Of the 20 pilots whose blood samples were analyzed, nine had >6% HbA(1c)-four were known diabetics, and five were unknown diabetics. Urinary glucose levels were elevated in all 13 known hyperglycemic pilots. A considerable number of pilots (30 of 43) had elevated glucose and HbA(1c) (5 of 20), suggesting undiagnosed/unreported diabetic conditions. Language: en

Currently, little is known about the influence of depressive symptoms and gender-specific aspects in rehabilitation outcome of patients with chronic low back pain. Effects of gender and depressive symptoms on rehabilitation outcome were examined immediately after rehabilitation, as well as three and six months after rehabilitation in 116 patients with chronic low back pain (43 women, 73 men; M=48 yrs.; ICD-10 diagnoses: M45.4/M45.5, M54.4/M54.5). Immediately after rehabilitation, general improvements with medium effect sizes in all rehabilitation measures were found. In contrast, six months after rehabilitation, only pain-related measures showed moderate improvements. Additionally, the mid-term outcomes were influenced by gender and depressive symptoms; women showed more stable rehabilitation outcomes in pain intensity, in the impaired function related to family/leisure, and the coping with pain strategies of "perceived self-competence" and "relaxation". In contrast, especially male patients with severe depressive symptoms revealed regressive rehabilitation outcomes, both in pain-related variables as well as marginally in the coping with pain strategy of "cognitive restructuring". In post-hoc analyses, in the mid-term, they even showed a deterioration of functional capacity and somatisation compared to prior to rehabilitation. Our results suggest that the outcome of orthopaedic rehabilitation may be persistently improved by implementing gender-specific treatments in general and elements of depression treatments for the patients with severe but sub-clinical depressive symptoms.

The present work investigated the potential of compensator‐based intensity‐modulated radiation therapy (CB‐IMRT) as an alternative to multileaf collimator (MLC)–based intensity‐modulated radiation therapy (IMRT) to treat malignant pleural mesothelioma (MPM) post extrapleural pneumonectomy. Treatment plans for 4 right‐sided and 1 left‐sided MPM post‐surgery cases were generated using a commercial treatment planning system, XIO/CMS (Computerized Medical Systems, St. Louis, MO). We used a 7‐gantry‐angle arrangement with 6 MV beams to generate these plans. The maximum required field size was 30×40 cm. We evaluated IMRT plans with brass compensators (•Decimal, Sanford, FL) by examining isodose distributions, dose–volume histograms, metrics to quantify conformal plan quality, and homogeneity. Quality assurance was performed for one of the compensator plans. Conformal dose distributions were achieved with CB‐IMRT for all 5 cases, the average planning target volume (PTV) coverage being 95.1% of the PTV volume receiving the full prescription dose. The average lung V20 (volume of lung receiving 20 Gy) was 1.8%, the mean lung dose was 6.7 Gy, and the average contralateral kidney V15 was 0.6%. The average liver dose V30 was 34.0% for the right‐sided cases and 10% for the left‐sided case. The average monitor units (MUs) per fraction were 980 MUs for the 45‐Gy prescriptions (mean: 50 Gy) and 1083 MUs for the 50‐Gy prescriptions (mean: 54 Gy). Post surgery, CB‐IMRT for MPM is a feasible IMRT technique for treatment with a single isocenter. Compensator plans achieved dose objectives and were safely delivered on a Siemens Oncor machine (Siemens Medical Solutions, Malvern, PA). These plans showed acceptably conformal dose distributions as confirmed by multiple measurement techniques. Not all linear accelerators can deliver large‐field MLC‐based IMRT, but most can deliver a maximum conformal field of 40×40 cm. It is possible and reasonable to deliver IMRT with compensators for fields this size with most conventional linear accelerators. PACS numbers: 87.56.ng, 87.56.N, 87.55.D, 87.55.dk

Dry beans are consumed around the world and contain a multitude of health benefits, some of which may be related to the gut microbiome. The objective of this study was to evaluate the effects of feeding a 25% cooked Navy Bean (NB) or Black Bean (BB) powder on the fecal microbiota of overweight and obese companion dogs undergoing calorically restricted weight loss, compared to dogs fed an iso-nutrient control diet using 454 pyrosequencing. A double-blinded, placebo-controlled, three-arm clinical trial was conducted. Thirty client-owned, clinically healthy, overweight or obese, adult, male and female dogs of diverse breeds were randomized to one of the three isocaloric, nutritionally complete weight loss diets containing either 0% bean powder (placebo-control); 25% cooked BB powder; or 25% cooked NB powder and calorically restricted to achieve weight loss of up to 2% body weight/wk. for 4 wks. Fresh fecal samples were collected from each dog immediately after completing the 4-wk diet intervention and weight loss phase. Fecal genomic DNA was extracted and used to create 16S rRNA gene amplicons, which were subjected to 454-pyrosequencing. Predominant bacterial phyla present in all dogs included Firmicutes, Fusobacteria, Actinobacteria, Proteobacteria, and Bacteroidetes. Predominant fecal bacterial genera included Clostridium, Blautia, Fusobacterium, and undefined Lachnospiraceae. Fecal undefined Ruminococcus were greater (P