Carbon Ion Fluxes at Mars: First Results of Tailward Flows From MAVEN-STATIC.

Characterizing C+ ions in the Martian ionosphere is important for understanding the history of the Martian atmosphere and surface due to its place in understanding carbon escape. Measuring minor ions, like C+, which are close in mass to major atmospheric ions, in this case O+, is difficult, requiring fitting algorithms and accurate background subtraction. Accurate measurement of these species is essential for understanding chemistry and transport in the ionosphere. In this paper, we use data from the Mars Atmospheric and Volatile EvolutioN SupraThermal And Thermal Ion Composition (MAVEN-STATIC) sensor to report the first C+ fluxes measured in the Martian magnetotail. We will describe a multistep method of background subtraction as well as fitting routines that are used to extract C+ fluxes from a 40-orbit subset of STATIC data. Our results show tailward fluxes in both optical shadow and the adjacent sunlit magnetotail at high altitudes ( > 3,000 km) and Mars-ward at low altitudes ( < 2,000 km) in shadow. These local flux values are similar to estimates of neutral carbon fluxes from photochemical escape. However, total carbon loss comparisons will require a more comprehensive study of integrated C+ loss over a larger data set from the Martian magnetotail.

Covid-19 Epidemic Impact on Clinical Training in Irish GP Training.

Aim To describe the effect of the Covid pandemic on the general practice workplace based learning of GP training in Ireland. Methods A prospective national survey of GP trainees who were in their GP practice placements on three separate occasions throughout the winter pandemic of 2020/2021 Results The average response rate to the three surveys was 19.4%. As the pandemic worsened, the number of face to face consultations dropped so that 51% (n=41) of trainees were seeing less than 5 patients face to face by the third survey. Conversely, the number of telephone/video consultations rose so that by the third survey 54% (n=44) of trainees were conducting more than 16 consultations per day remotely. Examinations and GP presentations expected to be daily occurrences diminished as the pandemic grew more severe, such that by the third survey 24-25% of trainees had not conducted a respiratory examination or dealt with new/unexpected hypertension in the previous month. Conclusion This study demonstrates abrupt change to the normal course of their training which was experienced by Irish GP trainees as a result of Covid, with examples from clinical practice. Adaptions of the training programme helped mitigate against the effects of the pandemic.

In Situ Measurements of Thermal Ion Temperature in the Martian Ionosphere.

In situ measurements of ionospheric and thermospheric temperatures are experimentally challenging because orbiting spacecraft typically travel supersonically with respect to the cold gas and plasma. We present O 2 + temperatures in Mars' ionosphere derived from data measured by the SupraThermal And Thermal Ion Composition instrument onboard the Mars Atmosphere and Volatile EvolutioN spacecraft. We focus on data obtained during nine special orbit maneuvers known as Deep Dips, during which MAVEN lowered its periapsis altitude from the nominal 150 to 120 km for 1 week in order to sample the ionospheric main peak and approach the homopause. We use two independent techniques to calculate ion temperatures from the measured energy and angular widths of the supersonic ram ion beam. After correcting for background and instrument response, we are able to measure ion temperatures as low as 100 K with associated uncertainties as low as 10%. It is theoretically expected that ion temperatures will converge to the neutral temperature at altitudes below the exobase region (∼180-200 km) due to strong collisional coupling; however, no evidence of the expected thermalization is observed. We have eliminated several possible explanations for the observed temperature difference between ions and neutrals, including Coulomb collisions with electrons, Joule heating, and heating caused by interactions with the spacecraft. The source of the energy maintaining the high ion temperatures remains unclear, suggesting that a fundamental piece of physics is missing from existing models of the Martian ionosphere.

Performance in practice; exploring trainer and trainee experiences of user-designed formative assessment tools.

INTRODUCTION: General Practice training in Ireland currently has various methods of formative assessment and feedback delivered to trainees. In 2018 the Irish College of General Practitioners commissioned the generation of two new user-designed formative feedback tools that would allow trainee feedback to drive learning. These tools became known as the Performance in Practice (PiP) tools. AIMS: To explore the experiences of General Practice (GP) trainers and trainees having completed a pilot of using the PiP tools for 4 months. METHODS: An explorative phenomenological approach was taken to understand the experiences of trainers and trainees. One to one interviews were conducted, and the transcripts analysed for themes and sub-theme via Template analysis. RESULTS: User experiences focused on two main areas; educational value and acceptability. In relation to educational value, the PiP tools were seen as an improvement over established forms of formative feedback, as they were centred around the curriculum and therefore reflected the unique multifaceted requirements of an independently practising GP. Acceptability primarily focused around data governance and structures, as well as practical issues such as ease of software use. CONCLUSIONS: Overall, the experience of using the PiP tools was positive for both trainers and trainees. Future plans to further explore implementation of the PiP tools have been significantly informed by this research.

Role of ghrelin isoforms in the mitigation of hepatic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress after bariatric surgery in rats.

BACKGROUND/OBJECTIVES: Bariatric surgery improves nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain elusive. We evaluated the potential role of ghrelin isoforms in the amelioration of hepatic inflammation after sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB). SUBJECTS/METHODS: Plasma ghrelin isoforms were measured in male Wistar rats (n = 129) subjected to surgical (sham operation, sleeve gastrectomy, or RYGB) or dietary interventions [fed ad libitum a normal (ND) or a high-fat diet (HFD) or pair-fed diet]. The effect of acylated and desacyl ghrelin on markers of inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in primary rat hepatocytes under palmitate-induced lipotoxic conditions was assessed. RESULTS: Plasma desacyl ghrelin was decreased after sleeve gastrectomy and RYGB, whereas the acylated/desacyl ghrelin ratio was augmented. Both surgeries diminished obesity-associated hepatic steatosis, CD68+- and apoptotic cells, proinflammatory JNK activation, and Crp, Tnf, and Il6 transcripts. Moreover, a postsurgical amelioration in the mitochondrial DNA content, oxidative phosphorylation (OXPHOS) complexes I and II, and ER stress markers was observed. Specifically, following bariatric surgery GRP78, spliced XBP-1, ATF4, and CHOP levels were reduced, as were phosphorylated eIF2α. Interestingly, acylated and desacyl ghrelin inhibited steatosis and inflammation of palmitate-treated hepatocytes in parallel to an upregulation of OXPHOS complexes II, III, and V, and a downregulation of ER stress transducers IRE1α, PERK, ATF6, their downstream effectors, ATF4 and CHOP, as well as chaperone GRP78. CONCLUSIONS: Our data suggest that the increased relative acylated ghrelin levels after bariatric surgery might contribute to mitigate obesity-associated hepatic inflammation, mitochondrial dysfunction, and ER stress.

Donegal Going against the Flow: National Differences in Long-Term Urinary Catheterisation Rates in Men (> 65 Years) With Benign Prostatic Hypertrophy.

An analysis of Primary Care Reimbursement Service (PCRS, 2013) data demonstrated high rates of urinary catheter changes in Donegal compared to other regions of Ireland. There is a catheter change rate of 10.2% in Donegal men over 65 with medical cards (GMS) compared to rates of 2.7% and 0.17% in Waterford and South Dublin, respectively1. This 60-fold difference between an area with perceived good access to services (South Dublin) and Donegal an area that does not, prompted a survey of general practitioners in each of these areas to assess whether true male catheterisation rates were similarly disproportionate in Donegal. Based on this, data was collected from a population of 23,794 GMS patients in GP training practices in Donegal (Rural), Leinster (Urban) and Waterford (Suburban). The data sampled for Donegal demonstrated 19 long-term catheters (LTCs per 8603 GMS) compared to four LTCs (per 5,800 GMS) in Leinster and 3 LTCs (per 9,391 GMS) in Waterford (Table 1). This anomaly in LTC rates may be a proxy for lack of access to basic Urology services.

Clinical outcomes and the role of adjuvant therapy sequencing in Type II uterine cancer following definitive surgical treatment.

PURPOSE OF INVESTIGATION: Because of rarity, consensus on adjuvant therapies for Type II endometrial cancers (BC) remains undefined. Reporting their institutional outcomes, the present authors assessed the impact of adjuvant therapies on recurrence and overall survival in women with 2009 FIGO Stage I-III Type II BC. MATERIAL AND METHODS: The authors identified 108 women, treated with definitive surgery between 2000-2013, with pathologically-confirmed Type II EC (non-endometrioid [NEM, n=801 and high grade endometrioid [G3EEC, n=28]) Cox proportional hazard models were used to assess the effect of prognostic variables on disease-free (DFS) and overall survival (OS). Kaplan-Meier method was used to assess survival. RESULTS: Of the 108 women, 83 (77%) were African American (AA). Fifty-nine (55%), 12 (11%), and 37 (34%) were Stage I, II, and III, respectively. Ninety-seven patients received adjuvant therapy: 52 (radiation only), four (chemotherapy only), and 40 (combined). During follow-up (median 41 months), 44 patients (41%) recurred. Five-year DFS was 53% overall (48% [NEM], 80% [G3EEC]). Five-year OS was 75% overall (68% [NEM], 95% [G3EEC]). On multivariate analysis, lower stage and adjuvant radiation improved DFS. Higher stage, NEM, and increasing age were poor prognostic indicators of OS. CONCLUSION: Representing a large single institutional cohort for Type II BC, the present study's observed sur- vival rates are consistent with previous studies, despite the relatively high frequency of carcinosarcoma and Stage III/nodal disease. The protective effect on recurrence was not lost when radiation was delayed for chemotherapy. The present results support a multimodal adjuvant approach for treating all stages of invasive NEM EC.

Rise and fall of vector infectivity during sequential strain displacements by mosquito-borne dengue virus.

Each of the four serotypes of mosquito-borne dengue virus (DENV-1-4) comprises multiple, genetically distinct strains. Competitive displacement between strains within a serotype is a common feature of DENV epidemiology and can trigger outbreaks of dengue disease. We investigated the mechanisms underlying two sequential displacements by DENV-3 strains in Sri Lanka that each coincided with abrupt increases in dengue haemorrhagic fever (DHF) incidence. First, the post-DHF strain displaced the pre-DHF strain in the 1980s. We have previously shown that post-DHF is more infectious than pre-DHF for the major DENV vector, Aedes aegypti. Then, the ultra-DHF strain evolved in situ from post-DHF and displaced its ancestor in the 2000s. We predicted that ultra-DHF would be more infectious for Ae. aegypti than post-DHF but found that ultra-DHF infected a significantly lower percentage of mosquitoes than post-DHF. We therefore hypothesized that ultra-DHF had effected displacement by disseminating in Ae. aegypti more rapidly than post-DHF, but this was not borne out by a time course of mosquito infection. To elucidate the mechanisms that shape these virus-vector interactions, we tested the impact of RNA interference (RNAi), the principal mosquito defence against DENV, on replication of each of the three DENV strains. Replication of all strains was similar in mosquito cells with dysfunctional RNAi, but in cells with functional RNAi, replication of pre-DHF was significantly suppressed relative to the other two strains. Thus, differences in susceptibility to RNAi may account for the differences in mosquito infectivity between pre-DHF and post-DHF, but other mechanisms underlie the difference between post-DHF and ultra-DHF.

Ecotoxicological characterization of biochars: role of feedstock and pyrolysis temperature.

Seven contrasting feedstocks were subjected to slow pyrolysis at low (300 or 350°C) and high temperature (550 or 600°C), and both biochars and the corresponding feedstocks tested for short-term ecotoxicity using basal soil respiration and collembolan reproduction tests. After a 28-d incubation, soil basal respiration was not inhibited but stimulated by additions of feedstocks and biochars. However, variation in soil respiration was dependent on both feedstock and pyrolysis temperature. In the last case, respiration decreased with pyrolysis temperature (r=-0.78; p<0.0001, n=21) and increased with a higher volatile matter content (r=0.51; p<0.017), these two variables being correlated (r=-0.86, p<0.0001). Collembolan reproduction was generally unaffected by any of the additions, but when inhibited, it was mostly influenced by feedstock, and generally without any influence of charring itself and pyrolysis temperature. Strong inhibition was only observed in uncharred food waste and resulting biochars. Inhibition effects were probably linked to high soluble Na and NH4 concentrations when both feedstocks and biochars were considered, but mostly to soluble Na when only biochars were taken into account. The general lack of toxicity of the set of slow pyrolysis biochars in this study at typical field application rates (≤20 Mg ha(-1)) suggests a low short-term toxicity risk. At higher application rates (20-540 Mg ha(-1)), some biochars affected collembolan reproduction to some extent, but only strongly in the food waste biochars. Such negative impacts were not anticipated by the criteria set in currently available biochar quality standards, pointing out the need to consider ecotoxicological criteria either explicitly or implicitly in biochar characterization schemes or in management recommendations.

Genetic and phenotypic characterization of sylvatic dengue virus type 4 strains.

Four serotypes of dengue virus (DENV 1-4) currently circulate between humans and domestic/peridomestic Aedes mosquitoes, resulting in 100 million infections per year. All four serotypes emerged, independently, from sylvatic progenitors transmitted among non-human primates by arboreal Aedes mosquitoes. This study investigated the genetic and phenotypic changes associated with emergence of human DENV-4 from its sylvatic ancestors. Analysis of complete genomes of 3 sylvatic and 4 human strains revealed high conservation of both the 5'- and 3'-untranslated regions but considerable divergence within the open reading frame. Additionally, the two ecotypes did not differ significantly in replication dynamics in cultured human liver (Huh-7), monkey kidney (Vero) or mosquito (C6/36) cells, although significant inter-strain variation within ecotypes was detected. These findings are in partial agreement with previous studies of DENV-2, where human strains produced a larger number of progeny than sylvatic strains in human liver cells but not in monkey or mosquito cells.

Who goes where? A prospective study of referral patterns within a newly established primary care team.

BACKGROUND: Since the introduction of primary care teams, referral patterns of General Practitioners (GPs) in Ireland have not been studied. AIMS: To study the referral patterns of GPs within a primary care team (PCT) to allied health care professionals in a PCT and to secondary care. To identify indirect referral pathways. To study variation in individual GP referral patterns. METHOD: Questionnaire based survey. Statistical analysis was carried out using Epi Info version 3.5.1. RESULTS: Of 3,166 consultations, 2,841 (89.7%) were dealt with by the GP and required no referral, 107 (3.4%) were referred within the PCT, and 218 (6.9%) were referred elsewhere. Therefore, 93.1% of consultations were managed in primary care alone. Ninety percent of GPs refer patients to the PCT. Indirect referrals constituted 17% of all outpatient referrals. Females have significantly higher referral rates than males. Referral rates of GPs in single-handed practices are higher than GPs in group practices. CONCLUSIONS: GPs alone can manage the vast majority of presentations in general practice. Greater GP access to diagnostic and therapeutic interventions may reduce outpatient referrals. GPs in group practices may collectively have greater experience and expertise and therefore can manage more patients in primary care. There is a significant variation in referral rates between both genders.

Survival of adenovirus types 2 and 41 in surface and ground waters measured by a plaque assay.

To manage artificial recharge systems, it is necessary to understand the inactivation process of microorganisms within aquifers so that requirements regarding storage times and treatment strategies for ground and surface waters can be developed and modeled to improve water management practices. This study was designed to investigate the survival of representative adenoviruses in surface- and groundwaters using a cell culture plaque assay with human lung carcinoma cells (A549) to enumerate surviving viruses. Adenovirus types 2 (Ad2) and 41 (Ad41) were seeded into 50 mL of three sterilized surface waters and groundwaters, and incubated at 10 and 19 °C for up to 301 days. Concentrations of Ad2 and Ad41 were relatively stable in all waters at 10 °C for at least 160 days and in some instances up to 301 days. At 19 °C, virus concentrations were reduced by 99.99% (4 log) after 301 days in surface water. There was approximately 90% (1 log) reduction of both viruses at 19 °C after 160 days of incubation in groundwater samples. There was no overall difference in survival kinetics in surface waters compared to groundwaters. The relatively high stability and long-term survival of adenoviruses in environmental waters at elevated temperatures should be considered in risk assessment models and drinking water management strategies.

Evaluation of new monoclonal antibodies in detection of estrogen receptor, progesterone receptor, and Her2 protein expression in breast carcinoma cell block sections using conventional microscopy and quantitative image analysis.

Accurate assessment of estrogen receptor (ER), progesterone receptor (PR), and Her2 status of breast carcinomas is critical for predicting response to systemic therapies. Recently, developed rabbit monoclonal antibodies (RMab) are reported to have higher sensitivity than murine monoclonal antibodies (Mab). This study compares RMabs against FDA-approved Mab (FMab) in breast carcinoma cell block sections using visual and image quantification. Cell blocks from 52 breast cancers were studied. Immunohistochemistry using RMab (ER, PR, and Her2) was compared with FMabs (ER, PR, Dako) and HercepTest (HerFDA). Fluorescent in situ hybridization (FISH) was used as a reference standard for Her2. Slides were later scanned and reanalyzed with an automated cellular imaging system (ACIS III, Dako). Frequency of ER (38.5% vs. 36.5% for visual; 55.8% vs. 57.7% for image) and PR (28.8% vs. 36.5% for visual; 50% vs. 51.9% for image), and concordance (overall agreement is 71.2% and 75% for visual and image ER; and 84.6% and 59.6% for visual and image PR) were similar for both FMab and RMab, respectively. Overall agreement (53.8% vs. 77.1% for visual and image detection, respectively, using HerFDA and RMab) is poor to moderate for Her2. Visual Her2 (RMab) has the highest concordance (94.1%), and visual HerFDA has the lowest concordance (35.3%) with FISH. ER and PR analysis (FMab vs. RMab) are almost comparable using both detection methods with good overall agreement. For Her2 overexpression, RMab proved to be superior to HerFDA and showed excellent agreement with FISH results with both quantitative detection methods.

Development of an HPLC-MS procedure for the quantification of N-acetyl-S-(n-propyl)-l-cysteine, the major urinary metabolite of 1-bromopropane in human urine.

An analytical procedure was developed for the detection and quantification of N-acetyl-S-(n-propyl)-l-cysteine (n-propylmercapturic acid, AcPrCys), a metabolite and biomarker for exposure to 1-bromopropane (1-BP). 1-BP is used as an industrial solvent and exposure is a health concern for industrial workers due to its toxicity. It has been associated with neurological disorders in both animals and humans. Urine sample preparation for the determination of AcPrCys consisted of solid phase extraction (SPE). Urine samples on preconditioned SPE (C18) columns were washed with 40% methanol/60% water solution prior to elution with acetone. Quantification was by means of a liquid chromatograph (LC) equipped with a mass spectrometer (MS) using an Aqua 3 microm C18 300A column and [d(7)]-AcPrCys was used as internal standard. Electrospray ionization (ESI) was used with the MS operated in the negative ion mode and selected ion monitoring (SIM) at m/z 204 for AcPrCys and m/z 211 for [d(7)]-AcPrCys. Demonstrated recovery of urine samples fortified at multiple levels (0.625-10 microg/ml) varied between 96 and 103% of theory with relative standard deviations (RSD) of 6.4% or less. The limit of detection (LOD) for the procedure was approximately 0.01 microg/ml AcPrCys in urine. These data will be discussed as well as other factors of the development of this test procedure.

Plant-produced idiotype vaccines for the treatment of non-Hodgkin's lymphoma: safety and immunogenicity in a phase I clinical study.

Plant-made vaccines have been the subject of intense interest because they can be produced economically in large scale without the use of animal-derived components. Plant-made therapeutic vaccines against challenging chronic diseases, such as cancer, have received little research attention, and no previous human clinical trials have been conducted in this vaccine category. We document the feasibility of using a plant viral expression system to produce personalized (patient-specific) recombinant idiotype vaccines against follicular B cell lymphoma and the results of administering these vaccines to lymphoma patients in a phase I safety and immunogenicity clinical trial. The system allowed rapid production and recovery of idiotypic single-chain antibodies (scFv) derived from each patient's tumor and immunization of patients with their own individual therapeutic antigen. Both low and high doses of vaccines, administered alone or co-administered with the adjuvant GM-CSF, were well tolerated with no serious adverse events. A majority (>70%) of the patients developed cellular or humoral immune responses, and 47% of the patients developed antigen-specific responses. Because 15 of 16 vaccines were glycosylated in plants, this study also shows that variation in patterns of antigen glycosylation do not impair the immunogenicity or affect the safety of the vaccines. Collectively, these findings support the conclusion that plant-produced idiotype vaccines are feasible to produce, safe to administer, and a viable option for idiotype-specific immune therapy in follicular lymphoma patients.

Urinary bromide and breathing zone concentrations of 1-bromopropane from workers exposed to flexible foam spray adhesives.

1-Bromopropane (1-BP) has been marketed as an alternative for ozone depleting solvents and suspect carcinogens and is in aerosol products, adhesives and solvents used for metal, precision and electronics cleaning. Toxicity of 1-BP is poorly understood, but it may be a neurologic, reproductive and hematologic toxin. Sparse exposure information prompted this exposure assessment study using air sampling, and measurement of urinary metabolites. Mercapturic acid conjugates are excreted in urine from 1-BP metabolism involving removal of bromide (Br) from the propyl group. One research objective was to evaluate the utility of urinary Br analysis for assessing 1-BP exposure using a relatively inexpensive, commercially available method. Complete 48 h urine specimens were obtained from 30 workers on two consecutive days at two facilities using 1-BP adhesives to construct polyurethane foam seat cushions and from seven unexposed control subjects. All of the workers' urine was collected into composite samples representing three daily time intervals (at work; after work but before bedtime; and upon wake-up) and analyzed for Br ion by inductively coupled plasma-mass spectrometry. Full-shift breathing zone samples were collected for 1-BP on Anasorb carbon molecular sieve sorbent tubes and analyzed by gas chromatography-flame ionization detection via NIOSH method 1025. Geometric mean (GM) breathing zone concentrations of 1-BP were 92 parts per million (p.p.m.) for adhesive sprayers and 11 p.p.m. for other jobs. For sprayers, urinary Br concentrations ranged from 77 to 542 milligrams per gram of creatinine [mg (g-cr)(-1)] at work; from 58 to 308 mg (g-cr)(-1) after work; and from 46 to 672 mg (g-cr)(-1) in wake-up samples. Pre-week urinary Br concentrations for sprayers were substantially higher than for the non-sprayers and controls, with GMs of 102, 31 and 3.8 mg (g-cr)(-1), respectively. An association of 48 h urinary Br concentration with 1-BP exposure was statistically significant (r(2) = 0.89) for all jobs combined. This study demonstrates that urinary elimination is an important excretion pathway for 1-BP metabolism, and Br may be a useful biomarker of exposure.

Patterns of epistasis in RNA viruses: a review of the evidence from vaccine design.

Epistasis results when the fitness effects of a mutation change depending on the presence or absence of other mutations in the genome. The predictions of many influential evolutionary hypotheses are determined by the existence and form of epistasis. One rich source of data on the interactions among deleterious mutations that has gone untapped by evolutionary biologists is the literature on the design of live, attenuated vaccine viruses. Rational vaccine design depends upon the measurement of individual and combined effects of deleterious mutations. In the current study, we have reviewed data from 29 vaccine-oriented studies using 14 different RNA viruses. Our analyses indicate that (1) no consistent tendency towards a particular form of epistasis exists across RNA viruses and (2) significant interactions among groups of mutations within individual viruses occur but are not common. RNA viruses are significant pathogens of human disease, and are tractable model systems for evolutionary studies--we discuss the relevance of our findings in both contexts.