Experimental evidence for recovery of mercury-contaminated fish populations.

Anthropogenic releases of mercury (Hg)1-3 are a human health issue4 because the potent toxicant methylmercury (MeHg), formed primarily by microbial methylation of inorganic Hg in aquatic ecosystems, bioaccumulates to high concentrations in fish consumed by humans5,6. Predicting the efficacy of Hg pollution controls on fish MeHg concentrations is complex because many factors influence the production and bioaccumulation of MeHg7-9. Here we conducted a 15-year whole-ecosystem, single-factor experiment to determine the magnitude and timing of reductions in fish MeHg concentrations following reductions in Hg additions to a boreal lake and its watershed. During the seven-year addition phase, we applied enriched Hg isotopes to increase local Hg wet deposition rates fivefold. The Hg isotopes became increasingly incorporated into the food web as MeHg, predominantly from additions to the lake because most of those in the watershed remained there. Thereafter, isotopic additions were stopped, resulting in an approximately 100% reduction in Hg loading to the lake. The concentration of labelled MeHg quickly decreased by up to 91% in lower trophic level organisms, initiating rapid decreases of 38-76% of MeHg concentration in large-bodied fish populations in eight years. Although Hg loading from watersheds may not decline in step with lowering deposition rates, this experiment clearly demonstrates that any reduction in Hg loadings to lakes, whether from direct deposition or runoff, will have immediate benefits to fish consumers.

A beneficial adaptive role for CHOP in driving cell fate selection during ER stress.

Cellular stresses elicit signaling cascades that are capable of either mitigating the inciting dysfunction or initiating cell death. During endoplasmic reticulum (ER) stress, the transcription factor CHOP is widely recognized to promote cell death. However, it is not clear whether CHOP also has a beneficial role during adaptation. Here, we combine a new, versatile, genetically modified Chop allele with single cell analysis and with stresses of physiological intensity, to rigorously examine the contribution of CHOP to cell fate. Paradoxically, we find that CHOP promotes death in some cells, but proliferation-and hence recovery-in others. Strikingly, this function of CHOP confers to cells a stress-specific competitive growth advantage. The dynamics of CHOP expression and UPR activation at the single cell level suggest that CHOP maximizes UPR activation, which in turn favors stress resolution, subsequent UPR deactivation, and proliferation. Taken together, these findings suggest that CHOP's function can be better described as a "stress test" that drives cells into either of two mutually exclusive fates-adaptation or death-during stresses of physiological intensity.

Estrous activity in nulliparous heifers with divergent genetic merit for fertility traits.

This observational study determined the effect of genetic merit for fertility traits on estrous activity and duration and inter-estrous interval in nulliparous dairy heifers. We also compared estrous activity between estrous events with or without conception and determined the effect of genetic merit for fertility traits on age and body weight at time of first detected estrous activity event. Activity monitoring devices (Heatime, SCR Engineers) were fitted to 7-9-mo aged Holstein-Friesian heifers with positive or negative genetic merit for fertility traits (POS FertBV: average +5%, n = 275; NEG FertBV: average -5%, n = 249) and activity data was collected to the end of the first breeding period (15-17-mo). An estrous event was defined as when the activity change index exceeded 19.2 activity units (AU) for ≥6 consecutive h. In total, 2,434 estrous events were identified (POS FertBV: n = 1454; NEG FertBV: n = 980). Estrous event duration was defined as the period when the threshold was first exceeded and when activity dropped below threshold, without another event starting within 24 h of the end of the previous event. This definition included occurrences where activity crossed the threshold multiple times in a day; these were classified as a single estrous event. A second measure, high activity duration, was defined as the total time activity exceeded the threshold. To characterize estrous activity, baseline activity was determined from the previous 7 d of activity. Peak activity and total activity (area under the curve of activity above baseline) were calculated. A fifth variable, inter-estrous interval, was calculated as a proxy for estrous cycle length. Total activity and peak activity were greater in POS than NEG FertBV heifers (total activity: 548 vs 464 AU, SED = 19.6 AU; peak activity: 72 vs 65 AU, standard error of the difference (SED) = 1.5 AU). The POS FertBV group had a mean estrous event duration and high activity duration of 15.1 h and 15.0 h, compared with 14.1 and 14.1 h for the NEG FertBV group (SED = 0.30 and 0.29 h, respectively). Inter-estrous interval did not differ between POS and NEG FertBV heifers (19.5 vs 20.0 d, SED = 0.49). Estrous events associated with conception were shorter than those not associated with conception (mean ± standard error of the mean, high activity duration: 13.0 ± 0.25 h vs 13.9 ± 0.31 h, estrous event duration: 13.1 ± 0.25 h vs 14 ± 0.32 h) and had less total activity (408 ± 15.2 vs 487 ± 18.2 AU). The POS FertBV heifers were more likely to have their first estrous activity event than NEG FertBV heifers by a given age (HR = 1.26, 95% CI = 1.0 to 1.6) or body weight (HR = 1.35, 95% CI = 1.1 to 1.6). The outcomes of this study provide evidence that positive genetic merit for fertility traits is associated with more overt estrous expression. Therefore, estrous expression traits may have potential to be used as earlier-in-life predictors of genetic merit for fertility.

Health impacts of poor water quality on an endangered shorebird breeding programme in Aotearoa New Zealand.

CASE HISTORY: Two clusters of mortality among endangered tuturuatu/tchuriwat'/shore plover (Thinornis novaeseelandiae) have occurred at captive breeding facilities around New Zealand in recent years. In the first, four chicks died at Pukaha National Wildlife Centre (Mount Bruce, NZ) in February 2016, and in the second five adult birds at the Cape Sanctuary (Cape Kidnappers, NZ) died in 2022. CLINICAL FINDINGS: In 2016, four chicks were noted to become weak, have increased vocalisations and closed eyes prior to death. The remaining chicks were treated for 5 days with amoxycillin/clavulanate orally twice daily. Water containers and brooders were cleaned and disinfected with chlorhexidine. No further mortality was seen.In the 2022 cluster, three adult breeding birds died acutely and five others showed inappetence, weight loss and diarrhoea approximately 10 days after heavy rains flooded the local river. The five birds were treated with amoxycillin/clavulanate orally twice daily and oral fluids for 5 days. Two birds died and three survived. No breeding occurred in the aviaries in the following season. PATHOLOGICAL FINDINGS: In 2016, the chicks showed pulmonary changes ranging from congestion and oedema to heterophilic inflammation consistent with septicaemia.In 2022, the adult birds showed proliferation of bacteria in the distal small intestine associated with mucosal ulceration and heterophilic infiltration. Acid-fast staining of the caecal contents in one bird showed organisms consistent with Cryptosporidium spp. LABORATORY FINDINGS: Aerobic bacterial cultures of the lung and liver of two affected chicks carried out in 2016 showed heavy growth of Plesiomonas shigelloides. The same organism was cultured from water trays and holding tanks containing water boatmen (Sigara arguta) on which the chicks were fed.In 2022, cultures from the livers of three dead birds each showed a mixed bacterial growth with differing dominant organisms (Aeromonas sobria, Hafnia alvei, Citrobacter freundii and an Enterococcus sp.). PCR and sequencing confirmed Cryptosporidium parvum in the caecum of one bird. Fresh faeces from 24 breeding birds from the captive breeding facilities were negative by PCR for Cryptosporidium spp.The captive breeding facilities obtain water for the aviaries and aquatic invertebrates to feed to the chicks from local freshwater sources. Water quality testing at the Cape Sanctuary revealed concentrations of faecal indicator bacteria in excess of safe drinking water guidelines, with peaks following heavy rainfall. CLINICAL RELEVANCE: Fluctuations in water quality associated with mammalian faecal bacteria can adversely affect bird health and impact on captive rearing of endangered wildlife.

Circular dichroism and UV-Vis detection of UV-induced damage to nucleic acids.

In this report, we demonstrate that CD spectroscopy can be used as a tool to detect changes to DNA upon irradiation with UV light. We follow the spectroscopic response of DNA samples irradiated at selected exposure times with both CD and UV-Vis spectroscopy. We analyzed four different nucleic acids to evaluate the effect of the sequence on photodegradation. Only one polymer, calf thymus DNA, was a natural nucleic acid and contained all four nucleobases. The other three were synthetic polymers and contained only one type of base pair: poly (deoxyadenylic-deoxythymidylic) acid [poly (dA-dT)2 ] and poly (deoxyadenylic acid) · poly (deoxythymidylic acid) [poly (dA) · poly (dT)], which contained only adenine and thymine; poly (deoxyguanylic-deoxycytidylic) acid [poly (dG-dC)2 ], which contained only guanine and cytosine. CD and UV-Vis spectra showed sequence dependent changes. In particular, poly (dA) · poly (dT) undergoes changes more rapidly than the other sequences investigated. The CD spectrum of poly (dA) · poly (dT) gradually undergoes an inversion, suggesting a change in helicity, before disappearing due to the unfolding of the double strand.

Speed of clinical improvement in the real-world setting from patient-reported Psoriasis Symptoms and Signs Diary: Secondary outcomes from the Psoriasis Study of Health Outcomes through 12 weeks.

BACKGROUND: Rapid skin improvement is a key treatment goal of patients with moderate-to-severe psoriasis (PsO). OBJECTIVES: To compare the speed of clinical improvement of approved biologics on the symptoms and signs of psoriasis assessed by patients using the validated Psoriasis Symptoms and Signs Diary (PSSD) through 12 weeks. METHODS: Psoriasis Study of Health Outcomes (PSoHO) is an international, prospective, non-interventional study that compares the effectiveness of anti-interleukin (IL)-17A biologics versus other biologics, together with pairwise comparisons of ixekizumab versus five individual biologics in patients with PsO. Using the PSSD 7-day recall period, patients assessed the symptoms (itch, skin tightness, burning, stinging and pain) and signs (dryness, cracking, scaling, shedding/flaking, redness and bleeding) of their psoriasis (0-10). Symptom and sign summary scores (0-100) are derived from the average of individual scores. Percentage change in summary scores and proportion of patients with clinically meaningful improvements (CMI) in PSSD summary and individual scores are evaluated weekly. Longitudinal PSSD data are reported as observed with treatment comparisons analysed using mixed model for repeated measures (MMRM) and generalized linear mixed models (GLMM). RESULTS: Across cohorts and treatments, eligible patients (n = 1654) had comparable baseline PSSD scores. From Week 1, the anti-IL-17A cohort achieved significantly larger score improvements in PSSD summary scores and a higher proportion of patients showed CMIs compared to the other biologics cohort through 12 weeks. Lower PSSD scores were associated with a greater proportion of patients reporting their psoriasis as no longer impacting their quality-of-life (DLQI 0,1) and a high level of clinical response (PASI100). Results also indicate a relationship between an early CMI in PSSD score at Week 2 and PASI100 score at Week 12. CONCLUSIONS: Treatment with anti-IL-17A biologics, particularly ixekizumab, resulted in rapid and sustained patient-reported improvements in psoriasis symptoms and signs compared with other biologics in a real-world setting.

Spatially Explicit Habitat Selection: Testing Contagion and the Ideal Free Distribution with Culex Mosquitoes.

AbstractSince its inception, attempts have been made to improve ideal free distribution (IFD) theory to make it better fit real-world data. Spatial contagion is a newer ecological concept that suggests that the perceived quality of a patch can be affected by the quality of its neighbor patches. Here, we present a series of experiments testing for potential contagion effects, examining how contagion can interact with the IFD and determining whether spatial context affects assessment of habitat quality. First, we tested whether the presence of conspecific competitors negatively impacts oviposition habitat selection by female mosquitoes (Culex restuans). We then used a more complex spatial landscape to determine whether competition can create a spatial contagion effect. Finally, we examined whether the density of conspecifics can adjust the contagion effect of nutrient availability. While females avoided patches containing conspecifics, there was no effect of competition/density on neighboring patches. Additionally, we found that resource availability was a significant predictor of where egg rafts were laid, but resource availability did not have a contagion effect. These results provide further support for the utility of the IFD, as individuals were able to accurately assess patch-level habitat quality.

Estrous activity in lactating cows with divergent genetic merit for fertility traits.

This observational study aimed to determine the effect of genetic merit for fertility traits on estrous expression and estrous cycle duration in grazing dairy cows, as measured by an activity monitoring device. A secondary aim was to describe changes in expression of estrus that occur during successive estrous cycles postpartum. Neck-mounted, activity-monitoring devices (Heatime, SCR Engineers Ltd.) were fitted to nulliparous Holstein-Friesian heifers with positive (POS FertBV) or negative genetic merit for fertility traits (NEG FertBV) to capture activity data during their first and second lactations (POS FertBV: n = 242, n = 188; NEG FertBV: n = 159, n = 87 in lactation 1 and 2, respectively). An estrous event was identified when the activity change index exceeded 26 activity units (AU) for 4 h. A total of 1,254 and 892 estrous events were identified in lactation 1 and 2, respectively. Estrous duration was defined as the interval between when the threshold was first exceeded and when activity dropped below the threshold, with no new event starting within 24 h of the end of the previous event. This definition of estrus included cows in which activity crossed the threshold multiple times in a day and were classified as a single estrous event. A second measure, high activity duration, was defined as the total hours that activity exceeded the threshold. To characterize estrous activity, peak activity (above baseline) and total activity (area under the curve of activity above baseline) were measured. Compared with NEG FertBV cows, POS FertBV cows had more active, longer estrous events. In lactation 1, the POS FertBV group had a mean estrous duration and a high activity duration of 12.5 and 12.4 h compared with 11.4 and 11.3 h for the NEG FertBV group [standard error of the difference (SED) = 0.5 and 0.4 h, respectively]. This significant difference also occurred in lactation 2, with a mean estrous duration of 13.1 versus 11.8 h (SED = 0.5 h) and a high activity duration of 13.0 versus 11.8 h (SED = 0.4 h) in the POS and NEG FertBV groups, respectively. Total activity and peak activity were greater in the POS compared with the NEG FertBV group in lactation 1 (peak activity: 65.5 vs. 55.8 AU, SED = 2.4 AU; total activity: 588 vs. 494 AU, SED = 25 AU) and lactation 2 (peak activity: 72.5 vs. 61.2 AU, SED = 2.9 AU; total activity: 648 vs. 541 AU, SED = 30 AU). Estrous cycle duration did not differ between the POS and NEG FertBV groups (lactation 1: 20.4 vs. 20.6 d, SED = 0.25; lactation 2: 20.8 vs. 21.0 d, SED = 0.28). Less estrous activity of the cow was associated with the first postpartum estrus. In contrast, the number of previous estrous events did not consistently affect the duration of the subsequent estrous cycle. The outcomes of this study provide evidence that positive genetic merit for fertility traits is associated with more overt estrous expression. Selection for these traits may improve estrous expression and thus estrous detection in commercial herds.

Response to kisspeptin and gonadotropin-releasing hormone agonist administration in Holstein-Friesian dairy heifers with positive or negative genetic merit for fertility traits.

Previous research has identified that Holstein-Friesian dairy heifers with positive (POS) genetic merit for fertility traits (FertBV) reach puberty earlier than heifers with negative (NEG) FertBV. The hypothalamus-pituitary-gonadal (HPG) axis is functional in heifers before the onset of puberty, with increased LH release evident as heifers progress toward puberty. We investigated the functionality of the HPG axis in peripubertal Holstein-Friesian dairy heifers with divergent POS or NEG FertBV, hypothesizing that the earlier puberty onset of POS heifers is associated with earlier activation of the HPG axis than in NEG heifers. In experiment 1, we tested the dose responsiveness of POS heifers to an intravenous injection of either kisspeptin [Kiss; 2, 4, or 8 µg/kg of body weight (BW); n = 3 per dose] or a GnRH agonist (buserelin; 5, 10, or 20 ng/kg of BW; n = 3 per dose). The use of these 2 agonists investigates the status of the HPG axis in both the hypothalamus (Kiss) and pituitary (buserelin) glands. Doses of 4 µg/kg BW of Kiss and 10 ng/kg BW of buserelin produced submaximal LH responses and were used in experiment 2, in which previously unused POS (n = 22) and NEG (n = 18) FertBV heifers were challenged with both agonists at 10 and 12 mo of age in a partial crossover design. Heifers were randomly allocated to treatment groups, balanced for age and BW. The LH response to buserelin was greater in POS heifers than NEG heifers at 10 mo of age, with no difference in response at 12 mo. The FSH response to buserelin and the LH and FSH responses to Kiss did not differ between the POS and NEG heifers at either age. These results indicate an association between divergent genetic merit for fertility and the LH release to buserelin at 10 mo of age, supporting the hypothesis that gonadotropin responsiveness to a GnRH agonist is more advanced in POS heifers than in NEG heifers.

The perceived costs and benefits of mentoring college students with intellectual disability on stereotype consistent and inconsistent tasks.

BACKGROUND: According to the stereotype content model, individuals with intellectual disability are perceived as having greater warmth-related traits (e.g. sociable and humorous) and fewer competence-related traits (e.g. independence and intelligence). METHODS: We examined college students' perceived costs and benefits of mentoring peers with intellectual disability on stereotype-consistent (i.e. socially oriented) or inconsistent (i.e. academically oriented) tasks. Participants read about peer mentoring programmes that helped college students with or without intellectual disability on socially or academically oriented tasks before reporting their perceived costs and benefits of peer mentoring. RESULTS: Mentoring students with intellectual disability was associated with greater benefits (i.e. connectedness between mentors and students, student utility and mentor benefits) on academically oriented tasks but greater costs for mentors on socially oriented tasks. Additionally, participants reported that they would experience greater positive feelings if they were to mentor a student with an intellectual disability. However, the perceived benefits to the student and some costs (i.e. discomfort, paternalism and costs to student) were not influenced by whether the student had an intellectual disability and the type of mentoring task. DISCUSSION: Results indicate individuals find greater rewards working with individuals with intellectual disability on stereotype-inconsistent tasks and offer suggestions for postsecondary education peer mentoring programmes.

Development of an intrauterine infection model in the postpartum dairy cow.

AIMS: To develop an intrauterine infection model for Trueperella pyogenes in postpartum dairy cows and to assess the effect of this infection on the degree of intrauterine inflammation and concentrations of progesterone in serum. METHODS: The oestrous cycles of 36 healthy, non-pregnant, postpartum dairy cows were synchronised. They were then treated by intrauterine infusion of 0.5 g cephapirin before being blocked by age and randomly assigned to treatment with intrauterine infusion of saline (n = 18), 107 (n = 9) or 109 (n = 9) cfu of T. pyogenes, approximately 4 days after the expected time of ovulation (Day 0). Prior to intrauterine infusion on Day 0 and again on Days 3, 7, 10, and 15, cytobrush samples were collected from the uterus of each cow for microbiology and assessment of the percentage of polymorphonuclear neutrophils (PMN%). Blood samples were collected on the same days for measurement of concentrations of progesterone in serum, and uterine lumen diameter was assessed daily using transrectal ultrasonography. RESULTS: Trueperella pyogenes was isolated from 5/18 (28%), 7/9 (78%) and 8/9 (89%) cows infused with saline, 107 or 109 cfu of T. pyogenes, respectively (p < 0.001). Mean PMN% in the control cows did not change over time (p > 0.05), whereas it was higher on Days 7 and 10 than Day 0 in the 107 cfu group, and higher on Days 3 and 10 than Day 0 in the 109 cfu group (p < 0.05). The percentage of observations with uterine lumen diameters >2 mm was higher in cows infused with 107 (29.3 (95% CI = 14.5-44.2)%) or 109 cfu (19.2 (95% CI = 7.0-31.5)%) than in control cows (3.1 (95% CI = 0.1-6.0)%) (p < 0.001). Mean concentrations of progesterone in serum were higher in cows infused with 107 cfu (2.01 (SE 0.19) ng/mL) than cows infused with 109 cfu (1.01 (SE 0.27) ng/mL), with the control group intermediate (1.41 (SE 0.19) ng/mL) (p = 0.03). CONCLUSIONS: Infusion of 107 or 109 cfu of T. pyogenes resulted in the establishment of intrauterine infection in 83% of cows. Infection resulted in increased uterine lumen diameter, and an inflammatory response, i.e. elevated PMN%. CLINICAL RELEVANCE: This intrauterine infection model may be useful for future research on, for example, the pathogenesis of intrauterine infection in postpartum dairy cows.

Disparities in colostomy reversal after Hartmann's procedure for diverticulitis.

BACKGROUND: Hartmann's procedure for diverticulitis is a common procedure, with highly variable rates and timing of colostomy reversal. The aim of this study was to evaluate the impact of race and insurance coverage on reversal within 2 years of Hartmann's procedure for diverticulitis. METHODS: The Healthcare Cost and Utilization Project (HCUP) State Inpatient Database of five states (2007-2010) was queried for patients who had Hartmann's procedure in the setting of diverticulitis. Patients were grouped by race and insurance status, and multivariable adjustment was performed to evaluate rate and timing of colostomy takedown at 2 years. RESULTS: Among 11,019 patients who had Hartmann's procedure for diverticulitis, 6900 (69%) patients had colostomy reversal by 2 years, with a median time to reversal of 19 weeks. Compared to white patients with private insurance, combinations of black race and non-private insurance significantly reduced likelihood of colostomy reversal at 2 years across all combinations. Black patients without insurance had the lowest likelihood of reversal at 2 years (OR 0.27, 95% CI 0.14-0.51, p < 0.001). For patients who had colostomy reversal within 2 years, black patients without insurance had a significant delay in time to reversal (11 weeks, 95% CI 6-16, p < 0.001) compared to white patients with private insurance, and delays persisted across all other groups. CONCLUSIONS: Black patients and those without private insurance experienced significantly lower rates of, and delayed time to, colostomy reversal compared to white patients with private insurance. These disparities must be considered for allocation of resources in marginalized communities.

Utility of state-level influenza disease burden and severity estimates to investigate an apparent increase in reported severe cases of influenza A(H1N1) pdm09 - Arizona, 2015-2016.

The Arizona Department of Health Services identified unusually high levels of influenza activity and severe complications during the 2015-2016 influenza season leading to concerns about potential increased disease severity compared with prior seasons. We estimated state-level burden and severity to compare across three seasons using multiple data sources for community-level illness, hospitalisation and death. Severity ratios were calculated as the number of hospitalisations or deaths per community case. Community influenza-like illness rates, hospitalisation rates and mortality rates in 2015-2016 were higher than the previous two seasons. However, ratios of severe disease to community illness were similar. Arizona experienced overall increased disease burden in 2015-2016, but not increased severity compared with prior seasons. Timely estimates of state-specific burden and severity are potentially feasible and may provide important information during seemingly unusual influenza seasons or pandemic situations.

Positive Impact of a Pilot Pharmacist-Run Diabetes Pharmacotherapy Clinic in Solid-Organ Transplant Recipients.

PURPOSE: Post-transplant diabetes mellitus (PTDM) can lead to significant morbidity and cardiovascular death with a functioning graft. A paucity of literature exists regarding glycemic control in solid-organ transplant (SOT) recipients, including pharmacist management of PTDM. This study aimed to assess the impact of pharmacist interventions on diabetes management in a pharmacist-run PTDM clinic. METHODS: This was a single-center, prospective, observational study of 24 adult SOT recipients enrolled in a pilot pharmacist-managed PTDM clinic from 1 January to 30 June 2015. RESULTS: Improvements were realized in markers of glycemic control, including changes in A1C, average daily self-monitoring of blood glucose (SMBG) results, fasting SMBG results, and pre-lunch SMBG results from enrollment through at least 3 months of follow-up. Median A1C decreased significantly from 8.05% (interquartile range [IQR] 6.33-11.75) at baseline to 6.45% (IQR 6.05-7.3) at the last follow-up encounter (P = 0.0010). Average daily SMBG results decreased significantly from a median of 191 mg/dL (IQR 138-232 mg/dL) at baseline to 125 mg/dL (IQR 111-167 mg/dL) at the final encounter (P = 0.0023). Median fasting and pre-lunch SMBG results decreased significantly from 153 mg/dL (IQR 117-208 mg/dL) at baseline to 120 mg/dL (IQR 102-134 mg/dL) (P = 0.0064) and from 212 mg/dL (IQR 159-258 mg/dL) to 122 mg/dL (IQR 110-169 mg/dL) (P = 0.0161), respectively. Changes from baseline in other SMBG values, lipid levels, and BMI were not statistically significant. CONCLUSION: The results of our study demonstrate that a pharmacist-managed PTDM clinic can significantly affect glycemic control in SOT recipients.

Effects of halogens on European air-quality.

Halogens (Cl, Br) have a profound influence on stratospheric ozone (O3). They (Cl, Br and I) have recently also been shown to impact the troposphere, notably by reducing the mixing ratios of O3 and OH. Their potential for impacting regional air-quality is less well understood. We explore the impact of halogens on regional pollutants (focussing on O3) with the European grid of the GEOS-Chem model (0.25° × 0.3125°). It has recently been updated to include a representation of halogen chemistry. We focus on the summer of 2015 during the ICOZA campaign at the Weybourne Atmospheric Observatory on the North Sea coast of the UK. Comparisons between these observations together with those from the UK air-quality network show that the model has some skill in representing the mixing ratios/concentration of pollutants during this period. Although the model has some success in simulating the Weybourne ClNO2 observations, it significantly underestimates ClNO2 observations reported at inland locations. It also underestimates mixing ratios of IO, OIO, I2 and BrO, but this may reflect the coastal nature of these observations. Model simulations, with and without halogens, highlight the processes by which halogens can impact O3. Throughout the domain O3 mixing ratios are reduced by halogens. In northern Europe this is due to a change in the background O3 advected into the region, whereas in southern Europe this is due to local chemistry driven by Mediterranean emissions. The proportion of hourly O3 above 50 nmol mol-1 in Europe is reduced from 46% to 18% by halogens. ClNO2 from N2O5 uptake onto sea-salt leads to increases in O3 mixing ratio, but these are smaller than the decreases caused by the bromine and iodine. 12% of ethane and 16% of acetone within the boundary layer is oxidised by Cl. Aerosol response to halogens is complex with small (∼10%) reductions in PM2.5 in most locations. A lack of observational constraints coupled to large uncertainties in emissions and chemical processing of halogens make these conclusions tentative at best. However, the results here point to the potential for halogen chemistry to influence air quality policy in Europe and other parts of the world.

Impact of a pharmacist-led vaccine recommendation program for pediatric kidney transplant candidates.

Pediatric transplant recipients commonly have deficient vaccination status at the time of transplantation. Utilizing transplant pharmacists to improve vaccination rates has not previously been described. This single-center, retrospective study evaluated the impact of transplant pharmacist interventions on the completion rate of vaccination schedules at time of kidney transplant. Patients who received pharmacist-led vaccination recommendations prior to transplant were compared to patients without pharmacist recommendations. Forty-seven pediatric patients were included: 24 intervention patients and 23 control patients. The median percentage of up-to-date vaccinations at time of transplant was significantly higher in intervention group (91%; IQR 86%-100%) vs. control group (80%; IQR 71%-80%) (P<.0001). The median change in up-to-date vaccinations from time of evaluation to time of transplant was also significantly higher in the intervention group (7.5%) compared to the control group (0%) (P<.0001). There was no difference in live vaccination rates. No patients in either group were readmitted for a vaccine-preventable disease within 6 months post-transplant. With pharmacist intervention, significantly more patients were up to date with vaccination schedules at the time of transplant. These results suggest that a transplant pharmacist may serve as a valuable resource to increase vaccination schedule compliance between time of evaluation and transplantation.

Spatial organization of AMPAR subtypes in ON RGCs.

Retinal ganglion cells (RGCs) receive glutamatergic input from bipolar cells through NMDA- and AMPA-type glutamate receptors. Both GluA2-containing, Ca(2+)-impermeable AMPA receptors (CI-AMPARs) and GluA2-lacking, Ca(2+)-permeable AMPA receptors (CP-AMPARs) contribute to light-evoked responses in ON RGCs; however, specific roles for each subtype are not well understood. Here, we present evidence that light intensity determines the subtype of AMPAR that is activated during the synaptic response in ON RGCs. Using current voltage analysis of the EPSC we show that light intensities near RGC threshold, intensities that travel through the well described primary rod pathway, evoke synaptic currents that are preferentially mediated by CP-AMPARs. Synaptic responses evoked by spontaneous release of transmitter from bipolar cell terminals also preferentially activate CP-AMPARs. Conversely, higher light intensities, most likely carried by secondary rod pathways, activate CI-AMPARs. The same pattern of CP-AMPAR and CI-AMPAR activation was observed in mice containing only functional rods, suggesting that the recruitment of CI-AMPARs at higher light intensity does not require cone stimulation. When glutamate spillover was induced by blocking transporters with TBOA, both the near threshold and spontaneous EPSCs contained a significant CI-AMPAR component. We propose that CI-AMPARs are activated by "spillover" of synaptic glutamate only during bright illumination, or when glutamate uptake is blocked. Glutamate may spill over to more distant sites at the same synapse, or perhaps as far as neighboring synapses. Together, our data suggest that the spatial organization of AMPARs at ON RGCs synapses allows for selective, intensity-dependent activation of AMPARs with distinct subunit composition.

G-protein-mediated inhibition of the Trp channel TRPM1 requires the Gßγ dimer.

ON bipolar cells are critical for the function of the ON pathway in the visual system. They express a metabotropic glutamate receptor (mGluR6) that, when activated, couples to the G(o) class of G protein. The channel that is primarily responsible for the synaptic response has been recently identified as the transient receptor potential cation channel subfamily M member 1 (TRPM1); TRPM1 is negatively coupled to the mGluR6/Go cascade such that activation of the cascade results in closure of the channel. Light indirectly opens TRPM1 by reducing transmitter release from presynaptic photoreceptors, resulting in a decrease in mGluR6 activation. Conversely, in the dark, binding of synaptic glutamate to mGluR6 inhibits TRPM1 current. Closure of TRPM1 by G-protein activation in the dark is a critical step in the process of ON bipolar cell signal transduction, but the precise pathway linking these two events is not understood. To address this question, we measured TRPM1 activity in retinal bipolar cells, in human ependymal melanocytes (HEMs) that endogenously express TRPM1, and in HEK293 cells transfected with TRPM1. Dialysis of the Gßγ subunit dimer, but not Gα(o), closed TRPM1 channels in every cell type that we tested. In addition, activation of an endogenous G-protein-coupled receptor pathway in HEK293 cells that releases Gßγ without activating Go protein also closed TRPM1 channels. These results suggest a model in which the Gßγ dimer that is released as a result of the dissociation from Gα(o) upon activation of mGluR6 closes the TRPM1 channel, perhaps via a direct interaction.

Phase II study of neoadjuvant therapy with docetaxel, cisplatin, panitumumab, and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051).

BACKGROUND: Preoperative chemoradiotherapy (CRT) improves outcomes in patients with locally advanced but resectable adenocarcinoma of the esophagus. ACOSOG Z4051 evaluated CRT with docetaxel, cisplatin, and panitumumab (DCP) in this patient group with a primary end point of a pathologic complete response (pCR) ≥35%. PATIENTS AND METHODS: From 15 January 2009 to 22 July 2011, 70 patients with locally advanced but resectable distal esophageal adenocarcinoma were enrolled. Patients received docetaxel (40 mg/m(2)), cisplatin (40 mg/m(2)), and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with RT (5040 cGy, 180 cGy/day × 28 days) beginning week 5. Resection was planned after completing CRT. PCR was defined as no viable residual tumor cells. Secondary objectives included near-pCR (≤10% viable cancer cells), toxicity, and overall and disease-free survival. Adverse events were graded using the CTCAE Version 3.0. RESULTS: Five of 70 patients were ineligible. Of 65 eligible patients (59 M; median age 61), 11 did not undergo surgery, leaving 54 assessable. PCR rate was 33.3% and near-pCR was 20.4%. Secenty-three percent of patients completed DCP (n = 70) and 92% completed RT. 48.5% had toxicity ≥grade 4. Lymphopenia (43%) was most common. Operative mortality was 3.7%. Adult respiratory distress syndrome was encountered in two patients (3.7%). At median follow-up of 26.3 months, median overall survival was 19.4 months and 3-year overall survival was 38.6% (95% confidence interval 24.5% to 60.8%). CONCLUSIONS: Neoadjuvant CRT with DCP is active (pCR + near-pCR = 53.7%) but toxicity is significant. Further evaluation of this regimen in an unselected population is not recommended. CLINICALTRIALSGOV IDENTIFIER: NCT00757172.