The A1/A2 ß-casein genotype of cows, but not their horn status, influences peptide generation during simulated digestion of milk.

The effect of the horn status of cows on their milk composition and quality is a controversial research topic. In this study, 128 milk samples from 64 horned and 64 disbudded Brown Swiss and Original Braunvieh cows were collected from alpine farms where both horned and disbudded cows were grazing on mountain pastures. The samples were analyzed for their detailed composition and protein digestion in a simulated in vitro digestion (INFOGEST). To exclude probable influences on digestion, the ß-casein genotype with its variants A1 and A2 was also included in the study. The effects of horn status and ß-casein genotype were investigated in linear mixed models, which included additional influencing random factors such as Original Braunvieh blood proportion, stage of lactation, and farm. Horn status did not have any effect on milk composition or digestion. In contrast, milk from A1A1 cows showed a different protein digestion than milk of A1A2 and A2A2 cows in the gastric phase, including smaller amounts of ß-casomorphin(BCM)21-associated peptides and larger amounts of BCM11-associated peptides. Abundances of BCM7 did not differ between ß-casein genotypes. At the end of the intestinal phase, the digested milk of A1A1 and A2A2 b-casein genotypes did not differ.

Influence of dietary fiber content and horn status on thermoregulatory responses of Brown Swiss dairy cows under thermoneutral and short-term heat stress conditions.

In the present experiment, 10 horned and 10 disbudded mid-lactating Brown Swiss cows were included in a crossover feeding trial with a hay or hay and concentrate diet. The effects of dietary neutral detergent fiber (NDF) content and horn status on thermoregulatory responses under thermoneutral and short-term heat stress conditions were studied, as both are considered to ease the cow's thermoregulation under an environmental heat load. Cows received either ad libitum hay and alfalfa pellets (85:15, C-, NDF content: 41.0%) or restricted amounts of hay and concentrate (70:30, C+, NDF content: 34.5%). The level of restriction applied with the C+ diet was determined from pre-experimental ad libitum intakes, ensuring that both diets provided the same intake of net energy for lactation (NEL). For data collection, cows were housed in respiration chambers for 5 d. The climatic conditions were 10°C and 60% relative humidity (RH), considered thermoneutral (TN) conditions (temperature-humidity index (THI): 52) for d 1 and 2, and 25°C and 70% RH, considered heat stress (HS) conditions (THI: 74), for d 4 and 5. On d 3, the temperature and RH were increased gradually. Compared with TN, HS conditions increased the water intake, skin temperature, respiration and heart rates, and endogenous heat production. They did not affect body temperature, feed intake, or milk production. Lowering dietary fiber content via concentrate supplementation lowered methane and increased carbon dioxide production. It did not mitigate physiological responses to HS. Although the responses of horned and disbudded cows were generally similar, the slower respiration rates of horned cows under HS conditions indicate a possible, albeit minor, role of the horn in thermoregulation. In conclusion, future investigations on nutritional strategies must be conducted to mitigate mild heat stress.

Effects of Acacia mearnsii added to silages differing in nutrient composition and condensed tannins on ruminal and manure-derived methane emissions of dairy cows.

This study investigated the effects of acacia (extract of Acacia mearnsii) and sainfoin (Onobrychis viciifolia) as condensed tannin (CT)-rich sources on ruminal and manure methane (CH4) emissions in comparison with non-CT silages characterized by different contents of the cell wall and water-soluble carbohydrates. In a 3 × 6 incomplete Latin square design, 30 Holstein cows (63 ± 23 d in milk; mean ± SD; 33.8 ± 7.6 kg of milk per day, body weight 642 ± 81 kg) were provided with ad libitum access to 1 of 6 total mixed rations comprising 790 g of silage and 210 g of concentrate per kilogram of dry matter (DM). The silages were either rich in sainfoin [neutral detergent fiber (NDF): 349 g/kg of DM], perennial ryegrass (NDF: 420 g/kg of DM), or red clover (NDF: 357 g/kg of DM). Each silage was supplemented with 20 g/kg (of total diet DM) of acacia or straw meal. Feed intake and milk yield were recorded daily. Milk composition and ruminal fluid characteristics and microbiota were analyzed. The individual ruminal CH4 production was determined using the GreenFeed system, and CH4 emissions from the manure of cows fed the same diets were measured in a parallel experiment over 30 d at 25°C using a dynamic flux chamber. The CT sources did not reduce CH4 yield or emission intensity. Acacia reduced milk production (from 26.3 to 23.2 kg/d) and DM intake (from 19.7 to 16.7 kg/d) when supplemented with ryegrass, and both CT sources reduced the milk protein content and yield. Acacia supplementation and ryegrass silage reduced the ruminal acetate:propionate ratio. Furthermore, during acacia treatment, the abundance of Methanobrevibacter archaea tended to be lower and that of Thermoplasmata was higher. Acacia reduced the CH4 emissions from manure for the ryegrass group by 17% but not for the sainfoin and clover groups. Feeding sainfoin silage resulted in the lowest manure-derived CH4 emissions (-47% compared with ryegrass). In conclusion, acacia reduced ruminal CH4 production by 10%, but not emission intensity, and the mitigation effect of sainfoin depended on the silage to which it was compared. Because mitigation was partially associated with animal productivity losses, careful evaluation is required before the implementation of tanniferous feeds in farm practice.

Are patients benefiting from participation in the German skin cancer screening programme? A large cohort study based on administrative data.

BACKGROUND: The German programme for skin cancer screening was established in 2008 with the aim of reducing skin cancer mortality. However, the effectiveness and risk-benefit ratio of the programme remain unclear. OBJECTIVES: To compare the mortality rates of patients with melanoma who participate in a screening programme to those who do not. METHODS: A retrospective cohort study, based on pseudonymized health insurance data of 1 431 327 individuals from Saxony, Germany, was conducted for the period 2010-2016. Patients with prevalent and incident melanoma were defined based on diagnosis, medical procedures and prescriptions. Patients who underwent screening and had a first diagnosis of melanoma within 2 years of screening were assigned to the intervention group. Relative survival and Cox regression were used to assess potential differences in mortality. RESULTS: We identified 4552 individuals with prevalent and 2475 individuals with incident melanoma. The percentage of screening participants (n = 1801) who had locoregional (4·2% vs. 13·5%) and/or distant metastases (4·3% vs. 8·0%), or who were treated with systemic anticancer therapies (11·6% vs. 21·8%) was lower vs. nonparticipants (n = 674). Screening participants had significantly better survival rates. The unadjusted Cox model gave a hazard ratio (HR) of 0·37 [95% confidence interval (CI) 0·30-0·46]. After adjusting for named confounders, the effect remained (HR 0·62, 95% CI 0·48-0·80). CONCLUSIONS: Patients who participated in the screening programme had lower mortality than those who had not undergone screening. However, these findings may result from a healthy screen bias and/or overdiagnosis associated with screening, and not from the screening itself.

Urban Water Storage Capacity Inferred From Observed Evapotranspiration Recession.

Water storage plays an important role in mitigating heat and flooding in urban areas. Assessment of the water storage capacity of cities remains challenging due to the inherent heterogeneity of the urban surface. Traditionally, effective storage has been estimated from runoff. Here, we present a novel approach to estimate effective water storage capacity from recession rates of observed evaporation during precipitation-free periods. We test this approach for cities at neighborhood scale with eddy-covariance based latent heat flux observations from 14 contrasting sites with different local climate zones, vegetation cover and characteristics, and climates. Based on analysis of 583 drydowns, we find storage capacities to vary between 1.3 and 28.4 mm, corresponding to e-folding timescales of 1.8-20.1 days. This makes the urban storage capacity at least five times smaller than all the observed values for natural ecosystems, reflecting an evaporation regime characterized by extreme water limitation.

High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the eccrine sweat glands. Due to the lack of effective therapies, metastasis is associated with a high mortality rate. OBJECTIVES: To investigate the drivers of EPC progression. METHODS: We carried out genomic and transcriptomic profiling of metastatic EPC (mEPC), validation of the observed alterations in an EPC patient-derived cell line, confirmation of relevant observations in a large patient cohort of 30 tumour tissues, and successful treatment of a patient with mEPC under the identified treatment regimens. RESULTS: mEPC was characterized by a high tumour mutational burden (TMB) with an ultraviolet signature, widespread copy number alterations and gene expression changes that affected cancer-relevant cellular processes such as cell cycle regulation and proliferation, including a pathogenic TP53 (tumour protein 53) mutation, a copy number deletion in the CDKN2A (cyclin dependent kinase inhibitor 2A) region and a CTNND1/PAK1 [catenin delta 1/p21 (RAC1) activated kinase 1] gene fusion. The overexpression of EGFR (epidermal growth factor receptor), PAK1 and MAP2K1 (mitogen-activated protein kinase kinase 1; also known as MEK1) genes translated into strong protein expression and respective pathway activation in the tumour tissue. Furthermore, a patient-derived cell line was sensitive to EGFR and MEK inhibition, confirming the functional relevance of the pathway activation. Immunohistochemistry analyses in a large patient cohort showed the relevance of the observed changes to the pathogenesis of EPC. Our results indicate that mEPC should respond to immune or kinase inhibitor therapy. Indeed, the advanced disease of our index patient was controlled by EGFR-directed therapy and immune checkpoint inhibition for more than 2 years. CONCLUSIONS: Molecular profiling demonstrated high TMB and EGFR/MAPK pathway activation to be novel therapeutic targets in mEPC.

Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in Germany - The non-interventional study NIELS.

BACKGROUND: Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC. OBJECTIVES: The aim of this non-interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany. METHODS: This non-interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive. RESULTS: Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n = 49 patients with response). The median progression-free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified. CONCLUSIONS: The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice.

GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma.

BACKGROUND: GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma. OBJECTIVES: To characterize these tumours in terms of clinical behaviour and genetic characteristics. METHODS: Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death-ligand 1 and BRCA1-associated protein (BAP)1. Existing whole-exome cutaneous and uveal melanoma data were analysed for mutation type and burden. RESULTS: We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X-linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%). CONCLUSIONS: Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed. What is already known about this topic? The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented. GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma. What does this study add? GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma. GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma. What is the translational message? Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma. As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed. Linked Comment: Rafei-Shamsabadi. Br J Dermatol 2020; 183:806-807.

Accuracy of methane emissions predicted from milk mid-infrared spectra and measured by laser methane detectors in Brown Swiss dairy cows.

Since heritability of CH4 emissions in ruminants was demonstrated, various attempts to generate large individual animal CH4 data sets have been initiated. Predicting individual CH4 emissions based on equations using milk mid-infrared (MIR) spectra is currently considered promising as a low-cost proxy. However, the CH4 emission predicted by MIR in individuals still has to be confirmed by measurements. In addition, it remains unclear how low CH4 emitting cows differ in intake, digestion, and efficiency from high CH4 emitters. In the current study, putatively low and putatively high CH4 emitting Brown Swiss cows were selected from the entire Swiss herdbook population (176,611 cows), using an MIR-based prediction equation. Eventually, 15 low and 15 high CH4 emitters from 29 different farms were chosen for a respiration chamber (RC) experiment in which all cows were fed the same forage-based diet. Several traits related to intake, digestion, and efficiency were quantified over 8 d, and CH4 emission was measured in 4 open circuit RC. Daily CH4 emissions were also estimated using data from 2 laser CH4 detectors (LMD). The MIR-predicted CH4 production (g/d) was quite constant in low and high emission categories, in individuals across sites (home farm, experimental station), and within equations (first available and refined versions). The variation of the MIR-predicted values was substantially lower using the refined equation. However, the predicted low and high emitting cows (n = 28) did not differ on average in daily CH4 emissions measured either with RC or estimated using LMD, and no correlation was found between CH4 predictions (MIR) and CH4 emissions measured in RC. When individuals were recategorized based on CH4 yield measured in RC, differences between categories of 10 low and 10 high CH4 emitters were about 20%. Low CH4 emitting cows had a higher feed intake, milk yield, and residual feed intake, but they differed only weakly in eating pattern and digesta mean retention times. Low CH4 emitters were characterized by lower acetate and higher propionate proportions of total ruminal volatile fatty acids. We concluded that the current MIR-based CH4 predictions are not accurate enough to be implemented in breeding programs for cows fed forage-based diets. In addition, low CH4 emitting cows have to be characterized in more detail using mechanistic studies to clarify in more detail the properties that explain the functional differences found in comparison with other cows.

Gene expression profiling in aggressive digital papillary adenocarcinoma sheds light on the architecture of a rare sweat gland carcinoma.

BACKGROUND: Sweat gland carcinomas are rare cutaneous adnexal malignancies. Aggressive digital papillary adenocarcinoma (ADPA) represents a very rare subentity, thought to arise almost exclusively from the sweat glands of the fingers and toes. The aetiology of sweat gland carcinomas and ADPA is largely unknown. ADPAs are most likely driven by somatic mutations. However, somatic mutation patterns are largely unexplored, creating barriers to the development of effective therapeutic approaches to the treatment of ADPA. OBJECTIVES: To investigate the transcriptome profile of ADPA using a sample of eight formalin-fixed, paraffin-embedded tissue samples of ADPA and healthy control tissue. METHODS: Transcriptome profiling was performed using the Affymetrix PrimeView Human Gene Expression Microarray and findings were validated via reverse transcription of RNA and real-time quantitative polymerase chain reaction. RESULTS: Transcriptome analyses showed increased tumour expression of 2266 genes, with significant involvement of cell cycle, ribosomal and crucial cancer pathways. Our results point to tumour overexpression of FGFR2 (P = 0·001). CONCLUSIONS: The results indicate the involvement of crucial oncogenic driver pathways, highlighting cell cycle and ribosomal pathways in the aetiology of ADPA. Suggested tumour overexpression of FGFR2 raises the hope that targeting the fibroblast growth factor (FGF)/FGF receptor axis might be a promising treatment for ADPA and probably for the overall group of sweat gland carcinomas.

Medical treatment of advanced cutaneous squamous-cell carcinoma.

Considering the rising incidence, cutaneous squamous-cell carcinoma (cSCC) has a high clinical relevance. In patients with localized cSCC, complete surgical resection is indicated. Radiotherapy should be performed in patients with non-resectable tumours or in patients who are not suitable for surgery. Systemic therapy is reserved for cSCC that are neither surgically nor radiotherapeutically curable due to their extensive local spread and/or local or distant metastasis. In the absence of prospective randomized phase 3 trials to evaluate and compare the efficacy and safety of chemotherapeutics, epidermal growth factor receptor (EGFR) inhibitors and anti-PD-1 antibodies, no final recommendation for systemic therapy can be given for patients with locally advanced or metastatic cSCC. Anti-PD-1 antibodies currently show promising results with response rates of up to 50% in both locally advanced and metastatic cSCC. Anti-PD-1 antibodies appear to achieve higher response rates compared with EGFR inhibitors, and the duration of response appears to be superior to both chemotherapy and EGFR inhibitors. Compared with chemotherapy, the side effect profile of anti-PD-1 antibodies appears to be favourable. Altogether, PD-1 inhibitors are expected to become the new standard of care for patients with locally advanced and metastatic cSCC. Currently, placebo-controlled clinical trials are investigating the adjuvant use of cemiplimab and pembrolizumab in patients undergoing resection and radiotherapy of high-risk cSCC. Patients not eligible for anti-PD-1 treatment, e.g. in organ transplant recipients, or in patients refractory to anti-PD-1 may be offered EGFR inhibitors and/or chemotherapies. Chemotherapies appear to be superior to EGFR inhibitors in terms of response rates, whereas EGFR inhibitors have a more favourable toxicity profile. EGFR inhibitors are therefore more suitable for multimorbid and/or frail elderly patients. By combining EGFR inhibitors with local therapy such as surgery or radiotherapy, response rates and duration of response may be improved.

Persistence of differences between dairy cows categorized as low or high methane emitters, as estimated from milk mid-infrared spectra and measured by GreenFeed.

Currently, various attempts are being made to implement breeding schemes aimed at producing low methane (CH4) emitting cows. We investigated the persistence of differences in CH4 emission between groups of cows categorized as either low or high emitters over a 5-mo period. Two feeding regimens (pasture vs. indoors) were used. Early- to mid-lactation Holstein Friesian cows were categorized as low or high emitters (n = 10 each) retrospectively, using predictions from milk mid-infrared (MIR) spectra, before the start of the experiment. Data from MIR estimates and from measurements with the GreenFeed (GF; C-Lock Technology Inc., Rapid City, SD) system over the 5-mo experiment were combined into 7-, 14-, and 28-d periods. Feed intake, eating and ruminating behavior, and ruminal fluid traits were determined in two 7-d measurement periods in the grazing season. The CH4 emission data were analyzed using a split-plot ANOVA, and the repeatability of each of the applied methods for determining CH4 emission was calculated. Traits other than CH4 emission were analyzed for differences between low and high emitters using a linear mixed model. The initial category-dependent differences in daily CH4 production persisted over the subsequent 5 mo and across 2 feeding regimens with both methods. The repeatability analysis indicated that the biweekly milk control scheme, and even a monthly scheme as practiced on farms, might be sufficient for confirming category differences. However, the relationship between CH4 data estimated by MIR and measured with GF for individual cows was weak (R2 = 0.26). The categorization based on CH4 production also generated differences in CH4 emission per kilogram of milk; differentiation between cow categories was not persistent based on milk MIR spectra and GF. Compared with the high emitters, low emitters tended to show a lower acetate-to-propionate ratio in ruminal volatile fatty acids, whereas feed intake and ruminating time did not differ. Interestingly, the low emitters spent less time eating than the high emitters. In conclusion, the CH4 estimation from analyzing the milk MIR spectra is an appropriate proxy to form and regularly control categories of cows with different CH4 production levels. The categorization was also sufficient to secure similar and persistent differences in emission intensity when estimated by MIR spectra of the milk. Further studies are needed to determine whether MIR data from individual cows are sufficiently accurate for breeding.

[Information services for melanoma patients and awareness among those affected]. / Informationsangebote für Melanompatienten und ihre Bekanntheit unter Betroffenen.

BACKGROUND: Besides medical consultations, various sources of information and support are available for melanoma patients (MP) in Germany from commercial and non-commercial providers; however, little is known about how they are perceived and accepted by MPs. MATERIAL AND METHODS: Between July and October 2016 a total of 529 melanoma patients were surveyed at 27 accredited German skin cancer centers by means of a standardized questionnaire. Their awareness and satisfaction with 12 given sources of information and counseling services (print, online and by telephone) were surveyed. The sources were recommended by renowned providers from the field of (dermatological) oncology for use by MPs. RESULTS: The MPs reported that the booklets called The blue advisor - skin cancer (Die Blauen Ratgeber - Hautkrebs, 43%) and Patient guidelines melanoma (Patientenleitlinie Melanom 24%) and the online domain www.hautkrebs-screening.de (23%) were the best known sources. These also met the information needs of the majority of users (65-80%). Booklets from commercial providers (between 8-16% known) were satisfactory for 42-56% of users. At 14% and 11%, respectively, the cancer counseling services (Krebsinformationsdienst) and INFONETZ Krebs as mainly telephone advisory offers were less well known. Few MPs were familiar with the skin cancer or melanoma booklets of the Austrian Cancer Aid and the Swiss Cancer League (2% each). CONCLUSION: The increased awareness and acceptance of booklets as well as information from principally non-commercial providers suggest that they are more often mediated to MPs and more frequently used and accepted by those affected.

Adrenal cortex reactivity in dairy cows differs between lactational stages and between different feeding levels.

Changes in ACTH challenge test characteristics in dairy cows changing their physiological status at different lactational stages and different feeding levels were not investigated in terms of repeatability yet. In 23 multiparous Holstein cows (10 cows fed a sole fresh herbage diet without concentrate, 13 cows fed with concentrate), three ACTH challenge tests were performed: once during pregnancy shortly prior to drying off (T1), and in week 3 (T2) and 8 (T3) after parturition. Test characteristics were correlated to performance and metabolic parameters: DMI, BW, energy balance (EB), plasma concentrations of free fatty acids (NEFA) and beta-hydroxybutyrate (BHB). Basal plasma cortisol concentrations were higher at T1 compared with T2 and T3 (p < .05). The adrenal cortex sensitivity (expressed as total AUC (AUCt ) of cortisol response after ACTH application) was lowest at T2 compared with T1 and T3 (p < .05). Ranking of the individual animals' responses was not repeatable between time points of the ACTH tests. Enhancing the energy deficiency during early lactation by omission of concentrate did not affect baseline cortisol concentrations in plasma, but decreased peak height at T2 (p < .05). Baseline plasma cortisol concentrations were positively correlated with cortisol peak values after ACTH application, previous lactation performance, milk yield and BW (p < .05). The AUCt was positively correlated with baseline cortisol concentrations, EB and DMI. Cortisol release after ACTH injection was lower in animals with high plasma concentrations of NEFA, BHB and with higher contents of fat and free fatty acids in milk (p < .05). Cortisol peak height after ACTH administration was higher in cows with a more positive EB, higher DMI and lower plasma concentrations of NEFA and BHB. In summary, cortisol responses to ACTH challenges in this study were not repeatable in dairy cows changing their physiological status.

Using plant wax markers to estimate the diet composition of grazing Holstein dairy cows.

The objective of this study was to test whether diet selection of dairy cows under grazing conditions could be estimated using plant wax markers. Furthermore, differences between 2 cow strains and the effect of concentrate supplementation on plant species selection were investigated. The experiment was a study with a crossover design performed on an organic farm with 12 Swiss Holstein cows and 12 New Zealand Holstein cows. Both experimental periods consisted of a 21-d adaptation and a 7-d measurement period. All cows grazed full time in a rotational stocking system and received either no concentrate or 6 kg/d of a commercial cereal-grain mix. Representative herbage samples of each grazed paddock were taken and botanical composition of subsamples was manually determined. The average proportions of the plant species were 27.8% Lolium perenne, 6.1% Dactylis glomerata, 10.4% Trifolium repens, and 9.0% Taraxacum officinale. Other grass species were merged as "other grass" (38.2%) and other forb species as "other forbs" (8.5%). n-Alkanes, long-chain fatty acids, and long-chain alcohols (LCOH) were analyzed in the samples of plant species, concentrate, and feces from each cow. A linear discriminant analysis indicated that diet components were differentiated best with LCOH (96%) and worst with the combination of all marker groups together (12%). For each marker, the fecal marker recovery (FR) relative to dosed ytterbium was determined in 2 ways. Estimation of diet composition was performed with the software "EatWhat," and results were compared with botanical composition with the Aitchison distance. The results indicate that the diet composition of grazing dairy cows can be estimated using plant wax markers. Additionally, the calculation of FR led to mostly reliable results, yet this approach needs further validation. The most accurate estimation was achieved with the marker combination of n-alkanes and LCOH with a correction for FR. Less accurate estimations were achieved with long-chain fatty acids alone or in combination with n-alkanes. No difference relating to diet selection between the 2 cow strains was recorded, but supplemented cows apparently ingested higher proportions of T. repens than nonsupplemented cows. Awareness that supplementation influences selection behavior of grazing dairy cows may lead to adaptations in botanical composition of the pasture according to the demand of the animals.

Metabolic load in dairy cows kept in herbage-based feeding systems and suitability of potential markers for compromised well-being.

Herbage feeding with only little input of concentrates plays an important role in milk production in grassland dominated countries like Switzerland. The objective was to investigate the effects of a solely herbage-based diet and level of milk production on performance, and variables related to the metabolic, endocrine and inflammatory status to estimate the stress imposed on dairy cows. Twenty-five multiparous Holstein cows were divided into a control (C+, n = 13) and a treatment group (C-, n = 12), according to their previous lactation yield (4679-10 808 kg) from week 3 ante partum until week 8 post-partum (p.p.). While C+ received fresh herbage plus additional concentrate, no concentrate was fed to C- throughout the experiment. Within C+ and C-, the median of the preceding lactation yields (7752 kg) was used to split cows into a high (HYC+, HYC-)- and low-yielding (LYC+, LYC-) groups. Throughout the study, HYC+ had a higher milk yield (35.9 kg/d) compared to the other subgroups (27.2-31.7 kg/d, p < 0.05). Plasma glucose (3.51 vs. 3.72 mmol/l) and IGF-1 (66.0 vs. 78.9ng/mL) concentrations were lower in HYC-/LYC- compared to HYC+/LYC+ cows (p < 0.05). Plasma FFA and BHBA concentrations were dramatically elevated in HYC- (1.1 and 1.6 mmol/l) compared to all other subgroups (mean values: 0.5 and 0.6 mmol/l, p < 0.05). Saliva cortisol, plasma concentrations of serum amyloid A (SAA), haptoglobin (Hp), beta-endorphin (BE) and activity of alkaline phosphatase (AP) were not different between C+ and C-. In conclusion, herbage-fed high-yielding cows without supplementary concentrate experienced a high metabolic load resulting in a reduced performance compared to cows of similar potential fed accordingly. Low-yielding cows performed well without concentrate supplementation. Interestingly, the selected markers for inflammation and stress such as cortisol, Hp, SAA, BE and AP gave no indication for the metabolic load being translated into compromised well-being.

Ocular Toxoplasmosis: Therapy-Related Adverse Drug Reactions and Their Management.

Background There are different treatment options for ocular toxoplasmosis (OT). "Classic" therapy consists of pyrimethamine, sulfadiazine and folinic acid combined with systemic steroids and is still widely used. However, potentially severe side effects of this therapy have been reported. The aim of this retrospective study was to evaluate the incidence and types of adverse drug reactions in patients treated for OT. Clinical management of each adverse drug reaction was assessed. Patients and Methods In this retrospective analysis, we reviewed data of patients with OT, who were consecutively examined between December 2011 and December 2015 at the Department of Ophthalmology, University Hospital Zurich. Results In total, 49 patients had at least one episode of active OT. In 54 (83.0 %) of 65 treated episodes, the classic regimen was used. Of the 37 patients who received classic treatment, 9 (24.3 %) developed at least one adverse drug reaction which led to drug discontinuation, including elevated creatinine (5.4 %), elevated liver enzymes (5.4 %), vomiting (5.4 %), rash (5.4 %) and facial swelling (2.7 %). In 5 patients, treatment was switched to another drug, while in the other 4 patients, therapy was stopped. In these 9 patients, inflammation was well controlled 8 weeks after onset of therapy. No patient suffered from severe side effects, such as potentially life-threatening allergic reactions or pancytopenia. Conclusions In OT patients who were treated with classic therapy, adverse drug reactions are common. Therefore, clinical and laboratory monitoring is mandatory. Adverse drug reactions may require interdisciplinary management.

Effects of the German skin cancer screening programme on melanoma incidence and indicators of disease severity.

BACKGROUND: In Germany a nationwide melanoma screening programme for adults aged ≥ 35 years was introduced in July 2008. Evidence on utilization and effects is limited. OBJECTIVES: To examine the uptake and effects of the German nationwide screening programme. METHODS: This analysis is based on pseudonymized outpatient routine data of a German health insurance company covering data of > 2 million individuals from Saxony for the years 2005-2012. Cases of melanoma and nonmelanoma skin cancer (NMSC) were identified using an algorithm based on the International Classification of Diseases, 10th Revision. Cross-sectional and longitudinal analyses were applied to determine the utilization of the screening programme and effects on skin cancer incidence and disease severity as a proxy for prognosis. RESULTS: Overall, 38·0% of eligible persons (≥ 35 years) were screened at least once between July 2008 and December 2012. The annual participation rate was 12·4%. Out of 533 393 persons screened, melanoma and NMSC were diagnosed in 0·3% and 2·5%, respectively. The 6-month melanoma incidence per 100 000 insured persons decreased from 12·8 before screening introduction (January to June 2008) to 10·2 after introduction (July to December 2008). NMSC incidence increased from 173·8 to 175·5 per 100 000. The numbers of screening participants receiving interferon alpha and/or being diagnosed with lymph node and/or distant metastasis (8·6%, 5·9%, 1·5%, respectively) were lower than in nonparticipants (11·2%, 8·5%, 3·5%). These differences were not significant. CONCLUSIONS: The results suggest that the introduction of a generic skin cancer screening programme in Germany was not associated with significant changes in incidence. No firm conclusions regarding the effects of skin cancer screening on prognosis can be drawn. Longer follow-up and linkage with clinical registry data are necessary to clarify the effect of screening participation on incidence and prognosis.

Imaging the Fano lattice to 'hidden order' transition in URu(2)Si(2).

Within a Kondo lattice, the strong hybridization between electrons localized in real space (r-space) and those delocalized in momentum-space (k-space) generates exotic electronic states called 'heavy fermions'. In URu(2)Si(2) these effects begin at temperatures around 55 K but they are suddenly altered by an unidentified electronic phase transition at T(o) = 17.5 K. Whether this is conventional ordering of the k-space states, or a change in the hybridization of the r-space states at each U atom, is unknown. Here we use spectroscopic imaging scanning tunnelling microscopy (SI-STM) to image the evolution of URu(2)Si(2) electronic structure simultaneously in r-space and k-space. Above T(o), the 'Fano lattice' electronic structure predicted for Kondo screening of a magnetic lattice is revealed. Below T(o), a partial energy gap without any associated density-wave signatures emerges from this Fano lattice. Heavy-quasiparticle interference imaging within this gap reveals its cause as the rapid splitting below T(o) of a light k-space band into two new heavy fermion bands. Thus, the URu(2)Si(2) 'hidden order' state emerges directly from the Fano lattice electronic structure and exhibits characteristics, not of a conventional density wave, but of sudden alterations in both the hybridization at each U atom and the associated heavy fermion states.