Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

[Curriculum "Tracheostomy management in dysphagia therapy"]. / Curriculum "Trachealkanülenmanagement in der Dysphagietherapie".

The number of tracheotomized patients with dysphagia and their need for treatment are continuously increasing in clinical and community settings. The revised version of the directive on home care and community-based intensive care of the Federal Joint Committee (G-BA) requires that tracheotomized patients are regularly evaluated with the aim of identifying and promoting the therapeutic potential after hospital discharge. Dysphagia treatment plays a crucial role as without improvement of severe dysphagia there is practically no possibility for decannulation. Tracheotomized patients with dysphagia are treated by speech and language therapists (SLT); however, the contents of tracheostomy management (TM) are not obligatory in the speech and language therapeutic training curricula, so that there is a need for further education and treatment standards must be secured. Therefore, the German Interdisciplinary Society for Dysphagia (DGD) in cooperation with the participating German medical and therapeutic societies developed a postgraduate curriculum for TM. This should serve as the basis for contents in TM and qualification of therapists within the framework of the delegation of medical services. The goals of the TM curriculum are the definition of theoretical and practical contents of TM, the qualification to perform TM according to current standards of care and quality assurance. The curriculum defines two qualification levels (user and trainer), entry requirements, curricular contents, examination and qualification criteria as well as transitional regulations for SLTs already experienced in TM.

[Curriculum "Tracheostomy management in dysphagia therapy"]. / Curriculum "Trachealkanülenmanagement in der Dysphagietherapie".

The number of tracheotomized patients with dysphagia and their need for treatment are continuously increasing in clinical and community settings. The revised version of the directive on home care and community-based intensive care of the Federal Joint Committee (G-BA) requires that tracheotomized patients are regularly evaluated with the aim of identifying and promoting the therapeutic potential after hospital discharge. Dysphagia treatment plays a crucial role as without improvement of severe dysphagia there is practically no possibility for decannulation. Tracheotomized patients with dysphagia are treated by speech and language therapists (SLT); however, the contents of tracheostomy management (TM) are not obligatory in the speech and language therapeutic training curricula, so that there is a need for further education and treatment standards must be secured. Therefore, the German Interdisciplinary Society for Dysphagia (DGD) in cooperation with the participating German medical and therapeutic societies developed a postgraduate curriculum for TM. This should serve as the basis for contents in TM and qualification of therapists within the framework of the delegation of medical services. The goals of the TM curriculum are the definition of theoretical and practical contents of TM, the qualification to perform TM according to current standards of care and quality assurance. The curriculum defines two qualification levels (user and trainer), entry requirements, curricular contents, examination and qualification criteria as well as transitional regulations for SLTs already experienced in TM.

Longterm course of neuropsychological symptoms and ME/CFS after SARS-CoV-2-infection: a prospective registry study.

A significant proportion of patients after SARS-CoV-2 infection suffer from long-lasting symptoms. Although many different symptoms are described, the majority of patients complains about neuropsychological symptoms. Additionally, a subgroup of patients fulfills diagnostic criteria for ME/CFS. We analyzed a registry of all patients presenting in the out-patients clinic at a German university center. For patients with more than one visit, changes in reported symptoms from first to second visit were analyzed. A total of 1022 patients were included in the study, 411 of them had more than one visit. 95.5% of the patients reported a polysymptomatic disease. At the first visit 31.3% of the patients fulfilled ME/CFS criteria after a median time of 255 days post infection and and at the second visit after a median of 402 days, 19.4% still suffered from ME/CFS. Self-reported fatigue (83.7-72.7%) and concentration impairment (66.2-57.9%) decreased from first to second visit contrasting non-significant changes in the structured screening. A significant proportion of SARS-CoV-2 survivors presenting with ongoing symptoms present with ME/CFS. Although the proportion of subjective reported symptoms and their severity reduce over time, a significant proportion of patients suffer from long-lasting symptoms necessitating new therapeutic concepts.

The use of 3-dimensional imaging of Holstein cows to estimate body weight and monitor the composition of body weight change throughout lactation.

Three-dimensional (3D) imaging offers new possibilities in animal phenotyping. Here, we investigated how this technology can be used to study the morphological changes that occur in dairy cows over the course of a single lactation. First, we estimated the individual body weight (BW) of dairy cows using traits measured with 3D images. To improve the quality of prediction, we monitored body growth (via 3D imaging), gut fill (via individual dry matter intake), and body reserves (via body condition score) throughout lactation. A group of 16 Holstein cows-8 in their first lactation, 4 in their second lactation, and 4 in their third or higher lactation-was scanned in 3D once a month for an entire lactation. Values of morphological traits (e.g., chest depth or hip width) increased continuously with parity, but cows in their first lactation experienced the largest increase during the monitoring period. Values of partial volume, estimated from point of shoulder to pin bone, predicted BW with an error of 25.4 kg (R2 = 0.92), which was reduced to 14.3 kg when the individual effect of cows was added to the estimation model. The model was further improved by the addition of partial surface area (from point of shoulder to pin bone), hip width, chest depth, diagonal length, and heart girth, which increased the R2 of BW prediction to 0.94 and decreased root mean square error to 22.1 kg. The different slopes for individual cows were partly explained by body condition score and morphological traits, indicating that they may have reflected differences in body density among animals. Changes in BW over the course of lactation were mostly due to changes in growth, which accounted for around two-thirds of BW gain regardless of parity. Body reserves and gut fill had smaller but still notable effects on body composition, with a higher gain in body reserves and gut fill for cows in their first lactation compared with multiparous cows. This work demonstrated the potential for rapid and low-cost 3D imaging to facilitate the monitoring of several traits of high interest in dairy livestock farming.

Poor long-term prognosis in patients admitted with strong suspicion of acute myocardial infarction but discharged with another diagnosis.

BACKGROUND: Characteristics and prognosis of patients admitted with strong suspicion of myocardial infarction (MI) but discharged without an MI diagnosis are not well-described. OBJECTIVES: To compare background characteristics and cardiovascular outcomes in patients discharged with or without MI diagnosis. METHODS: The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) trial compared 6629 patients with strong suspicion of MI randomized to oxygen or ambient air. The main composite end-point of this subgroup analysis was the incidence of all-cause death, rehospitalization with MI, heart failure (HF) or stroke during a follow-up of 2.1 years (median; range: 1-3.7 years) irrespective of randomized treatment. RESULTS: 1619 (24%) received a non-MI discharge diagnosis, and 5010 patients (76%) were diagnosed with MI. Groups were similar in age, but non-MI patients were more commonly female and had more comorbidities. At thirty days, the incidence of the composite end-point was 2.8% (45 of 1619) in non-MI patients, compared to 5.0% (250 of 5010) in MI patients with lower incidences in all individual end-points. However, for the long-term follow-up, the incidence of the composite end-point increased in the non-MI patients to 17.7% (286 of 1619) as compared to 16.0% (804 of 5010) in MI patients, mainly driven by a higher incidence of all-cause death, stroke and HF. CONCLUSIONS: Patients admitted with a strong suspicion of MI but discharged with another diagnosis had more favourable outcomes in the short-term perspective, but from one year onwards, cardiovascular outcomes and death deteriorated to a worse long-term prognosis.

Bedside hyperspectral imaging indicates a microcirculatory sepsis pattern - an observational study.

INTRODUCTION: Microcirculatory alterations are key mechanisms in sepsis pathophysiology leading to tissue hypoxia, edema formation, and organ dysfunction. Hyperspectral imaging (HSI) is an emerging imaging technology that uses tissue-light interactions to evaluate biochemical tissue characteristics including tissue oxygenation, hemoglobin content and water content. Currently, clinical data for HSI technologies in critical ill patients are still limited. METHODS AND ANALYSIS: TIVITA® Tissue System was used to measure Tissue oxygenation (StO2), Tissue Hemoglobin Index (THI), Near Infrared Perfusion Index (NPI) and Tissue Water Index (TWI) in 25 healthy volunteers and 25 septic patients. HSI measurement sites were the palm, the fingertip, and a suprapatellar knee area. Septic patients were evaluated on admission to the ICU (E), 6 h afterwards (E+6) and three times a day (t3-t9) within a total observation period of 72 h. Primary outcome was the correlation of HSI results with daily SOFA-scores. RESULTS: Serial HSI at the three measurement sites in healthy volunteers showed a low mean variance expressing high retest reliability. HSI at E demonstrated significantly lower StO2 and NPI as well as higher TWI at the palm and fingertip in septic patients compared to healthy volunteers. StO2 and TWI showed corresponding results at the suprapatellar knee area. In septic patients, palm and fingertip THI identified survivors (E-t4) and revealed predictivity for 28-day mortality (E). Fingertip StO2 and THI correlated to SOFA-score on day 2. TWI was consistently increased in relation to the TWI range of healthy controls during the observation time. Palm TWI correlated positively with SOFA scores on day 3. DISCUSSION: HSI results in septic patients point to a distinctive microcirculatory pattern indicative of reduced skin oxygenation and perfusion quality combined with increased blood pooling and tissue water content. THI might possess risk-stratification properties and TWI could allow tissue edema evaluation in critically ill patients. CONCLUSION: HSI technologies could open new perspectives in microcirculatory monitoring by visualizing oxygenation and perfusion quality combined with tissue water content in critically ill patients - a prerequisite for future tissue perfusion guided therapy concepts in intensive care medicine.

Stereoscopic particle image velocimetry in inhomogeneous refractive index fields of combustion flows.

Particle image velocimetry (PIV) measurements in reactive flows are disturbed by inhomogeneous refractive index fields, which cause measurement deviations in particle positions due to light refraction. The resulting measurement errors are known for standard PIV, but the measurement errors for stereoscopic PIV are still unknown. Therefore, for comparison, the velocity errors for standard and stereoscopic PIV are analyzed in premixed propane flames with different Reynolds numbers. For this purpose, ray-tracing simulations based on the time-averaged inhomogeneous refractive index fields of the studied non-swirled flame flows measured by the background-oriented Schlieren technique are performed to quantify the resulting position errors of the particles. In addition, the performance of the volumetric self-calibration relevant to tomographic PIV is analyzed with respect to the remaining position errors of the particles within the flames. The position errors cause significant standard PIV errors of 2% for the velocity component radial to the burner symmetry axis. Stereoscopic PIV measurements result in measurement errors of up to 3% radial to the burner axis and 13% for the velocity component perpendicular to the measurement plane. Due to the lower refractive index gradients in the axial direction, no significant velocity errors are observed for the axial velocity component. For the investigated flame configurations, the position errors and velocity errors increase with the Reynolds numbers. However, this dependence needs to be verified for other flame configurations such as swirled flame flows.

Fretting-corrosion of CoCr-alloys against TiAl6V4: The importance of molybdenum in oxidative biological environments.

Periprosthetic fluids often contain reactive oxygen species, including H2O2, that are generated during inflammatory processes. Here, we investigated the fretting-corrosion behavior of CoCrX-alloys (X = Mo, Fe) in a complex protein-containing lubricant, with and without the addition of H2O2. Given the known protective role of molybdenum as an alloying element in metal degradation, we considered its effects by designing a two-way factorial experiment. The aim of the study was to investigate tribocorrosive mechanisms in modular joints of knee and hip prostheses. A previously described test-rig was used to run fretting corrosion tests of CoCrX-alloys with (X=Mo) and without (X=Fe) molybdenum against TiAl6V4 in bovine calf serum (BCS) with and without a physiological relevant H2O2 level (3 mM) in gross slip mode (4 Hz, ±50 µm, pmax=0.18 GPa, 37 °C, 50,000 cycles). Two CoCr-pins were pressed against a cylindrical TiAl6V4-rod, forming a line contact. Normal and frictional forces, the displacement, and the open circuit potential (OCP) were measured and recorded continuously. The dissipated frictional work was independent of alloy composition. The addition of H2O2 lowered the dissipated frictional work and increased wear, and this was significant in the absence of Mo. The mean OCP value was lower with Mo-containing than with Mo-free alloy in both pure BCS (p = .042), and BCS ± H2O2 (p < .0005). The wear scar was deeper for the Mo-free alloy, and this was significant (p = .013) in the presence of H2O2. These findings suggest a marked weakening of the passive film in the presence of H2O2, which is mitigated by the availability of Mo.

An enhanced prognostic score for overall survival of patients with cancer derived from a large real-world cohort.

BACKGROUND: By understanding prognostic biomarkers, we gain insights into disease biology and may improve design, conduct, and data analysis of clinical trials and real-world data. In this context, we used the Flatiron Health Electronic Health Record-derived deidentified database that provides treatment outcome and biomarker data from >280 oncology centers in the USA, organized into 17 cohorts defined by cancer type. PATIENTS AND METHODS: In 122 694 patients, we analyzed demographic, clinical, routine hematology, and blood chemistry parameters within a Cox proportional hazard framework to derive a multivariable prognostic risk model for overall survival (OS), the 'Real wOrld PROgnostic score (ROPRO)'. We validated ROPRO in two independent phase I and III clinical studies. RESULTS: A total of 27 variables contributed independently and homogeneously across cancer indications to OS. In the largest cohort (advanced non-small-cell lung cancer), for example, patients with elevated ROPRO scores (upper 10%) had a 7.91-fold (95% confidence interval 7.45-8.39) increased death hazard compared with patients with low scores (lower 10%). Median survival was 23.9 months (23.3-24.5) in the lowest ROPRO quartile Q1, 14.8 months (14.4-15.2) in Q2, 9.4 months (9.1-9.7) in Q3, and 4.7 months (4.6-4.8) in Q4. The ROPRO model performance indicators [C-index = 0.747 (standard error 0.001), 3-month area under the curve (AUC) = 0.822 (0.819-0.825)] strongly outperformed those of the Royal Marsden Hospital Score [C-index = 0.54 (standard error 0.0005), 3-month AUC = 0.579 (0.577-0.581)]. We confirmed the high prognostic relevance of ROPRO in clinical Phase 1 and III trials. CONCLUSIONS: The ROPRO provides improved prognostic power for OS. In oncology clinical development, it has great potential for applications in patient stratification, patient enrichment strategies, data interpretation, and early decision-making in clinical studies.

Precision feed restriction improves feed and milk efficiencies and reduces methane emissions of less efficient lactating Holstein cows without impairing their performance.

A possible driver of feed inefficiency in dairy cows is overconsumption. The objective was therefore to test precision feed restriction as a lever to improve feed efficiency of the least efficient lactating dairy cows. An initial cohort of 68 Holstein lactating cows was monitored from calving to end of ad libitum feeding at 196 ± 16 d in milk, with the last 70 d being used to estimate feed efficiency. For a given expected dry matter (DM) intake (DMI) during ad libitum feeding, offered DMI during restriction was set to observed DMI of the 10% most efficient cows during ad libitum feeding for similar performance. Feed restriction lasted during 92 d, with only the last 70 d being used for data analyses. A single diet was fed during ad libitum and restriction periods, and was based on 64.9% of corn silage and 35.1% of concentrates on a DM basis. Individual DMI, body weight, milk production, milk composition, and body condition score were recorded, as well as methane emissions. Feed efficiency was defined as the repeatable part of the random effect of cow on the intercept in a mixed model predicting DMI with net energy in milk, maintenance and body weight gain and loss within parity, feeding level, and time. Milk energy efficiency was estimated in the same way, predicting net energy in milk instead of DMI. The 15 least efficient cows ate 2.6 kg of DM/d more than the 15 most efficient cows during ad libitum feeding with 2 g/kg of DMI lower methane yield, but similar daily methane emissions. Feed restriction decreased DMI by 2.6 kg of DMI/d for the least efficient cows, which was 1.8 kg of DMI/d more than the most efficient cows, and decreased daily methane emissions by 49.2 g/d for the least efficient cows, which was 22.4 g/d more than the most efficient cows. Feed restriction had no significant effect on milk, body weight, or body weight change. Feed restriction reduced the variability of both milk energy and feed efficiencies, as shown by a decrease of their standard deviation from 0.87 to 0.69 kg of DM/d for feed efficiency and from 1.14 to 0.65 UFL/d for milk energy efficiency. Despite narrow efficiency differences, the most efficient cows during ad libitum feeding remained more efficient during feed restriction (r = 0.46 for feed efficiency and 0.49 for milk energy efficiency). The 2 efficiency groups no longer differed in feed efficiency during precision feed restriction. Precision feed restriction seemed to bring the least efficient cows closer to the most efficient cows and to reduce their methane emissions without impairing their performance.

Characterization of the colostrum and transition milk proteomes from primiparous and multiparous Holstein dairy cows.

Colostrum plays a vital role in the nutrition, development, and immunity of a newborn calf. This study aimed to characterize the protein profile of colostrum and to identify changes in the colostrum proteome across parity during the transition to mature milk. Colostrum and transition milk samples were collected at milkings 1, 2, 4, and 14 after calving from multiparous (n = 10) and primiparous cows (n = 10). Samples were skimmed, fractionated, and enriched before analysis for low-abundance proteins by liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Changes in protein abundances were analyzed using PROC MIXED in SAS (SAS Institute Inc., Cary, NC) with determination of the adaptive false discovery rate adjustment using a MULTTEST procedure to identify effects of parity (P), milking number (MN), and their interaction (MN×P). We identified 86 proteins through LC-MS/MS, including 3 low-abundance proteins that were affected by P, 78 that were affected by MN, and 36 affected by MN×P. Prominent ontological groupings of proteins affected by MN included defense or immunity proteins, such as immunoglobulins. Proteins involved in the plasminogen activating cascade and more broadly, blood coagulation, were affected by MN×P. The results of this study add to increasing knowledge of the colostrum and transition milk proteomes, and this is the first study to find evidence of different abundances of these proteins when examined across P, MN, and MN×P. These findings aid in the identification of potential milk protein biomarkers for mammary health during the early postpartum period.

The bovine epimural microbiota displays compositional and structural heterogeneity across different ruminal locations.

Dairy cattle are globally important agricultural animals. Central to their biology is the rumen, which houses an essential microbial community, or microbiome, important for providing nutrition from otherwise host-inaccessible dietary components. The rumen environment is noted for its substantial spatial heterogeneity, as illustrated by the stratification into ruminal solid and liquid phases. A third microbiota found directly attached to the ruminal epithelium (the epimural microbiota) also exists but is less well understood because of challenges in sampling the ruminal epithelium. As a result, our understanding of the epimural microbiota is based on analyses of cannulated animals sampled at a single location-the ventral sac-and does not account for other ruminal locations, which may have importance for overall rumen function. To address this knowledge gap, we hypothesize that the epimural microbiota at different ruminal locations differs due to known morphological, physiological, and functional differences across the geographic spread of the rumen epithelium. Here, we characterized bacterial epimural communities at different sites within 8 lactating Holstein dairy cows using 16S rRNA gene sequencing. Four different sites were sampled via rumen tissue biopsy: cranial sac (CS), ventral sac (VS), caudodorsal blind sac (CDBS), and caudoventral blind sac (CVBS). We found that locations differed in both epimural bacterial community structure and composition, with the CDBS community displaying the greatest diversity. Across all sampling sites, epimural bacterial communities were dominated by members of the phyla Bacteroidetes, Firmicutes, and Proteobacteria. Bacteria within Prevotellaceae, Butyrivibrio, Campylobacter, Mogibacterium, and Desulfobulbus all showed high relative sequence abundance and differential distributions according to sample location. There appears to be a core epimural microbiota present across all locations in all cows, although relative abundance was highly variable. The difference in relative abundance in epimural microbial communities, perhaps influenced by host physiology and the diversity within rumen contents, likely has important consequences for nutrition acquisition and general health. To the best of our knowledge, this work represents the first characterization of the ruminal epimural microbiota across different epithelial locations for any bovine ruminant.

Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.

BACKGROUND: Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature. OBJECTIVES: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID. METHODS: We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature. RESULTS: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus. CONCLUSION: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID.

Altered mucosa-associated microbiota in the ileum and colon of neonatal calves in response to delayed first colostrum feeding.

The present study investigated whether delaying the first feeding of colostrum affected ileum and colon mucosa-associated microbiota in calves. Twenty-seven male Holstein calves were randomly assigned to 1 of 3 groups, fed colostrum at 45 min, 6 h, and 12 h after birth, respectively. Ileum and colon mucosa were collected at 51 h after birth, and their associated microbial profiles were assessed using amplicon sequencing. Both ileum and colon mucosa-associated microbiota were predominated by genus Escherichia-Shigella. The negative correlation between the molar proportion of short-chain fatty acids (SCFA) and ileum mucosa-associated opportunistic pathogens, and the positive correlation between the molar proportion of SCFA and colon mucosa-associated beneficial bacteria, suggest that SCFA might play an important role in maintaining the gut health of 2-d-old calves. A higher relative abundance of ileum mucosa-associated Enterococcus and Streptococcus was detected when the first colostrum feeding was delayed for 12 h. The relative abundance of colon mucosa-associated Lactobacillus tended to be lower in calves fed colostrum 12 h than those under the other 2 treatments, whereas that of Faecalibacterium tended to be lower in calves fed colostrum immediately after birth than those fed colostrum 6 and 12 h after birth, respectively. Our findings suggest that delayed first colostrum feeding affects the establishment of ileum and colon mucosa-associated bacteria, which may have long-term effects on gut health of calves.

The cost-effectiveness of public health interventions examined by the National Institute for Health and Care Excellence from 2005 to 2018.

BACKGROUND: Reviews of economic evaluations of public health (PH) interventions assessed by the National Institute for Health and Care Excellence (NICE) in the periods 2005-2010 and 2011-2016 have been undertaken. This study combines these analyses, adds six further guidelines published since then, and thus provides a summary of cost-effectiveness of NICE's PH interventions to the present. METHODS: As in previous studies, economic evaluations carried out between 2005 and 2018 were categorised by the type of economic analysis used to extract and summarise base-case ICERs. A number of 'sensitivity analyses' were carried out to test the validity of the approach. RESULTS: Of 71 guidelines examined, 27 used cost utility analysis (CUA) for specific interventions, yielding 380 individual base-case ICER estimates (or 221 taking into account clustering of interventions). The median cost per quality-adjusted life-year (QALY) ICER for the 380 estimates was £1,986. Of these, 21% were cost saving, and 54% ranged from £1 to £20,000, 3% were between £20,001 and £30,000, 16% were above £30,000 and 5% were dominated. Taking clustering into account made relatively little difference to these results. Reducing the threshold from £20,000/QALY to £15,000/QALY would result in 2% of ICERs moving across the threshold. CONCLUSIONS: Seventy-five percent of PH interventions assessed were cost-effective at a threshold of £20,000 per QALY when disregarding clustering, and 68% were cost-effective when clusters were represented by a single ICER. Other analyses gave similar results for the distribution of ICERs. Limitations of the analysis are discussed.

Evaluating the evidence for non-monotonic dose-response relationships: A systematic literature review and (re-)analysis of in vivo toxicity data in the area of food safety.

This study aims to evaluate the evidence for the existence of non-monotonic dose-responses (NMDRs) of substances in the area of food safety. This review was performed following the systematic review methodology with the aim to identify in vivo studies published between January 2002 and February 2015 containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. A set of six checkpoints was developed to establish the likelihood that the data retrieved contained evidence for NMDR. In this review, 49 in vivo studies were identified as relevant and reliable, of which 42 were used for dose-response analysis. These studies contained 179 in vivo dose-response datasets with at least five dose groups (and a control group) as fewer doses cannot provide evidence for NMDR. These datasets were extracted and analyzed using the PROAST software package. The resulting dose-response relationships were evaluated for possible evidence of NMDRs by applying the six checkpoints. In total, 10 out of the 179 in vivo datasets fulfilled all six checkpoints. While these datasets could be considered as providing evidence for NMDR, replicated studies would still be needed to check if the results can be reproduced to rule out that the non-monotonicity was caused by incidental anomalies in that specific study. This approach, combining a systematic review with a set of checkpoints, is new and appears useful for future evaluations of the dose response datasets regarding evidence of non-monotonicity.

Multicenter evaluation of first-line endoscopic treatment with the OTSC in acute non-variceal upper gastrointestinal bleeding and comparison with the Rockall cohort: the FLETRock study.

INTRODUCTION: The over-the-scope clip (OTSC) overcomes limitations of standard clips and achieves a more efficient and reliable hemostasis in non-variceal upper gastrointestinal bleeding (NVUGIB). The study aims to evaluate mortality, rebleeding, and mortality after rebleeding of patients in whom the OTSC was used as the first-line endoscopic treatment (FLET) of NVUGIB. PATIENTS AND METHODS: In total, 118 patients (FLET cohort) with a median age of 73.5 years (range 29-93 years; mean (±SD) 71.39 ± 12.39 years) were included. The distribution of patients with respect to risk category revealed a median Rockall score of 7 (range 3-10). For hypothesis testing, the FLET cohort was categorized into three risk groups taking into account the Rockall score: low risk [Rockall risk category (RRC ≤3)], moderate risk (RRC 4-7), and high risk (RRC ≥8). Event rates (mortality, rebleeding, and mortality after rebleeding) observed per risk group were compared to predicted event rates (Rockall cohort) using Fisher's Exact Test. RESULTS: Primary successful hemostasis (PSH) was achieved in 92.4% either by FLET alone or in combination with an additional hemostasis technique in 1.7% (SCS = secondary clinical success). In 7.5% of the FLET cohort PSH could not be achieved. Compared to RRC prediction, mortality after rebleeding was significantly reduced from 27.9 to 10.9% in the high-risk group (RRC ≥8) treated with FLET (p < 0.011). Furthermore, the occurrence of rebleeding or continued bleeding was significantly lower in the moderate risk group (RRC 4-7) with 4.9% as well as in the high-risk group (RRC ≥8) with 21.4% compared to the Rockall cohort 24.0 and 53.2%, respectively (p < 0.001). CONCLUSIONS: This study shows that OTSC is superior to standard care and FLET reduces significantly rebleeding and rebleeding-associated mortality in NVUGIB. For this reason, OTSC could be the treatment of choice as the first-line treatment as an alternative to standard hemostasis techniques in high-risk patients.

Identification of biological traits associated with differences in residual energy intake among lactating Holstein cows.

Residual feed intake, which is usually used to estimate individual variation of feed efficiency, requires frequent and accurate measurements of individual feed intake to be carried out. Developing a breeding scheme based on residual feed intake in dairy cows is therefore complicated, especially because feed intake is not measurable for a large population. Another solution could be to focus on biological determinants of feed efficiency, which could potentially be directly and broadband measurable on farm. Several phenotypes have been identified in literature as being associated with differences in feed efficiency. The present study therefore aims to identify which biological mechanisms are associated with residual energy intake (REI) differences among dairy cows. Several candidate phenotypes were recorded frequently and simultaneously throughout the first 238 d in milk for 60 Holstein cows fed on a constant diet based on maize silage. A multiple linear regression of the 238 d in milk average of net energy intake was fitted on the 238 d in milk averages for milk energy output, metabolic body weight, the sum over the 238 d in milk of both, body condition score loss and gain, and the residuals were defined as REI. A partial least square regression was fitted over all biological traits to explain REI variability. Linear multiple regression explained 93.6% of net energy intake phenotypic variation, with 65.5% associated with lactation requirement, 23.2% with maintenance, and 4.9% with body reserves change; the 6.4% residuals represented REI. Overall, measured biological traits contributed to 58.9% of REI phenotypic variability, which were mainly explained by activity (26.5%) and feeding behavior (21.3%). However, apparent confounding was observed between behavior, activity, digestibility, and rumen-temperature variables. Drawing a conclusion on biological traits that explain feed efficiency differences among dairy cows was not possible due to this apparent confounding between the measured variables. Further investigation is needed to validate these results and to characterize the causal relationship of feed efficiency with feeding behavior, digestibility, body reserves change, activity, and rumen temperature.

Short communication: The effect of delayed colostrum feeding on plasma concentrations of glucagon-like peptide 1 and 2 in newborn calves.

Glucagon-like peptide (GLP)-1 is involved in glucose homeostasis via its role in stimulating insulin secretion, whereas GLP-2 increases mucosal growth of the small intestine. To our knowledge, the effect of delayed colostrum feeding on plasma GLP-1 and GLP-2 in neonatal calves has not been evaluated. To investigate the effect of delayed colostrum feeding on plasma concentrations of GLP-1 and GLP-2 in newborn calves, we randomly assigned 27 Holstein bull calves to 1 of 3 treatment groups: those fed colostrum within 1 h after birth (control), 6 h after birth (6H), and 12 h after birth (12H; n = 9 for each treatment). Blood samples were obtained before the colostrum feeding and every 3 h after each colostrum feeding for a 36-h period, and plasma concentrations of GLP-1, GLP-2, insulin, and glucose were measured. Plasma GLP-1 concentration at 12 h after colostrum feeding was lower in 12H than in control calves. In addition, plasma insulin concentration was lower in the 6H and 12H calves than in the controls. Plasma glucose and GLP-2 concentrations were, however, not affected by treatment. These results indicate that delayed colostrum feeding can decrease plasma GLP-1 and insulin concentrations without affecting glucose or GLP-2 concentration.