Melanoma cells can be eliminated by sialylated CD43 × CD3 bispecific T cell engager formats in vitro and in vivo.

Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3ε. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues.

Morbidity and costs of diverting ileostomy in transanal total mesorectal excision with primary anastomosis for rectal cancer.

BACKGROUND: The role of diverting ileostomy is debated in rectal cancer surgery with primary anastomosis. The aim of this study was to evaluate the associated morbidity and hospital costs of diversion after sphincter saving TaTME surgery. METHODS: All patients undergoing TaTME with primary anastomosis for rectal cancer between January 2012 and December 2019 in a single centre in the Netherlands were included. Patients with diverting ileostomy creation during primary surgery were compared with those without ileostomy. Outcomes included length of hospital stay, anastomotic leakage rates and total hospital costs at 1 year. RESULTS: One hundred and one patients were included in the ileostomy group, and 46 patients were in the non-ileostomy group. The number of female patients was 31 (30.7%) in the ileostomy group and 21 (45.7%) in the non-ileostomy group Mean age was 64.5 ± 11.1 years in the ileostomy group and 62.6 ± 10.7 years in the non-ileostomy group The anastomotic leakage rate was 21.7% in the non-ileostomy group and 15.8% in the ileostomy group (p = 0.385). The grade of leakage and number of anastomotic takedowns did not differ between groups. Mean costs at 1 year after surgery was €26,500.13 in the ileostomy group and €16,852.61 in the non-ileostomy group. The main cost driver was longer total length of hospital stay at 1 year (mean 12.4 ± 13.3 days vs 20.6 ± 12.6 days, p = 0.000). CONCLUSIONS: Morbidity and associated costs after diverting ileostomy are high. The incidence and morbidity of anastomotic leakage was not reduced by creation of an ileostomy. Omission of a diverting ileostomy after TaTME could possibly result in a reduction in treatment associated morbidity and costs.

Easy Access to Phosphine-Borane Building Blocks.

In this paper, we highlight the synthesis of a variety of primary phosphine-boranes (RPH2 ⋅BH3 ) from the corresponding dichlorophosphines, simply by using Li[BH4 ] as reductant and provider of the BH3 protecting group. The method offers facile access not only to alkyl- and arylphosphine-boranes, but also to aminophosphine-boranes (R2 NPH2 ⋅BH3 ) that are convenient building blocks but without the protecting BH3 moiety thermally labile and notoriously difficult to handle. The borane-protected primary phosphines can be doubly deprotonated using n-butyllithium to provide soluble phosphanediides Li2 [RP⋅BH3 ] of which the phenyl-derivative Li2 [PhP⋅BH3 ] was structurally characterized in the solid state.

A large-scale study on the effect of age at first calving, dam parity, and birth and calving month on first-lactation milk yield in Holstein Friesian dairy cattle.

Milk yield during first lactation is an important economical trait. Age at first calving (AFC) is considered an important predictor of subsequent milk yield. In addition, both season of birth, as well as season of calving, have been shown to influence milk production, with conflicting results. Finally, higher parity of the dam has been associated with a lower performance of the offspring. The aim of the present study was to assess the effect of the above-mentioned factors based on a large-scale study and to rank the most important determinants for first-lactation milk yield. Data on 3,810,678 Holstein Friesian heifers, born in Belgium and the Netherlands between 2000 and 2015, were provided by Cooperative CRV and CRV BV (Arnhem, the Netherlands) and consisted of birth dates, calving dates, and first-lactation productions. In addition, herd, sire, and dam information was provided. Linear regression models were built with herd-calving year and sire as random effects and 305-d energy-corrected milk (ECM) yield during first lactation as outcome variable. Birth month, calving month, parity of the dam, and AFC were included as fixed effects in the model and a dominance analysis was performed to rank the associated factors according to importance. Results revealed AFC to be the most important factor (R2 = 0.047), with an increase in ECM up to an age of 33 mo. Calving month was a more important predictor than birth month (R2 = 0.010 vs. R2 = 0.002, respectively), with the highest first-lactation production in heifers calving in October to December, and the lowest in heifers calving in June and July. Birth month had a limited effect on first-lactation milk yield (R2 = 0.002), potentially masked by rearing strategies during early life. Finally, parity of the dam ≥3 was associated with a reduced ECM of the offspring (R2 = 0.002). In conclusion, our results show AFC to be an important determinant of milk yield during first lactation. In addition, seasonal patterns in milk production are seen, which should be further explored to identify the underlying mechanism.

Value of sharing cow reference population between countries on reliability of genomic prediction for milk yield traits.

Increasing the reliability of genomic prediction (GP) of economic traits in the pasture-based dairy production systems of New Zealand (NZ) and Australia (AU) is important to both countries. This study assessed if sharing cow phenotype and genotype data of NZ and AU improves the reliability of GP for NZ bulls. Data from approximately 32,000 NZ genotyped cows and their contemporaries were included in the May 2018 routine genetic evaluation of the Australian Dairy cattle in an attempt to provide consistent phenotypes for both countries. After the genetic evaluation, deregressed proofs of cows were calculated for milk yield traits. The April 2018 multiple across-country evaluation of Interbull was also used to calculate deregressed proofs for bulls on the NZ scale. Approximately 1,178 Jersey (Jer) and 6,422 Holstein (Hol) bulls had genotype and phenotype data. In addition to NZ cows, phenotype data of close to 60,000 genotyped Australian (AU) cows from the same genetic evaluation run as NZ cows were used. All AU and NZ females were genotyped using low-density SNP chips (<10K SNP) and were imputed first to 50K and then to ∼600K (referred to as high density; HD). We used up to 98,000 animals in the reference populations, both by expanding the NZ reference set (cow, bull, single breed to multi-breed set) and by adding AU cows. Reliabilities of GP were calculated for 508 Jer and 1,251 Hol bulls whose sires are not included in the reference set (RS) to ensure that real differences are not masked by close relationships. The GP was tested using 50K or high-density SNP chip using genomic BLUP in bivariate (considering country as a trait) or single trait models. The RS that gave the highest reliability for each breed were also tested using a hybrid GP method that combines expectation maximization with Bayes R. The addition of the AU cows to an NZ RS that included either NZ cows only, or cows and bulls, improved the reliability of GP for both NZ Hol and Jer validation bulls for all traits. Using single breed reference populations also increased reliability when NZ crossbred cows were added to reference populations that included only purebred NZ bulls and cows and AU cows. The full multi-breed RS (all NZ cows and bulls and AU cows) provided similar reliabilities in NZ Hol bulls, when compared with the single breed reference with crossbred NZ cows. For Jer validation bulls, the RS that included Jer cows and bulls and crossbred cows from NZ and Jer cows from AU was marginally better than the all-breed, all-country RS. In terms of reliability, the advantage of the HD SNP chip was small but captured more of the genomic variance than the 50K, particularly for Hol. The expectation maximization Bayes R GP method was slightly (up to 3 percentage points) better than genomic BLUP. We conclude that GP of milk production traits in NZ bulls improves by up to 7 percentage points in reliability by expanding the NZ reference population to include AU cows.

Minimally invasive transanal surgery is safe after incomplete polypectomy of low risk T1 rectal cancer: a systematic review.

AIM: In patients who have undergone a polypectomy of a malignant rectal polyp without histopathological risk factors other than an involved or unclear resection margin, additional local excision is often performed. Evidence to support this approach is lacking. The aim of this systematic review and meta-analysis was to determine the outcome in terms of local recurrence, disease-free survival (DFS) and overall survival (OS) of additional local excision following incomplete polypectomy for low risk T1 rectal cancer. METHODS: A comprehensive search for published studies was performed. Only studies in which there was incomplete (or ≤ 1 mm) removal of pT1 rectal polyps or in which the resection plane could not be assessed were included. For each included study data on tumour stage, histological factors, surgical technique, local recurrence rate, 5-year DFS and 5-year OS were extracted. The PROSPERO registration number is CRD42017062702. RESULTS: A total of 580 studies were retrieved by the search in the MEDLINE database, Embase and the Cochrane Library. After careful appreciation, four studies were included in the analysis, comprising 102 patients of whom the majority had undeterminable (Rx) resection margins. Local excision via transanal endoscopic microsurgery was reported most frequently. Only 1% of patients developed a local recurrence. One study reported 5-year DFS and 5-year OS of 96% and 87% respectively. CONCLUSION: This study supports the use of additional local excision techniques for rectal cancer patients who underwent an incomplete polypectomy for a malignant rectal polyp in the absence of risk factors other than an uncertain resection margin.

Genetic analysis of udder conformation traits derived from automatic milking system recording in dairy cows.

Cartesian teat coordinates measured by automatic milking systems (AMS) provide new opportunities to record udder conformation traits and to study changes in udder conformation genetically and phenotypically within and between parities. The objective of this study was to estimate heritabilities and repeatabilities of AMS-based udder conformation traits within parities, to estimate genetic correlations between parities for AMS-based udder conformation traits, and to estimate genetic correlations between AMS-based udder conformation traits and classifier-based udder conformation traits, longevity, and udder health. Data from 70 herds, including 12,663 first-parity cows, 10,206 second-parity cows, and 7,627 third-parity cows, were analyzed using univariate and bivariate mixed animal models. Heritabilities of the AMS udder conformation traits were large (0.37-0.67) and genetic correlations between the AMS udder conformation traits and classifier-based traits were strong (>0.91). Repeatabilities within parities were large as well (0.89-0.97), indicating that a single record on udder conformation per lactation reflects udder conformation well. Genetic correlations of AMS udder conformation traits between parities were strong (0.88-1.00) and were stronger than the permanent environmental correlations. This shows that udder conformation changes over parities, but this change is mostly due to nongenetic factors. Based on these results, the current herd classification system, where cows are scored on udder conformation once in first parity, is sufficient. The AMS udder conformation traits as defined in this study have limited value as replacement for classifier-based udder conformation traits because they have smaller genetic correlations with functional traits than classifier-based traits. In summary, udder conformation hardly changes genetically between parities and is highly repeatable within parities. Udder conformation traits based on AMS need fine-tuning before they can replace classifier-based traits, and AMS teat coordinates probably contain additional information about udder health that is yet to be explored.

A subset of walnut allergic adults is sensitized to walnut 11S globulin Jug r 4.

BACKGROUND: The role of sensitization to commercially available allergens of English walnut (Juglans regia) Jug r 1, 2 and 3 in walnut allergy has been previously investigated in walnut allergic adults and was unable to explain all cases of walnut allergy. OBJECTIVES: Identify recognized walnut allergens, other than the ones previously investigated (Jug r 1-3), in walnut allergic adults and determine the sensitization frequency and diagnostic value. METHODS: Three different in-house walnut extracts were prepared and analysed on SDS-PAGE blots to identify allergenic walnut proteins. Immunoblots and immunoprecipitation, followed by LC-MS analysis, were performed to screen for, and confirm, IgE binding to walnut allergens in selected walnut allergic adults. In a cohort of 55 walnut challenged adults, including 33 allergic and 22 tolerant, sensitization to native and recombinant walnut allergen Jug r 4 was assessed using immunoblotting and immuno-line blot (EUROLINE), respectively. RESULTS: Screening of sera of 8 walnut allergic adults identified Jug r 4 as an allergen in our population. In the total cohort of 55 subjects, 5 were positive for Jug r 4 on immunoblot and 10 on EUROLINE. All but one EUROLINE positive subject had a positive food challenge (sensitivity 27%, specificity 95%, PPV 90%, NPV 47%). All 5 subjects positive on immunoblot were also positive on EUROLINE. LC-MS analysis showed a lack of Jug r 4 in the ImmunoCAP extract. Co-sensitization to other 11S albumins (eg hazelnut Cor a 9) was common in Jug r 4 sensitized subjects, potentially due to cross-reactivity. CONCLUSIONS: Walnut 11S globulin Jug r 4 is a relevant minor allergen, recognized by 27% of walnut allergic adults. It has a high positive predictive value of 90% for walnut allergy. Specific IgE against Jug r 4 occurred mostly with concomitant sensitization to other walnut components, mainly Jug r 1.

Non-persistence in ischaemic stroke: Risk of recurrent vascular events.

OBJECTIVES: Ischaemic stroke is one of the leading causes of death and disability worldwide. Although the secondary preventive medication should be continued for life, its use commonly declines in time. This may lead to recurrent vascular events. In this study, we investigated if during a long follow-up period discontinuation of medication (non-persistence) in real life ischaemic stroke patients increased the risk of recurrent vascular events. MATERIALS AND METHODS: This was a retrospective cohort study with the data retrieved from a database and the original patient records. The occurrence of new vascular events was determined from the electronic medical record. Medication use at time of follow-up was ascertained using the pharmacy-link in the electronic medical file and through a telephone interview. Primary endpoint was recurrent vascular events. Patients with two or more vascular risk factors were considered as having a high-risk profile. RESULTS: A total of 286 patients (persistent n = 182 and non-persistent n = 104) were included. After median follow-up period of 5½ years in the persistent group 14.8% had a recurrent vascular event, vs 23.1% in the non-persistent group (P = .801). In the patients with a high-risk profile, the persistent group had significantly less recurrent vascular events than the non-persistent group (23.5% against 46.4% P = .021). CONCLUSION: After a long follow-up period, ischaemic stroke patients with a high vascular risk profile who stopped taking their secondary preventive medication had an increased risk of a recurrent vascular events.

Fluctuations in milk yield are heritable and can be used as a resilience indicator to breed healthy cows.

Automatic milking systems record an enormous amount of data on milk yield and the cow itself. These type of big data are expected to contain indicators for health and resilience of cows. In this study, the aim was to define and estimate heritabilities for traits related with fluctuations in daily milk yield and to estimate genetic correlations with existing functional traits, such as udder health, fertility, claw health, ketosis, and longevity. We used daily milk yield records from automatic milking systems of 67,025 lactations in the first parity from 498 herds in the Netherlands. We defined 3 traits related to the number of drops in milk yield using Student t-tests based on either a rolling average (drop rolling average) or a regression (drop regression) and the natural logarithm of the within-cow variance of milk yield (LnVar). Average milk yield was added to investigate the relationships between milk yield and these new traits. ASReml was used to estimate heritabilities, breeding values (EBV), and genetic correlations among these new traits and average milk yield. Approximate genetic correlations were calculated using correlations between EBV of the new traits and existing EBV for health and functional traits correcting for nonunity reliabilities using the Calo method. Partial genetic correlations controlling for persistency and average milk yield and relative contributions to reliability were calculated to investigate whether the new traits add new information to predict fertility, health, and longevity. Heritabilities were 0.08 for drop rolling average, 0.06 for drop regression, and 0.10 for LnVar. Approximate genetic correlations between the new traits and the existing health traits differed quite a bit, with the strongest correlations (-0.29 to -0.52) between LnVar and udder health, ketosis, persistency, and longevity. This study shows that fluctuations in daily milk yield are heritable and that the variance of milk production is best among the 3 fluctuations traits tested to predict udder health, ketosis, and longevity. Using the residual variance of milk production instead of the raw variance is expected to further improve the trait to breed healthy, resilient, and long-lasting dairy cows.

Invited review: Genetics and claw health: Opportunities to enhance claw health by genetic selection.

Routine recording of claw health status at claw trimming of dairy cattle has been established in several countries, providing valuable data for genetic evaluation. In this review, we examine issues related to genetic evaluation of claw health; discuss data sources, trait definitions, and data validation procedures; and present a review of genetic parameters, possible indicator traits, and status of genetic and genomic evaluations for claw disorders. Different sources of data and traits can be used to describe claw health. Severe cases of claw disorders can be identified by veterinary diagnoses. Data from lameness and locomotion scoring, activity information from sensors, and feet and leg conformation traits are used as auxiliary traits. The most reliable and comprehensive information is data from regular hoof trimming. In genetic evaluation, claw disorders are usually defined as binary traits, based on whether or not the claw disorder was present (recorded) at least once during a defined time period. The traits can be specific disorders, composite traits, or overall claw health. Data validation and editing criteria are needed to ensure reliable data at the trimmer, herd, animal, and record levels. Different strategies have been chosen, reflecting differences in herd sizes, data structures, management practices, and recording systems among countries. Heritabilities of the most commonly analyzed claw disorders based on data from routine claw trimming were generally low, with ranges of linear model estimates from 0.01 to 0.14, and threshold model estimates from 0.06 to 0.39. Estimated genetic correlations among claw disorders varied from -0.40 to 0.98. The strongest genetic correlations were found among sole hemorrhage (SH), sole ulcer (SU), and white line disease (WL), and between digital/interdigital dermatitis (DD/ID) and heel horn erosion (HHE). Genetic correlations between DD/ID and HHE on the one hand and SH, SU, or WL on the other hand were, in most cases, low. Although some of the studies were based on relatively few records and the estimated genetic parameters had large standard errors, there was, with some exceptions, consistency among studies. Various studies evaluate the potential of various data soureces for use in breeding. The use of hoof trimming data is recommended for maximization of genetic gain, although auxiliary traits, such as locomotion score and some conformation traits, may be valuable for increasing the reliability of genetic evaluations. Routine genetic evaluation of direct claw health has been implemented in the Netherlands (2010); Denmark, Finland, and Sweden (joint Nordic evaluation; 2011); and Norway (2014), and other countries plan to implement evaluations in the near future.

Genotype by environment interaction for production, somatic cell score, workability, and conformation traits in Dutch Holstein-Friesian cows between farms with or without grazing.

In this study, genotype by environment interaction was investigated for production traits, somatic cell score (SCS), workability traits, and conformation traits for Holstein-Friesian cows producing on farms with or without grazing in the Netherlands. Additionally, heritabilities and repeatabilities were estimated in both farm systems. Data were available for 1,019 Dutch farms, and farm type was known for those farms, 142 farms without grazing and 877 farms with grazing. The data set consisted of 428,600 test-day records for production from 49,412 cows, and from this data set a subset for SCS was created, consisting of 374,734 test-day records from 45,955 cows. For workability and conformation traits, the data set consisted of 30,180 cows. Bivariate mixed models with multiple fixed effects and random sire and random permanent environment effects were applied. The majority of sires had daughters in both farm types. The heritabilities for milk yield (0.27), fat yield (0.19), and protein yield (0.20) were higher in farms with grazing than in farms without grazing with heritabilities of 0.24 for milk yield, 0.18 for fat yield, and 0.18 for protein yield. Repeatability was lower in the grazing farms for milk yield, fat yield, and protein yield, probably because of alternating quality of dry matter intake during grazing. Genetic correlations between grazing and no grazing were 0.99, 0.98, 0.97, and 1.00 for milk yield, fat yield, protein yield, and SCS, respectively. Genetic correlations for workability traits and conformation traits between grazing and no grazing varied between 0.93 and 1.00. For all traits, genetic correlations were close to unity, indicating no genotype by environment interaction between farms with or without grazing for production traits, SCS, workability traits, and conformation traits in Dutch Holstein-Friesians. Therefore, the same sires can be used for farms both with and without grazing.

Genetic changes of survival traits over the past 25 yr in Dutch dairy cattle.

Genetic correlations and heritabilities for survival were investigated over a period of 25 yr to evaluate if survival in first lactation has become a different trait and if this is affected by adjusting for production level. Survival after first calving until 12mo after calving (surv_12mo) and survival of first lactation (surv_1st_lac) were analyzed in Dutch black-and-white cows. The data set contained 1,108,745 animals for surv_12mo and 1,062,276 animals for surv_1st_lac, with first calving between 1989 and 2013. The trait survival as recorded over 25 yr was split in five 5-yr intervals to enable a multitrait analysis. Bivariate models using subsets of the full data set and multitrait and autoregressive models using the full data set were used. Survival and functional survival were analyzed. Functional survival was defined as survival adjusted for within-herd production level for 305-d yield of combined kilograms of fat and protein. Mean survival increased over time, whereas genetic variances and heritability decreased. Bivariate models yielded large standard errors on genetic correlations due to poor connectedness between the extreme 5-yr intervals. The more parsimonious models using the full data set gave nonunity genetic correlations. Genetic correlations for survival were below 0.90 between intervals separated by 1 or more 5-yr intervals. Genetic correlations for functional survival did not indicate that definition of survival changed (≥0.90). The difference in genetic correlations between survival and functional survival is likely explained by lower emphasis of dairy farmers on culling in first lactation for low yield in more recent years. This suggests that genetic evaluation for longevity using historical data should analyze functional survival rather than survival.

Simultaneous assessment of protein heterogeneity and affinity by capillary electrophoresis-mass spectrometry.

Most conventional analytical tools for the assessment of protein-protein interactions yield information on the bulk sample. By employing the efficient separation of intact proteins, affinity capillary electrophoresis (ACE) can measure the interaction of components of heterogeneous proteins with a target protein. In this work, the hyphenation of ACE with mass spectrometry (MS) is presented as a novel, highly selective tool for the assessment of protein-protein interactions. The binding of the protease inhibitor aprotinin to trypsinogen was used as protein-protein affinity model. A trypsinogen sample comprising several modifications was analyzed using a background electrolyte of 25 mM ammonium acetate (pH 8.0) containing increasing concentrations of aprotinin (0-300 µM). A capillary coating of polybrene-dextran sulfate-polybrene (PB-DS-PB) was employed to prevent adsorption of the proteins to the capillary wall. The trypsinogen variants were separated and could be assigned based on detected molecular masses and relative migration. In presence of aprotinin, both free and aprotinin-bound trypsinogen were detected revealing a 1:1 binding stoichiometry. For most trypsinogen variants, shifts in electrophoretic mobility were observed upon raising the aprotinin concentration, allowing determination of their dissociation constants (Kd's). The interacting trypsinogen variants showed similar affinity toward aprotinin (Kd's of 3-9 µM), which were not significantly different from the values obtained with ACE-UV and were in agreement with an earlier reported value. The use of the ratio of obtained MS signal intensities of free and protein-protein complex for the determination of Kd's was also explored. Derived Kd values (20-104 µM) for the binding variants were similar to those obtained with direct-infusion MS, but higher and less precise as compared with values based on mobility shifts. The suitability of the ACE-MS methodology for the affinity profiling of heterogeneous protein samples was evaluated, and components with high, medium, or low affinity toward aprotinin could be successfully discriminated.

Genetic analysis of longevity in Dutch dairy cattle using random regression.

Longevity, productive life, or lifespan of dairy cattle is an important trait for dairy farmers, and it is defined as the time from first calving to the last test date for milk production. Methods for genetic evaluations need to account for censored data; that is, records from cows that are still alive. The aim of this study was to investigate whether these methods also need to take account of survival being genetically a different trait across the entire lifespan of a cow. The data set comprised 112,000 cows with a total of 3,964,449 observations for survival per month from first calving until 72 mo in productive life. A random regression model with second-order Legendre polynomials was fitted for the additive genetic effect. Alternative parameterizations were (1) different trait definitions for the length of time interval for survival after first calving (1, 3, 6, and 12 mo); (2) linear or threshold model; and (3) differing the order of the Legendre polynomial. The partial derivatives of a profit function were used to transform variance components on the survival scale to those for lifespan. Survival rates were higher in early life than later in life (99 vs. 95%). When survival was defined over 12-mo intervals survival curves were smooth compared with curves when 1-, 3-, or 6-mo intervals were used. Heritabilities in each interval were very low and ranged from 0.002 to 0.031, but the heritability for lifespan over the entire period of 72 mo after first calving ranged from 0.115 to 0.149. Genetic correlations between time intervals ranged from 0.25 to 1.00. Genetic parameters and breeding values for the genetic effect were more sensitive to the trait definition than to whether a linear or threshold model was used or to the order of Legendre polynomial used. Cumulative survival up to the first 6 mo predicted lifespan with an accuracy of only 0.79 to 0.85; that is, reliability of breeding value with many daughters in the first 6 mo can be, at most, 0.62 to 0.72, and changes of breeding values are still expected when daughters are getting older. Therefore, an improved model for genetic evaluation should treat survival as different traits during the lifespan by splitting lifespan in time intervals of 6 mo or less to avoid overestimated reliabilities and changes in breeding values when daughters are getting older.

Usability and outcomes of self-monitored surgical wound healing using a smartphone-based application by patients following neurosurgery.

BACKGROUND: The Radboudumc developed a smartphone application (WondGezond) to collect surgical wound-healing information provided by the patient. AIM: To evaluate usability and outcomes to assess its potential for early surgical site infection (SSI) detection. METHODS: Patients surgically treated for degenerative spinal disorders or carpal tunnel syndrome between August 2020 and February 2023 were enrolled one day post surgery and asked to download the app via a quick-response (QR) code. Participants uploaded a photo and answered four questions about their wound daily, for 14 days. Afterwards, participants indicated whether they received treatment for a suspected SSI (participant-reported outcome). Two neurosurgeons independently assessed photos and questionnaire answers for suspected SSIs (physician-assessed outcome). The association between both outcomes was determined by calculating sensitivity, specificity, and positive and negative predictive value (PPV/NPV). FINDINGS: After 2009 surgeries, 1695 QR-codes were distributed and 412 (21%) were activated. In all, 232 (56%) participants completed the 14-day period of whom 22 (10%) reported SSI treatment. Physician assessment identified 15 (7%) SSIs. Concordance was reached in 88% of cases. Among 27 discordant cases were 17 false-positives and 10 false-negatives, resulting in low sensitivity (33%) and PPV (23%), but high NPV (95%). CONCLUSION: WondGezond provides clinicians with information regarding wound healing and SSIs to follow-up on patients at risk, while possibly also reducing antibiotic (over)treatment and unnecessary visits for patients without issues in wound healing. However, the low participation and false-positive results render the app in its current form unsuitable for surveillance purposes. Further validation of WondGezond is required.

Baseline TGF-ß correlates with protection after immunization with Plasmodium falciparum sporozoites in the controlled human malaria infection model.

BACKGROUND: Here we assessed a possible relationship between baseline TGF-ß concentrations and acquisition of sterile immunity after Plasmodium falciparum sporozoite immunization. METHODS: TGF-ß concentrations were determined in samples of 65 malaria-naive volunteers in 4 studies either prior to and after challenge infection, or prior to and after first immunizing infection under chemoprophylaxis with P. falciparum sporozoites. RESULTS: High baseline TGF-ß concentrations were associated with rapid acquisition of sterile protection (p = 0.028). CONCLUSION: Baseline TGF-ß concentrations predict the efficiency of acquisition of sterile immunity following sporozoite immunization and may represent a steady-state regulatory mechanism to keep in check immune systems with a low threshold for activation.

Experimental study of radioimmunotherapy versus chemotherapy for colorectal cancer.

BACKGROUND: Radioimmunotherapy (RIT) has been shown to reduce the incidence of local recurrence of colorectal cancer in an experimental model. The aim of the present study was to investigate the survival benefit of RIT compared with chemotherapy. METHODS: An anastomosis was constructed in male Wag/Rij rats after intraluminal injection of CC531 tumour cells. The therapeutic efficacy of (177) Lu-labelled MG1 (single intravenous dose of 300 MBq/kg, n = 20) was compared with that of 5-fluorouracil-based chemotherapy (6 weekly cycles administered intraperitoneally, n = 20) and no treatment (n = 20). The primary endpoint was survival. Toxicity was monitored by bodyweight measurement. RESULTS: Both chemotherapy and RIT affected bodyweight, but the weight of animals in the RIT group remained significantly higher than in the chemotherapy group (median slope of bodyweight plot 0·48 versus 0·30 g/day; P < 0·001). Kaplan-Meier analysis showed that overall survival in the RIT and chemotherapy groups was significantly better than that in the control group (50 and 46 per cent versus 25 per cent respectively after 170 days; P = 0·024 and P = 0·029). Survival after treatment with RIT did not differ from that after chemotherapy (P = 0·911). CONCLUSION: RIT is as effective as chemotherapy in experimental colorectal cancer.

Optimization of dynamic pH junction for the sensitive determination of amino acids in urine by capillary electrophoresis.

A capillary electrophoresis method with UV-absorbance detection was studied and optimized for the determination of underivatized amino acids in urine. To improve concentration sensitivity the utility of in-capillary analyte stacking via dynamic pH junction was investigated with phenylalanine (Phe) and tyrosine (Tyr) as model amino acids. Before sample injection, a plug of ammonium hydroxide solution was injected to enable analyte concentration. Samples were 1:1 (v/v) mixed with background electrolyte (1 M formic acid) prior to injection. The effect of the injected sample volume, and the injected ammonium hydroxide volume and concentration on analyte stacking and separation performance was investigated. The optimal volume of ammonium hydroxide depended on the injected sample volume. Using a dynamic pH junction good resolution (1.4) was obtained for a sample injection volume of 10% of the capillary (196 nl) with Phe and Tyr dissolved in water. Limits of detection (LODs) were 0.036 and 0.049 µM for Phe and Tyr, respectively. For urine samples, the optimized procedure comprised a 1.7-nl injection of 12.5% ammonium hydroxide, followed by a 196-nl injection of urine spiked with Phe and Tyr. Satisfactory resolution was obtained and amino acid peak widths at half height were only 1.6 s indicating efficient stacking. Calibration plots for Phe and Tyr in urine showed good linearity (R(2) > 0.96) in the concentration range 10-175 µM, and LODs for Phe and Tyr were 0.054 and 0.019 µM, respectively. RSDs for peak area and migration time for Phe and Tyr were below 7.5% and 0.75%, respectively.