A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Pre-slaughter sound levels and pre-slaughter handling from loading at the farm till slaughter influence pork quality.

This study investigates the relationship between sound levels, pre-slaughter handling during loading and pork quality. Pre-slaughter variables were investigated from loading till slaughter. A total of 3213 pigs were measured 30 min post-mortem for pH(30LT) (M. Longissimus thoracis). First, a sound level model for the risk to develop PSE meat was established. The difference in maximum and mean sound level during loading, mean sound level during lairage and mean sound level prior to stunning remained significant within the model. This indicated that sound levels during loading had a significant added value to former sound models. Moreover, this study completed the global classification checklist (Vermeulen et al., 2015a) by developing a linear mixed model for pH(30LT) and PSE prevalence, with the difference in maximum and mean sound level measured during loading, the feed withdrawal period and the difference in temperature during loading and lairage. Hence, this study provided new insights over previous research where loading procedures were not included.

Lung lesions increase the risk of reduced meat quality of slaughter pigs.

Lung lesions of about 1000 pigs (nN) were scored in the slaughter line. Carcass weight, back fat thickness, loin muscle depth, pHi and PQMi were measured on 460 pigs. Twenty-four hours after slaughter pHu, PQMu, brightness, redness, yellowness and drip loss were measured on 59 carcasses. A score for lung lesions was assessed at batch level, based on observations of all pigs in that batch, i.e. about 130. Pigs systematically selected from batches scoring more than 25% lung lesions had a lower pH of LD muscle (P≤0.0003) and a six fold higher risk for P(ale)S(oft)E(xudative) traits (P≤0.050) compared to batches scoring less than 5%.

Pre-slaughter handling and pork quality.

Environmental variables, as sound levels, were collected during the pre-slaughter process in 18 different Belgian commercial slaughterhouses. Four pre-slaughter phases were determined: firstly after arrival of the truck at the slaughterhouse and just before unloading, secondly during unloading, thirdly at lairage and finally while moving to the stunner. A total of 8508 pigs was examined during the pre-slaughter process, of which the pH(LT) (M. longissimus thoracis), at 30 min post-mortem was measured. For each pre-slaughter phase, variables which might influence pork quality were determined. Moreover, this study made it possible to infer a checklist to represent and predict PSE traits of pork for all kind of pre-slaughter situations. The checklist shows also that the impact on pork quality is more decisive for the variables measured close to the stunning phase. Hence, this information is useful for the industry to optimize handling of pigs, reducing the risk for PSE traits.

Sound levels above 85 dB pre-slaughter influence pork quality.

This study investigates whether sound levels above 85 dB(A), determined in literature as a critical sound level to induce stress in pigs, has also an effect on the pH of pork. Sound levels were recorded during pre-slaughter phases. A measure was taken after the arrival of the truck at the slaughterhouse, during unloading, lairage and just before stunning. The pH of the Longissimus thoracis or lumborum, 30 min after sticking (pH(30LT)) was measured. 8508 pigs were examined and the pH was measured on the carcasses. The results show that the cut-off value of 85 dB(A) during the pre-slaughtering phase is not only a threshold to evaluate animal welfare but can also be associated with a slower drop of pH if sound levels are b85 dB(A). Finally a linear mixed model for pH(30LT) was built with the sound level during lairage and the sound level prior to stunning as independent variables, having statistically the highest impact on pH(30LT) of pork.

Sick leave due to back pain in a cohort of young workers.

PURPOSE: Evidence on risk factors for sick leave from prospective studies in work settings is limited. Furthermore, most available studies focused on workers with substantial low back disorders. These studies consistently report that physical work factors constitute a hindrance to work. However, it remains unclear whether the same risk factors are relevant in workers with less severe conditions or in early phases of the development of back pain. Therefore, this article aims to study risk factors for the occurrence of sick leave due to low back pain (LBP) among young workers with no or a modest history of back pain. METHODS: Participants were 716 young healthcare or distribution workers with no or minimal antecedents of LBP in the year before inclusion. We investigated the role of potential physical, psychosocial and individual risk factors at baseline on the occurrence of sick leave due to LBP 1 year later. To this purpose, we used Cox regression with a constant risk period. RESULTS: Six per cent (95 % CI 4.1-7.6) of the workers reported sick leave 1 year later; they accounted for 12 % of the sick-leave days independent of cause. A non-stimulating psychosocial work environment turned out to be the strongest risk factor for sick leave due to LBP (RR 6.08; 95 % CI 1.42-26.07). Physical factors were not predictive. CONCLUSIONS: In the early phases of back pain and in less severe conditions, the main benefit of interventions lies in targeting the organisation and design of jobs to create a challenging professional environment.

Interactions between climatological variables and sheltering behavior of pastoral beef cattle during sunny weather in a temperate climate.

Concerns in regard to thermal discomfort experienced by cattle are increasing, especially in the summer time. It is important to determine whether or not pastured beef cattle would make use of shade during sunny circumstances in a temperate climate. If so, scientifically based guidelines may need to be formulated for translation into legislation aiming to protect animal welfare. Approximately 255 beef cattle on 18 pastures were observed from July 2010 through November 2010 in central Belgium. Pastures having either natural or artificial shelter for animal protection but similar with respect to agricultural and climatological characteristics were included in the study. The analysis of data focused on the effect of weather conditions on sheltering behavior of cattle, with pasture as a random factor. During sunny weather, ambient temperature had a significant influence on the use of shade (P < 0.0001): the greater the environmental temperature was, the more cattle on a pasture were located in a shaded area. Ambient temperature (Ta) and relative humidity (RH) both tended to have a positive relation with shade use. However, the expected impact of their combined effect was not found, probably because of the strong negative correlation between RH and Ta (r = -0.7122) in the studied region. Greater wind speed (WS) reduced the need for shade, even at a greater Ta (P < 0.0001). Both Ta and solar radiation (RAD) influenced use of shade, but the interaction or combined effect was not significant. The variability of shade use between the pastures in this study could be explained by the surface of shade present on the pasture. It is rather self-evident that cows made more use of shade when a greater percentage of the surface area was shaded, but the presence of remaining nonshaded area kept the alternative choice reliable. On the basis of the fact that more cattle being observed in a shaded area was associated with a higher dry air temperature, it can be concluded that providing shelter could also be valuable for pastured cattle living in a temperate region.

Behavior of piglets after castration with or without carbon dioxide anesthesia.

Surgical castration of male piglets without anesthesia is a routine management practice conducted on commercial pig farms. For animal welfare reasons, it would be beneficial to develop methods of practical pain relief. The objective of this study was to evaluate the effect of providing CO2 anesthesia before castration on the behavior of piglets for up to 8 d after castration in comparison with piglets castrated without anesthesia. In 3 successive replicates, the behavior of 186 male piglets castrated with (n = 95) or without (n = 91) anesthesia was observed for up to 8 d after castration. All piglets in a given replicate were castrated on the same day, before 8 d of age. Behavioral observations were carried out in accordance with a continuous focal sampling procedure that began immediately after castration and continued for a period of 1 wk. Barrows anesthetized with CO2 before castration displayed more interactive behaviors during the overall observation period than the other barrows (P = 0.0412), which may indicate better welfare. Assessing all observation periods separately, differences in activity at the udder, lying, walking, and interactive behaviors appeared to support the beneficial effect of providing CO2 anesthesia before castration. However, these differences varied over time between treatment groups. The most important conclusion was that piglets castrated with or without CO2 anesthesia displayed behaviors indicative of pain and discomfort for up to 6 d after castration. Therefore, additional analgesia may be necessary to eliminate the long-term pain caused by castration even in piglets anesthetized with CO2 before castration.

Effect of unloading, lairage, pig handling, stunning and season on pH of pork.

A total of 12,725 pigs originating from 90 transports were followed up at 17 Belgian commercial slaughterhouses. The effects of several pre-slaughter parameters concerning transport, unloading, lairage, pig handling, stunning and season on fresh meat quality based on pH measurements 30 minutes (min) after slaughter were investigated. Meat quality was measured on 4285 pigs. Ten pre-slaughter parameters had a significant effect on meat pH after separate introduction of the variable as a fixed effect in the model. Simultaneous analysis of these variables in the global model revealed that the pH was influenced by four main risk factors, namely the mean noise level produced during unloading, the percentage of panting pigs, the use of an electric prod and season. Meat quality in terms of the percentage of potentially PSE carcasses was better in summer than spring or autumn and could be explained by a lower observed pre-stunning stress in summer.

Validation of a behavioral observation tool to assess pig welfare.

Accurately measuring and monitoring of animal behavior is an important factor when assessing on-farm animal welfare. First we developed a feasible and simple method aiming at consistently on-farm measuring of pig's behavior. This test should cover a broad range of welfare-related pig behavior. The reaction towards a novel object, startling, tail and ear biting, play and aggressive behavior, stereotypies, coughing, sneezing, skin lesions, defecation, urination and cleanliness of body and pen are included. The development of accurate measures of on-farm behavior first requires the reliability assessment of the procedure. Therefore, the methodology was tested in a first part by three observers scoring simultaneously and independently pre-defined behavioral characteristics of 108 group-housed fattening pigs. The inter-observer repeatability of the measures was calculated using intraclass correlation coefficients, which ranged from 0.7 to 1. In a second part, the objective was to validate the behavioral characteristics against salivary cortisol, urinary epinephrine and norepinephrine and production traits. Salivary cortisol concentrations significantly increased in ear-bitten pigs and in pigs with tail lesions. Growth rate significantly dropped when cortisol levels rose. An age effect was also found. The percentage of animals approaching the novel object is positively correlated with the urinary epinephrine concentration. Pigs defecating during the test showed significantly higher epinephrine levels. Urinary norepinephrine concentration decreased significantly with age. Faster growing animals and animals with tail lesions showed significantly higher levels of norepinephrine. Pen dirtiness and number of animals per pen were associated with higher norepinephrine concentrations. Finally, barrows had higher norepinephrine concentrations than sows.

The role of physical workload and pain related fear in the development of low back pain in young workers: evidence from the BelCoBack Study; results after one year of follow up.

AIMS: To study the influence of work related physical and psychosocial factors and individual characteristics on the occurrence of low back pain among young and pain free workers. METHODS: The Belgian Cohort Back Study was designed as a prospective cohort study. The study population of this paper consisted of 716 young healthcare or distribution workers without low back pain lasting seven or more consecutive days during the year before inclusion. The median age was 26 years with an interquartile range between 24 and 29 years. At baseline, these workers filled in a questionnaire with physical exposures, work related psychosocial factors and individual characteristics. One year later, the occurrence of low back pain lasting seven or more consecutive days and some of its characteristics were registered by means of a questionnaire. To assess the respective role of predictors at baseline on the occurrence of low back pain in the following year, Cox regression with a constant risk period for all subjects was applied. RESULTS: After one year of follow up, 12.6% (95% CI 10.1 to 15.0) of the 716 workers had developed low back pain lasting seven or more consecutive days. An increased risk was observed for working with the trunk in a bent and twisted position for more than two hours a day (RR 2.2, 95% CI 1.2 to 4.1), inability to change posture regularly (RR 2.1, 95% CI 1.3 to 3.5), back complaints in the year before inclusion (RR 1.7, 95% CI 1.1 to 2.8), and high scores of pain related fear (RR 1.8, 95% CI 1.0 to 3.1). Work related psychosocial factors and physical factors during leisure time were not predictive. CONCLUSION: This study highlighted the importance of physical work factors and revealed the importance of high scores of pain related fear in the development of low back pain among young workers.

Risk factors for first-ever low back pain among workers in their first employment.

BACKGROUND: Low back pain has been estimated to be the most costly ailment of people of working age. Both work characteristics and individual factors have been identified as risk factors. The first interaction between work characteristics and individual factors occurs when workers start in their first job. AIMS: To investigate work-related risk factors for first-ever low back pain in young workers in their first employment. METHODS: A cross-sectional analysis was performed on 278 young workers in their first employment and without a history of low back pain prior to working. Work-related physical factors, psychosocial work characteristics, individual variables and first-ever low back pain were queried by means of a questionnaire. RESULTS: About half of the workers who developed low back pain after job start did so in the first year of employment. An increased risk was observed for (i) long periods of seated work [relative risk (RR) = 3.2, 95% confidence interval (CI) = 1.6-6.4]; (ii) more than 12 flexion or rotation movements of the trunk per hour (RR = 3.0, 95%CI = 1.4-6.4); and (iii) more than 3 years seniority in a job involving lifting more than 25 kg at least once an hour (RR = 3.7, 95%CI = 1.4-9.4). As to psychosocial work characteristics, first-ever low back pain was associated with a combination of low psychological job demands and low supervisor support. CONCLUSION: Work-related physical factors and psychosocial work characteristics should be considered as risk factors for first-ever low back pain. First-ever episodes of low back pain are common in the first year of employment. This may reflect a lack of work experience or training.

Frictional behavior of stainless steel bracket-wire combinations subjected to small oscillating displacements.

In orthodontic treatment, sliding is frequently used to cause tooth movement. Inherent to this technique is the generation of a counteracting frictional force. In this pilot study, a fretting test consisting of reciprocating tangential displacements was used to investigate test parameters influencing frictional forces during sliding processes. Tests were run at a normal load of 2 N and a frequency of 1 Hz for tangential displacement strokes of 200 microm. Stainless steel orthodontic wires with cross-sections of .017 x .025 in (W17) and .018 x .025 in (W18), and brackets with slot sizes of .018 in (B18) and .022 in (B22) were used. A specific centered positioning method was developed to achieve a parallel alignment of the wire and the bracket slot. The experimental results indicated the significant role of the centered positioning method on the friction value. Implementation of the centered positioning method resulted in a friction force ranging from 0.89 N to 0.97 N at a 200 microm displacement amplitude and 1 Hz frequency, corresponding to a coefficient of friction ranging from 0.45 to 0.49 for the B18-W17 and the B22-W17 bracket-wire combinations, respectively. When the centered positioning method was not used, significantly higher values for the coefficient of friction were found for both bracket-wire combinations. The slot-filling, bracket-wire combinations (B18-W18 and B22-W22) resulted in an increased coefficient of friction and therefore are not recommended as sliding systems.

Sensitivity analysis for nonrandom dropout: a local influence approach.

Diggle and Kenward (1994, Applied Statistics 43, 49-93) proposed a selection model for continuous longitudinal data subject to nonrandom dropout. It has provoked a large debate about the role for such models. The original enthusiasm was followed by skepticism about the strong but untestable assumptions on which this type of model invariably rests. Since then, the view has emerged that these models should ideally be made part of a sensitivity analysis. This paper presents a formal and flexible approach to such a sensitivity assessment based on local influence (Cook, 1986, Journal of the Royal Statistical Society, Series B 48, 133-169). The influence of perturbing a missing-at-random dropout model in the direction of nonrandom dropout is explored. The method is applied to data from a randomized experiment on the inhibition of testosterone production in rats.

An overview of group sequential methods in longitudinal clinical trials.

During the last decade, several papers have been published on group sequential methods in general and on sequential longitudinal clinical trials in particular. This paper gives an overview of the proposed methods, emphasizing longitudinal clinical trials. Furthermore, it tries to answer some practical questions that may arise during the conduct of interim analyses in longitudinal trials. Simulations have been carried out to obtain insight in these practical considerations.

Variceal pressure is a strong predictor of variceal haemorrhage in patients with cirrhosis as well as in patients with non-cirrhotic portal hypertension.

BACKGROUND: Variceal pressure is a strong predictor for a first variceal bleed in patients with cirrhosis. AIMS: To evaluate whether variceal pressure is also a determinant of the risk of a first variceal bleed in patients with non-cirrhotic portal hypertension. METHODS: Variceal pressure was measured non-invasively in 25 patients with non-cirrhotic portal hypertension and large varices while receiving a stable therapeutic regimen. Factors predictive of bleeding were compared with those observed in 87 cirrhotics. RESULTS: The one year incidence of variceal bleeding was 32% (n=28) for the cirrhotic and 20% (n=5) for the non-cirrhotic patients. There was no difference in factors predicting the risk of bleeding between the groups, except for variceal pressure. For the same level of variceal pressure, the risk of variceal bleeding was lower in patients with non-cirrhotic portal hypertension. Multiple logistic regression analysis revealed the following variables as having a significant predictive power: variceal pressure (p=0.0001), red spots (p=0.004), and the time interval between the first observation of the varices and the moment of variceal pressure measurement (p=0. 0046). For the non-cirrhotics the risk of bleeding increased with higher Child-Pugh score (p=0.0024); this was not the case for the cirrhotic patients (p=0.9521). CONCLUSION: Variceal pressure is a major predictor of variceal bleeding in patients with cirrhosis as well as in patients with non-cirrhotic portal hypertension. The risk of bleeding in non-cirrhotics is less than in cirrhotics for the same level of variceal pressure. In patients with non-cirrhotic portal hypertension the risk of variceal bleeding increases more with advancing disease.

Assessing the goodness-of-fit of the Laird and Ware model--an example: the Jimma Infant Survival Differential Longitudinal Study.

The Jimma Infant Survival Differential Longitudinal Study is an Ethiopian study, set up to establish risk factors affecting infant survival and to investigate socio-economic, maternal and infant-rearing factors that contribute most to the child's early survival. Here, a subgroup of about 1500 children born in Jimma town is examined for their first year's weight gain. Of special interest is the impact of certain cultural practices like uvulectomy, milk teeth extraction and butter swallowing, on child's weight gain; these have never been thoroughly investigated in any study. In this context, the linear mixed model (Laird and Ware) is employed. The purpose of this paper is to illustrate the practical issues when constructing the longitudinal model. Recently developed diagnostics will be used herefor. Finally, special attention will be paid to the two-stage interpretation of the linear mixed model.

Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis.

Both a decrease in bone formation and an increase in bone resorption have been implicated in the pathogenesis of age-related (type II) femoral neck osteoporosis. While the increase in the bone resorption rate has been shown to be partially related to secondary hyperparathyroidism, the mechanisms underlying the decline in bone formation have not yet been identified. The aim of the present study was to test the hypothesis that the bone formation deficit associated with type II osteoporosis might be due to secondary hyperparathyroidism and/or to a deficiency of the insulin-like growth factor (IGF) system. Circulating concentrations of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, 25-hydroxycholecalciferol (25(OH)D3), and intact parathyroid hormone (PTH) were measured in 50 elderly women after sustaining a hip fracture and in 50 healthy age-matched controls. In addition, serum levels of osteocalcin (OC), skeletal alkaline phosphatase, and N-terminal procollagen peptide and urinary pyridinium cross-links were determined as markers of bone remodeling, and bone mineral density (BMD) was assessed at the proximal femur. In the patient group, serum was drawn within 18 h of the fracture and prior to surgery. Circulating protein concentrations did not change over this time frame. No difference was found between mean IGFBP-4 serum levels in the two groups studied, while mean levels of IGF-I, IGF-II, IGFBP-3, IGFBP-5, 25(OH)D3, and markers of bone formation were significantly lower (p < 0.006) in patients as compared with healthy subjects. Serum PTH and urinary pyridinium cross-links, however, were markedly increased (p < 0.001) in the osteoporotic group. In pooled data from the normal and osteoporotic populations, age-adjusted multiple regression models based on IGF-I, IGF-II, IGFBP-3, and IGFBP-5 were found to be highly predictive of serum OC (R2 = 19%, p < 0.001) and BMD of femoral neck (R2 = 49%, p < 0.0001), consistent with an effect of the anabolic IGF components on overall bone formation rate. Similar models based on 25(OH)D3 and PTH, however, were statistically unrelated to OC. To address further the potential impact of trauma on circulating IGF system components, we measured IGF system component levels in 10 male patients within 18 h following tibial fracture and in 10 age-matched normal male subjects. There was no significant difference in serum level of any of the IGF system components between the two groups. Although limited by its cross-sectional design, the present study suggests that, in addition to bone resorption resulting from secondary hyperparathyroidism, impaired bone formation associated with deficiency of the IGF system might predispose elderly women to fragility fracture of the proximal femur.

Comparative effects of neonatal and prepubertal castration on craniofacial growth in rats.

The role of endogenous testosterone in the craniofacial growth of the young male rat was investigated. First, the effect of neonatal surgical castration was examined in a randomized, cross-sectional study in which male Wistar rats were allocated to be either castrated or sham-operated 4 h after birth. Then, the effect of prepubertal chemical castration was analysed in a second, randomized longitudinal study in which male Wistar rats were randomly allocated either to a control group or to two experimental groups, one injected with triptorelin at day 25 and the other injected on day 25 and on day 45. Every tenth day between 20 and 70 days of age for the first study, and between 30 and 110 days of age for the second, body length and weight were measured, cephalometric X-rays taken, and blood samples obtained. Neonatal and prepubertal castration resulted in decreased plasma concentrations of testosterone and in delayed growth of somatic and craniofacial components. The initiation, duration and magnitude of the effect was dependent on individual bones (cranial base, skull roof) and on the lower incisor, and related to the testosterone concentrations. These results suggest that testosterone effects participate in the process of normal craniofacial growth, particularly during puberty.