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Background/Objectives: Bordetella bronchiseptica is a Gram-negative bacterium that, either acting alone or in concert with other bacterial or viral pathogens, is a major cause of the canine infectious respiratory disease (CIRD) complex in dogs. Most currently available vaccines are given intranasally or orally and, whilst providing satisfactory reduction in disease severity, can be difficult to use especially in aggressive or anxious dogs. Whilst a small number of injectable B. bronchiseptica vaccines have been developed, little is known about their characteristics with regard to the age at first vaccination, the onset of immunity, duration of immunity, induction of antibody responses, concurrent use with the core vaccines used in most dogs, efficacy in the face of maternally derived antibodies (MDAs) or existing immunity and safety in pregnant animals. Here we describe the development of a safe and efficacious injectable B. bronchiseptica vaccine that utilises a novel process to purify fimbriae. Methods: The fimbrial antigen was formulated with a vitamin E-based oil-in-water adjuvant known to be safe in dogs (Nobivac® Respira Bb). To evaluate dose response, thirty-nine naïve 5–6-week-old Beagle puppies were allocated to four groups and vaccinated subcutaneously with Nobivac® Respira Bb at 69 U, 25 U, and 7 U (with a booster at two weeks). All groups were challenged with B. bronchiseptica two weeks after the booster. To evaluate the onset of immunity at 5–6 weeks of age, twenty-one naïve Beagle dogs were split into two groups: group 1 received Nobivac Respira Bb (88 U/dose) plus Nobivac DHPPi and Nobivac L4; group 2 received DHPPi and L4 only. Both groups were challenged with B. bronchiseptica two weeks after the second vaccination. Safety in pregnancy was evaluated by vaccinating pregnant dams and monitoring whelping outcomes and puppy health. Protection in puppies with maternally derived antibodies (MDAs) was studied in 28 pups (11 MDA-negative and 17 MDA-positive from vaccinated and unvaccinated dams). Pups were vaccinated at 5–6 weeks; one group remained unvaccinated to monitor MDA kinetics. All puppies were challenged with B. bronchiseptica at 19 weeks, after MDAs became undetectable. Serology was monitored throughout; daily clinical observations and nasal swabs post-challenge assessed protection and bacterial shedding. Results: Nobivac Respira Bb (MSD Animal Health), was safe for use in 5–6-week-old puppies alongside other Nobivac core canine vaccines without vaccine interference. The vaccine has an onset of immunity of two weeks and significantly reduces both the clinical signs of B. bronchiseptica-induced disease and bacterial excretion into the environment. Furthermore, the vaccine is equally efficacious in puppies with maternally derived antibodies derived from vaccinated dams and can be used safely in pregnant bitches. Conclusions: This vaccine represents a convenient, safe and efficacious alternative to vaccines delivered via the oral or intranasal routes and is a positive addition to the range of vaccines targeted at reducing disease induced by B. bronchiseptica.

PurposeTo assess the independent association between ICU-acquired neuromuscular complications and 5-year mortality and morbidity. To explore the optimal threshold of the Medical Research Council (MRC) sum score, assessing weakness, for the prediction of 5-year outcomes.MethodsSub-analyses of a prospective, 5-year follow-up study including 883 EPaNIC patients (Early versus Late Parenteral Nutrition in Intensive Care) (Clinicaltrials.gov:NCT00512122), systematically screened in ICU for neuromuscular complications with MRC sum score (‘MRC-cohort’, N = 600), electrophysiology on day 8 ± 1 to quantify compound muscle action potential (‘CMAP-cohort’, N = 689), or both (‘MRC&CMAP-cohort’, N = 415). Associations between ICU-acquired neuromuscular complications and 5-year mortality, hand-grip strength (HGF, %predicted), 6-min-walk distance (6-MWD, %predicted) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36) at 5-years were assessed with Cox regression and linear regression, adjusted for confounders. The optimal threshold for MRC at ICU discharge to predict 5-year outcomes was determined by martingale residual plots (survival) and scatterplots (morbidity).ResultsBoth lower MRC sum score at ICU discharge, indicating less strength [HR, per-point-increase: 0.946 (95% CI 0.928–0.968), p = 0.001], and abnormal CMAP, indicating nerve/muscle dysfunction [HR: 1.568 (95% CI 1.165–2.186), p = 0.004], independently associated with increased 5-year mortality. In the MRC&CMAP-cohort, MRC [HR: 0.956 (95% CI 0.934–0.980), p = 0.001] but not CMAP [HR: 1.478 (95% CI 0.875–2.838), p = 0.088] independently associated with 5-year mortality. Among 205 survivors, low MRC independently associated with low HGF [0.866 (95% CI 0.237–1.527), p = 0.004], low 6-MWD [105.1 (95% CI 12.1–212.9), p = 0.043] and low PF-SF-36 [− 0.119 (95% CI − 0.186 to − 0.057), p = 0.002], whereas abnormal CMAP did not correlate with these morbidity endpoints. Exploratory analyses suggested that MRC ≤ 55 best predicted poor long-term morbidity and mortality. Both MRC ≤ 55 and abnormal CMAP independently associated with 5-year mortality.ConclusionsICU-acquired neuromuscular complications may impact 5-year morbidity and mortality. MRC sum score, even if slightly reduced, may affect long-term mortality, strength, functional capacity and physical function, whereas abnormal CMAP only related to long-term mortality.

In this multicenter randomized, controlled trial, withholding parenteral nutrition from critically ill children in the pediatric intensive care unit for 1 week was clinically superior to providing early parenteral nutrition. Fluid loading was provided in both groups. Critically ill children cannot normally be fed by mouth, and as a result a pronounced macronutrient deficit often develops after a few days. This macronutrient deficit has been associated with infections, weakness, prolonged mechanical ventilation, and delayed recovery. 1 – 3 In order to prevent or limit the development of this macronutrient deficit, current guidelines, which are based largely on small studies with surrogate end points and on expert opinion, advise care providers to initiate nutritional support soon after a child’s admission to the pediatric intensive care unit (ICU). 4 – 6 The preferred route for the administration of nutritional support in the pediatric . . .

Abstract Rationale Intensive care unit (ICU)-acquired weakness is a frequent complication of critical illness. It is unclear whether it is a marker or mediator of poor outcomes. Objectives To determine acute outcomes, 1-year mortality, and costs of ICU-acquired weakness among long-stay (≥8 d) ICU patients and to assess the impact of recovery of weakness at ICU discharge. Methods Data were prospectively collected during a randomized controlled trial. Impact of weakness on outcomes and costs was analyzed with a one-to-one propensity-score-matching for baseline characteristics, illness severity, and risk factor exposure before assessment. Among weak patients, impact of persistent weakness at ICU discharge on risk of death after 1 year was examined with multivariable Cox proportional hazards analysis. Measurements and Main Results A total of 78.6% were admitted to the surgical ICU; 227 of 415 (55%) long-stay assessable ICU patients were weak; 122 weak patients were matched to 122 not-weak patients. As compared with matched not-weak patients, weak patients had a lower likelihood for live weaning from mechanical ventilation (hazard ratio [HR], 0.709 [0.549–0.888]; P = 0.009), live ICU (HR, 0.698 [0.553–0.861]; P = 0.008) and hospital discharge (HR, 0.680 [0.514–0.871]; P = 0.007). In-hospital costs per patient (+30.5%, +5,443 Euro per patient; P = 0.04) and 1-year mortality (30.6% vs. 17.2%; P = 0.015) were also higher. The 105 of 227 (46%) weak patients not matchable to not-weak patients had even worse prognosis and higher costs. The 1-year risk of death was further increased if weakness persisted and was more severe as compared with recovery of weakness at ICU discharge (P < 0.001). Conclusions After careful matching the data suggest that ICU-acquired weakness worsens acute morbidity and increases healthcare-related costs and 1-year mortality. Persistence and severity of weakness at ICU discharge further increased 1-year mortality. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

This controlled, randomized, multicenter trial compared early initiation (<2 days) with late initiation (≥8 days) of parenteral nutrition in adults in the intensive care unit. Late initiation was associated with less morbidity and enhanced recovery. Critical illness induces anorexia and the inability to eat normally, predisposing patients to serious nutritional deficits, muscle wasting, weakness, and delayed recovery. Whether artificial nutritional support improves the outcome for critically ill patients is unclear. The administration route, the time until the initiation of artificial nutrition, the number of calories, and the type of nutrients may be important. 1 – 3 Enteral nutrition is associated with fewer complications than parenteral nutrition and is less expensive to administer. 4 – 6 However, the use of enteral nutrition alone often does not achieve caloric targets. 7 In addition, underfeeding is associated with weakness, infection, 8 an increased duration . . .

•Assessment of dogs inoculated with Nobivac Rabies vaccine stored at high temperatures.•Neutralizing antibody response not inferior after vaccine stored at 30°C for 3months.•Nobivac Rabies vaccine likely to be efficacious if exposed to elevated temperatures.•Flexible vaccine delivery models can be explored using the Nobivac Rabies vaccine. This study provides the first robust data that the antibody response of dogs vaccinated with Nobivac® Rabies vaccine stored for several months at high temperatures (up to 30°C) is not inferior to that of dogs vaccinated with vaccine stored under recommended cold-chain conditions (2–8°C). A controlled and randomized non-inferiority study was carried out comparing the four-week post vaccination serological responses of Tanzanian village dogs inoculated with vaccine which had been stored at elevated temperatures for different periods of time with those of dogs vaccinated with the same product stored according to label recommendations. Specifically, the neutralizing antibody response following the use of vaccine which had been stored for up to six months at 25°C or for three months at 30°C was not inferior to that following the use of cold-chain stored vaccine. These findings provide reassurance that the vaccine is likely to remain efficacious even if exposed to elevated temperatures for limited periods of time and, under these circumstances, it can safely be used and not necessarily destroyed or discarded. The availability of thermotolerant vaccines has been an important factor in the success of several disease control and elimination programs and could greatly increase the capacity of rabies vaccination campaigns to access hard to reach communities in Africa and Asia. We have not confirmed a 3-year duration of immunity for the high temperature stored vaccine, however because annual re-vaccination is usually practiced for dogs presented for vaccination during campaigns in Africa and Asia this should not be a cause for concern. These findings will provide confidence that, for rabies control and elimination programs using this vaccine in low-income settings, more flexible delivery models could be explored, including those that involve limited periods of transportation and storage at temperatures higher than that currently recommended.

Background/Objective: The poultry industry requires extensive vaccination of chickens against IBV in an effort to prevent the disease in animals and significant economic losses. Current vaccination strategies often lack effectiveness, and the continual emergence of new IBV variants makes disease control increasingly challenging. We have developed an inactivated vaccine for poultry containing nine different antigens (Nobilis Multriva), including two IBDV strains, two ARV strains, one NDV strain, one AMPV strain, one EDSV strain and two IBV strains: M41 (genotype GI-1) and 4–91 (genotype GI-13). In this study, the IB efficacy of this novel inactivated vaccine was investigated against homologous and heterologous IBV strains. Methods: Inactivated IBV vaccine containing the M41 and 4–91 strains (Nobilis Multriva) was administered intramuscularly, either alone or following vaccine priming, in SPF and commercial chickens. Birds were challenged with homologous and heterologous IBV strains at defined ages (peak of lay, mid-lay and end of lay). Vaccine efficacy was evaluated through serological assays, clinical observations, and monitoring of egg production post-challenge. Results: This vaccine provided excellent broad protection against different IBV strains circulating in different parts of the world, including IBV M41, 4–91, QX, Q1 and Var2. Furthermore, the vaccine provided long-lasting IBV serological response against IB M41 and IB 4–91 until at least 96 weeks of age in SPF and commercial layers and breeder birds. This vaccine will allow farmers to reduce the number of vaccination moments, thereby minimizing stress to the birds, while also decreasing labor demands and the risk of human error, ultimately contributing to lower overall vaccination costs. Conclusions: Given its demonstrated broad cross-protection and sustained serological responses, this nine-valent inactivated vaccine (Nobilis Multriva) represents a key component of an effective vaccination regimen for controlling IBV infections in the poultry industry.

Early parenteral nutrition to supplement insufficient enteral feeding during intensive care (early PN) delays recovery as compared with withholding parenteral nutrition for 1 week (late PN). To assess whether deleterious effects of early PN relate to severity of illness or to the dose or type of macronutrients. Secondary analyses of a randomized controlled trial (EPaNIC; n = 4,640) performed in seven intensive care units from three departments in two Belgian hospitals. In part 1, all patients were included to assess the effect of the randomized allocation to early PN or late PN in subgroups of patients with increasing-on-admission severity of illness. In part 2, observationally, the association of the amount and type of macronutrients with recovery was documented in those patient cohorts still present in intensive care on Days 3, 5, 7, 10, and 14. The primary end point was time to live discharge from the intensive care unit. For part 1, a secondary end point, acquisition of new infections, was also analyzed. All statistical analyses were performed by univariable and adjusted multivariable methods. In none of the subgroups defined by type or severity of illness was a beneficial effect of early PN observed. The lowest dose of macronutrients was associated with the fastest recovery and any higher dose, administered parenterally or enterally, was associated with progressively more delayed recovery. The amount of proteins/amino acids rather than of glucose appeared to explain delayed recovery with early feeding. Early combined parenteral/enteral nutrition delayed recovery irrespective of severity of critical illness. No dose or type of macronutrient was found to be associated with improved outcome. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

PurposeIn critically ill adults, withholding parenteral nutrition until 1 week after intensive care admission (Late-PN) facilitated recovery as compared with early supplementation of insufficient enteral nutrition with parenteral nutrition (Early-PN). However, the impact on long-term mortality and functional outcome, in relation to the estimated nutritional risk, remains unclear.MethodsIn this prospective follow-up study of the multicenter EPaNIC randomized controlled trial, we investigated the impact of Late-PN on 2-year mortality (N = 4640) and physical functioning, assessed by the 36-Item Short Form Health Survey (SF-36; in 3292 survivors, responding 819 [738–1058] days post-randomization). To account for missing data, we repeated the analyses in two imputed models. To identify potential heterogeneity of treatment effects, we investigated the impact of Late-PN in different nutritional risk subgroups as defined by Nutritional Risk Screening-2002-score, modified NUTrition Risk in the Critically Ill-score, and age (above/below 70 years), and we evaluated whether there was statistically significant interaction between classification to a nutritional risk subgroup and the effect of the randomized intervention. Secondary outcomes were SF-36-derived physical and mental component scores (PCS & MCS).ResultsTwo-year mortality (20.5% in Late-PN, 19.8% in Early-PN; P = 0.54) and physical functioning (70 [40–90] in both study-arms; P = 0.99) were similar in both groups, also after imputation of missing physical functioning data. Likewise, Late-PN had no impact on 2-year mortality and physical functioning in any nutritional risk subgroup. PCS and MCS were similar in both groups.ConclusionLate-PN did not alter 2-year survival and physical functioning in adult critically ill patients, independent of anticipated nutritional risk.

PurposeFor patients suffering from prolonged critical illness, it is unknown whether and when the hypothalamus–pituitary–adrenal axis alterations recover, and to what extent adrenocortical function parameters relate to sepsis/septic shock, to clinical need for glucocorticoid treatment, and to survival.MethodsPatients still in ICU on day 7 (N = 392) and 20 matched healthy subjects were included. Morning blood and 24-h urine were collected daily and cosyntropin tests (250 µg) performed weekly, repeated 1 week after ICU discharge on the regular ward.ResultsIn all patients free of glucocorticoid treatment up until ICU day 28 (N = 347), plasma ACTH always remained low/normal, whereas free cortisol remained high (P ≤ 0.002) explained by reduced binding proteins (P ≤ 0.02) and suppressed cortisol breakdown (P ≤ 0.001). Beyond ICU day 28 (N = 64 long-stayers), plasma (free)cortisol was no longer elevated. One week after ICU discharge, plasma ACTH and (free)cortisol always rose to supra-normal levels (P ≤ 0.006), most pronounced in long-stayers. Long-stayers always showed low incremental total (P ≤ 0.001), but normal incremental free cortisol responses to weekly cosyntropin tests, explained by low cortisol plasma binding proteins. Sepsis/septic shock patients were not different from others, patients subsequently receiving glucocorticoids (N = 45) were not different from those who did not, and non-survivors were distinguishable from survivors only by higher (free)cortisol.ConclusionsIrrespective of sepsis/septic shock, need for glucocorticoids and survival, low cortisol plasma binding proteins and suppressed cortisol breakdown determine systemic (free)cortisol availability in prolonged critical illness, the latter no longer elevated beyond ICU day 28. The uniform rise in ACTH and cortisol to supra-normal levels 1 week after ICU discharge indicates recovery of a central adrenocortical suppression while in ICU. Low cortisol plasma binding invalidates the cosyntropin test.