A multicentre, randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of early nutritional support via the parenteral versus the enteral route in critically ill patients (CALORIES)

BACKGROUND: Malnutrition is a common problem in critically ill patients in UK NHS critical care units. Early nutritional support is therefore recommended to address deficiencies in nutritional state and related disorders in metabolism. However, evidence is conflicting regarding the optimum route (parenteral or enteral) of delivery. OBJECTIVES: To estimate the effect of early nutritional support via the parenteral route compared with the enteral route on mortality at 30 days and on incremental cost-effectiveness at 1 year. Secondary objectives were to compare the route of early nutritional support on duration of organ support; infectious and non-infectious complications; critical care unit and acute hospital length of stay; all-cause mortality at critical care unit and acute hospital discharge, at 90 days and 1 year; survival to 90 days and 1 year; nutritional and health-related quality of life, resource use and costs at 90 days and 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Adult general critical care units in 33 NHS hospitals in England. PARTICIPANTS: 2400 eligible patients. INTERVENTIONS: Five days of early nutritional support delivered via the parenteral (n = 1200) and enteral (n = 1200) route. MAIN OUTCOME MEASURES: All-cause mortality at 30 days after randomisation and incremental net benefit (INB) (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: By 30 days, 393 of 1188 (33.1%) patients assigned to receive early nutritional support via the parenteral route and 409 of 1195 (34.2%) assigned to the enteral route had died [p = 0.57; absolute risk reduction 1.15%, 95% confidence interval (CI) -2.65 to 4.94; relative risk 0.97 (0.86 to 1.08)]. At 1 year, INB for the parenteral route compared with the enteral route was negative at -£1320 (95% CI -£3709 to £1069). The probability that early nutritional support via the parenteral route is more cost-effective - given the data - is < 20%. The proportion of patients in the parenteral group who experienced episodes of hypoglycaemia (p = 0.006) and of vomiting (p < 0.001) was significantly lower than in the enteral group. There were no significant differences in the 15 other secondary outcomes and no significant interactions with pre-specified subgroups. LIMITATIONS: Blinding of nutritional support was deemed to be impractical and, although the primary outcome was objective, some secondary outcomes, although defined and objectively assessed, may have been more vulnerable to observer bias. CONCLUSIONS: There was no significant difference in all-cause mortality at 30 days for early nutritional support via the parenteral route compared with the enteral route among adults admitted to critical care units in England. On average, costs were higher for the parenteral route, which, combined with similar survival and quality of life, resulted in negative INBs at 1 year. FUTURE WORK: Nutritional support is a complex combination of timing, dose, duration, delivery and type, all of which may affect outcomes and costs. Conflicting evidence remains regarding optimum provision to critically ill patients. There is a need to utilise rigorous consensus methods to establish future priorities for basic and clinical research in this area. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17386141. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 28. See the NIHR Journals Library website for further project information

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Was Dinosaurian Physiology Inherited by Birds? Reconciling Slow Growth in Archaeopteryx

Archaeopteryx is the oldest and most primitive known bird (Avialae). It is believed that the growth and energetic physiology of basalmost birds such as Archaeopteryx were inherited in their entirety from non-avialan dinosaurs. This hypothesis predicts that the long bones in these birds formed using rapidly growing, well-vascularized woven tissue typical of non-avialan dinosaurs. We report that Archaeopteryx long bones are composed of nearly avascular parallel-fibered bone. This is among the slowest growing osseous tissues and is common in ectothermic reptiles. These findings dispute the hypothesis that non-avialan dinosaur growth and physiology were inherited in totality by the first birds. Examining these findings in a phylogenetic context required intensive sampling of outgroup dinosaurs and basalmost birds. Our results demonstrate the presence of a scale-dependent maniraptoran histological continuum that Archaeopteryx and other basalmost birds follow. Growth analysis for Archaeopteryx suggests that these animals showed exponential growth rates like non-avialan dinosaurs, three times slower than living precocial birds, but still within the lowermost range for all endothermic vertebrates. The unexpected histology of Archaeopteryx and other basalmost birds is actually consistent with retention of the phylogenetically earlier paravian dinosaur condition when size is considered. The first birds were simply feathered dinosaurs with respect to growth and energetic physiology. The evolution of the novel pattern in modern forms occurred later in the group's history

Access to Adequate Outpatient Depression Care for Mothers in the USA: A Nationally Representative Population-Based Study

Maternal depression is often untreated, resulting in serious consequences for mothers and their children. Factors associated with receipt of adequate treatment for depression were examined in a population-based sample of 2,130 mothers in the USA with depression using data from the 1996–2005 Medical Expenditure Panel Survey. Chi-squared analyses were used to evaluate differences in sociodemographic and health characteristics by maternal depression treatment status (none, some, and adequate). Multivariate regression was used to model the odds of receiving some or adequate treatment, compared to none. Results indicated that only 34.8% of mothers in the USA with depression received adequate treatment. Mothers not in the paid workforce and those with health insurance were more likely to receive treatment, while minority mothers and those with less education were less likely to receive treatment. Understanding disparities in receipt of adequate treatment is critical to designing effective interventions, reducing treatment inequities, and ultimately improving the mental health and health of mothers and their families

Striking Denervation of Neuromuscular Junctions without Lumbar Motoneuron Loss in Geriatric Mouse Muscle

Reasons for the progressive age-related loss of skeletal muscle mass and function, namely sarcopenia, are complex. Few studies describe sarcopenia in mice, although this species is the mammalian model of choice for genetic intervention and development of pharmaceutical interventions for muscle degeneration. One factor, important to sarcopenia-associated neuromuscular change, is myofibre denervation. Here we describe the morphology of the neuromuscular compartment in young (3 month) compared to geriatric (29 month) old female C57Bl/6J mice. There was no significant difference in the size or number of motoneuron cell bodies at the lumbar level (L1–L5) of the spinal cord at 3 and 29 months. However, in geriatric mice, there was a striking increase (by ∼2.5 fold) in the percentage of fully denervated neuromuscular junctions (NMJs) and associated deterioration of Schwann cells in fast extensor digitorum longus (EDL), but not in slow soleus muscles. There were also distinct changes in myofibre composition of lower limb muscles (tibialis anterior (TA) and soleus) with a shift at 29 months to a faster phenotype in fast TA muscle and to a slower phenotype in slow soleus muscle. Overall, we demonstrate complex changes at the NMJ and muscle levels in geriatric mice that occur despite the maintenance of motoneuron cell bodies in the spinal cord. The challenge is to identify which components of the neuromuscular system are primarily responsible for the marked changes within the NMJ and muscle, in order to selectively target future interventions to reduce sarcopenia

Optimising the palatability and longevity of stoat baits

In New Zealand, introduced stoats (Mustela erminea) are significant predators of many native bird species. Trapping for stoat control is currently undertaken, but imposes logistical and cost constraints on the frequency and area over which their impacts can be mitigated. We sought to identify a highly acceptable stoat bait formulation with an extended field life that could be used for delivery of appropriate poisons. In feeding trials with wild-caught stoats, we screened 6 meat bases and > 20 humectant, preservative, binder or palatant compounds for acceptance and palatability. Significant differences in bait acceptance between female and male stoats were found. A humectant-preservative combination of polyethylene glycol (PEG 20,000) and sorbitol in rabbit mince was identified as optimal with over 80% acceptance by both male and female stoats and higher palatability (73.5%) than plain rabbit mince. This bait combination was acceptably ‘long-life’, with 80% of stoats eating PEG sorbitol bait weathered for 28 days. This bait formulation thus has useful application in current stoat trapping programmes but also potential in future delivery of selective poisons, such as para-aminopropiophenone, to manage field populations of stoats