Overall Survival in Patients with Endometrial Cancer Treated with Dostarlimab plus Carboplatin-Paclitaxel in the Randomized ENGOT-EN6/GOG-3031/RUBY Trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint. RESULTS: A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.

Quantitative functional imaging of the pigeon brain: implications for the evolution of avian powered flight.

The evolution of flight is a rare event in vertebrate history, and one that demands functional integration across multiple anatomical/physiological systems. The neuroanatomical basis for such integration and the role that brain evolution assumes in behavioural transformations remain poorly understood. We make progress by (i) generating a positron emission tomography (PET)-based map of brain activity for pigeons during rest and flight, (ii) using these maps in a functional analysis of the brain during flight, and (iii) interpreting these data within a macroevolutionary context shaped by non-avian dinosaurs. Although neural activity is generally conserved from rest to flight, we found significant increases in the cerebellum as a whole and optic flow pathways. Conserved activity suggests processing of self-movement and image stabilization are critical when a bird takes to the air, while increased visual and cerebellar activity reflects the importance of integrating multimodal sensory information for flight-related movements. A derived cerebellar capability likely arose at the base of maniraptoran dinosaurs, where volumetric expansion and possible folding directly preceded paravian flight. These data represent an important step toward establishing how the brain of modern birds supports their unique behavioural repertoire and provide novel insights into the neurobiology of the bird-like dinosaurs that first achieved powered flight.

Mandibular condylar process remodeling in rats with different bite-altering devices.

The objective was to compare different dental splint models and materials for inducing abnormal loading on the gross morphology and histological appearance of the mandibular condylar processes of Sprague Dawley rats. Three different types of dental splints (resin molar, aluminum incisor, stainless-steel incisor) were placed unilaterally to induce occlusal perturbation for 4 weeks. At that time, mandibular condylar processes were assessed by gross appearance and histology. Quantitative measurements were also conducted on the hematoxylin and eosin images for condyle shape. The results showed that although the condylar cartilage was affected by all splint types, the resin molar splint was associated with the most extensive mandibular condylar process remodeling, which was primarily a slant (skewness) of the lateral aspect of the condylar process. Additionally, quantitative measurements on the histological specimens demonstrated that the split and tilt angle of the left (ipsilateral) condylar processes in the resin molar group (124.8 ± 12.7° and 104.1 ± 12.7°, respectively) increased significantly (p < 0.05) when compared to right (contralateral) condylar processes (104.7 ± 5.8°and 91.6 ± 4.4°, respectively). However, no changes were noted on the thickness of the fibrocartilage layer at medial, central, and lateral regions of the condylar process. Another major finding is the high variability of morphology of the naïve animals. Future studies will assess the impact of longer durations of splinting, age, and sex on the remodeling of the mandibular condylar process, allowing for the development of diagnostics and therapies.

First Leptophobic Dark Matter Search from the Coherent-CAPTAIN-Mills Liquid Argon Detector.

We report the first results of a search for leptophobic dark matter (DM) from the Coherent-CAPTAIN-Mills (CCM) liquid argon (LAr) detector. An engineering run with 120 photomultiplier tubes (PMTs) and 17.9×10^{20} protons on target (POT) was performed in fall 2019 to study the characteristics of the CCM detector. The operation of this 10-ton detector was strictly light based with a threshold of 50 keV and used coherent elastic scattering off argon nuclei to detect DM. Despite only 1.5 months of accumulated luminosity, contaminated LAr, and nonoptimized shielding, CCM's first engineering run has already achieved sensitivity to previously unexplored parameter space of light dark matter models with a baryonic vector portal. With an expected background of 115 005 events, we observe 115 005+16.5 events which is compatible with background expectations. For a benchmark mediator-to-DM mass ratio of m_{V_{B}}/m_{χ}=2.1, DM masses within the range 9 MeV≲m_{χ}≲50 MeV are excluded at 90% C. L. in the leptophobic model after applying the Feldman-Cousins test statistic. CCM's upgraded run with 200 PMTs, filtered LAr, improved shielding, and 10 times more POT will be able to exclude the remaining thermal relic density parameter space of this model, as well as probe new parameter space of other leptophobic DM models.

Black soldier fly larvae meal and fat as a replacement for soybeans in organic broiler diets: effects on performance, body N retention, carcase and meat quality.

1. Due to the increasing global demand for more sustainably produced animal protein, there is an intensive search for feeds to replace soybeans. Black soldier fly larvae (BSFL) appear to have great potential for replacing soybeans in poultry diets. The main objective of this study was to determine if the nutritional value of BSFL is superior to soybeans when feeding organic broilers, since smaller amounts of BSFL could replace the soybean content in the feed, thus saving even more resources.2. Eighty Hubbard S757, a slow growing organic broiler type, were fattened for 63 d, spending the last 49 d on one of five diets. Two soybean cake- and soybean oil-based diets (SS, SS-) were compared with three diets based on partially defatted BSFL meal and BSFL fat from two origins (AA-, AB-, BB-). Different from diet SS, diets SS-, AA-, AB-and BB- were designed with approximately 20% less lysine and methionine. Growth (n = 16), metabolisability, body nitrogen retention, carcase and meat quality (n = 8) were evaluated.3. Broilers of the insect-based feeding groups, AA- and AB-, grew similarly well compared to those of group SS. They also retained more nitrogen in the body than those fed BB- and SS-. Breast meat yield was higher with AA- and AB- than with BB- and SS-, but still lower than with SS. Dietary variations in physicochemical meat quality were of low practical relevance. Diet BB- resulted in a more yellow skin and meat. The fatty acid profile of the breast meat lipids reflected the high lauric acid proportion of the BSFL lipids, resulting in up to 80 times higher proportions than when feeding the soybean-based diets.4. The results indicate that high-quality BSFL, depending on their origin, may indeed be superior to soybean protein, but that the meat lipids from BSFL-fed broilers can contain significant amounts of lauric acid, which, from a human nutrition perspective, could have a negative impact on meat quality.

Anatomical variations of the mandibular canal and their clinical implications in dental practice: a literature review.

INTRODUCTION: The anatomical variations of the mandibular canal have been described according to the number of additional branches it presents, bifid and trifid. Within the bifids we can also find subtypes of variations such as the retromolar mandibular canal. These anatomical variations can have important clinical implications for the work of dental professionals. METHODS: A systematic search of the literature was carried out in different databases that met the following criteria: articles published between 2000 and 2020, and articles that established a clinical correlation with variations in the mandibular canal. RESULTS: After applying inclusion and exclusion criteria, 32 articles were obtained, in which the variations of the mandibular canal were identified, their prevalence and incidence, which was very varied between the different articles, it was also found that the CBCT was the main technique to identify the anatomical variations of the mandibular canal. Lastly, the anatomical variations of the mandibular canal have a direct clinical correlation with pre-surgical, intra-surgical and postsurgical complications in pathologies that require surgical intervention. CONCLUSIONS: The anatomical variations of the mandibular canal have a high incidence, so knowing them is of vital importance both for clinicians and anatomy professors who provide morphological training. We believe that research should focus on describing and diagnosing the causes of these anatomical variations. That said, there is also a continuous challenge for all health professionals to learn about the different anatomical variations that the human body presents and how these can affect clinical practice.

A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study.

BACKGROUND: Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells. PATIENTS AND METHODS: Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile. RESULTS: From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent. CONCLUSIONS: Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials. CLINICALTRIALS.GOV NUMBER: NCT01197885.

First Measurement of the Total Neutron Cross Section on Argon between 100 and 800 MeV.

We report the first measurement of the neutron cross section on argon in the energy range of 100-800 MeV. The measurement was obtained with a 4.3-h exposure of the Mini-CAPTAIN detector to the WNR/LANSCE beam at LANL. The total cross section is measured from the attenuation coefficient of the neutron flux as it traverses the liquid argon volume. A set of 2631 candidate interactions is divided in bins of the neutron kinetic energy calculated from time-of-flight measurements. These interactions are reconstructed with custom-made algorithms specifically designed for the data in a time projection chamber the size of the Mini-CAPTAIN detector. The energy averaged cross section is 0.91±0.10(stat)±0.09(syst) b. A comparison of the measured cross section is made to the GEANT4 and FLUKA event generator packages, where the energy averaged cross sections in this range are 0.60 and 0.68 b, respectively.

Recovery of brain structural abnormalities in morbidly obese patients after bariatric surgery.

BACKGROUND/OBJECTIVES: Obesity-related brain structural abnormalities have been reported extensively, and bariatric surgery (BS) is currently the most effective intervention to produce sustained weight reduction in overtly obese (OB) people. It is unknown whether BS can repair the brain circuitry abnormalities concomitantly with long-term weight loss. SUBJECTS/METHODS: In order to investigate whether BS promotes neuroplastic structural recovery in morbidly OB patients, we quantified fractional anisotropy (FA), mean diffusivity (MD) and gray (GM) and white (WM) matter densities in 15 morbidly OB patients and in 18 normal weight (NW) individuals. OB patients were studied at baseline and also 1 month after laparoscopic sleeve gastrectomy surgery. RESULTS: Two-sample t-test between OB (baseline) and NW groups showed decreased FA values, GM/WM densities and increased MD value in brain regions associated with food intake control (that is, caudate, orbitofrontal cortex, body and genu of corpus callosum) and cognitive-emotion regulation (that is, inferior frontal gyrus, hippocampus, insula, external capsule) (P<0.05, family-wise error correction). Paired t-test in the OB group between before and after surgery showed that BS generated partial neuroplastic structural recovery in the OB group, but the differences had relative less strength and smaller volume (P<0.001). CONCLUSIONS: This study provides the first anatomical evidence for BS-induced acute neuroplastic recovery that might in part mediate the long-term benefit of BS in weight reduction. It also highlights the importance of this line of gut-brain axis research employing the combined BS and neuroimaging model for identifying longitudinal changes in brain structure that correlated with obesity status.

Does providing written dietary advice improve the ingestion of non-allergic nuts in children with existing nut allergies? - A randomized controlled trial.

BACKGROUND: Allergy to one or more nuts is common in children and often complete nut avoidance is advised. More recently, introduction of non-allergic nuts into the diet is advised by some allergists. OBJECTIVE: This study aims to determine whether the provision of additional written dietary advice increases the ingestion of non-allergic nuts by children with nut allergy. Secondary aims include determining which factors facilitate or prevent successful inclusion of non-allergic nuts in the diet, and how inclusion influences quality of life, sensitization and the rate of nut reactions. METHODS: This is a randomized, double-blinded, controlled trial of children with nut allergy who were asked to ingest one or more non-allergic nuts. Participants were 75 children aged 2-16 years (Intervention=36, Control=39), recruited in Adelaide, Australia. Randomized participants were supplied with the intervention (recipe booklet and monthly reminder text messages) or provided standard verbal dietary advice. After 6 months participants were assessed by a blinded investigator with regard to nut ingestion, quality of life, sensitization and nut reactions. RESULTS: The intervention did not increase the ingestion of non-allergic nuts. A negative hospital challenge was a predictor of successful introduction. Parental report of child concern about a reaction was the greatest barrier. Ingestion of non-allergic nuts did not improve quality of life or change nut sensitization. Few nut reactions occurred during the study. CONCLUSIONS AND CLINICAL RELEVANCE: Ingestion of non-allergic nuts by children with nut allergy was not improved by additional dietary intervention. Selective introduction of non-allergic nuts is difficult to achieve when the child is anxious about introduction and challenges cannot be done in a medically supervised setting. CAPSULE SUMMARY: This dietary intervention did not improve non-allergic nut ingestion by nut allergic children. Hospital challenge increased introduction rates, whilst parentally reported child concern about a reaction reduced success. Non-allergic nut ingestion did not change quality of life or sensitization.

Elevated IL-5 and IL-13 responses to egg proteins predate the introduction of egg in solid foods in infants with eczema.

BACKGROUND: Egg allergy is a leading cause of food allergy in young infants; however, little is known about early allergen-specific T-cell responses which predate the presentation of egg allergy, and if these are altered by early egg exposure. OBJECTIVE: To investigate the early T-cell responses to multiple egg proteins in relation to patterns of egg exposure and subsequent IgE-mediated egg allergy. METHODS: Egg-specific T-cell cytokine responses (IL-5, IL-13, IL-10, IFNγ and TNFα) to ovomucoid (OM), ovalbumin (OVA), conalbumin (CON) and lysozyme (LYS) were measured in infants with eczema at 4 months of age (n = 40), before randomization to receive 'early egg' or a placebo as part of a randomized controlled trial (Australian New Zealand Clinical Trials Registry number 12609000415202) and at 12 months of age (n = 58), when IgE-mediated egg allergy was assessed by skin prick test and food challenge. RESULTS: In 4-month-old infants, who had not directly ingested egg, those who subsequently developed egg allergy already had significantly higher Th2 cytokine responses to multiple egg allergens, particularly elevated IL-13 responses to OVA (P = 0.004), OM (P = 0.012) and LYS (P = 0.003) and elevated IL-5 to the same antigens (P = 0.031, 0.04 and 0.003, respectively). IL-13 responses (to OVA and LYS) and IL-5 responses (to LYS) at 4 months significantly predicted egg allergy at 12 months. All responses significantly declined with age in the egg-allergic infants, and this did not appear to be modified by 'early' introduction of egg. CONCLUSIONS & CLINICAL RELEVANCE: Elevated egg-specific Th2 cytokine responses were established prior to egg ingestion at 4 months and were not significantly altered by introduction of egg. Th2 responses at 4 months of age predicted egg allergy at 12 months, suggesting that this could be used as a biomarker to select infants for early prevention and management strategies.

Prebiotic-supplemented partially hydrolysed cow's milk formula for the prevention of eczema in high-risk infants: a randomized controlled trial.

BACKGROUND: Prevention guidelines for infants at high risk of allergic disease recommend hydrolysed formula if formula is introduced before 6 months, but evidence is mixed. Adding specific oligosaccharides may improve outcomes. OBJECTIVE: To evaluate whether partially hydrolysed whey formula containing oligosaccharides (0.8 g/100 ml) (pHF-OS) can prevent eczema in high-risk infants [ISRCTN65195597]. METHODS: We conducted a parallel-group, multicentre, randomized double-blind controlled trial of pHF-OS vs standard cow's milk formula. Infants with a family history of allergic disease were randomized (stratified by centre/maternal allergy) to active (n = 432) or control (n = 431) formula until 6 months of age if formula was introduced before 18 weeks. Primary outcome was cumulative incidence of eczema by 12 months in infants randomized at 0-4 weeks (375 pHF-OS, 383 control). Secondary outcomes were cumulative incidence of eczema by 12 or 18 months in all infants randomized, immune markers at 6 months and adverse events. RESULTS: Eczema occurred by 12 months in 84/293 (28.7%) infants allocated to pHF-OS at 0-4 weeks of age, vs 93/324 (28.7%) control (OR 0.98 95% CI 0.68, 1.40; P = 0.90), and 107/347 (30.8%) pHF-OS vs 112/370 (30.3%) control in all infants randomized (OR 0.99 95% CI 0.71, 1.37; P = 0.94). pHF-OS did not change most immune markers including total/specific IgE; however, pHF-OS reduced cow's milk-specific IgG1 (P < 0.0001) and increased regulatory T-cell and plasmacytoid dendritic cell percentages. There was no group difference in adverse events. CONCLUSION: pHF-OS does not prevent eczema in the first year in high-risk infants. The immunological changes found require confirmation in a separate cohort.

Predicting distress among people who care for patients living longer with high-grade malignant glioma.

PURPOSE: Caregivers of patients living longer with high-grade malignant glioma (HGG) have the unique challenge of caring for a person who may have cognitive impairment, along with cancer-related issues over a prolonged period of time. This study aims to detail the psychosocial profile of long-term caregivers, to describe their perceptions of the patient's quality of life and to examine predictors of their psychological distress. METHODS: Sixty-nine caregivers (48%) of eligible patients with HGG surviving over 2 years were recruited from two Australian metropolitan tertiary hospitals. Caregivers completed cross-sectional measures of psychological distress (GHQ-12), caregiver impact (FACQ-PC) and patient functional well-being (FACT-Br TOI). Correlational analyses identified factors related to caregiver psychological distress. Those of significance (p ≤ .01) were examined using multiple regression models to determine their predictive value. RESULTS: Caregivers were mostly female (73%), spouses (67%), cohabiting (78%) and were caring for patients surviving a median of 5.9 years since diagnosis. Whilst caregivers overall reported minimal psychological distress, 28% endorsed moderate to severe psychological distress, warranting clinical attention. Caregiver strain and low patient functional well-being both significantly predicted caregiver psychological distress (adjusted R(2) = .35, F(4, 60) = 17.7, p < .001), accounting for a moderate amount (35%) of variance. Other typical factors such as duration of caregiving, performance status, symptom burden and disease or demographic related factors were not predictive. CONCLUSIONS: Psychological distress affects a significant proportion of caregivers of patients living longer with HGG. The presence of caregiver strain and low patient functional well-being are the most important predictors of psychological distress among this cohort of caregivers.

Sunny with a chance of gastroenteritis: predicting swimmer risk at California beaches.

Traditional beach management that uses concentrations of cultivatable fecal indicator bacteria (FIB) may lead to delayed notification of unsafe swimming conditions. Predictive, nowcast models of beach water quality may help reduce beach management errors and enhance protection of public health. This study compares performances of five different types of statistical, data-driven predictive models: multiple linear regression model, binary logistic regression model, partial least-squares regression model, artificial neural network, and classification tree, in predicting advisories due to FIB contamination at 25 beaches along the California coastline. Classification tree and the binary logistic regression model with threshold tuning are consistently the best performing model types for California beaches. Beaches with good performing models usually have a rainfall/flow related dominating factor affecting beach water quality, while beaches having a deteriorating water quality trend or low FIB exceedance rates are less likely to have a good performing model. This study identifies circumstances when predictive models are the most effective, and suggests that using predictive models for public notification of unsafe swimming conditions may improve public health protection at California beaches relative to current practices.

The properties, distribution and function of Na(+)-Ca(2+) exchanger isoforms in rat cutaneous sensory neurons.

The Na(+)-Ca(2+) exchanger (NCX) appears to play an important role in the regulation of the high K(+)-evoked Ca(2+) transient in putative nociceptive dorsal root ganglion (DRG) neurons. The purpose of the present study was to (1) characterize the properties of NCX activity in subpopulations of DRG neurons, (2) identify the isoform(s) underlying NCX activity, and (3) begin to assess the function of the isoform(s) in vivo. In retrogradely labelled neurons from the glabrous skin of adult male Sprague-Dawley rats, NCX activity, as assessed with fura-2-based microfluorimetry, was only detected in putative nociceptive IB4+ neurons. There were two modes of NCX activity: one was evoked in response to relatively large and long lasting (∼325 nm for >12 s) increases in the concentration of intracellular Ca(2+) ([Ca(2+)]i), and a second was active at resting [Ca(2+)]i > ∼150 nm. There also were two modes of evoked activity: one that decayed relatively rapidly (<5 min) and a second that persisted (>10 min). Whereas mRNA encoding all three NCX isoforms (NCX1-3) was detected in putative nociceptive cutaneous neurons with single cell PCR, pharmacological analysis and small interfering RNA (siRNA) knockdown of each isoform in vivo suggested that NCX2 and 3 were responsible for NCX activity. Western blot analyses suggested that NCX isoforms were differentially distributed within sensory neurons. Functional assays of excitability, action potential propagation, and nociceptive behaviour suggest NCX activity has little influence on excitability per se, but instead influences axonal conduction velocity, resting membrane potential, and nociceptive threshold. Together these results indicate that the function of NCX in the regulation of [Ca(2+)]i in putative nociceptive neurons may be unique relative to other cells in which these exchanger isoforms have been characterized and it has the potential to influence sensory neuron properties at multiple levels.

Deteriorating patients managed with end-of-life care following Medical Emergency Team calls.

AIM: To describe the characteristics of patients whose end-of-life care was initiated in response to a Medical Emergency Team (MET) call and to develop a predictive score to aid prospective identification of these patients. METHODS: Retrospective cohort study of all MET calls in a tertiary teaching hospital between April 2010 and March 2011. All inpatients attended by the hospital MET. The main outcome measures were patient demographics, admission features and comorbidities in active and palliative patients, timing, frequency, physiology, and interventions in active and palliative MET calls. RESULTS: One thousand, five hundred and sixty-seven MET calls were called for 1073 patients. Sixty (5.6%) patients had at least one MET call resulting in initiation of end-of-life care. Palliative MET call patients compared with active patients were older (76.4 vs 65.9 years; P < 0.0001), had a shorter hospital stay (7.5 vs 12 days; P = 0.0002), had increased in-hospital mortality (73.3% vs 13.5%; P < 0.001), had higher Charlson comorbidity scores (3.1 vs 2.1; P = 0.0002) and were more likely to receive multiple MET calls (1.95/patient vs 1.43/patient; P = 0.011). Patient physiological parameters were worse at palliative MET calls. Prior history of malignancy, hemiplegia and peripheral vascular disease, and increasing age were independently associated with initiation of end-of-life care and were used to derive a 13-point predictive score. Patients with a score of 7 or more had a 20% chance of having a palliative MET call. CONCLUSION: Prospective identification of patients requiring palliative care may be possible prior to MET involvement. This may allow more timely and appropriate end-of-life discussions.

Reliability analysis of the resting state can sensitively and specifically identify the presence of Parkinson disease.

Parkinson disease (PD) is characterized by a number of motor and behavioral abnormalities that could be considered deficits of a "no task" or "resting" state, including resting motor findings and defects in emerging from a resting state (e.g., resting tremor, elevated resting tone, abulia, akinesia, apathy). PET imaging, and recently, the MRI technique of continuous arterial spin labeling (CASL) have shown evidence of changes in metabolic patterns in individuals with PD. The purpose of this study was to learn if the presence of PD could be "predicted" based on resting fluctuations of the BOLD signal. Participants were 15 healthy controls, 14 subjects with PD, and 1 subject who presented as a control but later developed PD. The amplitude of the low frequency fluctuation (ALFF) was used as an index of brain activity level in the resting state. Participants with PD using this index showed a reliable decrease in activity in a number of regions, including the supplementary motor cortex, the mesial prefrontal cortex, the right middle frontal gyrus, and the left cerebellum (lobule VII/VIII) as well as increased activity in the right cerebellum (lobule IV/V). Using a cross validation approach we term "Reliability Mapping of Regional Differences" (RMRD) to analyze our sample, we were able to reliably distinguish participants with PD from controls with 92% sensitivity and 87% specificity. Our "pre-diagnostic" subject segregated in our analysis with the PD group. These results suggest that resting fMRI should be considered for development as a biomarker and analytical tool for evaluation of PD.

Apathy, depression, and motor symptoms have distinct and separable resting activity patterns in idiopathic Parkinson disease.

Apathy and depression are heterogeneous syndromes with symptoms that overlap clinically. This clinical overlap leads to problems with classification and diagnosis in clinical populations. No functional imaging study has attempted to separate brain regions altered in apathy from those altered in depression in a clinical population. Parkinson disease (PD) is a disorder in which apathy and depression co-exist in a single population. We evaluate the relationship between apathy, depression, and motor severity of disease in PD, focusing on the relationship between these factors and the amplitude of the low frequency fluctuation (ALFF) in the resting state. We first evaluated if the resting ALFF signal is a reliable measure for our clinical question. For this, we develop and introduce a cross validation approach we term the "Regional Mapping of Reliable Differences" (RMRD) method to evaluate reliability of regions of interest deemed "significant" by standard voxel-wise techniques. Using this approach, we show that the apathy score in this sample is best predicted by ALFF signal in the left supplementary motor cortex, the right orbitofrontal cortex, and the right middle frontal cortex, whereas depression score is best predicted by ALFF signal in the right subgenual cingulate. Disease severity was best predicted by ALFF signal in the right putamen. A number of additional regions are also statistically (but not reliably) correlated with our neuropsychological measures and disease severity. Our results support the use of resting fMRI as a means to evaluate neuropsychiatric states and motor disease progression in Parkinson disease, and the clinical and epidemiologic observation that apathy and depression are distinct pathological entities. Our finding that "significance" and "reliability" are dissociated properties of regions of interest identified as significant using standard voxel-wise techniques suggests that including reliability analyses may add useful scientific information in neurobehavioral research.

Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies.

BACKGROUND: Diets high in n-3 long chain polyunsaturated fatty acids (LCPUFA) may modulate the development of IgE-mediated allergic disease and have been proposed as a possible allergy prevention strategy. The aim of this study was to determine whether n-3 LCPUFA supplementation of pregnant women reduces IgE-mediated allergic disease in their children. METHODS: Follow-up of children (n = 706) at hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome randomized controlled trial. The intervention group (n = 368) was randomly allocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks' gestation until birth; the control group (n = 338) received matched vegetable oil capsules without n-3 LCPUFA. The diagnosis of allergic disease was made during medical assessments at 1 and 3 years of age. RESULTS: No differences were seen in the overall percentage of children with IgE-mediated allergic disease in the first 3 years of life between the n-3 LCPUFA and control groups (64/368 (17.3%) vs 76/338 (22.6%); adjusted relative risk 0.78; 95% CI 0.58-1.06; P = 0.11). Eczema was the most common allergic disease; 13.8% of children in the n-3 LCPUFA group had eczema with sensitization compared with 19.0% in the control group (adjusted relative risk 0.75; 95% CI 0.53-1.05; P = 0.10). CONCLUSIONS: Overall, n-3 LCPUFA supplementation during pregnancy did not significantly reduce IgE-associated allergic disease in the first 3 years of life. Further studies should examine whether the nonsignificant reductions in IgE-associated allergies are of clinical and public health significance.

A phase II evaluation of motesanib (AMG 706) in the treatment of persistent or recurrent ovarian, fallopian tube and primary peritoneal carcinomas: a Gynecologic Oncology Group study.

OBJECTIVES: Vascular endothelial growth factors (VEGF) and their receptors have a critical role in stimulating the growth of ovarian cancer cells. Motesanib is a small molecule inhibitor of multiple receptor tyrosine kinases including VEGF receptors 1-3, as well as c-KIT and platelet-derived growth factor which are related to the VEGF family. PATIENTS AND METHODS: Twenty-two eligible patients with recurrent ovarian, fallopian tube or primary peritoneal carcinoma were treated with an oral daily dose of 125 mg of motesanib. Peripheral blood was analyzed for circulating tumor cells (CTC) and circulating endothelial cells/circulating endothelial progenitors (CEC/CEP), VEGF levels and cell-free circulating DNA (cfDNA). RESULTS: The study was abruptly halted after four patients developed posterior reversible encephalopathy syndrome. One patient had a partial response and seven patients had stable disease at the time they were removed from study treatment. Twelve of the 22 patients (50%) had indeterminate responses at trial closure. Early closure without clinical efficacy data precludes meaningful correlative studies. CONCLUSIONS: The serious central nervous system toxicity observed in patients with recurrent ovarian cancer precluded full examination of this agent in this population. There were no clear cut explanations for the high incidence of this known class effect in the study population compared with patients with other cancers.