Association between morbidity among term newborns and low-risk caesarean delivery rates.

OBJECTIVE: To examine the association between county-level caesarean delivery (CD) rates among women at low risk and morbidity among term newborns. DESIGN: Cross-sectional study. SETTING: Population-based study of US county-level birth data from 2015 to 2017. POPULATION: Nulliparous women with term, singleton, vertex-presenting infants (NTSV) at low risk for morbidity. METHODS: The primary exposure was county-level CD rates. MAIN OUTCOME MEASURES: The outcome was morbidity among the low-risk NTSV cohort, categorised as severe (5-minute Apgar score of ≤3, assisted ventilation for ≥6 hours, severe neurologic injury or seizure, transfer or death) or moderate (5-minute Apgar score of <7 but >3, administration of antibiotics or assisted ventilation at delivery). We used linear regression models to determine the association between county NTSV CD and neonatal morbidity rates with cluster robust standard errors. RESULTS: The analysis included data from 2 753 522 births in 952 counties from all 48 states. The mean NTSV CD rate was 23.6% (standard deviation 4.8%). The median severe and moderate neonatal morbidity rates were 15.2 (interquartile range, IQR 9.4-23.6) and 52.5 (IQR 33.4-75.7) per 1000 births, respectively. In the unadjusted analysis using the risk-adjusted exposure and outcome, every percentage point increase in the CD rate of a county was associated with 0.6 (95% CI -0.9, -0.3) and 2.3 fewer (95% CI -3.4, -1.1) cases of severe and moderate neonatal morbidity per 1000 live births. After adjustment for other county factors, the relationships remained significant. These findings were tested in multiple sensitivity analyses. CONCLUSIONS: Lower county-level NTSV CD rates were associated with a small increase in morbidity among term newborns in the USA. TWEETABLE ABSTRACT: Lower county-level caesarean delivery rates were associated with an increase in morbidity among term newborns in the USA.

Contingent negative variation: a biomarker of abnormal attention in functional movement disorders.

BACKGROUND AND PURPOSE: Contingent negative variation (CNV) is a negative cortical wave that precedes a pre-cued imperative stimulus requiring a quick motor response. It has been related to motor preparation and anticipatory attention. The aim was to ascertain whether the clinical improvement of functional movement disorders after physiotherapy would be associated with faster reaction times and modulation of CNV. METHODS: Motor performance and CNV were analysed during a pre-cued choice reaction time task with varying cue validity. Twenty-one patients with functional movement disorders and 13 healthy controls at baseline were compared. Patients then underwent physiotherapy. At follow-up after physiotherapy, patients were categorized as clinically improved (responders) or not improved (non-responders) and retested. RESULTS: At baseline, patients did not generate CNV, contrary to controls [mean amplitude (µV) at the end of preparation to move: patients -0.47 (95% CI -1.94, 1.00) versus controls -2.59 (95% CI -4.46, -0.72)]. Responders performed faster after physiotherapy [mean natural logarithm (ln) reaction time (RT) (ms): follow-up 6.112 (95% CI 5.923, 6.301) versus baseline 6.206 (95% CI 6.019, 6.394), P = 0.010], contrary to non-responders. Simultaneously, responders showed a recovery of CNV after physiotherapy [follow-up -1.95 (95% CI -3.49, -0.41) versus baseline -0.19 (95% CI -1.73, 1.35), P < 0.001], contrary to non-responders [follow-up -0.32 (95% CI -1.79, 1.14) versus baseline -0.72 (95% CI -2.19, 0.75), P = 0.381]. CONCLUSIONS: Clinical improvement of functional movement disorders after physiotherapy was associated with faster reaction times and normalization of CNV, which was absent at baseline. These findings suggest that CNV may constitute a useful neurophysiological biomarker related to abnormal attention in functional movement disorders.

Oral immunotherapy with omalizumab reverses the Th2 cell-like programme of regulatory T cells and restores their function.

BACKGROUND: Oral immunotherapy (OIT) successfully desensitizes patients with food allergies, but the immune mechanisms mediating its efficacy remain obscure. OBJECTIVES: We tested the hypothesis that allergen-specific regulatory T (Treg) cell function is impaired in food allergy and is restored by anti-IgE antibody (omalizumab)-supplemented OIT. METHODS: Peanut-specific T effector (Teff) and Treg cell proliferative responses, activation markers and cytokine expression were analysed by flow cytometry in 13 peanut-allergic subjects before the start of omalizumab-supplemented OIT and periodically in some subjects thereafter for up to 2 years. Peripheral blood regulatory T cells (Treg cells) were analysed for their peanut-specific suppressor function before and at 1 year following OIT. This study was registered on ClinicalTrials.gov (NCT01290913). RESULTS: Proliferation of allergen-specific Teff and Treg cells precipitously declined following the initiation of omalizumab therapy prior to OIT, followed by partial recovery after the initiation of OIT. At baseline, peanut-specific Treg cells exhibited a Th2 cell-like phenotype, characterized by increased IL-4 expression, which progressively reversed upon OIT. Peanut-specific Treg cell suppressor activity was absent at the start of omalizumab/OIT therapy but became robust following OIT. Absent peanut-specific Treg cell function could also be recovered by the acute blockade of IL-4/IL-4R receptor signalling in Treg cells, which inhibited their IL-4 production. CONCLUSIONS AND CLINICAL RELEVANCE: OIT supplemented by omalizumab promotes allergen desensitization through an initial omalizumab-dependent step that acutely depletes allergen-reactive T cells, followed by an increase in allergen-specific Treg cell activity due to the reversal of their Th2 cell-like programme. Improved Treg cell function may be a key mechanism by which OIT ameliorates food allergy.

Rhinitis in Elite and Non-Elite Field Hockey Players.

Rhinitis has been demonstrated to impose a significant disease burden upon the general population. We sought to determine the prevalence of rhinitis in athletes; to investigate its relationship with co-existing allergic symptoms; and to quantify the impact of rhinitis on quality of life in the athlete.3 subgroups were studied: elite field hockey players (FHP); non-elite FHP; and a sedentary control group.Participants were asked to complete a rhinitis self-report questionnaire; the "Allergic Questionnaire for Athletes" (AQUA), and quality of life Sinonasal Outcome Test - 22 (SNOT-22).142 participants completed the study (52 elite FHP; 40 non-elite FHP; 50 controls). There was a significantly higher prevalence of rhinitis in the elite and non-elite FHP groups than the sedentary control group (52% and 43% vs. 22%, p<0.05). Mean AQUA score was significantly higher in athletes with rhinitis. Quality of life scores were significantly worse in athletes with rhinitis than those without rhinitis (p<0.05).This study suggests regular exercise is associated with a significant increase in the prevalence of rhinitis. Elite FHP were most likely to report rhinitis, but the least likely to be using regular treatment. Quality of life was negatively affected, confirming the importance of nasal health to athlete welfare.

Characterizing problematic hypoglycaemia: iterative design and preliminary psychometric validation of the Hypoglycaemia Awareness Questionnaire (HypoA-Q).

AIMS: To design and conduct preliminary validation of a measure of hypoglycaemia awareness and problematic hypoglycaemia, the Hypoglycaemia Awareness Questionnaire. METHODS: Exploratory and cognitive debriefing interviews were conducted with 17 adults (nine of whom were women) with Type 1 diabetes (mean ± sd age 48 ± 10 years). Questionnaire items were modified in consultation with diabetologists/psychologists. Psychometric validation was undertaken using data from 120 adults (53 women) with Type 1 diabetes (mean ± sd age 44 ± 16 years; 50% with clinically diagnosed impaired awareness of hypoglycaemia), who completed the following questionnaires: the Hypoglycaemia Awareness Questionnaire, the Gold score, the Clarke questionnaire and the Problem Areas in Diabetes questionnaire. RESULTS: Iterative design resulted in 33 items eliciting responses about awareness of hypoglycaemia when awake/asleep and hypoglycaemia frequency, severity and impact (healthcare utilization). Psychometric analysis identified three subscales reflecting 'impaired awareness', 'symptom level' and 'symptom frequency'. Convergent validity was indicated by strong correlations between the 'impaired awareness' subscale and existing measures of awareness: (Gold: rs =0.75, P < 0.01; Clarke: rs =0.76, P < 0.01). Divergent validity was indicated by weaker correlations with diabetes-related distress (Problem Areas in Diabetes: rs =0.25, P < 0.01) and HbA1c (rs =-0.05, non-significant). The 'impaired awareness' subscale and other items discriminated between those with impaired and intact awareness (Gold score). The 'impaired awareness' subscale and other items contributed significantly to models explaining the occurrence of severe hypoglycaemia and hypoglycaemia when asleep. CONCLUSIONS: This preliminary validation shows the Hypoglycaemia Awareness Questionnaire has robust face and content validity; satisfactory structure; internal reliability; convergent, divergent and known groups validity. The impaired awareness subscale and other items contribute significantly to models explaining recall of severe and nocturnal hypoglycaemia. Prospective validation, including determination of a threshold to identify impaired awareness, is now warranted.

Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial.

BACKGROUND: Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management. PATIENTS AND METHODS: All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms. RESULTS: Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome. CONCLUSIONS: Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.

High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers.

BACKGROUND: Germline BRCA2 mutations are associated with poorer outcome prostate cancer (PCa) compared with sporadic tumours but this association remains to be characterised. In this study, we aim to assess if there is a signature set of copy number alterations (CNA) that could aid to the identification of BRCA2-mutated tumours and would assist us to understand their aggressive clinical behaviour. METHODS: High-resolution array comparative genomic hybridisation profiling of DNA from PCa and matched morphologically normal prostate samples from 9 BRCA2 germline mutation carriers and 16 non-carriers in combination with unsupervised analysis was used to define copy number features. RESULTS: PCa from BRCA2 germline mutation carriers (B2T) harbour significantly more CNA than non-carrier tumours (NCTs) (P = 14 × 10(-6)). A hundred and sixteen regions had a significantly different distribution with both false discovery rate (FDR) and P value <0.01, including CNA in the genomic region containing c-MYC that was present in 89% B2T versus 12.5% NCT (P = 3 × 10(-4)). Loss of heterozygosity (LOH) at the BRCA2 locus was observed in 67% of B2T. Elevated CNA are already present in 50% of the morphologically normal prostate tissue from BRCA2 carriers. CONCLUSION: The relative high amount of CNAs in morphologically normal prostate tissue of BRCA2 carriers implies a field effect and together with the observed LOH could be used as a marker of PCa risk in these men. Several features previously associated with poor PCa outcome have been found to be significantly more common in BRCA2-mutated PCa than in sporadic tumours and may help to explain their adverse prognosis and be of relevance for targeted therapies.

Prevalence of the HOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes.

BACKGROUND: A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. PATIENTS AND METHODS: This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. RESULTS: HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. CONCLUSIONS: The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. CLINICAL TRIALS NUMBERS: Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172. UK GENETIC PROSTATE CANCER STUDY: Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.

Scaling up self-assembly: bottom-up approaches to macroscopic particle organization.

This review presents an overview of recent work in the field of non-Brownian particle self-assembly. Compared to nanoparticles that naturally self-assemble due to Brownian motion, larger, non-Brownian particles (d > 6 µm) are less prone to autonomously organize into crystalline arrays. The tendency for particle systems to experience immobilization and kinetic arrest grows with particle radius. In order to overcome this kinetic limitation, some type of external driver must be applied to act as an artificial "thermalizing force" upon non-Brownian particles, inducing particle motion and subsequent crystallization. Many groups have explored the use of various agitation methods to overcome the natural barriers preventing self-assembly to which non-Brownian particles are susceptible. The ability to create materials from a bottom-up approach with these characteristics would allow for precise control over their pore structure (size and distribution) and surface properties (topography, functionalization and area), resulting in improved regulation of key characteristics such as mechanical strength, diffusive properties, and possibly even photonic properties. This review will highlight these approaches, as well as discuss the potential impact of bottom-up macroscale particle assembly. The applications of such technology range from customizable and autonomously self-assembled niche microenvironments for drug delivery and tissue engineering to new acoustic dampening, battery, and filtration materials, among others. Additionally, crystals made from non-Brownian particles resemble naturally derived materials such as opals, zeolites, and biological tissue (i.e. bone, cartilage and lung), due to their high surface area, pore distribution, and tunable (multilevel) hierarchy.

Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.

BACKGROUND: Prostate cancer (PrCa) is one of the most common diseases to affect men worldwide and among the leading causes of cancer-related death. The purpose of this study was to use second-generation sequencing technology to assess the frequency of deleterious mutations in 22 tumour suppressor genes in familial PrCa and estimate the relative risk of PrCa if these genes are mutated. METHODS: Germline DNA samples from 191 men with 3 or more cases of PrCa in their family were sequenced for 22 tumour suppressor genes using Agilent target enrichment and Illumina technology. Analysis for genetic variation was carried out by using a pipeline consisting of BWA, Genome Analysis Toolkit (GATK) and ANNOVAR. Clinical features were correlated with mutation status using standard statistical tests. Modified segregation analysis was used to determine the relative risk of PrCa conferred by the putative loss-of-function (LoF) mutations identified. RESULTS: We discovered 14 putative LoF mutations in 191 samples (7.3%) and these mutations were more frequently associated with nodal involvement, metastasis or T4 tumour stage (P=0.00164). Segregation analysis of probands with European ancestry estimated that LoF mutations in any of the studied genes confer a relative risk of PrCa of 1.94 (95% CI: 1.56-2.42). CONCLUSIONS: These findings show that LoF mutations in DNA repair pathway genes predispose to familial PrCa and advanced disease and therefore warrants further investigation. The clinical utility of these findings will become increasingly important as targeted screening and therapies become more widespread.

Community HIV-1 drug resistance is associated with transmitted drug resistance.

OBJECTIVES: As community viral load (CVL) measurements are associated with the incidence of new HIV-1 infections in a population, we hypothesized that similarly measured community drug resistance (CDR) could predict the prevalence of transmitted drug resistance (TDR). METHODS: Between 2001 and 2011, the prevalences of HIV-1 drug resistance for patients with established infection receiving HIV care (i.e. CDR) and TDR in recently infected patients were determined in San Diego. At each position in HIV-1 reverse transcriptase (RT) and protease (pro), drug resistance was evaluated both as the overall prevalence of resistance-associated mutations and by weighting each resistance position to the concurrent viral load of the patient and its proportion to the total viral load of the clinic (CVL). The weighting was the proportion of the CVL associated with patients identified with resistance at each residue. Spearman ranked correlation coefficients were used to determine associations between CDR and TDR. RESULTS: We analysed 1088 resistance tests for 971 clinic patients and baseline resistance tests for 542 recently infected patients. CDR at positions 30, 46, and 88 in pro was associated with TDR between 2001 and 2011. When CDR was weighted by the viral load of patients, CDR was associated with TDR at position 103 in RT. Each of these associations was corroborated at least once using shorter measurement intervals. CONCLUSIONS: Despite evaluation of a limited percentage of chronically infected patients in San Diego, CDR correlated with TDR at key resistance positions and therefore may be a useful tool with which to predict the prevalence of TDR.

Severe hypoglycaemia in type 1 diabetes mellitus: underlying drivers and potential strategies for successful prevention.

Hypoglycaemia remains an over-riding factor limiting optimal glycaemic control in type 1 diabetes. Severe hypoglycaemia is prevalent in almost half of those with long-duration diabetes and is one of the most feared diabetes-related complications. In this review, we present an overview of the increasing body of literature seeking to elucidate the underlying pathophysiology of severe hypoglycaemia and the limited evidence behind the strategies employed to prevent episodes. Drivers of severe hypoglycaemia including impaired counter-regulation, hypoglycaemia-associated autonomic failure, psychosocial and behavioural factors and neuroimaging correlates are discussed. Treatment strategies encompassing structured education, insulin analogue regimens, continuous subcutaneous insulin infusion pumps, continuous glucose sensing and beta-cell replacement therapies have been employed, yet there is little randomized controlled trial evidence demonstrating effectiveness of new technologies in reducing severe hypoglycaemia. Optimally designed interventional trials evaluating these existing technologies and using modern methods of teaching patients flexible insulin use within structured education programmes with the specific goal of preventing severe hypoglycaemia are required. Individuals at high risk need to be monitored with meticulous collection of data on awareness, as well as frequency and severity of all hypoglycaemic episodes.

Macroparasites at peripheral sites of infection are major and dynamic modifiers of systemic antimicrobial pattern recognition responses.

Immune defences and the maintenance of immunological homeostasis in the face of pathogenic and commensal microbial exposures are channelled by innate antimicrobial pattern recognition receptors (PRRs) such as toll-like receptors (TLRs). Whilst PRR-mediated response programmes are the result of long-term host-pathogen or host-commensal co-evolutionary dynamics involving microbes, an additional possibility is that macroparasitic co-infections may be a significant modifier of such interactions. We demonstrate experimentally that macroparasites (the model gastrointestinal nematode, Heligmosomoides) at peripheral sites of infection cause substantial alteration of the expression and function of TLRs at a systemic level (in cultured splenocytes), predominantly up-regulating TLR2, TLR4 and TLR9-mediated cytokine responses at times of high standing worm burdens. We consistently observed such effects in BALB/c and C57BL/6 mice under single-pulse and trickle exposures to Heligmosomoides larvae and in SWR and CBA mice under single-pulse exposures. A complementary long-term survey of TLR2-mediated tumour necrosis factor-alpha responses in wild wood mice (Apodemus sylvaticus) was consistent with substantial effects of macroparasites under some environmental conditions. A general pattern, though, was for the associations of macroparasites with TLR function to be temporally dynamic and context-dependent: varying with different conditions of infection exposure in the field and laboratory and with host genetic strain in the laboratory. These results are compelling evidence that macroparasites are a major and dynamic modifier of systemic innate antimicrobial responsiveness in naturally occurring mammals and thus likely to be an important influence on the interaction between microbial exposures and the immune system.

HTS driven by fluorescence lifetime detection of FRET identifies activators and inhibitors of cardiac myosin.

Small molecules that bind to allosteric sites on target proteins to alter protein function are highly sought in drug discovery. High-throughput screening (HTS) assays are needed to facilitate the direct discovery of allosterically active compounds. We have developed technology for high-throughput time-resolved fluorescence lifetime detection of fluorescence resonance energy transfer (FRET), which enables the detection of allosteric modulators by monitoring changes in protein structure. We tested this approach at the industrial scale by adapting an allosteric FRET sensor of cardiac myosin to high-throughput screening (HTS), based on technology provided by Photonic Pharma and the University of Minnesota, and then used the sensor to screen 1.6 million compounds in the HTS facility at Bristol Myers Squibb. The results identified allosteric activators and inhibitors of cardiac myosin that do not compete with ATP binding, demonstrating high potential for FLT-based drug discovery.

Life-cycle assessment of greenhouse gas emissions from dairy production in Eastern Canada: a case study.

The objective of this study was to conduct a life-cycle assessment (LCA) of greenhouse gas (GHG) emissions from a typical nongrazing dairy production system in Eastern Canada. Additionally, as dairying generates both milk and meat, this study assessed several methods of allocating emissions between these coproducts. An LCA was carried out for a simulated farm based on a typical nongrazing dairy production system in Quebec. The LCA was conducted over 6 yr, the typical lifespan of dairy cows in this province. The assessment considered 65 female Holstein calves, of which 60 heifers survived to first calving at 27 mo of age. These animals were subsequently retained for an average of 2.75 lactations. Progeny were also included in the analysis, with bulls and heifers in excess of replacement requirements finished as grain-fed veal (270 kg) at 6.5 mo of age. All cattle were housed indoors and fed forages and grains produced on the same farm. Pre-farm gate GHG emissions and removals were quantified using Holos, a whole-farm software model developed by Agriculture and Agri-Food Canada and based on the Intergovernmental Panel for Climate Change Tier 2 and 3methodologies with modifications for Canadian conditions. The LCA yielded a GHG intensity of 0.92 kg of CO(2) Eq/kg of fat- and protein-corrected milk yield. Methane (CH(4)) accounted for 56% of total emissions, with 86% originating from enteric fermentation. Nitrous oxide accounted for 40% of total GHG emissions. Lactating cows contributed 64% of total GHG emissions, whereas calves under 12 mo contributed 10% and veal calves only 3%. Allocation of GHG emissions between meat and milk were assessed as (1) 100% allocation to milk, (2) economics, (3) dairy versus veal animals, and (4) International Dairy Federation equation using feed energy demand for meat and milk production. Comparing emissions from dairy versus veal calves resulted in 97% of the emissions allocated to milk. The lowest allocation of emissions to milk (78%) was associated with the International Dairy Federation equation. This LCA showed that greatest reductions in GHG emissions would be achieved by applying mitigation strategies to reduce enteric CH(4) from the lactating cow, with minimal reductions being achievable in young stock. Choice of coproduct allocation method can also significantly affect the relative allocation of GHG emissions to milk and meat.

High incidence of dyspnoea and pulmonary aspiration in giant hiatus hernia: a previously unrecognised cause of dyspnoea.

INTRODUCTION: Dyspnoea is common in patients with giant paraoesophageal hernia (PEH). Pulmonary aspiration has not previously been recognised as a significant contributory factor. Aspiration pneumonia in association with both gastro-oesophageal reflux disease (GORD) and PEH has a high mortality rate. There is debate about routine anti-reflux measures with surgical repair. Reflux aspiration has been examined in a consecutive cohort using scintigraphic scanning and symptoms. METHODS: Reflux aspiration scintigraphy (RASP) results and symptoms were evaluated in consecutive patients with PEH managed in our service between January 2012 and March 2017. RESULTS: PEH was diagnosed in 96 patients. Preoperative reflux pulmonary scanning was performed in 70 patients: 54 were female (77.1%) and the mean age was 68 years (range 49-85). Dyspnoea was the most common symptom (77.1%), and a symptomatic history of aspiration was seen in 18 patients (25.7%). Clinical aspiration was confirmed by RASP in 13 of these cases. Silent RASP aspiration occurred in a further 27 patients without clinical symptoms. RASP was negative in five patients with clinical symptoms of aspiration. No aspiration by either criterion was present in 27 patients. Dysphagia was negatively related to aspiration on RASP (p<0.01), whereas dyspnoea was not (p=0.857). CONCLUSION: GORD, dyspnoea and silent pulmonary aspiration are frequent occurrences in the presence of giant PEH. Subjective aspiration was the most specific and positive predictor of pulmonary aspiration. Dyspnoea in PEH patients may be caused by pulmonary aspiration, cardiac compression and gas trapping. The high rate of pulmonary aspiration in PEH patients may support anti-reflux repair.

Water consumption and wastage behaviour in pigs: implications for antimicrobial administration and stewardship.

Daily water use and wastage patterns of pigs have major effects on the efficacy of in-water antimicrobial dosing events when conducted for metaphylaxis or to treat clinical disease. However, daily water use and wastage patterns of pigs are not routinely quantified on farms and are not well understood. We conducted a prospective, observational 27-day study of the daily water use and wastage patterns of a pen group of 15 finisher pigs reared in a farm building. We found that the group of pigs wasted a median of 36.5% of the water used per day. We developed models of the patterns of water used and wasted by pigs over each 24-h period using a Bayesian statistical method with the brm() function in the brms package. Both patterns were uni-modal, peaking at 1400-1700, and closely aligned. Wastage was slightly greater during hours of higher water use. We have shown that it is feasible to quantify the water use and wastage patterns of pigs in farm buildings using a system that records and aggregates data, and analyses them using hierarchical generalised additive models. This system could support more efficacious in-water antimicrobial dosing on farms, and better antimicrobial stewardship, by helping to reduce the quantities of antimicrobials used and disseminated into the environment.

Noncontrast MRI Protocol for Selected Pediatric Pituitary Endocrinopathies: A Procedure with High Diagnostic Yield and Potential to Reduce Anesthesia and Gadolinium-Based Contrast Exposure.

BACKGROUND AND PURPOSE: Although many pediatric neuroradiology practices empirically use noncontrast brain and pituitary MR imaging for evaluation of growth hormone deficiency, central precocious puberty, and short stature, there are currently insufficient published data to support this practice in an evidence-based fashion. Therefore, the use of contrast-enhanced MR imaging for all pediatric pituitary endocrinopathies remains widespread. We evaluated whether noncontrast MR imaging has adequate diagnostic yield for the evaluation of pediatric growth hormone deficiency, central precocious puberty, and short stature. MATERIALS AND METHODS: Pituitary MR imaging studies obtained for growth hormone deficiency, central precocious puberty, or short stature in patients 0-18 years of age from 2010 to 2019 were analyzed. Separate blinded review of noncontrast images in cases with abnormalities on the original radiology report was performed by 2 subspecialty-trained pediatric neuroradiologists, with discrepancies resolved by consensus. RESULTS: Of the 134/442 MR imaging studies obtained for growth hormone deficiency, central precocious puberty, or short stature with hypothalamic-pituitary region abnormalities, there was 70% concordance with the original reports on blinded review of noncontrast images. Twenty-two of 40 discrepancies were deemed unrelated to the indication, and 9 cases originally interpreted as possible microadenoma were read as having normal findings on blinded review. Only 9 of 40 discrepancies required contrast for further characterization. CONCLUSIONS: In our study, most relevant radiologic findings in patients with growth hormone deficiency, central precocious puberty, and short stature were detectable without contrast, providing evidence that contrast can be avoided in routine MR imaging evaluation of these indications. We propose a "rapid noncontrast pituitary" MR imaging protocol for pediatric patients presenting with growth hormone deficiency, central precocious puberty, or short stature, which may increase efficiency and decrease contrast and anesthesia exposure.