A new direction for tackling phosphorus inefficiency in the UK food system.

The UK food system is reliant on imported phosphorus (P) to meet food production demand, though inefficient use and poor stewardship means P is currently accumulating in agricultural soils, wasted or lost with detrimental impacts on aquatic environments. This study presents the results of a detailed P Substance Flow Analysis for the UK food system in 2018, developed in collaboration with industry and government, with the key objective of highlighting priority areas for system interventions to improve the sustainability and resilience of P use in the UK food system. In 2018 the UK food system imported 174.6 Gg P, producing food and exportable commodities containing 74.3 Gg P, a P efficiency of only 43%. Three key system hotspots for P inefficiency were identified: Agricultural soil surplus and accumulation (89.2 Gg P), loss to aquatic environments (26.2 Gg P), and waste disposal to landfill and construction (21.8 Gg P). Greatest soil P accumulation occurred in grassland agriculture (85% of total accumulation), driven by loadings of livestock manures. Waste water treatment (12.5 Gg P) and agriculture (8.38 Gg P) account for most P lost to water, and incineration ashes from food system waste (20.3 Gg P) accounted for nearly all P lost to landfill and construction. New strategies and policy to improve the handling and recovery of P from manures, biosolids and food system waste are therefore necessary to improve system P efficiency and reduce P accumulation and losses, though critically, only if they effectively replace imported mineral P fertilisers.

Management of humeral impending or pathological fractures with intramedullary nailing: reaming versus non reaming technique-a retrospective comparative study.

PURPOSE: To compare reamed intramedullary nailing (RIM) versus un-reamed intramedullary nailing (URIM) for the treatment of impending and pathological fractures of the humeral shaft in terms of 24-h postoperative pain, blood transfusion requirements, surgical time, surgical complications, medical complications, length of stay and consolidation rates. METHODS: A retrospective comparative study between January 2013 and December 2018 was conducted. Student's t test, Mann-Whitney U and Chi-square tests were used to detect differences within the two study groups. Multiple linear regression was done to adjust for possible confounders. RESULTS: A total of 53 patients (33 RIM vs. 20 URIM) underwent humeral nailing. Fifteen (28%) were impending fractures (7 RIM vs. 8 URIM). Multiple myeloma (49%) and metastatic carcinoma (39.6%) were the most common etiologies. Pain score (5.13 ± 0.68 RIM vs. 6.78 ± 0.62 URIM; p = 0.082) and total dose of opioids (33.125 ± 27.6 RIM vs. 33.3 ± 22.28 URIM; p = 0.462) showed similar results. Blood transfusion was more prevalent within RIM group (34.48% RIM vs. 20% URIM; p = 0.044) with a clinical tendency of higher blood loss (207.86 ± 150.83RIM vs. 127.00 ± 179.98 URIM; p = 0.092). There was a consolidation rate of 71.05% (27/38) with no statistical difference (73.08% (19/26) RIM vs. 66.67% (8/12) URIM; p = 0.685). CONCLUSION: Our study suggests possible benefit of URIM in terms of less blood transfusions with no difference in consolidation rates. Even though without significance, a tendency to less blood loss, less events of systemic complication and lower length of stay was observed with URIM. Despite its limitations, this study can be used to design future prospective ventures that quantify patient-reported outcomes and provide more clear evidence.

Female-specific decreases in alcohol binge-like drinking resulting from GABAA receptor delta-subunit knockdown in the VTA.

Binge drinking is short-term drinking that achieves blood alcohol levels of 0.08 g/dl or above. It exhibits well-established sex differences in GABAergic inhibitory neurotransmission, including extrasynaptic δ subunit-containing GABAA receptors (δ-GABAARs) that mediate tonic inhibition, or synaptic γ2-containing GABAARs which underlie fast, synaptic, phasic inhibition have been implicated in sex differences in binge drinking. Ovarian hormones regulate δ-GABAARs, further implicating these receptors in potential sex differences. Here, we explored the contribution of extrasynaptic δ-GABAARs to male and female binge-like drinking in a critical area of mesolimbic circuitry-the ventral tegmental area (VTA). Quantitative PCR revealed higher Gabrd transcript levels and larger tonic currents in the VTA of females compared to males. In contrast, male and female Gabrg2 transcript levels and measures of phasic inhibition were equivalent. Intra-VTA infusion of AAV-Cre-GFP in floxed Gabrd mice downregulated δ-GABAARs and decreased binge-like drinking in females. There was no significant difference in either male or female mice after GABAAR γ2 subunit reduction in the VTA following AAV-Cre-GFP infusion in floxed Gabrg2 mice. Collectively, these findings suggest sex differences and GABAAR subunit specificity in alcohol intake.

New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine.

During the last thirty years since the discovery of endothelin-1, the therapeutic strategy that has evolved in the clinic, mainly in the treatment of pulmonary arterial hypertension, is to block the action of the peptide either at the ET(A) subtype or both receptors using orally active small molecule antagonists. Recently, there has been a rapid expansion in research targeting ET receptors using chemical entities other than small molecules, particularly monoclonal antibody antagonists and selective peptide agonists and antagonists. While usually sacrificing oral bio-availability, these compounds have other therapeutic advantages with the potential to considerably expand drug targets in the endothelin pathway and extend treatment to other pathophysiological conditions. Where the small molecule approach has been retained, a novel strategy to combine two vasoconstrictor targets, the angiotensin AT(1) receptor as well as the ET(A) receptor in the dual antagonist sparsentan has been developed. A second emerging strategy is to combine drugs that have two different targets, the ET(A) antagonist ambrisentan with the phosphodiesterase inhibitor tadalafil, to improve the treatment of pulmonary arterial hypertension. The solving of the crystal structure of the ET(B) receptor has the potential to identify allosteric binding sites for novel ligands. A further key advance is the experimental validation of a single nucleotide polymorphism that has genome wide significance in five vascular diseases and that significantly increases the amount of big endothelin-1 precursor in the plasma. This observation provides a rationale for testing this single nucleotide polymorphism to stratify patients for allocation to treatment with endothelin agents and highlights the potential to use personalized precision medicine in the endothelin field.

Human S-cone electroretinograms obtained by silent substitution stimulation.

We used triple silent substitution stimuli to characterize human S-cone electroretinograms (ERGs) in normal trichromats. Short-wavelength-cone (S-cone) ERGs were found to have different morphological features and temporal frequency response characteristics compared to ERGs derived from L-cones, M-cones, and rod photoreceptors in normal participants. Furthermore, in two cases of retinal pathology, blue cone monochromatism (BCM) and enhanced S-cone syndrome (ESCS), S-cone ERGs elicited by our stimuli were preserved and enhanced, respectively. The results from both normal and pathological retinae demonstrate that triple silent substitution stimuli can be used to generate ERGs that provide an assay of human S-cone function.

CNGB3 mutations cause severe rod dysfunction.

PURPOSE: Congenital achromatopsia or rod monochromatism is a rare autosomal recessive condition defined by a severe loss of cone photoreceptor function in which rods purportedly retain normal or near-to-normal function. This report describes the results of electroretinography in two siblings with CNGB3-associated achromatopsia. METHODS: Full field light- and dark-adapted electroretinograms (ERGs) were recorded using standard protocols detailed by the International Society for Clinical Electrophysiology of Vision (ISCEV). We also examined rod-mediated ERGs using series of stimuli that varied over a 6 log unit range of retinal illuminances (-1.9-3.5 log scotopic trolands). RESULTS: Dark-adapted ERGs in achromatopsia patients exhibited severely reduced b-wave amplitudes with abnormal b:a ratios (1.3 and 0.6). In comparison, the reduction in a-wave amplitude was less marked. The rod-mediated ERG took on an electronegative appearance at high-stimulus illuminances. CONCLUSION: Although the defect that causes achromatopsia is primarily in the cone photoreceptors, our results reveal an accompanying disruption of rod function that is more severe than has previously been reported. The differential effects on the b-wave relative to the a-wave points to an inner-retinal locus for the disruption of rod function in these patients.

Three year Experience of Non-Melanoma Skin Cancer in a General Practice.

We report 85 lesions of non-melanoma skin cancer in 58 patients, representing 9% of the minor surgical workload of a single general practitioner. Cases were studied in order to describe pathology, management and outcomes. Eighteen percent of lesions were referred, mainly because of central facial site and larger size. Of the lesions treated in the surgery, all but four were treated surgically. Quantitative margins of lateral and deep excision were reported for 50% and 30% of specimens respectively. Lateral histological margins of clearance were narrower for head and neck lesions. Incomplete excision occurred in 4%. There was one recurrent lesion after two years of follow-up. A majority of non-melanoma skin cancers at this clinic were managed safely without referral to secondary care. Quantitative reporting of tumour free margins for skin cancer is lacking.

The morphology of human rod ERGs obtained by silent substitution stimulation.

PURPOSE: To record transient ERGs from the light-adapted human retina using silent substitution stimuli which selectively reflect the activity of rod photoreceptors. We aim to describe the morphology of these waveforms and examine how they are affected by the use of less selective stimuli and by retinal pathology. METHODS: Rod-isolating stimuli with square-wave temporal profiles (250/250 ms onset/offset) were presented using a 4 primary LED ganzfeld stimulator. Experiment 1: ERGs were recorded using a rod-isolating stimulus (63 ph Td, rod contrast, C rod = 0.25) from a group (n = 20) of normal trichromatic observers. Experiment 2: Rod ERGs were recorded from a group (n = 5) using a rod-isolating stimulus (C rod = 0.25) which varied in retinal illuminance from 40 to 10,000 ph Td. Experiment 3: ERGs were elicited using 2 kinds of non-isolating stimuli; (1) broadband and (2) rod-isolating stimuli which contained varying degrees of L- and M-cone excitation. Experiment 4: Rod ERGs were recorded from two patient groups with rod monochromacy (n = 3) and CSNB (type 1; n = 2). RESULTS: The rod-isolated ERGs elicited from normal subjects had a waveform with a positive onset component followed by a negative offset. Response amplitude was maximal at retinal illuminances <100 ph Td and was virtually abolished at 400 ph Td. The use of non-selective stimuli altered the ERG waveform eliciting more photopic-like ERG responses. Rod ERGs recorded from rod monochromats had similar features to those recorded from normal trichromats, in contrast to those recorded from participants with CSNB which had an electronegative appearance. CONCLUSIONS: Our results demonstrate that ERGs elicited by silent substitution stimuli can selectively reflect the operation of rod photoreceptors in the normal, light-adapted human retina.

The impact of daycare attendance on outdoor free play in young children.

Background: Outdoor free play is important for healthy growth and development in early childhood. Recent studies suggest that the majority of time spent in daycare is sedentary. The objective of this study was to determine whether there was an association between daycare attendance and parent-reported outdoor free play. Methods: Healthy children aged 1-5 years recruited to The Applied Research Group for Kids! (TARGet Kids!), a primary care research network, were included. Parents reported daycare use, outdoor free play and potential confounding variables. Multivariable linear regression was used to determine the association between daycare attendance and outdoor free play, adjusted for age, sex, maternal ethnicity, maternal education, neighborhood income and season. Results: There were 2810 children included in this study. Children aged 1 to <3 years (n = 1388) and ≥3 to 5 years (n = 1284) who attended daycare had 14.70 min less (95% CI -20.52, -8.87; P < 0.01) and 9.44 min less (95% CI -13.67, -5.20; P < 0.01) per day of outdoor free play compared with children who did not attend daycare, respectively. Conclusions: Children who spend more time in daycare have less parent-reported outdoor free play. Parents may be relying on daycare to provide opportunity for outdoor free play and interventions to promote increased active play opportunities outside of daycare are needed.

The concurrent and longitudinal associations of temperament and nutritional risk factors in early childhood.

BACKGROUND: Early childhood temperament is increasingly recognized as an important attribute that may impact screen time use, outdoor play and childhood obesity. The relationship between temperament and nutrition in preschool children is less clear. OBJECTIVE: The objective of the study is to investigate if temperament dimensions (negative affectivity, effortful control and surgency) in early childhood are associated with nutritional risk factors. METHODS: Six hundred seventy-eight children were followed (mean age at baseline visit 3.1 years; mean time to follow-up 16.5 months). Parents reported on child temperament and nutritional risk factors during regularly scheduled well-child clinic visits. RESULTS: A mixed effect model demonstrated a significant association between higher negative affectivity (1.03; 95% CI 0.69 to 1.37) and higher effortful control (-0.88; 95% CI -1.27 to -0.49) on concurrent nutritional risk, independent of covariates. Multivariate linear regression analysis identified that higher effortful control, and not negative affectivity, was significantly associated with a decrease in nutritional risk (-0.67; 95% CI -1.10 to -0.24) over time, independent of covariates. There was no relationship identified between surgency and nutritional risk. CONCLUSION: Three-year-old children with higher effortful control had reduced nutritional risk at 5 years of age. Future nutritional risk prevention strategies may benefit from interventions to increase effortful control in early childhood.

Opinions of key stakeholders concerning involuntary admission of patients under the Mental Health Act 2001.

OBJECTIVES: To evaluate and compare the opinions of key stakeholders involved in the involuntary admission and treatment of patients under the Mental Health Act (MHA) 2001 regarding their views towards the operation of the legislation. METHODS: We employed a descriptive survey design. A questionnaire was distributed to stakeholders involved in the operation of the MHA 2001 (except service users, whose views were explored in a separate qualitative study) via paper or online versions evaluating their opinions regarding the operation of the MHA 2001 in relation to assessment, care, rights, transfer and information available. RESULTS: Stakeholders agreed that in their opinion that patients generally benefit from the care they receive (79%) and that the MHA 2001 ensures an independent and fair review of the person's detention (65%). However, only 23% of stakeholders were satisfied with the process of transferring patients to hospital and with the clinical assessment procedures therein (37%), with the greatest levels of dissatisfaction amongst Gardai (Police), general practitioners (GPs) and family members. CONCLUSIONS: While the introduction of the MHA 2001 has assisted delivery of care to patients with improved adherence to international human rights frameworks applicable at the time of its enactment, substantial dissatisfaction with the implementation of the MHA 2001 in practice is experienced by stakeholders particularly at the distressing phase of clinical assessment and transfer to hospital.

Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state.

Major depressive disorder (MDD) is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABAA receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST+) GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST+ interneurons, we inactivated the γ2 subunit gene of GABAA receptors selectively in these neurons (SSTCre:γ2f/f mice). Loss of inhibitory synaptic input resulted in increased excitability of SST+ interneurons. In turn, pyramidal cell targets of SST+ neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2f/f mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2f/f mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of the effects of ketamine. Importantly, these effects occurred without altered activity of the mammalian target of rapamycin pathway nor did they involve altered expression of SST. However, they were associated with reduced Ca2+/calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus enhancing GABAergic inhibitory synaptic inputs from SST+ interneurons to pyramidal cells and corresponding chronic reductions in the synaptic excitation:inhibition ratio represents a novel strategy for antidepressant therapies that reproduces behavioral and biochemical end points of rapidly acting antidepressants.

Tuning Nonlinear Mechanical Mode Coupling in GaAs Nanowires Using Cross-Section Morphology Control.

We investigate the nonlinear mechanical properties of GaAs nanowires with anisotropic cross-section. Fundamental and second order flexural modes are studied using laser interferometry with good agreement found between experiment and theory describing the nonlinear response under mechanical excitation. In particular, we demonstrate that the sign of the nonlinear coupling between orthogonal modes is dependent on the cross-section aspect ratio. The findings are of interest for applications such as amplitude to frequency conversion and vectorial force sensing.

Hepatic fat and abdominal adiposity in early pregnancy together predict impaired glucose homeostasis in mid-pregnancy.

Hepatic fat and abdominal adiposity individually reflect insulin resistance, but their combined effect on glucose homeostasis in mid-pregnancy is unknown. A cohort of 476 pregnant women prospectively underwent sonographic assessment of hepatic fat and visceral (VAT) and total (TAT) adipose tissue at 11-14 weeks' gestation. Logistic regression was used to assess the relation between the presence of maternal hepatic fat and/or the upper quartile (Q) of either VAT or TAT and the odds of developing the composite outcome of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or gestational diabetes mellitus at 24-28 weeks' gestation, based on a 75 g OGTT. Upon adjusting for maternal age, ethnicity, family history of DM and body mass index (BMI), the co-presence of hepatic fat and quartile 4 (Q4) of VAT (adjusted odds ratio (aOR) 6.5, 95% CI: 2.3-18.5) or hepatic fat and Q4 of TAT (aOR 7.8 95% CI 2.8-21.7) were each associated with the composite outcome, relative to women with neither sonographic feature. First-trimester sonographic evidence of maternal hepatic fat and abdominal adiposity may independently predict the development of impaired glucose homeostasis and GDM in mid-pregnancy.

Heritability of young- and old-onset ischaemic stroke.

BACKGROUND AND PURPOSE: Although the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. METHODS: This analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age < 55 years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age ≥ 55 years). RESULTS: Heritabilities for young-onset stroke and old-onset stroke were estimated at 42% (±8%, P < 0.001) and 34% (±10%, P < 0.001), respectively. CONCLUSIONS: Our data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant.

Vitamin D exposure during pregnancy, but not early childhood, is associated with risk of childhood wheezing.

The association between vitamin D and wheezing in early childhood is unclear. The primary objective of this study was to evaluate the association between vitamin D exposure, during both pregnancy and childhood, and early childhood wheezing. Secondary objectives were to evaluate the associations between vitamin D exposures and asthma and wheezing severity. We conducted a cohort study of children (0-5 years) recruited from 2008 to 2013 through the TARGet Kids! primary-care research network. Vitamin D exposures included maternal vitamin D supplement use during pregnancy, child vitamin D supplementation and children's 25-hydroxyvitamin D (25(OH)D) concentrations. The outcomes measured were parent-reported childhood wheezing, diagnosed asthma and wheezing severity. Vitamin D supplement and wheezing data were available for 2478 children, and blood samples were available for 1275 children. Adjusted odds ratios (aOR) were estimated using logistic regression adjusted for age, sex, ethnicity, body mass index, birth weight, outdoor play, breastfeeding duration, daycare status, parental smoking and family history of asthma. Vitamin D supplementation during pregnancy was associated with lower odds of childhood wheezing (aOR=0.65; 95% CI: 0.46-0.93). In early childhood, neither 25(OH)D (aOR per 10 nmol/l=1.01; 95% CI: 0.96-1.06) nor vitamin D supplementation (aOR=1.00; 95% CI: 0.81-1.23) was associated with wheezing. No significant associations were observed with diagnosed asthma or wheezing severity. Vitamin D supplementation during pregnancy was associated with reduced odds of wheezing, but child vitamin D supplementation and childhood 25(OH)D were not associated with reduced wheezing. The timing of exposure may be important in understanding the association between vitamin D and childhood wheezing.

SOCCAR: A randomised phase II trial comparing sequential versus concurrent chemotherapy and radical hypofractionated radiotherapy in patients with inoperable stage III Non-Small Cell Lung Cancer and good performance status.

BACKGROUND: Cure of lung cancer is impossible without local tumour control. This can be compromised by accelerated repopulation of tumour cells during radiotherapy and chemotherapy. A strategy to minimise accelerated repopulation might improve local control. We investigated whether concurrent chemo-radiotherapy could be given safely over four weeks. METHODS: We conducted a randomised phase II trial in which patients with inoperable Stage III Non-Small Cell Lung Cancer (NSCLC) received a radical radiation dose over four weeks rather than conventional fractionation. Treatment was given either sequentially or concurrently with three to four cycles of cisplatinum and vinorelbine. 130 patients with inoperable stage III NSCLC and PS 0-1 were randomised to receive cisplatinum and vinorelbine with either sequential or concurrent chemo-radiation using 55Gy in 20 fractions over four weeks. The primary end-point was treatment related mortality. Secondary end-points were toxicity and survival. FINDINGS: Treatment related mortality was: 2.9% (exact 95% confidence interval [CI] 0.36-10.2%) and 1.7% (exact 95% CI 0.043-9.1%) for the Concurrent and Sequential group respectively; relative risk (RR) 1.25; (95% CI 0.55, 2.84). Toxicity was similar between arms; grade 3 or worse oesophagitis was 8.8% versus 8.5%; RR 1.02 (95% CI 0.58, 1.79). OS HR was 0.92; 95% CI (0.60-1.39; p=0.682). The 2 year overall survival rates were: 50% versus 46%; RR 1.06 (95% CI 0.77, 1.46) for Concurrent versus Sequential. INTERPRETATION: A strategy to minimise the effects of accelerated repopulation using accelerated hypofractionated radiotherapy with chemotherapy is feasible, and reasonably safe for patients with stage III NSCLC. The reported two year survival is promising and suggests that a four week regime of radiotherapy should be compared with conventionally fractionated radiotherapy in an adequately powered randomised controlled phase III trial.