Trade-offs constrain the success of glyphosate-free farming.

Glyphosate, the most widely used herbicide, is linked with environmental harm and there is a drive to replace it in agricultural systems. We model the impacts of discontinuing glyphosate use and replacing it with cultural control methods. We simulate winter wheat arable systems reliant on glyphosate and typical in northwest Europe. Removing glyphosate was projected to increase weed abundance, herbicide risk to the environment, and arable plant diversity and decrease food production. Weed communities with evolved resistance to non-glyphosate herbicides were not projected to be disproportionately affected by removing glyphosate, despite the lack of alternative herbicidal control options. Crop rotations with more spring cereals or grass leys for weed control increased arable plant diversity. Stale seedbed techniques such as delayed drilling and choosing ploughing instead of minimum tillage had varying effects on weed abundance, food production, and profitability. Ploughing was the most effective alternative to glyphosate for long-term weed control while maintaining production and profit. Our findings emphasize the need for careful consideration of trade-offs arising in scenarios where glyphosate is removed. Integrated Weed Management (IWM) with more use of cultural control methods offers the potential to reduce chemical use but is sensitive to seasonal variability and can incur negative environmental and economic impacts.

Bayesian emulation and history matching of JUNE.

We analyze JUNE: a detailed model of COVID-19 transmission with high spatial and demographic resolution, developed as part of the RAMP initiative. JUNE requires substantial computational resources to evaluate, making model calibration and general uncertainty analysis extremely challenging. We describe and employ the uncertainty quantification approaches of Bayes linear emulation and history matching to mimic JUNE and to perform a global parameter search, hence identifying regions of parameter space that produce acceptable matches to observed data, and demonstrating the capability of such methods. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

A novel somatic mutation in GNAQ in a capillary malformation provides insight into molecular pathogenesis.

Sturge-Weber syndrome (SWS) is a sporadic, congenital, neuro-cutaneous disorder characterized by a mosaic, capillary malformation. SWS and non-syndromic capillary malformations are both caused by a somatic activating mutation in GNAQ encoding the G protein subunit alpha-q protein. The missense mutation R183Q is the sole GNAQ mutation identified thus far in 90% of SWS-associated or isolated capillary malformations. In this study, we sequenced skin biopsies of capillary malformations from 9 patients. We identified the R183Q mutation in nearly all samples, but one sample exhibited a Q209R mutation. This new mutation occurs at the same residue as the constitutively-activating Q209L mutation, commonly seen in tumors. However, Q209R is a rare variant in this gene. To compare the effect of the Q209R mutation on downstream signaling, we performed reporter assays with a GNAQ-responsive reporter co-transfected with either GNAQ WT, R183Q, Q209L, Q209R, or C9X (representing a null allele). Q209L showed the highest reporter activation, with R183Q and Q209R showing significantly lower activation. To determine whether these mutations had similar or different downstream consequences we performed RNA-seq analysis in microvascular endothelial cells (HMEC-1) electroporated with the same GNAQ variants. The R183 and Q209 missense variants caused extensive dysregulation of a broad range of transcripts compared to the WT or null allele, confirming that these are all activating mutations. However, the missense variants exhibited very few differentially expressed genes (DEGs) when compared to each other. These data suggest that these activating GNAQ mutations differ in magnitude of activation but have similar downstream effects.

Meta-analysis reveals that pollinator functional diversity and abundance enhance crop pollination and yield.

How insects promote crop pollination remains poorly understood in terms of the contribution of functional trait differences between species. We used meta-analyses to test for correlations between community abundance, species richness and functional trait metrics with oilseed rape yield, a globally important crop. While overall abundance is consistently important in predicting yield, functional divergence between species traits also showed a positive correlation. This result supports the complementarity hypothesis that pollination function is maintained by non-overlapping trait distributions. In artificially constructed communities (mesocosms), species richness is positively correlated with yield, although this effect is not seen under field conditions. As traits of the dominant species do not predict yield above that attributed to the effect of abundance alone, we find no evidence in support of the mass ratio hypothesis. Management practices increasing not just pollinator abundance, but also functional divergence, could benefit oilseed rape agriculture.

Country-specific effects of neonicotinoid pesticides on honey bees and wild bees.

Neonicotinoid seed dressings have caused concern world-wide. We use large field experiments to assess the effects of neonicotinoid-treated crops on three bee species across three countries (Hungary, Germany, and the United Kingdom). Winter-sown oilseed rape was grown commercially with either seed coatings containing neonicotinoids (clothianidin or thiamethoxam) or no seed treatment (control). For honey bees, we found both negative (Hungary and United Kingdom) and positive (Germany) effects during crop flowering. In Hungary, negative effects on honey bees (associated with clothianidin) persisted over winter and resulted in smaller colonies in the following spring (24% declines). In wild bees (Bombus terrestris and Osmia bicornis), reproduction was negatively correlated with neonicotinoid residues. These findings point to neonicotinoids causing a reduced capacity of bee species to establish new populations in the year following exposure.

Evidence-based management of adult trigger digits.

The aim of this systematic review was to develop an evidence-based guideline to assist clinicians in the treatment of adult trigger digits. There is moderate evidence to suggest that local corticosteroid injection is a safe and effective short-term treatment and it may, therefore, be recommended as an initial treatment for this condition. However, when compared with surgery, there is strong evidence that corticosteroid injection is associated with increased rates of ongoing or recurrent symptoms at 6 months after intervention. There is strong evidence suggesting that trigger digit can be managed safely by surgical release. There is weak evidence to support the use of splinting or other non-operative modalities. Hence a single corticosteroid injection may be offered as the first line in treatment of adult trigger digits, but percutaneous release is a safe alternative. Surgery should be the next line if the injection fails, symptoms recur or the patient chooses. LEVEL OF EVIDENCE: I.

Empirical validation of the InVEST water yield ecosystem service model at a national scale.

A variety of tools have emerged with the goal of mapping the current delivery of ecosystem services and quantifying the impact of environmental changes. An important and often overlooked question is how accurate the outputs of these models are in relation to empirical observations. In this paper we validate a hydrological ecosystem service model (InVEST Water Yield Model) using widely available data. We modelled annual water yield in 22 UK catchments with widely varying land cover, population and geology, and compared model outputs with gauged river flow data from the UK National River Flow Archive. Values for input parameters were selected from existing literature to reflect conditions in the UK and were subjected to sensitivity analyses. We also compared model performance between precipitation and potential evapotranspiration data sourced from global- and UK-scale datasets. We then tested the transferability of the results within the UK by additional validation in a further 20 catchments. Whilst the model performed only moderately with global-scale data (linear regression of modelled total water yield against empirical data; slope=0.763, intercept=54.45, R(2)=0.963) with wide variation in performance between catchments, the model performed much better when using UK-scale input data, with closer fit to the observed data (slope=1.07, intercept=3.07, R(2)=0.990). With UK data the majority of catchments showed <10% difference between measured and modelled water yield but there was a minor but consistent overestimate per hectare (86m(3)/ha/year). Additional validation on a further 20 UK catchments was similarly robust, indicating that these results are transferable within the UK. These results suggest that relatively simple models can give accurate measures of ecosystem services. However, the choice of input data is critical and there is a need for further validation in other parts of the world.

Interfacial Engineering of Semiconductor-Superconductor Junctions for High Performance Micro-Coolers.

The control of electronic and thermal transport through material interfaces is crucial for numerous micro and nanoelectronics applications and quantum devices. Here we report on the engineering of the electro-thermal properties of semiconductor-superconductor (Sm-S) electronic cooler junctions by a nanoscale insulating tunnel barrier introduced between the Sm and S electrodes. Unexpectedly, such an interface barrier does not increase the junction resistance but strongly reduces the detrimental sub-gap leakage current. These features are key to achieving high cooling power tunnel junction refrigerators, and we demonstrate unparalleled performance in silicon-based Sm-S electron cooler devices with orders of magnitudes improvement in the cooling power in comparison to previous works. By adapting the junctions in strain-engineered silicon coolers we also demonstrate efficient electron temperature reduction from 300 mK to below 100 mK. Investigations on junctions with different interface quality indicate that the previously unexplained sub-gap leakage current is strongly influenced by the Sm-S interface states. These states often dictate the junction electrical resistance through the well-known Fermi level pinning effect and, therefore, superconductivity could be generally used to probe and optimize metal-semiconductor contact behaviour.

Applications of physiologically based pharmacokinetic (PBPK) modeling and simulation during regulatory review.

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision-making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.

Evaluation of pharmacokinetic and pharmacodynamic interaction between the dipeptidyl peptidase IV inhibitor vildagliptin, glyburide and pioglitazone in patients with Type 2 diabetes.

BACKGROUND: Vildagliptin is a selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control and pancreatic b-cell function in patients with Type 2 diabetes. Vildagliptin may be an appropriate agent to combine with other antihyperglycemic agents in patients requiring combination therapy to achieve optimal glycemic control. Two studies were performed to determine the potential for pharmacokinetic and pharmacodynamic interactions between vildagliptin and the sulfonylurea, glyburide, or pioglitazone in patients with Type 2 diabetes. METHODS: Two open-label, multiple-dose, 3-period, randomized, crossover studies in patients with Type 2 diabetes were carried out. Steady state drug pharmacokinetics and postprandial plasma glucose and insulin responses were assessed during treatment with vildagliptin 100 mg b.i.d. alone and in combination with glyburide 10 mg q.d. (n = 17) or with vildagliptin 100 mg q.d. alone or in combination with pioglitazone 45 mg q.d. (n = 15). RESULTS: Coadministration of vildagliptin with either glyburide or pioglitazone had no clinically significant effect on the pharmacokinetics of any of the 3 drugs. Changes in AUC and Cmax during combination treatment were small ( pound 15%), and 90% confidence intervals for the geometric mean ratios (drug coadministration/monotherapy) were generally contained within the acceptance range for bioequivalence (0.80 - 1.25). Vildagliptin/glyburide coadministration significantly reduced the area under the plasma glucose-time curve compared with glyburide alone (AUE0-5h reduced by 12% (p = 0.005) and AUE0-15h by 13% (p = 0.003)), and increased the area under the plasma insulin-time curve (AUE0-15h increased by 12% (p = 0.041)). Vildagliptin/pioglitazone coadministration also significantly reduced postprandial glucose exposure compared with pioglitazone alone (AUE0.5-5.5h reduced by 11% (p = 0.029) and AUE0-15.5h by 10% (p = 0.019)). Vildagliptin was generally well tolerated whether administered alone or in combination with glyburide or pioglitazone, and was not associated with hypoglycemia. CONCLUSIONS: Coadministration of vildagliptin with either glyburide or pioglitazone in patients with Type 2 diabetes improves postprandial glycemic control without notable effects on drug pharmacokinetics.

The collection and processing of human brain tissue for research.

To further understand the neuroanatomy, neurochemistry and neuropathology of the normal and diseased human brain, it is essential to have access to human brain tissue where the biological and chemical nature of the tissue is optimally preserved. We have established a human brain bank where brain tissue is optimally processed and stored in order to provide a resource to facilitate neuroscience research of the human brain in health and disease. A donor programme has been established in consultation with the community to provide for the post-mortem donation of brain tissue to the brain bank. We are using this resource of human brain tissue to further investigate the basis of normal neuronal functioning in the human brain as well as the mechanisms of neuronal dysfunction and degeneration in neurodegenerative diseases. We have established a protocol for the preservation of post-mortem adult human brain tissue firstly by snap-freezing unfixed brain tissue and secondly by chemical fixation and then storage of this tissue at -80 degrees C in a human brain bank. Several research techniques such as receptor autoradiography, DNA and RNA analysis, are carried out on the unfixed tissue and immunohistochemical and histological analysis is carried out on the fixed human tissue. Comparison of tissue from normal control cases and from cases with neurodegenerative disorders is carried out in order to document the changes that occur in the brain in these disorders and to further investigate the underlying pathogenesis of these devastating neurological diseases.

Fitness of hybrids between rapeseed (Brassica napus) and wild Brassica rapa in natural habitats.

Fitness of hybrids between genetically modified (GM) crops and wild relatives influences the likelihood of ecological harm. We measured fitness components in spontaneous (non-GM) rapeseed x Brassica rapa hybrids in natural populations. The F1 hybrids yielded 46.9% seed output of B. rapa, were 16.9% as effective as males on B. rapa and exhibited increased self-pollination. Assuming 100% GM rapeseed cultivation, we conservatively predict < 7000 second-generation transgenic hybrids annually in the United Kingdom (i.e. approximately 20% of F1 hybrids). Conversely, whilst reduced hybrid fitness improves feasibility of bio-containment, stage projection matrices suggests broad scope for some transgenes to offset this effect by enhancing fitness.

Picosecond transient photoconductivity in functionalized pentacene molecular crystals probed by terahertz pulse spectroscopy.

We have measured transient photoconductivity in functionalized pentacene molecular crystals using ultrafast optical pump-terahertz probe techniques. The single crystal samples were excited using 800 nm, 100 fs pulses, and the change in transmission of time-delayed, subpicosecond terahertz pulses was used to probe the photoconducting state over a temperature range from 10 to 300 K. A subpicosecond rise in photoconductivity is observed, suggesting that mobile carriers are a primary photoexcitation. At times longer than 4 ps, a power-law decay is observed consistent with dispersive transport.

Social implications of blepharoptosis and dermatochalasis.

PURPOSE: To investigate the social implications of blepharoptosis and dermatochalasis. METHODS: Two hundred ten individuals rated whole-face photographs of a series of patients based on 11 different personal characteristics: intelligence, threat, friendliness, health, trustworthiness, hard work, mental illness, financial success, attractiveness, alcoholism, and happiness. Preoperative and postoperative photographs of both male and female patients with bilateral blepharoptosis and/or dematochalasis were used. The paired t test was used to compare preoperative versus postoperative ratings on the 11 characteristics. RESULTS: The preoperative photographs were rated more negatively than were the postoperative photographs (p < 0.01) on all 11 characteristics for both male and female patients by the 210 study subjects. CONCLUSIONS: Members of our society view individuals with blepharoptosis and dermatochalasis negatively. These social attitudes may lead to unjust bias toward affected patients, and surgical correction probably provides benefits beyond improved visual function.

ACHS Quality Awards 2000. Quality is the way we do business.

Hollywood Private Hospital recognized that the use of quality management processes can achieve numerous benefits; however, for this to occur quality must be regarded as normal business practice rather than a separate programme. Therefore, the means of ensuring a quality service must be embedded in the strategic plans of both the organization and individual departments. The Hollywood Private Hospital Executive committed the organization to this approach further building on the 'core values' of the hospital by: integrating quality into the Strategic Planning of the organization; integrating risk management into the existing quality system; further embedding of the core values into the culture of the organisation; introducing systems thinking into the organization; taking a process improvement approach to improving quality; involving staff in Quality Action Teams and utilizing the Evaluation and Quality Improvement Programme as the management framework to co-ordinate all the above.

Gastrin-releasing peptide: a potential growth factor expressed in human neuroblastoma tumors(1).

PURPOSE:Gastrin-releasing peptide (GRP) is a 27-amino acid neuropeptide that has been identified in the cytoplasm of many neuroendocrine tumors. Gastrin releasing peptide has been labeled as an autocrine growth factor in small cell lung carcinomas. Recent work has also shown this to be true in the growth of neuroblastoma cells in vitro. The purpose of this study was to demonstrate GRP and its receptor (GRP-R) in resected human neuroblastomas and to correlate the presence or absence with other known predictors of poor prognosis.To demonstrate the presence of GRP and GRP-R mRNA, total RNA was extracted from human neuroblastoma cells. A reverse transcription-polymerase chain reaction (RT-PCR) was then performed using specific primers. The products of the RT-PCR were then confirmed to be GRP and GRP-R cDNA by Southern blot analysis. The RT-PCR products were then sequenced, and these sequences were compared with the know sequences of GRP and GRP-R DNA.N = 19. GRP and GRP-R mRNA were present in all neuroblastoma specimens. Although no correlation with other known predictors of poor prognosis existed, transcripts of four different sizes (400, 450, 500, and 950 bp) were seen in the GRP-R transcripts. The sequences of the 950 bp-sized transcript reverse transcription PCR products were identical to the known GRP-R.We conclude that gastrin releasing peptide and gastrin releasing peptide receptor mRNA are present in all human neuroblastomas. Although qualitatively it appears to lack prognostic significance, its ubiquitous nature in the tumor suggests it may be a useful target on which to base future treatment modalities.

Mechanisms for cholesterol homeostasis in rat jejunal mucosa: effects of cholesterol, sitosterol, and lovastatin.

The effects of feeding cholesterol, sitosterol, and lovastatin on cholesterol absorption, biosynthesis, esterification, and LDL receptor function were examined in the rat jejunal mucosa. Cholesterol absorption was measured by the dual-isotope plasma ratio method; the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, was measured as total and expressed enzyme activities (in the absence and presence of a phosphatase inhibitor, NaF, respectively); mucosal total and esterified cholesterol concentrations were determined by gas-liquid chromatography; LDL receptor function was assayed as receptor-mediated binding of (125)I-labeled LDL to mucosal membranes. Feeding 2% sitosterol or 0.04% lovastatin for 1 week significantly (P < 0.01) decreased the amounts of cholesterol absorbed per day (-85% and -63%, respectively). In contrast, feeding 2% cholesterol for 1 week increased the amounts of absorbed cholesterol 27-fold, even though the percent absorption significantly decreased. With all three treatments, there was a coordinate regulation of total HMG-CoA reductase activity and receptor-mediated LDL binding. Cholesterol feeding downregulated both total jejunal HMG-CoA reductase activity (P < 0.05) and receptor-mediated LDL binding (P < 0.01), whereas lovastatin- and sitosterol-supplemented diets significantly upregulated both of these parameters. In the control, cholesterol-fed, and sitosterol-fed animals, about half of the total jejunal HMG-CoA reductase activity was expressed (in functional dephosphorylated form). However, in the lovastatin-treated rats with 4-fold stimulation of HMG-CoA reductase, only 23% of the total enzyme activity was expressed. Changes in total HMG-CoA reductase activity and receptor-mediated LDL binding in all tested groups occurred with no change in total concentrations of mucosal cholesterol, and only cholesterol-fed animals had increased mucosal esterified cholesterol concentrations. Thus, in response to various fluxes of dietary or newly formed cholesterol, HMG-CoA reductase and receptor-mediated LDL binding are coordinately regulated to maintain constant cellular cholesterol concentrations in the jejunum.

Post hoc, ergo propter hoc.

Three cases are described in which patients sought damages for retinal detachments that followed minor trauma. In fact, the traumatic incidents were not responsible for the detachments. Criteria for diagnosing traumatic retinal detachments are summarized, and ophthalmologists and attorneys are cautioned to be wary of post hoc reasoning.

Psychosocial implications of blepharoptosis and dermatochalasis.

PURPOSE: To investigate, for the first time, the psychosocial implications of blepharoptosis and dermatochalasis. METHODS: Two hundred ten individuals rated whole-face photographs of a series of patients on the basis of 11 different personal characteristics: intelligence, throat, friendliness, health, trustworthiness, hard work, mental illness, financial success, attractiveness, alcoholism, and happiness. Preoperative and postoperative photographs of both male and female patients with bilateral blepharoptosis and/or dermatochalasis were used. The paired t test was used to compare preoperative and postoperative ratings on the 11 characteristics. RESULTS: The preoperative photographs were rated more negatively than the postoperative photographs (P < .01-P < .001) on all 11 characteristics for both male and female patients by the 210 study subjects. CONCLUSIONS: Members of society seem to view individuals with blepharoptosis and dermatochalasis negatively. These psychosocial attitudes may lead to unjust bias toward affected patients, and surgical correction likely provides benefits beyond improved visual function.