Systemic Anti-Inflammatory Therapy Aided by Curcumin-Laden Double-Headed Nanoparticles Combined with Injectable Long-Acting Insulin in a Rodent Model of Diabetes Eye Disease.

Therapeutic interventions that counter emerging targets in diabetes eye diseases are lacking. We hypothesize that a combination therapy targeting inflammation and hyperglycemia can prevent diabetic eye diseases. Here, we report a multipronged approach to prevent diabetic cataracts and retinopathy by combining orally bioavailable curcumin-laden double-headed (two molecules of gambogic acid conjugated to terminal carboxyl groups of poly(d,l-lactide-co-glycolide)) nanoparticles and injectable basal insulin. The combination treatment led to a significant delay in the progression of diabetic cataracts and retinopathy, improving liver function and peripheral glucose homeostasis. We found a concurrent reduction in lens aggregate protein, AGEs, and increased mitochondrial ATP production. Importantly, inhibition of Piezo1 protected against hyperglycemia-induced retinal vascular damage suggesting possible involvement of Piezo1 in the regulation of retinal phototransduction. Histologic evaluation of murine small intestines revealed that chronic administration of curcumin-laden double-headed nanoparticles was well tolerated, circumventing the fear of nanoparticle toxicity. These findings establish the potential of anti-inflammatory and anti-hyperglycemic combination therapy for the prevention of diabetic cataracts and retinopathy.

Approaches to screening for hyperglycaemia in pregnant women during and after the COVID-19 pandemic.

AIM: To evaluate the diagnostic and prognostic performance of alternative diagnostic strategies to oral glucose tolerance tests, including random plasma glucose, fasting plasma glucose and HbA1c , during the COVID-19 pandemic. METHODS: Retrospective service data (Cambridge, UK; 17 736 consecutive singleton pregnancies, 2004-2008; 826 consecutive gestational diabetes pregnancies, 2014-2019) and 361 women with ≥1 gestational diabetes risk factor (OPHELIA prospective observational study, UK) were included. Pregnancy outcomes included gestational diabetes (National Institute of Health and Clinical Excellence or International Association of Diabetes and Pregnancy Study Groups criteria), diabetes in pregnancy (WHO criteria), Caesarean section, large-for-gestational age infant, neonatal hypoglycaemia and neonatal intensive care unit admission. Receiver-operating characteristic curves and unadjusted logistic regression were used to compare random plasma glucose, fasting plasma glucose and HbA1c performance. RESULTS: Gestational diabetes diagnosis was significantly associated with random plasma glucose at 12 weeks [area under the receiver-operating characteristic curve for both criteria 0.81 (95% CI 0.79-0.83)], fasting plasma glucose [National Institute of Health and Clinical Excellence: area under the receiver-operating characteristic curve 0.75 (95% CI 0.65-0.85); International Association of Diabetes and Pregnancy Study Groups: area under the receiver-operating characteristic curve 0.92 (95% CI 0.85-0.98)] and HbA1c at 28 weeks' gestation [National Institute of Health and Clinical Excellence: 0.83 (95% CI 0.75-0.90); International Association of Diabetes and Pregnancy Study Groups: 0.84 (95% CI 0.77-0.91)]. Each measure predicts some, but not all, pregnancy outcomes studied. At 12 weeks, ~5% of women would be identified using random plasma glucose ≥8.5 mmol/l (sensitivity 42%; specificity 96%) and at 28 weeks using HbA1c ≥39 mmol/mol (sensitivity 26%; specificity 96%) or fasting plasma glucose ≥5.2-5.4 mmol/l (sensitivity 18-41%; specificity 97-98%). CONCLUSIONS: Random plasma glucose at 12 weeks, and fasting plasma glucose or HbA1c at 28 weeks identify women with hyperglycaemia at risk of suboptimal pregnancy outcomes. These opportunistic laboratory tests perform adequately for risk stratification when oral glucose tolerance testing is not available.

First Precision Measurement of the Parity Violating Asymmetry in Cold Neutron Capture on

We report the first precision measurement of the parity-violating asymmetry in the direction of proton momentum with respect to the neutron spin, in the reaction ^{3}He(n,p)^{3}H, using the capture of polarized cold neutrons in an unpolarized active ^{3}He target. The asymmetry is a result of the weak interaction between nucleons, which remains one of the least well-understood aspects of electroweak theory. The measurement provides an important benchmark for modern effective field theory and potential model calculations. Measurements like this are necessary to determine the spin-isospin structure of the hadronic weak interaction. Our asymmetry result is A_{PV}=[1.55±0.97(stat)±0.24(sys)]×10^{-8}, which has the smallest uncertainty of any hadronic parity-violating asymmetry measurement so far.

Systemic anti-inflammatory therapy aided by double-headed nanoparticles in a canine model of acute intraocular inflammation.

Novel approaches circumventing blood-ocular barriers in systemic drug delivery are lacking. We hypothesize receptor-mediated delivery of curcumin (CUR) across intestinal and ocular barriers leads to decreased inflammation in a model of lens-induced uveitis. CUR was encapsulated in double-headed polyester nanoparticles using gambogic acid (GA)-coupled polylactide-co-glycolide (PLGA). Orally administered PLGA-GA2-CUR led to notable aqueous humor CUR levels and was dosed (10 mg/kg twice daily) to adult male beagles (n = 8 eyes) with induced ocular inflammation. Eyes were evaluated using a semiquantitative preclinical ocular toxicology scoring (SPOTS) and compared to commercial anti-inflammatory treatment (oral carprofen 2.2 mg/kg twice daily) (n = 8) and untreated controls (n = 8). PLGA-GA2-CUR offered improved protection compared with untreated controls and similar protection compared with carprofen, with reduced aqueous flare, miosis, and chemosis in the acute phase (<4 hours). This study highlights the potential of PLGA-GA2 nanoparticles for systemic drug delivery across ocular barriers.

Field effects studies in the Chernobyl Exclusion Zone: Lessons to be learnt.

In the initial aftermath of the 1986 Chernobyl accident there were detrimental effects recorded on wildlife, including, mass mortality of pine trees close to the reactor, reduced pine seed production, reductions in soil invertebrate abundance and diversity and likely death of small mammals. More than 30 years after the Chernobyl accident there is no consensus on the longer-term impact of the chronic exposure to radiation on wildlife in what is now referred to as the Chernobyl Exclusion Zone. Reconciling this lack of consensus is one of the main challenges for radioecology. With the inclusion of environmental protection in, for instance, the recommendations of the International Commission on Radiological Protection (ICRP), we need to be able to incorporate knowledge of the potential effects of radiation on wildlife within the regulatory process (e.g. as a basis on which to define benchmark dose rates). In this paper, we use examples of reported effects on different wildlife groups inhabiting the Chernobyl Exclusion Zone (CEZ) as a framework to discuss potential reasons for the lack of consensus, consider important factors influencing dose rates organisms receive and make some recommendations on good practice.

Risk factors and patterns of household clusters of respiratory viruses in rural Nepal.

Viral pneumonia is an important cause of death and morbidity among infants worldwide. Transmission of non-influenza respiratory viruses in households can inform preventative interventions and has not been well-characterised in South Asia. From April 2011 to April 2012, household members of pregnant women enrolled in a randomised trial of influenza vaccine in rural Nepal were surveyed weekly for respiratory illness until 180 days after birth. Nasal swabs were tested by polymerase chain reaction for respiratory viruses in symptomatic individuals. A transmission event was defined as a secondary case of the same virus within 14 days of initial infection within a household. From 555 households, 825 initial viral illness episodes occurred, resulting in 79 transmission events. The overall incidence of transmission was 1.14 events per 100 person-weeks. Risk of transmission incidence was associated with an index case age 1-4 years (incidence rate ratio (IRR) 2.35; 95% confidence interval (CI) 1.40-3.96), coinfection as initial infection (IRR 1.94; 95% CI 1.05-3.61) and no electricity in household (IRR 2.70; 95% CI 1.41-5.00). Preventive interventions targeting preschool-age children in households in resource-limited settings may decrease the risk of transmission to vulnerable household members, such as young infants.

Measuring pain in dogs and cats using structured behavioural observation.

The contemporary approach to pain measurement in people and animals seeks to measure the affective (emotional) component of the pain experience using structured questionnaires with formal scoring methodology. Chronic pain has wide-ranging impacts which affects the quality of life (QOL) of the individual, whether that is a person or an animal. Accordingly instruments to measure chronic pain are designed to measure its impact on QOL and are called health-related quality of life (HRQL) instruments. In veterinary science instruments to measure pain are based on behavioural observation by the veterinary surgeon/nurse in the case of acute pain and by the owner in the case of chronic pain. The development of HRQL instruments is an expanding field in veterinary science, not just for the measurement of pain, but for other chronic diseases, and it has a wide application in pharmaceutical research and clinical practice to improve patient care. This review highlights the challenges involved in creating such measures for dogs and cats, seeking to provide the reader with an understanding of their development process. It then provides an overview of the current status with regard to acute and chronic pain measurement.

A transdiagnostic study of education, employment, and training outcomes in young people with mental illness.

BACKGROUND: Optimizing functional recovery in young individuals with severe mental illness constitutes a major healthcare priority. The current study sought to quantify the cognitive and clinical factors underpinning academic and vocational engagement in a transdiagnostic and prospective youth mental health cohort. The primary outcome measure was 'not in education, employment or training' ('NEET') status. METHOD: A clinical sample of psychiatric out-patients aged 15-25 years (n = 163) was assessed at two time points, on average, 24 months apart. Functional status, and clinical and neuropsychological data were collected. Bayesian structural equation modelling was used to confirm the factor structure of predictors and cross-lagged effects at follow-up. RESULTS: Individually, NEET status, cognitive dysfunction and negative symptoms at baseline were predictive of NEET status at follow-up (p < 0.05). Baseline cognitive functioning was the only predictor of follow-up NEET status in the multivariate Bayesian model, while controlling for baseline NEET status. For every 1 s.d. deficit in cognition, the probability of being disengaged at follow-up increased by 40% (95% credible interval 19-58%). Baseline NEET status predicted poorer negative symptoms at follow-up (ß = 0.24, 95% credible interval 0.04-0.43). CONCLUSIONS: Disengagement with education, employment or training (i.e. being NEET) was reported in about one in four members of this cohort. The initial level of cognitive functioning was the strongest determinant of future NEET status, whereas being academically or vocationally engaged had an impact on future negative symptomatology. If replicated, these findings support the need to develop early interventions that target cognitive phenotypes transdiagnostically.

Flow-directed PCA for monitoring networks.

Measurements recorded over monitoring networks often possess spatial and temporal correlation inducing redundancies in the information provided. For river water quality monitoring in particular, flow-connected sites may likely provide similar information. This paper proposes a novel approach to principal components analysis to investigate reducing dimensionality for spatiotemporal flow-connected network data in order to identify common spatiotemporal patterns. The method is illustrated using monthly observations of total oxidized nitrogen for the Trent catchment area in England. Common patterns are revealed that are hidden when the river network structure and temporal correlation are not accounted for. Such patterns provide valuable information for the design of future sampling strategies.

Circadian clocks, obesity and cardiometabolic function.

Life on earth is governed by the continuous 24-h cycle of light and dark. Organisms have adapted to this environment with clear diurnal rhythms in their physiology and metabolism, enabling them to anticipate predictable environmental fluctuations over the day and to optimize the timing of relevant biological processes to this cycle. These rhythms are regulated by molecular circadian clocks, and current evidence suggests that interactions between the central and peripheral molecular clocks are important in metabolic and vascular functions. Disrupting this process through mutations in the core clock genes or by interfering with the environmental zeitgebers that entrain the clock appear to modulate the function of cells and tissues, leading to an increased risk for cardiometabolic disease.

Spatially weighted functional clustering of river network data.

Incorporating spatial covariance into clustering has previously been considered for functional data to identify groups of functions which are similar across space. However, in the majority of situations that have been considered until now the most appropriate metric has been Euclidean distance. Directed networks present additional challenges in terms of estimating spatial covariance due to their complex structure. Although suitable river network covariance models have been proposed for use with stream distance, where distance is computed along the stream network, these models have not been extended for contexts where the data are functional, as is often the case with environmental data. The paper develops a method of calculating spatial covariance between functions from sites along a river network and applies the measure as a weight within functional hierarchical clustering. Levels of nitrate pollution on the River Tweed in Scotland are considered with the aim of identifying groups of monitoring stations which display similar spatiotemporal characteristics.

Neuropsychological and functional outcomes in recent-onset major depression, bipolar disorder and schizophrenia-spectrum disorders: a longitudinal cohort study.

Functional disability is the lead contributor to burden of mental illness. Cognitive deficits frequently limit functional recovery, although whether changes in cognition and disability are longitudinally associated in recent-onset individuals remains unclear. Using a prospective, cohort design, 311 patients were recruited and assessed at baseline. One hundred and sixty-seven patients met eligibility criteria (M=21.5 years old, s.d.=4.8) and returned for follow-up (M=20.6 months later, s.d.=7.8). Two-hundred and thirty participants were included in the final analysis, comprising clinically stable patients with major depression (n=71), bipolar disorder (BD; n=61), schizophrenia-spectrum disorders (n=35) and 63 healthy controls. Neuropsychological functioning and self-rated functional disability were examined using mixed-design, repeated-measures analysis, across diagnoses and cognitive clusters, covarying for relevant confounds. Clinical, neuropsychological and functional changes did not differ between diagnoses (all P>0.05). Three reliable neuropsychological subgroups emerged through cluster analysis, characterized by psychomotor slowing, improved sustained attention, and improved verbal memory. Controlling for diagnosis and changes in residual symptoms, clusters with improved neuropsychological functioning observed greater reductions in functional disability than the psychomotor slowing cluster, which instead demonstrated a worsening in disability (P<0.01). Improved sustained attention was independently associated with greater likelihood of follow-up employment (P<0.01). Diagnosis of BD uniquely predicted both follow-up employment and independent living. Neuropsychological course appears to be independently predictive of subjective and objective functional outcomes. Importantly, cognitive phenotypes may reflect distinct pathophysiologies shared across major psychiatric conditions, and be ideal targets for personalized early intervention.

Development of a behaviour-based measurement tool with defined intervention level for assessing acute pain in cats.

OBJECTIVES: To develop a composite measure pain scale tool to assess acute pain in cats and derive an intervention score. METHODS: To develop the prototype composite measure pain scale-feline, words describing painful cats were collected, grouped into behavioural categories and ranked. To assess prototype validity two observers independently assigned composite measure pain scale-feline and numerical rating scale scores to 25 hospitalised cats before and after analgesic treatment. Following interim analysis the prototype was revised (revised composite measure pain scale-feline). To determine intervention score, two observers independently assigned revised composite measure pain scale-feline and numerical rating scale scores to 116 cats. A further observer, a veterinarian, stated whether analgesia was necessary. RESULTS: Mean ± sd decrease in revised composite measure pain scale-feline and numerical rating scale scores following analgesia were 2 · 4 ± 2 · 87 and 1 · 9 ± 2 · 34, respectively (95% confidence interval for mean change in revised composite measure pain scale-feline between 1 · 21 and 3 · 6). Changes in revised composite measure pain scale-feline and numerical rating scale were significantly correlated (r = 0 · 8) (P < 0001). Intervention level score of ≥4/16 was derived for revised composite measure pain scale-feline (26 · 7% misclassification) and ≥3/10 for numerical rating scale (14 · 5% misclassification). CLINICAL SIGNIFICANCE: A valid instrument with a recommended analgesic intervention level has been developed to assess acute clinical pain in cats that should be readily applicable in practice.

Evaluation of facial expression in acute pain in cats.

OBJECTIVES: To describe the development of a facial expression tool differentiating pain-free cats from those in acute pain. METHODS: Observers shown facial images from painful and pain-free cats were asked to identify if they were in pain or not. From facial images, anatomical landmarks were identified and distances between these were mapped. Selected distances underwent statistical analysis to identify features discriminating pain-free and painful cats. Additionally, thumbnail photographs were reviewed by two experts to identify discriminating facial features between the groups. RESULTS: Observers (n = 68) had difficulty in identifying pain-free from painful cats, with only 13% of observers being able to discriminate more than 80% of painful cats. Analysis of 78 facial landmarks and 80 distances identified six significant factors differentiating pain-free and painful faces including ear position and areas around the mouth/muzzle. Standardised mouth and ear distances when combined showed excellent discrimination properties, correctly differentiating pain-free and painful cats in 98% of cases. Expert review supported these findings and a cartoon-type picture scale was developed from thumbnail images. CLINICAL SIGNIFICANCE: Initial investigation into facial features of painful and pain-free cats suggests potentially good discrimination properties of facial images. Further testing is required for development of a clinical tool.

The association of weather and bathing water quality on the incidence of gastrointestinal illness in the west of Scotland.

SUMMARY: The associations with weather and bathing water quality on infectious intestinal disease (IID) were investigated using data from two Scottish NHS Board areas. Monthly counts of viral and non-viral gastrointestinal infections were modelled as a smooth function of temperature, relative humidity and average monthly counts of faecal indicator organisms, respectively, adjusting for season and long-term trend effects. Strong seasonal patterns were observed for each group of pathogens. Peak viral gastrointestinal infection was in May while that of non-viral gastrointestinal infections was in July. A statistically significant negative association existed between weather (temperature and humidity) and viral infection. Average levels of non-viral gastrointestinal infections increased as temperature and relative humidity increased. Increasing levels of faecal indicator organisms in bathing waters were also associated with an increase in the average number of viral and non-viral gastrointestinal infections at the ecological level. Future climate change and prolonged precipitation events may result in increasing levels of faecal indicator organisms in bathing waters leading to likely increases in IIDs.

Spatiotemporal statistical modelling of long-term change in river nutrient concentrations in England & Wales.

Concentrations of nutrient nitrogen (N) and phosphorus (P) are elevated in rivers across large areas of Europe (European Nitrogen Assessment (ENA), Sutton et al., 2011). Environmental policies have been implemented over the past 20 years with the aim of reducing nitrogen inputs to surface waters. However, environmental and ecological status is still below set targets (ENA, Sutton et al., 2011). Identification of patterns in long-term change for nutrient trends in hydrological catchments in England & Wales is required to assess impacts of nutrient management policy and provide better evidence for future policy. Such information could provide essential evidence for supporting policy by combining information from the wider catchment, rather than relying on the analysis of data from individual sites. Surface water quality is subject to considerable spatial and short-period temporal variability, reflecting variability in loading and dilution. This makes it difficult to determine temporal trends at individual monitoring sites with relatively sparse sampling. Here we apply spatiotemporal statistical additive models for both nitrogen and phosphorus in river networks across England & Wales to investigate the overall pattern of nutrient concentrations in these river surface waters over the past 20-40 years. Concentrations of Orthophosphate (OP) have generally decreased over time for many of the Large Hydrological Areas with a seasonal pattern highlighting one peak in the summer months. Over the past ten years, Total Oxidised Nitrogen (Nitrate+Nitrite, TON) concentrations have generally been slowly decreasing or fairly constant. However, prior to 2000, concentrations were generally on an upward trend. The seasonal pattern highlights one trough in the summer months. The highest levels for OP and TON broadly occur in the same general areas across England & Wales. On average, over time, the lowest values are evident in the north-west and south-west (particularly for OP) and highest values are evident in the Midlands, Anglian and Southern regions.

The radium legacy: Contaminated land and the committed effective dose from the ingestion of radium contaminated materials.

The manufacture and use of radium in the early to mid-20th century within industrial, medicinal and recreational products have resulted in a large number of contaminated sites across a number of countries with notable examples in the USA and Europe. These sites, represent a significant number of unregulated sources of potential radiological exposure that have collectively and hitherto not been well characterised. In 2007, the Radioactive Contaminated Land (RCL) Regulations came into force in the UK, providing the statutory guidance for regulators to classify and deal with RCL. Here we report on results derived from digestion experiments to estimate committed effective dose, a key aspect of the RCL Regulations, from the ingestion of radium contaminated sources that can be found in the environment. This case study includes particles, clinker and artefacts that arise from past military activities on a site that was once an airfield at Dalgety Bay on the Firth of Forth, UK. Since 2011 the number of radium contaminated finds has increased by one order of magnitude on the foreshore areas of Dalgety Bay. The increase in finds may in large part be attributed to a change in monitoring practice. A subsample of sixty sources was selected, on the basis of their activity and dimensions, and subjected to digestion in simulated stomach and lower intestine solutions. The study demonstrated that more radium-226 ((226)Ra) and lead-210 ((210)Pb; driven by Polonium solubility) are dissolved from sources in artificial 'stomach' solutions compared with 'lower intestine' solutions. The combined 'gut' solubility for (226)Ra and apparent (210)Pb varied from less than 1% to up to 35% ICRP 72 conversion factors were used to convert the activities measured in solution to committed effective dose. A little over 10% of the sources tested dissolved sufficient radioactivity to result in 100mSv committed effective dose to an infant. Using the solubility of 35% as a worst case, minimum source activities necessary to deliver 100mSv to the full age range of users of the foreshore were estimated. All the estimated activities have been detected and recovered through routine monitoring.

Sleep-wake cycle and melatonin rhythms in adolescents and young adults with mood disorders: comparison of unipolar and bipolar phenotypes.

This study evaluated the potential of circadian measures as early markers of mood disorders subtypes. Patients with bipolar disorders had significantly lower levels and later onset of melatonin secretion than those with unipolar depression. Furthermore, abnormal phase angles between sleep, melatonin and temperature were found in several patients.

Microstructural white matter changes are correlated with the stage of psychiatric illness.

Microstructural white matter changes have been reported in the brains of patients across a range of psychiatric disorders. Evidence now demonstrates significant overlap in these regions in patients with affective and psychotic disorders, thus raising the possibility that these conditions share common neurobiological processes. If affective and psychotic disorders share these disruptions, it is unclear whether they occur early in the course or develop gradually with persistence or recurrence of illness. Utilisation of a clinical staging model, as an adjunct to traditional diagnostic practice, is a viable mechanism for measuring illness progression. It is particularly relevant in young people presenting early in their illness course. It also provides a suitable framework for determining the timing of emergent brain alterations, including disruptions of white matter tracts. Using diffusion tensor imaging, we investigated the integrity of white matter tracts in 74 patients with sub-syndromal psychiatric symptoms as well as in 69 patients diagnosed with established psychosis or affective disorder and contrasted these findings with those of 39 healthy controls. A significant disruption in white matter integrity was found in the left anterior corona radiata and in particular the anterior thalamic radiation for both the patients groups when separately contrasted with healthy controls. Our results suggest that patients with sub-syndromal symptoms exhibit discernable early white matter changes when compared with healthy control subjects and more significant disruptions are associated with clinical evidence of illness progression.