The topographical relationship between visual field loss and peripapillary retinal nerve fibre layer thinning arising from long-term exposure to vigabatrin

Background The antiepileptic drug vigabatrin is associated with characteristic visual field loss (VAVFL) and thinning of the peripapillary retinal nerve fibre layer (PPRNFL); however, the relationship is equivocal. Objective The aim of this study was to determine the function–structure relationship associated with long-term exposure to vigabatrin, thereby improving the risk/benefit analysis of the drug. Methods A cross-sectional observational design identified 40 adults who had received long-term vigabatrin for refractory seizures, who had no evidence of co-existing retino-geniculo-cortical visual pathway abnormality, and who had undergone a standardized protocol of perimetry and of optical coherence tomography (OCT) of the PPRNFL. Vigabatrin toxicity was defined as the presence of VAVFL. The function–structure relationship for the superior and inferior retinal quadrants was evaluated by two established models applicable to other optic neuropathies. Results The function–structure relationship for each model was consistent with an optic neuropathy. PPRNFL thinning, expressed in micrometres, asymptoted at an equivalent visual field loss of worse than approximately − 10.0 dB, thereby preventing assessment of more substantial thinning. Transformation of the outcomes to retinal ganglion cell soma and axon estimates, respectively, resulted in a linear relationship. Conclusions Functional and structural abnormality is strongly related in individuals with vigabatrin toxicity and no evidence of visual pathway comorbidity, thereby implicating retinal ganglion cell dysfunction. OCT affords a limited measurement range compared with perimetry: severity cannot be directly assessed when the PPRNFL quadrant thickness is less than approximately 65 µm, depending on the tomographer. This limitation can be overcome by transformation of thickness to remaining axons, an outcome requiring input from perimetry

Objective derivation of the morphology and staging of visual field loss associated with long-term vigabatrin therapy

BACKGROUND: The morphology and between-eye symmetry of the visual field loss associated with the antiepileptic drug vigabatrin (VAVFL) has received little attention. OBJECTIVE: Our objective was to model the appearance and ensuing staging of VAVFL derived with the European Medicines Agency-approved perimetric protocol. METHODS: This was a retrospective, cross-sectional, observational study that identified 123 adults who had received vigabatrin for refractory seizures and who had no evidence of co-existing retino-geniculo-cortical visual pathway abnormality. A further 38 adults with refractory seizures and identical inclusion criteria but no exposure to vigabatrin acted as controls. For each group, the median outcome at each stimulus location in each eye (of absolute loss, relative loss or Pattern Deviation probability level, as appropriate) was derived for each successive ten pairs of fields, ranked for severity. Between-eye symmetry was quantified by an index that accounted for severity of loss and that was referenced to the likelihood of the occurrence of symmetry due to chance. RESULTS: The modelled VAVFL was bilateral and highly symmetrical and was described by six stages that were all independent of the extent of vigabatrin exposure. The loss originated in the extreme temporal periphery and encroached centripetally along all meridians towards fixation. The initial appearance within the central field (Stage 2) occurred inferior-nasally. Subsequent stages exhibited increasing loss, which was greater nasally than temporally. Stage 6 described concentric loss extending to approximately 15° eccentricity from fixation. CONCLUSION: The model exhibited a consistent pattern of VAVFL. The staging of the loss could assist the risk:benefit analysis of vigabatrin for the treatment of epilepsy

Use of remote-sensing reflectance to constrain a data assimilating marine biogeochemical model of the Great Barrier Reef

Skillful marine biogeochemical (BGC) models are required to understand a range of coastal and global phenomena such as changes in nitrogen and carbon cycles. The refinement of BGC models through the assimilation of variables calculated from observed in-water inherent optical properties (IOPs), such as phytoplankton absorption, is problematic. Empirically derived relationships between IOPs and variables such as chlorophyll-a concentration (Chl a), total suspended solids (TSS) and coloured dissolved organic matter (CDOM) have been shown to have errors that can exceed 100% of the observed quantity. These errors are greatest in shallow coastal regions, such as the Great Barrier Reef (GBR), due to the additional signal from bottom reflectance. Rather than assimilate quantities calculated using IOP algorithms, this study demonstrates the advantages of assimilating quantities calculated directly from the less error-prone satellite remote-sensing reflectance (RSR). To assimilate the observed RSR, we use an in-water optical model to produce an equivalent simulated RSR and calculate the mismatch between the observed and simulated quantities to constrain the BGC model with a deterministic ensemble Kalman filter (DEnKF). The traditional assumption that simulated surface Chl a is equivalent to the remotely sensed OC3M estimate of Chl a resulted in a forecast error of approximately 75 %. We show this error can be halved by instead using simulated RSR to constrain the model via the assimilation system. When the analysis and forecast fields from the RSR-based assimilation system are compared with the non-assimilating model, a comparison against independent in situ observations of Chl a, TSS and dissolved inorganic nutrients (NO3, NH4 and DIP) showed that errors are reduced by up to 90 %. In all cases, the assimilation system improves the simulation compared to the non-assimilating model. Our approach allows for the incorporation of vast quantities of remote-sensing observations that have in the past been discarded due to shallow water and/or artefacts introduced by terrestrially derived TSS and CDOM or the lack of a calibrated regional IOP algorithm

Marked improvements in glycaemic outcomes following insulin pump therapy initiation in people with type 1 diabetes:a nationwide observational study in Scotland

This study was supported by funding from Diabetes UK (17/0005627) and the Chief Scientist Office (ref. ETM/47).Aims/hypothesis Our aim was to assess the use of continuous subcutaneous insulin infusion (CSII) in people with type 1 diabetes in Scotland and its association with glycaemic control, as measured by HbA1c levels, frequency of diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH), overall and stratified by baseline HbA1c. Methods We included 4684 individuals with type 1 diabetes from the national Scottish register, who commenced CSII between 2004 and 2019. We presented crude within-person differences from baseline HbA1c over time since initiation, crude DKA and SHH event-rates pre-/post-CSII exposure. We then used mixed models to assess the significance of CSII exposure, taking into account: (1) the diffuse nature of the intervention (i.e. structured education often precedes initiation); (2) repeated within-person measurements; and (3) background time-trends occurring pre-intervention. Results HbA1c decreased after CSII initiation, with a median within-person change of −5.5 mmol/mol (IQR −12.0, 0.0) (−0.5% [IQR −1.1, 0.0]). Within-person changes were most substantial in those with the highest baseline HbA1c, with median −21.0 mmol/mol (−30.0, −11.0) (−1.9% [−2.7, −1.0]) change in those with a baseline >84 mmol/mol (9.8%) within a year of exposure, that was sustained: −19.0 mmol/mol (−27.6, −6.5) (−1.7% [−2.5, −0.6]) at ≥5 years. Statistical significance and magnitude of change were supported by the mixed models results. The crude DKA event-rate was significantly lower in post-CSII person-time compared with pre-CSII person-time: 49.6 events (95% CI 46.3, 53.1) per 1000 person-years vs 67.9 (64.1, 71.9); rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.61 (95% credible interval [CrI] 0.47, 0.77; posterior probability of reduction pp = 1.00). The crude overall SHH event-rate in post-CSII vs pre-CSII person-time was also lower: 17.8 events (95% CI 15.8, 19.9) per 1000 person-years post-exposure vs 25.8 (23.5, 28.3) pre-exposure; rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.67 (95% CrI 0.45, 1.01; pp = 0.97). Conclusions/interpretation CSII therapy was associated with marked falls in HbA1c especially in those with high baseline HbA1c. CSII was independently associated with reduced DKA and SHH rates. CSII appears to be an effective option for intensive insulin therapy in people with diabetes for improving suboptimal glycaemic control.Publisher PDFPeer reviewe

American Society of Clinical Oncology Summit on Addressing Obesity Through Multidisciplinary Provider Collaboration: Key Findings and Recommendations for Action

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139117/1/oby21987.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139117/2/oby21987_am.pd

Rising Rates And Widening Socio-economic Disparities In Diabetic Ketoacidosis In Type 1 Diabetes In Scotland:A Nationwide Retrospective Cohort Observational Study

OBJECTIVE: Whether advances in the management of type 1 diabetes are reducing rates of diabetic ketoacidosis (DKA) is unclear. We investigated time trends in DKA rates in a national cohort of individuals with type 1 diabetes monitored for 14 years, overall and by socioeconomic characteristics. RESEARCH DESIGN AND METHODS: All individuals in Scotland with type 1 diabetes who were alive and at least 1 year old between 1 January 2004 and 31 December 2018 were identified using the national register (N 5 37,939). DKA deaths and hospital admissions were obtained through linkage to Scottish national death and morbidity records. Bayesian regression was used to test for DKA time trends and association with risk markers, including socioeconomic deprivation. RESULTS: There were 30,427 DKA admissions and 472 DKA deaths observed over 393,223 person-years at risk. DKA event rates increased over the study period (incidence rate ratio [IRR] per year 1.058 [95% credibility interval 1.054–1.061]). Males had lower rates than females (IRR male-to-female 0.814 [0.776–0.855]). DKA incidence rose in all age-groups other than 10- to 19-year-olds, in whom rates were the highest, but fell over the study. There was a large socioeconomic differential (IRR least-to-most deprived quintile 0.446 [0.406–0.490]), which increased during follow-up. Insulin pump use or completion of structured education were associated with lower DKA rates, and antidepressant and methadone prescription were associated with higher DKA rates. CONCLUSIONS: DKA incidence has risen since 2004, except in 10- to 19-year-olds. Of particular concern are the strong and widening socioeconomic disparities in DKA outcomes. Efforts to prevent DKA, especially in vulnerable groups, require strengthening

Global total ozone recovery trends attributed to ozone-depleting substance (ODS) changes derived from five merged ozone datasets

We report on updated trends using different merged zonal mean total ozone datasets from satellite and ground-based observations for the period from 1979 to 2020. This work is an update of the trends reported in Weber et al. (2018) using the same datasets up to 2016. Merged datasets used in this study include NASA MOD v8.7 and NOAA Cohesive Data (COH) v8.6, both based on data from the series of Solar Backscatter Ultraviolet (SBUV), SBUV-2, and Ozone Mapping and Profiler Suite (OMPS) satellite instruments (1978–present), as well as the Global Ozone Monitoring Experiment (GOME)-type Total Ozone – Essential Climate Variable (GTO-ECV) and GOME-SCIAMACHY-GOME-2 (GSG) merged datasets (both 1995–present), mainly comprising satellite data from GOME, SCIAMACHY, OMI, GOME-2A, GOME-2B, and TROPOMI. The fifth dataset consists of the annual mean zonal mean data from ground-based measurements collected at the World Ozone and Ultraviolet Radiation Data Centre (WOUDC). Trends were determined by applying a multiple linear regression (MLR) to annual mean zonal mean data. The addition of 4 more years consolidated the fact that total ozone is indeed slowly recovering in both hemispheres as a result of phasing out ozone-depleting substances (ODSs) as mandated by the Montreal Protocol. The near-global (60∘ S–60∘ N) ODS-related ozone trend of the median of all datasets after 1995 was 0.4 ± 0.2 (2σ) %/decade, which is roughly a third of the decreasing rate of 1.5 ± 0.6 %/decade from 1978 until 1995. The ratio of decline and increase is nearly identical to that of the EESC (equivalent effective stratospheric chlorine or stratospheric halogen) change rates before and after 1995, confirming the success of the Montreal Protocol. The observed total ozone time series are also in very good agreement with the median of 17 chemistry climate models from CCMI-1 (Chemistry-Climate Model Initiative Phase 1) with current ODS and GHG (greenhouse gas) scenarios (REF-C2 scenario). The positive ODS-related trends in the Northern Hemisphere (NH) after 1995 are only obtained with a sufficient number of terms in the MLR accounting properly for dynamical ozone changes (Brewer–Dobson circulation, Arctic Oscillation (AO), and Antarctic Oscillation (AAO)). A standard MLR (limited to solar, Quasi-Biennial Oscillation (QBO), volcanic, and El Niño–Southern Oscillation (ENSO)) leads to zero trends, showing that the small positive ODS-related trends have been balanced by negative trend contributions from atmospheric dynamics, resulting in nearly constant total ozone levels since 2000

Tandem quadruplication of HMA4 in the zinc (Zn) and cadmium (Cd) hyperaccumulator noccaea caerulescens

Zinc (Zn) and cadmium (Cd) hyperaccumulation may have evolved twice in the Brassicaceae, in Arabidopsis halleri and in the Noccaea genus. Tandem gene duplication and deregulated expression of the Zn transporter, HMA4, has previously been linked to Zn/Cd hyperaccumulation in A. halleri. Here, we tested the hypothesis that tandem duplication and deregulation of HMA4 expression also occurs in Noccaea. A Noccaea caerulescens genomic library was generated, containing 36,864 fosmid pCC1FOSTM clones with insert sizes ~20–40 kbp, and screened with a PCR-generated HMA4 genomic probe. Gene copy number within the genome was estimated through DNA fingerprinting and pooled fosmid pyrosequencing. Gene copy numbers within individual clones was determined by PCR analyses with novel locus specific primers. Entire fosmids were then sequenced individually and reads equivalent to 20-fold coverage were assembled to generate complete whole contigs. Four tandem HMA4 repeats were identified in a contiguous sequence of 101,480 bp based on sequence overlap identities. These were flanked by regions syntenous with up and downstream regions of AtHMA4 in Arabidopsis thaliana. Promoter-reporter b-glucuronidase (GUS) fusion analysis of a NcHMA4 in A. thaliana revealed deregulated expression in roots and shoots, analogous to AhHMA4 promoters, but distinct from AtHMA4 expression which localised to the root vascular tissue. This remarkable consistency in tandem duplication and deregulated expression of metal transport genes between N. caerulescens and A. halleri, which last shared a common ancestor >40 mya, provides intriguing evidence that parallel evolutionary pathways may underlie Zn/Cd hyperaccumulation in Brassicaceae

The association of polypharmacy and high-risk drug classes with adverse health outcomes in the Scottish population with type 1 diabetes

This study was supported by funding from the Diabetes UK (17/0005627). The funder had no role in designing the study or in analysing and interpreting data and results.Aims/hypothesis The aim of this work was to map the number of prescribed drugs over age, sex and area-based socioeconomic deprivation, and to examine the association between the number of drugs and particular high-risk drug classes with adverse health outcomes among a national cohort of individuals with type 1 diabetes. Methods Utilising linked healthcare records from the population-based diabetes register of Scotland, we identified 28,245 individuals with a diagnosis of type 1 diabetes on 1 January 2017. For this population, we obtained information on health status, predominantly reflecting diabetes-related complications, and information on the total number of drugs and particular high-risk drug classes prescribed. We then studied the association of these baseline-level features with hospital admissions for falls, diabetic ketoacidosis (DKA), and hypoglycaemia or death within the subsequent year using multivariate Cox proportional hazards models. Results Not considering insulin and treatment for hypoglycaemia, the mean number of prescribed drugs was 4.00 (SD 4.35). The proportion of individuals being prescribed five or more drugs at baseline consistently increased with age (proportion [95% CI]: 0–19 years 2.04% [1.60, 2.49]; 40–49 years 28.50% [27.08, 29.93]; 80+ years 76.04% [67.73, 84.84]). Controlling for age, sex, area-based socioeconomic deprivation and health status, each additional drug at baseline was associated with an increase in the hazard for hospitalisation for falls, hypoglycaemia and death but not for DKA admissions (HR [95% CI]: falls 1.03 [1.01, 1.06]; DKA 1.01 [1.00, 1.03]; hypoglycaemia 1.05 [1.02, 1.07]; death 1.04 [1.02, 1.06]). We found a number of drug classes to be associated with an increased hazard of one or more of these adverse health outcomes, including antithrombotic/anticoagulant agents, corticosteroids, opioids, antiepileptics, antipsychotics, hypnotics and sedatives, and antidepressants. Conclusions Polypharmacy is common among the Scottish population with type 1 diabetes and is strongly patterned by sociodemographic factors. The number of prescribed drugs and the prescription of particular high-risk drug classes are strong markers of an increased risk of adverse health outcomes, including acute complications of diabetes.Publisher PDFPeer reviewe