dataesr/scientific-paragraphs-categorization huggingface dataset:
Results Overall, 66 subjects with early AMD, 17 with intermediate AMD, and 50 healthy subjects were included. All subjects were aged between 55 and 87 years. Patient demographic data and STARS questionnaire score results are summarized in Table  1. The mean age tended to increase in patients with intermediate AMD compared with patients with early AMD. Acuity was decreased in both early and intermediate patients with AMD compared with controls. There was also a significant difference between the two groups of patients. A substantial proportion of patients with early AMD and patients with intermediate AMD had systemic hypertension, although few had NIDD and a smoking history. As expected, the STARS score tended to increase in patients with intermediate AMD compared with patients with early AMD.
Acknowledgments The authors thank the writing assistance of  Karl Patrick Göritz , SMWS Scientific and Medical Writing Services, France. Disclosure:  A. M. Minnella ,  Allergan ,  Bayer ,  Novartis ,  Thea Laboratoires ;  M. Piccardi , None;  G. Placidi , None;  A. García-Layana ,  Allergan ,  Bayer ,  Novartis ,  Roche ,  Thea Laboratoires ;  C. Delcourt ,  Allergan, Bausch+Lomb, Thea Laboratoires, Novartis ;  P. Valentini , None;  B. Falsini , None.
This can be improved to > 98% absorbance at 532 nm with an optimized value of 260 nm for the GaInP NW diameter. Simulation data regarding the FoM for GaInP NW array structures embedded in PDMS for other incident wavelengths relevant to this work (405 and 532 nm) are included in the Supplementary Information, Fig. S2. Due to the better incoupling of light (nearly zero surface reflectance) at the specific wavelengths, the overall absorption is higher in the GaInP NW arrays embedded in PDMS compared to a planar (unstructured) slab with a surface PDMS AR layer (80 nm thick). At 450 nm, with an optimized 80 nm PDMS AR layer, surface reflectance of ~ 9% and ~ 0. 05% are obtained for the GaInP slab and optimized NW array in PDMS, respectively. Additional advantages are that the NW array structures show a broader angular acceptance of the incident light and have a higher light extraction compared to an unstructured slab.
The calculated absorbance for the GaInP NW arrays in PDMS with tapered NW shapes similar to those fabricated in this work, indicates high absorbance > 96% can be obtained at 450 and 532 nm incident light wavelength. The average diameter (AvD) for the tapered NWs, defined as the arithmetic average of the top and bottom diameters, is in the range 230 to 290 nm. For these calculations, the PDMS AR layer was taken as 100 nm and is close to what is obtained in the fabricated samples. The simulated absorbance data for the tapered GaInP NW arrays in PDMS showing the influence of the NW shape are detailed in the Supplementary Information, Fig. S3. These results show that the overall absorbance is affected by the tapered shape. More importantly, for the average diameter range (230-300 nm) typically obtained in the fabricated tapered NWs the calculated absorbance (FoM) is comparable to the ideal case of cylindrical NW arrays (see Fig.
Representative SEM images are shown in the Supplementary Information, Fig. S4. The reflectance (R) and transmittance (T) of the fabricated GaInP structures were measured by spectrophotometry in the wavelength range of 300-650 nm. The absorbance (A) was obtained as 100% -(R(%) + T(%)). The measured data together with the corresponding FDTD simulation data results are shown in Fig. 4. Figure  4a  shows the simulated optical response for an infinite 1 µm-thick film (slab) embedded in PDMS. The simulation data shows that an absorbance of ~ 80% can be obtained for the embedded GaInP slab at source wavelengths of 450 and 532 nm; the absorbance is mainly limited by surface reflection which is ~ 20% at these wavelengths. The simulated result for the slab can be taken as a reference to compare the structured (MS or tapered NW array) converter layers.
Room-temperature time-resolved photoluminescence (TRPL) measurements of the fabricated GaInP structures (as-processed) showed best lifetimes for the GaInP MD and lowest for the tapered NW array  70. Representative TRPL data for the relevant structures are included in the Supplementary Information, Fig. S9. The PL decay times can be determined by fitting the TRPL data with a double exponential decay. The dominant PL decay times are ~ 3 ns, ~ 2. 5 ns, and ~ 0. 5 ns for the MDs, MS arrays, and NW arrays, respectively. For the NW arrays surface recombination dominates, as expected from their geometric dimensions. Reported values for the radiative lifetimes in GaInP with similar composition are in the range ~ 10 to 40 ns  71, 72. Following Schubert  30  , the IQE is given by the ratio of probabilities of radiative (1/τ R ) and total recombination (1/τ = 1/(1/τ R + 1/τ NR )), where τ R and τ NR are the radiative and non-radiative recombination lifetimes.
Background Hypoglycaemia is the most frequent complication of treatment with insulin or insulin secretagogues in people with diabetes. Severe hypoglycaemia, i. e. an event requiring external help because of cognitive dysfunction, is associated with a higher risk of adverse cardiovascular outcomes and all-cause mortality, but underlying mechanism(s) are poorly understood. There is also a gap in the understanding of the clinical, psychological and health economic impact of 'non-severe' hypoglycaemia and the glucose level below which hypoglycaemia causes harm. Aim To increase understanding of hypoglycaemia by addressing the above issues over a 4-year period. Methods Hypo-RESOLVE is structured across eight work packages, each with a distinct focus. We will construct a large, sustainable database including hypoglycaemia data from >100 clinical trials to examine predictors of hypoglycaemia and establish glucose threshold(s) below which hypoglycaemia constitutes a risk for adverse biomedical and psychological outcomes, and increases healthcare costs.
Hypo-RESOLVE database: WP3 and WP4 It is standard practice for hypoglycaemic events to be secondary or safety outcomes in clinical trials involving insulin treatment. A key objective of Hypo-RESOLVE is to collect these events alongside a range of clinical outcomes from over 100 clinical trials on insulin treatment and/or glucose monitoring in people with type 1 or type 2 diabetes, to construct a large, sustainable database, offering the statistical power needed to establish the glucose threshold (s) below which hypoglycaemia constitutes a risk. Entry criteria for these trials are: randomized trials initiated in 2001 or later; participants with type 1 or type 2 diabetes; insulin treatment alone or in combination with other drugs; and trial duration of at least 12 weeks. After a process of deidentification to ensure participant anonymity, original data from each trial will be extracted, reformatted and harmonized to the standard Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model (SDTM) format (http://www.
cdisc. org/; Fig. 2 ). De-identified trial data will be uploaded to a secure server behind a firewall, inaccessible for downloads or changes, and subsequently harmonized and pooled into a single database, reachable for a variety of statistical analysis tools, implemented in the R statistical framework. After agreeing on categorization of hypoglycaemia, e. g. defined by presence (or absence) of symptoms, help from another person, certain glucose thresholds and duration, the associations with (un)known clinical and psychological consequences will be examined. A statistical analysis plan is being constructed and tested to perform analyses on the risk factors for, and consequences of, hypoglycaemia. Using data from the Scottish Diabetes Research Network Type 1 Bioresource  [27] , a Bayesian posterior distribution method was found to be a better fit to model the risk factors for the prediction of hypoglycaemia than the standard approach of negative binomial regression (manuscript in preparation).
Mechanistic studies: WP2 The focus of basic research will be first on further elucidation of the pathogenesis of impaired awareness of hypoglycaemia. Animal studies with state-of-the-art transgenic approaches will also be used to discover novel pathways that contribute to the development of impaired awareness of hypoglycaemia as well as to identify therapeutic targets that may help to restore hypoglycaemia awareness. A second crucial element of the project is to reveal the potential mechanism(s) underlying the association between (severe) hypoglycaemia and cardiovascular outcomes, which would complement analyses of the above-mentioned Hypo-RESOLVE clinical database. Recent research has shown hypoglycaemia to be a pro-inflammatory, potentially proatherogenic, stimulus  [28] , with the resulting response potentially modifiable by prior exposure to hypoglycaemia or the level of overall glucose control.
One group of volunteers without diabetes (n=16), matched to those with type 2 diabetes, will undergo the same procedure. Another group (n=32), matched to participants with type 1 diabetes, will be randomized to prior exposure to either two episodes of hypoglycaemia or normoglycaemia on the day before the clamp procedure. Sample sizes are based on a power calculation to meet the primary outcome for each subgroup separately, with comparisons between groups to be conducted in subsequent analyses. The broad inclusion criteria of this study, registered at clinicaltrials. gov (NCT03976271), will enable us to assess the impact of awareness of hypoglycaemia, HbA 1c , prior hypoglycaemia and duration of diabetes. Moreover, complimentary rodent studies will determine whether the effects in immune cells are replicated in specific organs (e.
Glucose sensor data collected and harmonized in the constructed database (WP3) will enable analysis of the optimum duration of glucose sensor use and the relative contribution of sampling interval to determine an individual's risk of hypoglycaemia. We will use in silico modelling techniques to glucose sensor data to identify behavioural factors, including self-monitoring of blood glucose, carbohydrate counting and missed insulin administration, that modify the risk of hypoglycaemia. Recent data show that, even in those with intact awareness of hypoglycaemia, up to 60% of episodes are asymptomatic and undetected by the individual  [29]. This causes a clinical dilemma as to whether such events need to be treated or ignored, and raises issues about how people deal, psychologically, with visibility of the potentially overwhelming amount of (semi-)continuous data.
A sample size calculation based on the number of expected episodes of patient-reported hypoglycaemia and sensor-detected hypoglycaemia taken from a series of large observational datasets, calculated that 180 adults with type 1 and 325 with type 2 diabetes are required to meet our primary objective. Allowing for withdrawals and to be able to evaluate outcomes in those with impaired awareness, we aim to recruit 250 participants with type 1 diabetes, 50 of whom have impaired awareness, and 350 with type 2 diabetes (n=600 in total). We will investigate differences in the impact of hypoglycaemia between type 1 and type 2 diabetes, and the impact of other aspects such as sleep and baseline hypoglycaemia rate on these factors. Psychological burden and health-economic impact: WP6 and.
Integration of the results of Hypo-RESOLVE: WP8 The findings from Hypo-RESOLVE will be collated into a comprehensive summary for high-level communication with stakeholders and development of a consensus guideline with uniformly agreed definitions and data collection methods for the standardization of clinical investigations with regard to hypoglycaemia. A dialogue has thus been established with key European and American regulators, Health Technology Assessment (HTA) body representatives, professional and diabetes organizations and other stakeholders.
Hypo-RESOLVE limitations Although comprehensive, Hypo-RESOLVE will not provide answers to all questions relating to hypoglycaemia in people with diabetes. In particular, the Hypo-RESOLVE database may be (too) limited for directly examining harm of sensor-detected hypoglycaemia and investigating hypoglycaemia in certain populations. Children, the elderly, pregnant women, ethnic subgroups and people at highest risk of (severe) hypoglycaemia, including those with impaired awareness of hypoglycaemia, chronic kidney disease or other chronic comorbidities are usually excluded from most clinical trials. However, the harm of sensor-detected hypoglycaemia may be derived indirectly from the observational clinical study on continuous glucose monitoring. Also, examining the impact of hypoglycaemia on children, and in particular their carers, is a specific objective of the 'psychology' WP, whereas elderly populations will be included in the health-economic work.
Expected impact of Hypo-RESOLVE for stakeholders Further delineation of mechanisms underlying the link between hypoglycaemia and cardiovascular risks Setting the standard for glucose levels to be used in experimental hypoglycaemia research (e. g. clamps) Invitation to scientists to use the constructed Hypo-RESOLVE database to answer new research questions Industry Enabling better comparisons of glucose-lowering interventions and strategies across trials and benchmarking industry's products against those of competitors Harmonization of hypoglycaemia measures by SMBG or CGM will inform the industry how to best apply CGM in future clinical trials Discovering new targets for intervention will open avenues for the development of novel hypoglycaemic risk reducing pharmaceutical agents and technological solutions Helping to better define populations most in need of hypoglycaemia risk reducing interventions in clinical trials CGM, continuous glucose monitoring; SMBG, self-monitoring of blood glucose.
Funding sourcesHypo-RESOLVE has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 777460. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA and T1D Exchange, JDRF, International Diabetes Federation (IDF) and The Leona M. and Harry B. Helmsley Charitable Trust. The industry partners supporting the JU include Abbott Diabetes Care, Eli Lilly, Medtronic, Novo Nordisk and Sanofi-Aventis. The funder had no role in the design of the project or its WPs, the collection or analysis of data, the writing of the manuscript or the decision to submit for publication.
Methods: We aimed to get insight into the penetrance of CF for fifteen CFTR variants: 5 frequent CFcausing and 10 classified as of varying clinical consequence (VCC) or associated with a CFTR-related disorder (CFTR-RD) in CFTR2 or CFTR -France databases. The penetrance was approached by: (1) comparison of variant allelic frequencies in CF patients (CFTR2) and in the general population; (2) estimation of the likelihood of a positive NBS test for the 14 compound heterozygous with F508del and the F508del homozygous genotypes, defined as the ratio of detected/expected number of neonates with a given genotype in the 2002-2017 period. Results: A full penetrance was observed for severe CF-causing variants. Five variants were more frequently found in the general population than in CF patients: TG11T5, TG12T5, TG13T5, L997F and R117H;T7.
It is thus a challenge to accurately assess the disease liability of variants, both for diagnosis and genetic counselling purposes. This requires to take into account available clinical information in databases and the literature, electrophysiological test results, functional analysis at the mRNA and protein level, and population genetics  [6, 7]. Databases may provide discordant information one should be aware of, notably because of https://doi. org/10. 1016/j. jcf. 2020. 03. 019 1569-1993/© 2020 European Cystic Fibrosis Society. Published by Elsevier B. V. All rights reserved. different designs, so that the message given to the parents of a neonate may differ when referring to them. CFTR2 collects data from North American and European CF registries  [8]  , i. e. only from patients diagnosed with CF.
7%  [12]. For the present study, we selected a set of 15 CFTR variants, comprising frequent CF-causing variants included in the French NBS panel as controls and variants frequently detected in inconclusive cases of NBS in France after extended CFTR gene analysis and which may have been differently classified by CFTR2 and CFTR -France databases ( Table  1  ). They include (i) variants classified as "CFTR-RD-causing" in CFTR -France, which are observed in patients with a CFTR-RD when combined in trans with a CF-causing variant, and (ii) variants of varying clinical consequences (VCC), which are reported as well in CF patients as in patients with a CFTR-RD, when in trans with a CF-causing variant. In CFTR2, as the CFTR-RD class is not stated, VCC refers to variants observed in patients with CF and in patients who do not have CF.
Variants were described according to Human Genome Variation Society recommendations and to traditional names in Table  1. Traditional names were used in the text for better readability. Their allelic frequency (p) in the general population was mostly taken from gnomAD in the European non-Finnish population  [11]. GnomAD v2. 1. 1 collects exome and genome data from 125,748 and 15,708 unrelated individuals, respectively, who were enrolled in various disease-specific and population genetic studies. Allelic frequencies of the most frequent variants were taken in the French population: in a sample of 10,490 alleles for F508del and R117H  [10]  and in a sample of 4380 alleles for the TG11T5, TG12T5 and TG13T5 variants. As an approach to assess the penetrance of CF, in a first step, allelic frequencies in the general population were compared with those observed in CF patients, taken from CFTR2.
Indeed, the number of neonates carrying R117H and detected at birth dramatically decreased since the removal of the variant in January 2015  [13]. Statistical analysis was carried out using the R statistical software (version 3. 2. 3). All tests were performed two-tailed at a level of significance of 5%. For each genotype, the likelihood of a positive NBS was estimated as described above and its 95% confidence interval (CI) was determined. The exact binomial test was used to compare the observed genotype frequency (i. e. the number of neonates carrying this genotype divided by the total number of neonates born in the period) with the expected frequency (estimated from database frequencies and assuming Hardy-Weinberg equilibrium).
Results Of the 15 variants, five were classified as CF-causing and two as VCC in both databases (CFTR2 and CFTR -France). Discrepancies were observed for the other eight: CF in CFTR2 and VCC in CFTR -France ( n = 3); CF in CFTR2 and CFTR-RD in CFTR -France ( n = 1); VCC in CFTR2 and CFTR-RD in CFTR -France ( n = 3); and non-CF in CFTR2 and CFTR-RD in CFTR -France ( n = 1) ( Table  1  ). The five CF-causing variants (R334W, F508del, G542X, R553X and N1303K) were found 65-88 times more frequently in CF patients than in the general population. Five VCC or CFTR-RD variants according to CFTR -France (R117C, T338I, L206W, D1152H and D110H) were found 3 to 13 times more frequently in CF patients than in the general population. The last five variants had an allelic frequency in the general population higher than in CF patients: all three T5 variants (TG11T5, TG12T5 and TG13T5), L997F and R117H.
Discussion Referral to clinical databases is most often the first step in the process for assessing the disease liability of variants identified in patients and asymptomatic individuals. Importantly, observations in CF patients only, i. e. CFTR2, represent the 'tip of the iceberg' of all possible phenotypes associated with a given genotype and CFTR -France may report a more substantial part of them. Other criteria should be taken into account, such as population, computational, functional and segregation data, according to international guidelines  [15, 16]. We used population data to assess the penetrance associated with a panel of CFTR genotypes that have been identified in infants with a positive NBS result and an inconclusive diagnosis, and compared the results with those obtained for known CF-causing genotypes.
It is important to note that the frequency of some variants found in gnomAD may not be used for accurate calculation, especially when differing from that of the local population. As a reference, the allelic frequency of variants assessed as CFcausing in the two databases was 65-88 times higher in the population of CF patients than in the general population. As expected, the likelihood of a positive NBS test evaluated for CF-causing variants G542X, R553X and N1303K in trans of F508del was around 100%. The figure of 71. 3% for the F508del homozygous genotype would be brought to 95. 6% if considering TOPs following prenatal diagnoses, as documented above. The reduced likelihood of a positive NBS test of 57. 6% associated with the CF-causing R334W variant could be explained by a residual function of the mutant protein  [8, 17]  , which is consistent with a mild form of CF as compared with other CF-causing genotypes.
An intermediate penetrance was observed for R117C, D110H and L206W, which have been reported as CF-causing in CFTR2 while VCC in CFTR -France, and for D1152H, reported as VCC in both databases. D110H, L206W and D1152H were found around 10 times more frequently in CF alleles (CFTR2) than in the general population and the likelihood of a positive NBS test in neonates carrying these variants in trans of F508del was around 50% for D110H and L206W, and 12% for D1152H. This disparity for D1152H is likely due to normal or intermediate sweat chloride values associated with this variant  [20]. The penetrance associated with R117C was even lower, being found only 3 times more frequently in CF patients than in the general population, with the likelihood of a positive NBS test being 5. 1%. Although these data do not question the required follow-up of neonates detected with an inconclusive diagnosis, they could be considered to adapt infants care and frequency of medical visits, and eventually to shorten duration of follow-up  [21, 22].
In conclusion, taking into account the frequencies of variants in the general population is critical to assess the disease liability of variants, especially in asymptomatic conditions and this emphasizes the utility of population genetic databases such as gnomAD. Our study shows that a number of variants identified in inconclusive cases of NBS for CF in asymptomatic infants are associated with a low or very low likelihood of a positive NBS test. These data stress the importance to document the penetrance of variants included in NBS panels and argue against the implementation of CFTR gene extended sequencing as a second-tier test after immuno-reactive trypsinogen measurement. Indeed, this would lead to a huge increase of inconclusive cases who would not develop CF during their lifetime, carrying variants of VCC or of unknown significance.
Acknowledgments R. C. is funded through a  Humboldt Research Fellowship  from the  Alexander von Humboldt Foundation. S. B. is supported by the  Swiss National Science Foundation  (grants  31003A_179491  and  31BD30_184114 ) and the  Belmont Forum-BiodivERsA International  joint call project  InvasiBES  ( PCI2018-092939 ). F. C. , F. E. , G. L. , and B. L. are funded by the  BiodivERsA AlienScenario project. F. C. and C. D. are also funded by the  AXA Research Fund Chair for Invasion Biology. A. P. is supported by  CONI-CYT PIA AFB-170008. P. P. is supported by  EXPRO  grant  19-28807X  ( Czech Science Foundation ) and long-term research development project  RVO 67985939  ( Czech Academy of Sciences ). D. R. acknowledges funding from the  Oppenheimer Memorial Trust  (grant  18576/03 ). J. R.