Insights into the mechanisms and structure of breakage-fusion-bridge cycles in cervical cancer using long-read sequencing.

Cervical cancer is caused by human papillomavirus (HPV) infection, has few approved targeted therapeutics, and is the most common cause of cancer death in low-resource countries. We characterized 19 cervical and four head and neck cancer cell lines using long-read DNA and RNA sequencing and identified the HPV types, HPV integration sites, chromosomal alterations, and cancer driver mutations. Structural variation analysis revealed telomeric deletions associated with DNA inversions resulting from breakage-fusion-bridge (BFB) cycles. BFB is a common mechanism of chromosomal alterations in cancer, and our study applies long-read sequencing to this important chromosomal rearrangement type. Analysis of the inversion sites revealed staggered ends consistent with exonuclease digestion of the DNA after breakage. Some BFB events are complex, involving inter- or intra-chromosomal insertions or rearrangements. None of the BFB breakpoints had telomere sequences added to resolve the dicentric chromosomes, and only one BFB breakpoint showed chromothripsis. Five cell lines have a chromosomal region 11q BFB event, with YAP1-BIRC3-BIRC2 amplification. Indeed, YAP1 amplification is associated with a 10-year-earlier age of diagnosis of cervical cancer and is three times more common in African American women. This suggests that individuals with cervical cancer and YAP1-BIRC3-BIRC2 amplification, especially those of African ancestry, might benefit from targeted therapy. In summary, we uncovered valuable insights into the mechanisms and consequences of BFB cycles in cervical cancer using long-read sequencing.

A Geometrically Flexible Three-Dimensional Nanocarbon.

The development of architecturally unique molecular nanocarbons by bottom-up organic synthesis is essential for accessing functional organic materials awaiting technological developments in fields such as energy, electronics, and biomedicine. Herein, we describe the design and synthesis of a triptycene-based three-dimensional (3D) nanocarbon, GFN-1, with geometrical flexibility on account of its three peripheral π-panels being capable of interconverting between two curved conformations. An effective through-space electronic communication among the three π-panels of GFN-1 has been observed in its monocationic radical form, which exhibits an extensively delocalized spin density over the entire 3D π-system as revealed by electron paramagnetic resonance and UV-vis-NIR spectroscopies. The flexible 3D molecular architecture of GFN-1, along with its densely packed superstructures in the presence of fullerenes, is revealed by microcrystal electron diffraction and single-crystal X-ray diffraction, which establish the coexistence of both propeller and tweezer conformations in the solid state. GFN-1 exhibits strong binding affinities for fullerenes, leading to host-guest complexes that display rapid photoinduced electron transfer within a picosecond. The outcomes of this research could pave the way for the utilization of shape and electronically complementary nanocarbons in the construction of functional coassemblies.

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies.

PURPOSE: Recruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. METHODS: We used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala. Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala. RESULTS: We recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001). CONCLUSION: Guatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

A life in the surf zone: Age and feeding habits of the pompano (Trachinotus ovatus, Linnaeus, 1758) on the beaches of the Gulf of Cádiz (south-west Iberian Peninsula).

Surf zones are crucial habitats for many fish species, where they spend the initial stages of their lives, finding food and shelter. One such species is the pompano (Trachinotus ovatus). The aim of this study was to examine the age and diet of the pompano within the surf zone, along with any potential variations in the environment. The average size of the specimens was 10.61 ± 4.91 cm. The length-weight relationship was total weight (TW) = 0.0136*total length (TL)2.8512 (parameter a: 95% C.I.: 0.0130-0.0142 and parameter b: 95% C.I.: 2.8318-2.8705). The most abundant age classes were 0+ and 1+, making up 97% of the captured specimens, with significant differences in the abundance of age classes depending on the time of the day and season. The pompano primarily fed on clupeiforms, copepods, and mysids, with significant variations in diet based on the time of the day, season, and size of the specimens. This study contributes new information about the use of the surf zone by T. ovatus in its early years of life, underscoring the importance of these areas and their role as an additional ecosystem service.

Cytologic features of meningioma: An analysis of common and uncommon subtypes and diagnostic difficulties during intraoperative procedures.

Despite common histogenesis meningiomas have a wide morphologic spectrum, and the World Health Organization (WHO) recognizes 15 subtypes. They are the most common brain tumour in adults and typically have an extra-axial location. Although there have been important advances in the molecular biology of meningiomas its diagnosis is based on histopathologic features. The great majority are benign WHO grade 1 tumours. There are specific criteria for assigning WHO grade 2 and 3 that can be applied to all meningioma subtypes. Regardless of these criteria, chordoid and clear cell morphologic subtypes are considered grade 2. WHO grade 3 tumours exhibit a very high mitotic index, frank anaplasia or specific molecular abnormalities. The impressive morphologic diversity shown by meningiomas makes them a diagnostic challenge, which can be even greater in intraoperative studies. The focus of this article is to describe and illustrate their main cytologic features, with emphasis on the most infrequent subtypes.

Cytological features of diffuse and circumscribed gliomas.

The current World Health Organization classification of gliomas is based on morphological, genetic, and molecular parameters. In this review, we intend to present the most relevant cytological features of these tumours, with a particular focus on their analysis during intraoperative studies. Rapid diagnosis is required in this context, and at present it is not possible to evaluate the genetic or molecular profile of a tumour intraoperatively. New terminology and diagnostic parameters have been introduced, but the essence of intraoperative recognition remains the same. The main challenge in astrocytoma IDH-mutant, grade 2 is recognising the tissue as neoplastic. Since glioma grades 3 and 4 are assigned based on histological and genetic variables that are not necessarily measurable on cytology, the term high-grade glioma is often used for intraoperative diagnosis. Oligodendroglioma, IDH-mutant and 1p/19q-codeleted shows peculiar cytological findings as well as the common subtypes of glioblastoma IDH-wildtype (giant cell, epithelioid, gliosarcoma and small cell). Many of the paediatric-type-diffuse gliomas have been described very recently and there are no cytological reports of proven cases. Finally, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, and astroblastoma MN1-altered constitute the group of circumscribed astrocytic gliomas. They are remarkable entities that the pathologist must be able to recognise since most are low-grade neoplasms that can show atypical morphological features.

miR-124 as a Liquid Biopsy Prognostic Biomarker in Small Extracellular Vesicles from NSCLC Patients.

Despite advances in non-small cell lung cancer (NSCLC) research, this is still the most common cancer type that has been diagnosed up to date. microRNAs have emerged as useful clinical biomarkers in both tissue and liquid biopsy. However, there are no reliable predictive biomarkers for clinical use. We evaluated the preclinical use of seven candidate miRNAs previously identified by our group. We collected a total of 120 prospective samples from 88 NSCLC patients. miRNA levels were analyzed via qRT-PCR from tissue and blood samples. miR-124 gene target prediction was performed using RNA sequencing data from our group and interrogating data from 2952 NSCLC patients from two public databases. We found higher levels of all seven miRNAs in tissue compared to plasma samples, except for miR-124. Our findings indicate that levels of miR-124, both free-circulating and within exosomes, are increased throughout the progression of the disease, suggesting its potential as a marker of disease progression in both advanced and early stages. Our bioinformatics approach identified KPNA4 and SPOCK1 as potential miR-124 targets in NSCLC. miR-124 levels can be used to identify early-stage NSCLC patients at higher risk of relapse.

Development of a Prediction Model for Short-Term Remission of Patients with Crohn's Disease Treated with Anti-TNF Drugs.

Therapy with anti-tumor necrosis factor (TNF) has dramatically changed the natural history of Crohn's disease (CD). However, these drugs are not without adverse events, and up to 40% of patients could lose efficacy in the long term. We aimed to identify reliable markers of response to anti-TNF drugs in patients with CD. A consecutive cohort of 113 anti-TNF naive patients with CD was stratified according to clinical response as short-term remission (STR) or non-STR (NSTR) at 12 weeks of treatment. We compared the protein expression profiles of plasma samples in a subset of patients from both groups prior to anti-TNF therapy by SWATH proteomics. We identified 18 differentially expressed proteins (p ≤ 0.01, fold change ≥ 2.4) involved in the organization of the cytoskeleton and cell junction, hemostasis/platelet function, carbohydrate metabolism, and immune response as candidate biomarkers of STR. Among them, vinculin was one of the most deregulated proteins (p < 0.001), whose differential expression was confirmed by ELISA (p = 0.054). In the multivariate analysis, plasma vinculin levels along with basal CD Activity Index, corticosteroids induction, and bowel resection were factors predicting NSTR.

[Performance of severity indexes for the prediction of adverse events among patients hospitalized for SARS-CoV-2]. / Rendimiento de los índices predictores de gravedad en pacientes adultos hospitalizados por neumonía adquirida en la comunidad por coronavirus SARS-CoV-2.

BACKGROUND: Severity assessment in adult patients with community-acquired pneumonia (CAP) allows to guide the site of care (ambulatory or hospitalization), diagnostic workup and treatment. AIM: To examine the performance of twelve severity predictive indexes (CRB65, CURB65, PSI, SCAP, SMART-COP, REA-ICU, ATS minor criteria, qSOFA, CALL, COVID GRAM, 4C, STSS) in adult patients hospitalized for CAP associated with SARS-CoV-2. MATERIAL AND METHODS: Prospective clinical study conducted between April 1 and September 30, 2020 in adult patients hospitalized for CAP associated with COVID-19 in a clinical hospital. The recorded adverse events were admission to the critical care unit, use of mechanical ventilation (MV), prolonged length of stay, and hospital mortality. The predictive rules were compared based on their sensitivity, specificity, predictive values, and area under the receiver operator characteristic (ROC) curve. RESULTS: Adverse events were more common and hospital stay longer in the high-risk categories of the different prognostic indices. CURB-65, PSI, SCAP, COVID GRAM, 4 C and STSS predicted the risk of death accurately. PSI, SCAP, ATS minor criteria, CALL and 4 C criteria were sensitive in predicting the risk of hospital mortality with high negative predictive value. The performance of different prognostic indices decreased significantly for the prediction of ICU admission, use of mechanical ventilation, and prolonged hospital length of stay. CONCLUSIONS: The performance of the prognostic indices differs significantly for the prediction of adverse events in immunocompetent adult patients hospitalized for community-acquired pneumonia associated with COVID-19.

Apremilast and biologics: Characteristics of patients treated with apremilast before, during, or after a biological treatment.

Apremilast is an oral small molecule approved for the treatment of psoriasis, psoriatic arthritis and oral ulcers associated with Behçet's disease. This research was conducted to describe the characteristics of patients who received treatment with apremilast for a skin disorder, either before, during, or after a biological treatment, with the aim of analyze the reasons that lead to start this drug in real clinical practice or suspend it for another. A total of 41 patients were enrolled: nine (22.0%) had received biological treatment prior to apremilast, seven (17.0%) both before and after apremilast and 25 (61.0%) after apremilast. One patient received concomitant treatment with adalimumab and apremilast. Most patients (85.4%) received apremilast as treatment for psoriasis. Reasons for starting apremilast were lack of efficacy with previous treatments (85.4%) and adverse effects or contraindication to previous treatments (14.6%), without statistically significant differences between patients who had received a previous biologic and those who had not. Drug survival was not influenced by previous biological treatment, but we found an increased risk of drug discontinuation in patients with chronic kidney disease (log-rank p = 0.028). The main reason of apremilast withdrawal was lack of adequate disease control (60.0%), most of whom required treatment with biologics. Therefore, despite the extensive development of new therapies for psoriasis and other dermatological conditions, apremilast is a widely used drug even in patients who are candidates for biologic treatment. Its initiation is more frequent due to poor disease control than because of other therapies contraindications.

The CCN2 Polymorphism rs12526196 Is a Risk Factor for Ascending Thoracic Aortic Aneurysm.

Cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-ß and angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and acute and lethal aortic aneurysm development induced by angiotensin II in the absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of a thoracic aortic aneurysm (TAA). Patients with and without TAA retrospectively selected were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to the CCN2 gene. Multivariable logistic regression models were performed. In our population of 366 patients (69 with TAA), no associations were found between rs6918698 and rs9402373 and TAA. However, the presence of one C allele from rs12526196 was associated with TAA comparing with the TT genotype, independently of risk factors such as sex, age, hypertension, type of valvulopathy and the presence of a bicuspid aortic valve (OR = 3.17; 95% CI = 1.30-7.88; p = 0.011). In conclusion, we demonstrated an association between the C allele of rs12526196 in the CCN2 gene and the presence of TAA. This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulates, for the first time, a potential protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants in the CCN2 gene that could be predisposed to TAA development.

Longitudinal Analysis of Urinary Cytokines and Biomarkers in COVID-19 Patients with Subclinical Acute Kidney Injury.

In hospitalized COVID-19 patients, disease progression leading to acute kidney injury (AKI) may be driven by immune dysregulation. We explored the role of urinary cytokines and their relationship with kidney stress biomarkers in COVID-19 patients before and after the development of AKI. Of 51 patients, 54.9% developed AKI. The principal component analysis indicated that in subclinical AKI, epidermal growth factor (EGF) and interferon (IFN)-α were associated with a lower risk of AKI, while interleukin-12 (IL-12) and macrophage inflammatory protein (MIP)-1ß were associated with a higher risk of AKI. After the manifestation of AKI, EGF and IFN-α remained associated with a lower risk of AKI, while IL-1 receptor (IL-1R), granulocyte-colony stimulating factor (G-CSF), interferon-gamma-inducible protein 10 (IP-10) and IL-5 were associated with a higher risk of AKI. EGF had an inverse correlation with kidney stress biomarkers. Subclinical AKI was characterized by a significant up-regulation of kidney stress biomarkers and proinflammatory cytokines. The lack of EGF regenerative effects and IFN-α antiviral activity seemed crucial for renal disease progression. AKI involved a proinflammatory urinary cytokine storm.

[Acute myeloid leukemia. Analysis of 114 patients]. / Actualización de resultados demográficos y terapéuticos de pacientes con Leucemia Mieloide Aguda no promielocítica en el Hospital Clínico de la Pontificia Universidad Católica de Chile.

BACKGROUND: Acute myeloid leukemia (AML) is the most common leukemia in adults. AIM: To Describe our population of patients with AML and report the outcomes of our treatments. MATERIAL AND METHODS: Review of electronic clinical records of 114 patients with AML with a median age of 57 years (59% men). RESULTS: Seventeen percent of patients were classified as low risk, 38% as intermediate risk and 33% as high risk. Seventy-six percent of patients were treated with intensive chemotherapy. Five years overall survival according to cytogenetic risk was 59, 41, and 12% in low, intermediate, and high-risk patients, respectively. The outcomes were better in patients under 60 years. The median survival of patients treated with intensive chemotherapy aged less than 60 years and 60 years and above was 3.4 and 1 year, respectively. CONCLUSIONS: Our results are comparable to those reported in developed countries. Improving the survival of patients 60 years and older is our main challenge.

Novel SLC12A2-ROS1 Fusion in Non-Small Cell Lung Cancer with a Significant Response to Crizotinib: The Importance of Choosing the Appropriate Next-Generation Sequencing Assay.

Identifying the druggable target is crucial for patients with nonsquamous advanced non-small cell lung cancer (NSCLC). This article adds to the spectrum of ROS1 fusion cases described in NSCLC. We describe a novel SLC12A2-ROS1 rearrangement that has not been previously reported in other cancers: a fusion that has clinical and radiological sensitivity to crizotinib. Fluorescence in situ hybridization detected the SLC12A2-ROS1 fusion and it was confirmed through hybrid capture-based next-generation sequencing (NGS); however, the fusion could not be detected by amplicon-based assay. The success of implementing NGS into routine clinical practice depends on the accuracy of testing. The test's methodological features should then be considered because they significantly affect the results. Given this patient's response to crizotinib, identifying patients with undescribed ROS1 fusions has important therapeutic implications. KEY POINTS: This is the first known description of an SLC12A2-ROS1 fusion. Considering the patient's clinical features and tumor response observed after crizotinib therapy, the authors confirm that this new rearrangement has relevant clinical impact for patients with non-small cell lung cancer. The success of implementing next-generation sequencing (NGS) into routine clinical practice depends on the accuracy of the testing. Different assays and NGS platforms can achieve differing results. Each assay's limitations need to be considered to ensure the quality of precision medicine in clinical practice.

Roll-to-roll nanoimprint lithography of high efficiency Fresnel lenses for micro-concentrator photovoltaics.

Roll-to-roll nanoimprint lithography (R2R-NIL) is an enabling technology for the low-cost mass production of high-quality micro- and nano-sized optical elements. Particularly, the fabrication of Fresnel lenses using R2R-NIL is a promising approach to produce optical arrays for micro-concentrator photovoltaic modules. This work investigates the application of a continuous R2R imprinting process based on ultraviolet curing of transparent photopolymer resins (UV-NIL) to fabricate high-efficiency and low-cost Fresnel lenses. The morphological attributes and the related optical performance of the lenses fabricated using roll-to-roll UV-NIL on flexible PET sheets yielded optical efficiency values up to ∼ 69% at a concentration ratio of 178X, whereas a value of ∼ 77% was obtained for the UV-NIL batch processed on a flat rigid substrate. Further improvement of the optical efficiency has been achieved by adding moth-eye inspired antireflective (AR) features on the side opposite to the Fresnel motifs via a double-sided R2R UV-NIL process. The process developed paves the way for cost-effective mass production of high-efficiency Fresnel lenses for micro-concentrator photovoltaics.

CYP24A1 and KL polymorphisms are associated with the extent of vascular calcification but do not improve prediction of cardiovascular events.

BACKGROUND: Novel ways of determining cardiovascular risk are needed as a consequence of population ageing and the increased prevalence of chronic kidney disease (CKD), both of which favour vascular calcification. Since the formation of arterial calcium deposits has a genetic component, single nucleotide polymorphisms (SNPs) could predict cardiovascular events. METHODS: A selection of 1927 CKD patients and controls recruited by the NEFRONA study were genotyped for 60 SNPs from 22 candidate genes. A calcium score was calculated from the echogenicity of arterial atherosclerotic plaques and the presence of cardiovascular events during a 4-year period was recorded. Association of SNPs with the calcium score was identified by multiple linear regression models and their capacity to predict events was assessed by means of Cox proportional hazards regression and receiver operating characteristics curves. RESULTS: Two variants, rs2296241 of CYP24A1 and rs495392 of KL, were associated with the calcium score. Despite this, only heterozygotes for rs495392 had a lower risk of suffering an event compared with homozygotes for the major allele {hazard ratio (HR) 0.67 [95% confidence interval (CI) 0.48-0.93]}. Of note, the calcium score was associated with an increased risk of cardiovascular events [HR 1.71 (95% CI 1.35-2.17)]. The addition of the rs495392 genotype to classical cardiovascular risk factors did not increase the predictive power [area under the curve (AUC) 71.3 (95% CI 61.1-85.5) versus 71.4 (61.5-81.4)]. CONCLUSIONS: Polymorphisms of CYP24A1 and KL are associated with the extent of calcification but do not predict cardiovascular events. However, the echogenic determination of the extent of calcium deposits seems a promising non-irradiating method for the scoring of calcification in high-risk populations.

Serial DaT-SPECT imaging in asymptomatic carriers of LRRK2 G2019S mutation: 8 years' follow-up.

BACKGROUND: Carriers of the G2019S mutation of LRRK2 provide a great opportunity to investigate the premotor stages of Parkinson's disease (PD). We have studied by serial clinical and dopamine transporter single photon emission computed tomography (DaT-SPECT) evaluations a cohort of asymptomatic carriers of the LRRK2-G2019S mutation in order to evaluate the usefulness of these tools as biomarkers. Here we report the results of the extended follow-up of this cohort at 8 years. METHODS: Seventeen participants, of the 25 available from the 4-year evaluation, completed the 8-year assessment. UPDRS-III, UPSIT test and DaT-SPECT imaging (123 I-ioflupane) were performed. We used repeated-measures linear mixed effects models to examine the changes in DaT binding over time. RESULTS: Three carriers had converted to PD at 4 years. One additional carrier converted at 8 years. PD-converters had lower striatal DaT binding at baseline than non-converters. There was a significant decline of DaT binding over time, with a mean annual rate of 3.5%, with somewhat inter-individual and intra-individual variability and comparable between PD-converters and non-converters. No carrier with DAT binding ratio above an undefined threshold between 0.5 and 0.8 developed PD symptoms. The age-adjusted UPSIT score did not change significantly over time. CONCLUSIONS: The rate of conversion to PD at 8 years in this cohort aged ~58 years at baseline was 16%. The observed decline of DaT binding over time and its association with the phenotype render DaT-SPECT a potentially useful tool for monitoring the premotor stage of the disease, although at the individual level its ability to predict phenoconversion is limited.

Evidence for uncoupling of clinical and 18-FDG activity of PET/CT scan improvement in tocilizumab-treated patients with large-vessel giant cell arteritis.

OBJECTIVES: Clinical improvement following tocilizumab (TCZ) therapy in patients with large-vessel (LVV) giant cell arteritis (GCA) is well established. However, information on TCZ effect on imaging vascular activity is limited. We aimed to determine if clinical improvement correlated with reduction of vascular 18F-fluorodeoxyglucose (18F-FDG) uptake in positron emission tomography (PET/CT) scans. METHODS: Observational study of patients with refractory LVV-GCA treated with TCZ who had a baseline and a follow-up 18F-FDG-PET/CT scan. For the visual analysis of 18F-FDG vascular uptake, a total vascular score (TVS) was defined, ranging from 0 to 15. Besides, a semiquantitative analysis was performed as a target to background ratio (TBR)= SUVmax thoracic aorta wall/SUVmax aortic vascular pool. The baseline and follow-up TVS and TBR were compared. Clinical and lab¬oratory outcomes were also assessed. RESULTS: We included 30 patients (24 women/6 men); mean age± standard deviation 65.7± 9.8 years. Baseline PET/CT scans were performed due to active disease at a median [interquartile range-IQR] of 1.5 [0.0-4.0] months before TCZ onset. Following TCZ therapy, 25 (83.33%) patients achieved clinical remission and reduction of 18F-FDG vascular uptake was also observed after a mean ± standard deviation of 10.8±3.7 months. TBR decreased from 1.70 ± 0.52 to 1.48 ± 0.25 (p=0.005) and TVS from 4.97±2.62 to 3.13±1.89 (p< 0.001). However, only 9 (30.0%) patients showed complete normalisation of TBR and only 3 (10%) normalisation of TVS. TBR and TVS showed a good correlation (r=0.576). CONCLUSIONS: Although most of LVV-GCA patients achieve clinical remission after TCZ therapy, less than one-third show normalisation of 18F-FDG vascular uptake.

Improved thermal stability of antireflective moth-eye topography imprinted on PMMA/TiO2surface nanocomposites.

The thermal stability of antireflective moth-eye topographical features fabricated by nanoimprint lithography on poly (methyl methacrylate) (PMMA) incorporating TiO2nanoparticles is explored. The effect of nanoparticle load on the relaxation dynamics of the moth-eye nanostructure is evaluated via grazing incidence small angle x-ray scattering measurements byin situmonitoring the structural decay of the nanopatterns upon thermal annealing. It is demonstrated that the incorporation of TiO2nanoparticles to the imprinted surface nanocomposite films delays greatly the pattern relaxation which, in turn, enhances the stability of the patterned topography even at temperatures well above the polymer glass transition (Tg). The improved thermal behavior of the antireflective films will significantly enhance their functionality and performance in light-trapping applications where temperatures typically rise, such as solar devices or solar glass panels.