A new nonlocal nonlinear diffusion equation for image denoising and data analysis

In this paper we introduce and study a new feature-preserving nonlinear anisotropic diffusion for denoising signals. The proposed partial differential equation is based on a novel diffusivity coefficient that uses a nonlocal automatically detected parameter related to the local bounded variation and the local oscillating pattern of the noisy input signal. We provide a mathematical analysis of the existence of the solution of our nonlinear and nonlocal diffusion equation in the two dimensional case (images processing). Finally, we propose a numerical scheme with some numerical experiments which demonstrate the effectiveness of the new method

The still under-investigated role of cognitive deficits in PML diagnosis

Background: Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods: Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result: After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion: Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment

Cabinet clock distribution network for low-frequency aperture array

Square Kilometer Array (SKA)-Low is the radio telescope operating in the lowest frequency band of the SKA, from 50 up to 350 MHz. It consists of 512 stations, each composed of 256 dual-polarization log-periodic antennas for a total of 262,144 independent signal paths. The low-frequency aperture array (LFAA) is the portion of the SKA-Low telescope including the antennas and the related electronics. Signal processing is hosted in a temperature controlled and shielded facility: the central processing facility (CPF), for all the core stations, or remote processing facilities (RPF), for stations in the array arms, to limit the maximum fiber length. Such a geographically distributed and interconnected radio telescope, spanning ∼65  km in diameter, requires that frequency and timing reference signals are distributed to the processing facilities with high stability and precision to ensure the required system performances. We present the realization of the clock and pulse per second distribution network inside the LFAA signal processing cabinet where subracks containing signal acquisition boards are housed. We describe the different parts of the chain, and we report on the total jitter introduced by this structure

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Discovery of sustainable drugs for Alzheimers disease: cardanol-derived cholinesterase inhibitors with antioxidant and anti-amyloid properties.

As part of our efforts to develop sustainable drugs for Alzheimers disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liquid (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compounds with concomitant anti-amyloid and antioxidant activities. Ten new derivatives, carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). 5 and 11 were found to inhibit human BChE at a single-digit micromolar concentration. Transmission electron microscopy revealed the potential of five derivatives to modulate Aβ aggregation, including 5 and 11. In HORAC assays, 5 and 11 performed similarly to standard antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in in vitro studies in neuronal cell cultures, 5 and 11 were found to effectively inhibit reactive oxygen species production at a 10 μM concentration. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD

Application of ChatGPT as a content generation tool in continuing medical education: acne as a test topic

The large language model (LLM) ChatGPT can answer open-ended and complex questions, but its accuracy in providing reliable medical information requires a careful assessment. As part of the AICHECK (Artificial Intelligence for CME Health E-learning Contents and Knowledge) Study, aimed at evaluating the potential of ChatGPT in continuous medical education (CME), we compared ChatGPT-generated educational contents to the recommendations of the National Institute for Health and Care Excellence (NICE) guidelines on acne vulgaris. ChatGPT version 4 was exposed to a 23-item questionnaire developed by an experienced dermatologist. A panel of five dermatologists rated the answers positively in terms of “quality” (87.8%), “readability” (94.8%), “accuracy” (75.7%), “thoroughness” (85.2%), and “consistency” with guidelines (76.8%). The references provided by ChatGPT obtained positive ratings for “pertinence” (94.6%), “relevance” (91.2%), and “update” (62.3%). The internal reproducibility was adequate both for answers (93.5%) and references (67.4%). Answers related to issues of uncertainty and/or controversy in the scientific community scored the lowest. This study underscores the need to develop rigorous evaluation criteria for AI-generated medical content and for expert oversight to ensure accuracy and guideline adherence

Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-associated Pulmonary Abnormalities

RATIONALE: Congenital diaphragmatic hernia (CDH) results in lung hypoplasia. In severe cases, tracheal occlusion (TO) can be offered to promote lung growth. However the benefit is limited, and novel treatments are required to supplement TO. Vascular endothelial growth factor (VEGF) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known. OBJECTIVES: To investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology. METHODS: Fetal lungs from CDH patients were used to determine pulmonary morphology and VEGF expression. A novel human ex vivo model of fetal lung compression recapitulating CDH features was developed and used to determine the effect of exogenous VEGF supplementation. A nanoparticle-based approach for intra-pulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds (ND-VEGF) and was tested in experimental CDH in vivo. MEASUREMENTS AND MAIN RESULTS: VEGF expression was downregulated in distal pulmonary epithelium of human CDH fetuses in conjunction with attenuated cell proliferation. The compression model resulted in impaired branching morphogenesis similar to CDH and downregulation of VEGF expression in conjunction with reduced proliferation of terminal bud epithelial progenitors; these could be reversed by exogenous supplementation of VEGF. Prenatal delivery of VEGF with the ND-VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodelling that was complementary to that achieved by TO alone with appearances comparable to healthy controls. CONCLUSIONS: This innovative approach could have a significant impact on the treatment of CDH

The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT)

objective multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. this multicentre, case-control study involving 18 Italian MS centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy. methods we identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were white Europeans and white northern americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) country and 241 (17.9%) in a low-middle-income (LMI) country. medical records and patients interviews were used to collect demographic and disease data. results we included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. at onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. at recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). at disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032). discussion our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective

Epidemiology and economic burden of herpes zoster and post-herpetic neuralgia in Italy: A retrospective, population-based study

<p>Abstract</p> <p>Background</p> <p>Data on the epidemiology and cost of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in Italy are limited. This retrospective, population-based study was designed to determine the incidence of HZ and the proportion developing PHN in Italy and the associated medical resource utilisation and costs. It focused primarily on immunocompetent patients aged ≥50 years who would be eligible for preventive vaccination.</p> <p>Method</p> <p>Data were extracted from a primary-care database and national hospital-discharge records covering four major regions in Italy for 2003-2005. Cases of HZ and PHN (1 and 3 months' duration; PHN1 and PHN3) were identified by ICD9-CM codes and, additionally for PHN, prescription of neuropathic pain medication.</p> <p>Results</p> <p>Over 3 years, 5675 incident cases of HZ were documented in adults, of which 3620 occurred in immunocompetent patients aged ≥50 years (incidence of 6.31 per 1000 person-years [95% CI: 6.01-6.62]). Of the immunocompetent patients aged ≥50 years with HZ, 9.4% (95% CI: 8.2-10.7) and 7.2% (95% CI: 6.2-8.2) developed PHN1 and PHN3, respectively. Increasing age, female sex, and being immunologically compromised conferred increased risk for both HZ and PHN. Overall, about 1.3% of HZ and almost 2% of PHN cases required inpatient care, with 16.9% of all HZ-related hospitalisations due specifically to PHN. In patients aged ≥50 years, mean stay was 7.8 ± 5.4 days for HZ and 10.2 ± 8.6 days for PHN, and direct costs associated with inpatient care were more than 20 times outpatient costs per HZ case (mean ± SD: €2592 ± €1313 vs. €122.68 ± €97.51) and over 5 times more per episode of PHN (mean ± SD: €2806 ± €2641 vs. €446.10 ± €442.97). Total annual costs were €41.2 million, of which €28.2 million were direct costs and €13.0 million indirect costs.</p> <p>Conclusions</p> <p>This study, the largest to date on the epidemiology and economic impact of HZ and PHN in Italy, confirms the considerable disease and economic burden posed by HZ. As HZ and PHN disproportionately affect the elderly, without intervention this problem is likely to grow as the proportion of elderly in the Italian population continues to increase.</p