Miracle-dz/UniFAR-FTUs huggingface dataset:
Pulmonary Hypertension in Acute and Chronic High Altitude Maladaptation Disorders

Alveolar hypoxia is the most prominent feature of high altitude environment with well-known consequences for the cardio-pulmonary system, including development of pulmonary hypertension. Pulmonary hypertension due to an exaggerated hypoxic pulmonary vasoconstriction contributes to high altitude pulmonary edema (HAPE), a life-threatening disorder, occurring at high altitudes in non-acclimatized healthy individuals. Despite a strong physiologic rationale for using vasodilators for prevention and treatment of HAPE, no systematic studies of their efficacy have been conducted to date. Calcium-channel blockers are currently recommended for drug prophylaxis in high-risk individuals with a clear history of recurrent HAPE based on the extensive clinical experience with nifedipine in HAPE prevention in susceptible individuals. Chronic exposure to hypoxia induces pulmonary vascular remodeling and development of pulmonary hypertension, which places an increased pressure load on the right ventricle leading to right heart failure. Further, pulmonary hypertension along with excessive erythrocytosis may complicate chronic mountain sickness, another high altitude maladaptation disorder. Importantly, other causes than hypoxia may potentially underlie and/or contribute to pulmonary hypertension at high altitude, such as chronic heart and lung diseases, thrombotic or embolic diseases. Extensive clinical experience with drugs in patients with pulmonary arterial hypertension suggests their potential for treatment of high altitude pulmonary hypertension. Small studies have demonstrated their efficacy in reducing pulmonary artery pressure in high altitude residents. However, no drugs have been approved to date for the therapy of chronic high altitude pulmonary hypertension. This work provides a literature review on the role of pulmonary hypertension in the pathogenesis of acute and chronic high altitude maladaptation disorders and summarizes current knowledge regarding potential treatment options.
Simplified Geriatric Assessment in Older Patients With Diffuse Large B-Cell Lymphoma: The Prospective Elderly Project of the Fondazione Italiana Linfomi.

PURPOSE To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL). METHODS We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050). RESULTS We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases. CONCLUSION The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL.
Approaches to Sequence the HTT CAG Repeat Expansion and Quantify Repeat Length Variation

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of the HTT CAG repeat. Affected individuals inherit ≥36 repeats and longer alleles cause earlier onset, greater disease severity and faster disease progression. The HTT CAG repeat is genetically unstable in the soma in a process that preferentially generates somatic expansions, the proportion of which is associated with disease onset, severity and progression. Somatic mosaicism of the HTT CAG repeat has traditionally been assessed by semi-quantitative PCR-electrophoresis approaches that have limitations (e.g., no information about sequence variants). Genotyping-by-sequencing could allow for some of these limitations to be overcome. Objective: To investigate the utility of PCR sequencing to genotype large (>50 CAGs) HD alleles and to quantify the associated somatic mosaicism. Methods: We have applied MiSeq and PacBio sequencing to PCR products of the HTT CAG repeat in transgenic R6/2 mice carrying ∼55, ∼110, ∼255 and ∼470 CAGs. For each of these alleles, we compared the repeat length distributions generated for different tissues at two ages. Results: We were able to sequence the CAG repeat full length in all samples. However, the repeat length distributions for samples with ∼470 CAGs were biased towards shorter repeat lengths. Conclusion: PCR sequencing can be used to sequence all the HD alleles considered, but this approach cannot be used to estimate modal allele size or quantify somatic expansions for alleles ⪢250 CAGs. We review the limitations of PCR sequencing and alternative approaches that may allow the quantification of somatic contractions and very large somatic expansions.
Motor Developmental Outcomes in Children Exposed to Maternal Diabetes during Pregnancy: A Systematic Review and Meta-Analysis

Studies on the association of maternal diabetes with motor development in children provide inconsistent findings. We searched MEDLINE/PubMed, EMBASE, Emcare, PsycINFO, and Google Scholar databases for primary observational, case–control, or cohort studies that report on the motor development of children exposed to maternal diabetes during pregnancy. Quality appraisal and data extraction were performed independently and in duplicate. A meta-analysis of summary measures was performed using random-effect models. Eighteen studies were identified for inclusion, however, only 13 were included in the meta-analysis. Exposure to maternal diabetes during pregnancy was associated with a lower pooled motor development in children and a decrease in both gross and fine motor development. Among all other factors, pre-existing diabetes and other gestational comorbidities, such as hypertension and obesity, or low socioeconomic status, also affect child development. Therefore, among children of diabetic mothers, those with other gestational comorbidities or pre-existing diabetes were more likely to be at risk developmentally.
Design of synthetic promoters for controlled expression of therapeutic genes in retinal pigment epithelial cells

Age‐related macular degeneration (AMD) associated with dysfunction of retinal pigment epithelial (RPE) cells is the most common cause of untreatable blindness. To advance gene therapy as a viable treatment for AMD there is a need for technologies that enable controlled, RPE‐specific expression of therapeutic genes. Here we describe design, construction and testing of compact synthetic promoters with a pre‐defined transcriptional activity and RPE cell specificity. Initial comparative informatic analyses of RPE and photoreceptor (PR) cell transcriptomic data identified conserved and overrepresented transcription factor regulatory elements (TFREs, 8–19 bp) specifically associated with transcriptionally active RPE genes. Both RPE‐specific TFREs and those derived from the generically active cytomegalovirus‐immediate early (CMV‐IE) promoter were then screened in vitro to identify sequence elements able to control recombinant gene transcription in model induced pluripotent stem (iPS)‐derived and primary human RPE cells. Two libraries of heterotypic synthetic promoters varying in predicted RPE specificity and transcriptional activity were designed de novo using combinations of up to 20 discrete TFREs in series (323–602 bp) and their transcriptional activity in model RPE cells was compared to that of the endogenous BEST1 promoter (661 bp, plus an engineered derivative) and the highly active generic CMV‐IE promoter (650 bp). Synthetic promoters with a highpredicted specificity, comprised predominantly of endogenous TFREs exhibited a range of activities up to 8‐fold that of the RPE‐specific BEST1 gene promoter. Moreover, albeit at a lower predicted specificity, synthetic promoter transcriptional activity in model RPE cells was enhanced beyond that of the CMV‐IE promoter when viral elements were utilized in combination with endogenous RPE‐specific TFREs, with a reduction in promoter size of 15%. Taken together, while our data reveal an inverse relationship between synthetic promoter activity and cell‐type specificity, cell context‐specific control of recombinant gene transcriptional activity may be achievable.
Is the NHS Diabetes Prevention Programme Intervention Delivered as Planned? An Observational Study of Fidelity of Intervention Delivery

Abstract Background The NHS Diabetes Prevention Programme (NHS-DPP) has been delivered by four commercial organizations across England, to prevent people with impaired glucose tolerance developing Type 2 diabetes. Evidence reviews underpinning the NHS-DPP design specification identified 19 Behavior Change Techniques (BCTs) that are the intervention “active ingredients. ” It is important to understand the discrepancies between BCTs specified in design and BCTs actually delivered. Purpose To compare observed fidelity of delivery of BCTs that were delivered to (a) the NHS-DPP design specification, and (b) the programme manuals of four provider organizations. Methods Audio-recordings were made of complete delivery of NHS-DPP courses at eight diverse sites (two courses per provider organization). The eight courses consisted of 111 group sessions, with 409 patients and 35 facilitators. BCT Taxonomy v1 was used to reliably code the contents of NHS-DPP design specification documents, programme manuals for each provider organization, and observed NHS-DPP group sessions. Results The NHS-DPP design specification indicated 19 BCTs that should be delivered, whereas only seven (37%) were delivered during the programme in all eight courses. By contrast, between 70% and 89% of BCTs specified in programme manuals were delivered. There was substantial under-delivery of BCTs that were designed to improve self-regulation of behavior, for example, those involving problem solving and self-monitoring of behavior. Conclusions A lack of fidelity in delivery to the underlying evidence base was apparent, due to poor translation of design specification to programme manuals. By contrast, the fidelity of delivery to the programme manuals was relatively good. Future commissioning should focus on ensuring the evidence base is more accurately translated into the programme manual contents.
Nanostructures for Biosensing, with a Brief Overview on Cancer Detection, IoT, and the Role of Machine Learning in Smart Biosensors

Biosensors are essential tools which have been traditionally used to monitor environmental pollution and detect the presence of toxic elements and biohazardous bacteria or virus in organic matter and biomolecules for clinical diagnostics. In the last couple of decades, the scientific community has witnessed their widespread application in the fields of military, health care, industrial process control, environmental monitoring, food-quality control, and microbiology. Biosensor technology has greatly evolved from in vitro studies based on the biosensing ability of organic beings to the highly sophisticated world of nanofabrication-enabled miniaturized biosensors. The incorporation of nanotechnology in the vast field of biosensing has led to the development of novel sensors and sensing mechanisms, as well as an increase in the sensitivity and performance of the existing biosensors. Additionally, the nanoscale dimension further assists the development of sensors for rapid and simple detection in vivo as well as the ability to probe single biomolecules and obtain critical information for their detection and analysis. However, the major drawbacks of this include, but are not limited to, potential toxicities associated with the unavoidable release of nanoparticles into the environment, miniaturization-induced unreliability, lack of automation, and difficulty of integrating the nanostructured-based biosensors, as well as unreliable transduction signals from these devices. Although the field of biosensors is vast, we intend to explore various nanotechnology-enabled biosensors as part of this review article and provide a brief description of their fundamental working principles and potential applications. The article aims to provide the reader a holistic overview of different nanostructures which have been used for biosensing purposes along with some specific applications in the field of cancer detection and the Internet of things (IoT), as well as a brief overview of machine-learning-based biosensing.
Modifiers of CAG/CTG Repeat Instability: Insights from Mammalian Models

At fifteen different genomic locations, the expansion of a CAG/CTG repeat causes a neurodegenerative or neuromuscular disease, the most common being Huntington’s disease and myotonic dystrophy type 1. These disorders are characterized by germline and somatic instability of the causative CAG/CTG repeat mutations. Repeat lengthening, or expansion, in the germline leads to an earlier age of onset or more severe symptoms in the next generation. In somatic cells, repeat expansion is thought to precipitate the rate of disease. The mechanisms underlying repeat instability are not well understood. Here we review the mammalian model systems that have been used to study CAG/CTG repeat instability, and the modifiers identified in these systems. Mouse models have demonstrated prominent roles for proteins in the mismatch repair pathway as critical drivers of CAG/CTG instability, which is also suggested by recent genome-wide association studies in humans. We draw attention to a network of connections between modifiers identified across several systems that might indicate pathway crosstalk in the context of repeat instability, and which could provide hypotheses for further validation or discovery. Overall, the data indicate that repeat dynamics might be modulated by altering the levels of DNA metabolic proteins, their regulation, their interaction with chromatin, or by direct perturbation of the repeat tract. Applying novel methodologies and technologies to this exciting area of research will be needed to gain deeper mechanistic insight that can be harnessed for therapies aimed at preventing repeat expansion or promoting repeat contraction.
Word Recognition and Frequency Selectivity in Cochlear Implant Simulation: Effect of Channel Interaction

In cochlear implants (CI), spread of neural excitation may produce channel interaction. Channel interaction disturbs the spectral resolution and, among other factors, seems to impair speech recognition, especially in noise. In this study, two tests were performed with 20 adult normal-hearing (NH) subjects under different vocoded simulations. First, there was a measurement of word recognition in noise while varying the number of selected channels (4, 8, 12 or 16 maxima out of 20) and the degree of simulated channel interaction (“Low”, “Medium” and “High”). Then, there was an evaluation of spectral resolution function of the degree of simulated channel interaction, reflected by the sharpness (Q10dB) of psychophysical tuning curves (PTCs). The results showed a significant effect of the simulated channel interaction on word recognition but did not find an effect of the number of selected channels. The intelligibility decreased significantly for the highest degree of channel interaction. Similarly, the highest simulated channel interaction impaired significantly the Q10dB. Additionally, a strong intra-individual correlation between frequency selectivity and word recognition in noise was observed. Lastly, the individual changes in frequency selectivity were positively correlated with the changes in word recognition when the degree of interaction went from “Low” to “High”. To conclude, the degradation seen for the highest degree of channel interaction suggests a threshold effect on frequency selectivity and word recognition. The correlation between frequency selectivity and intelligibility in noise supports the hypothesis that PTCs Q10dB can account for word recognition in certain conditions. Moreover, the individual variations of performances observed among subjects suggest that channel interaction does not have the same effect on each individual. Finally, these results highlight the importance of taking into account subjects’ individuality and to evaluate channel interaction through the speech processor.
Simulations of monosaccharide on calcite surfaces

Abstract Organic molecules control calcite growth by adsorbing preferentially onto particular surfaces of the crystal. Adsorption of a monosaccharide (-galactose) on various calcite surfaces has been simulated with molecular dynamics. The calculations of Z-density, mean square displacement (MSD) and adsorption energyindicate that the adsorption of monosaccharide on the acute-stepped calcite (31.8) surface is more favourable than that on the obtuse-stepped (31.16) surface, which suggests that monosaccharides maybe able to selectively cover some surfaces, inhibit crystal growth on these surfaces, and as a result shape the calcite crystals as seen in biominerals, e.g. coccoliths.
Plasma oscillation method for measurements of absolute electron density in plasma

A new and simple method for precise measurements of electron density in a plasma with use of plasma oscillations is described. A weak electron beam is injected from a hot filament and excites electron waves oscillating at the plasma frequency ? p, whose sharp spectrum, obtained using a detector, gives the electron density. This plasma oscillation method is free of many difficulties often encountered with a Langmuir probe, such as thin film deposition, plasma potential fluctuation, and magnetic fields. The measurement technique is theoretically analyzed and experimentally demonstrated in the density measurements of an inductively coupled rf plasma, together with a comparison with the Langmuir probe method.
EXTRACTION OF COPPER, CADMIUM AND RELATED METALS WITH POLY(SODIUM ACRYLATE - ACRYLIC ACID)HYDROGELS.

ABSTRACT The extraction of copper, cadmium and related metals (M2+) with poly(sodium acrylate - acrylic acid) PAA hydrogels has been studied. pH variations are consistent with a cation exchange process. Saturation of the gel is achieved for a metal/carboxylate ratio R ≈ 1/2 and a gel swelling of ≈ 40 which is that of the uncharged gel : (-COO)2M complexes are expected to be formed, but also complexes of higher stoichiometry (R = 1/3 for Cu and Cd, R = 1/4 for Pb) at low metal concentrations. The selectivity is that observed in liquid-liquid extraction of metal cations with fatty carboxylic acids (Pb > Cu > Cd > Zn > Ni ≈ Co). Metal stripping from the gel is readily achieved by washing with 0.1 M HNO3. PAA hydrogel extraction allows to remove cadmium from a diluted aqueous solution down to a final concentration of 5 ppb.
Radiation Tolerance and Charge Trapping Enhancement of ALD HfO2/Al2O3 Nanolaminated Dielectrics

High-k dielectric stacks are regarded as a promising information storage media in the Charge Trapping Non-Volatile Memories, which are the most viable alternative to the standard floating gate memory technology. The implementation of high-k materials in real devices requires (among the other investigations) estimation of their radiation hardness. Here we report the effect of gamma radiation (60Co source, doses of 10 and 10 kGy) on dielectric properties, memory windows, leakage currents and retention characteristics of nanolaminated HfO2/Al2O3 stacks obtained by atomic layer deposition and its relationship with post-deposition annealing in oxygen and nitrogen ambient. The results reveal that depending on the dose, either increase or reduction of all kinds of electrically active defects (i.e., initial oxide charge, fast and slow interface states) can be observed. Radiation generates oxide charges with a different sign in O2 and N2 annealed stacks. The results clearly demonstrate a substantial increase in memory windows of the as-grown and oxygen treated stacks resulting from enhancement of the electron trapping. The leakage currents and the retention times of O2 annealed stacks are not deteriorated by irradiation, hence these stacks have high radiation tolerance.
Clinical and Translational Implications of an Emerging Developmental Substructure for Autism.

A vast share of the population-attributable risk for autism relates to inherited polygenic risk. A growing number of studies in the past five years have indicated that inherited susceptibility may operate through a finite number of early developmental liabilities that, in various permutations and combinations, jointly predict familial recurrence of the convergent syndrome of social communication disability that defines the condition. Here, we synthesize this body of research to derive evidence for a novel developmental substructure for autism, which has profound implications for ongoing discovery efforts to elucidate its neurobiological causes, and to inform future clinical and biomarker studies, early interventions, and personalized approaches to therapy. Expected final online publication date for the Annual Review of Clinical Psychology, Volume 17 is May 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Serum cholinesterase as a prognostic biomarker for acute heart failure.

AIMS The association between serum cholinesterase and prognosis in acute heart failure (AHF) remains to be elucidated. We investigated the serum cholinesterase level at discharge from hospitalization for AHF and its association with clinical outcomes in patients with AHF. METHODS AND RESULTS Among 4056 patients enrolled in the Kyoto Congestive Heart Failure multicentre registry, we analysed 2228 patients with available serum cholinesterase data. The study population was classified into three groups according to serum cholinesterase level at discharge: low tertile (<180 U/L, N = 733), middle tertile (≥180 U/L and <240 U/L, N = 746), and high tertile (≥240 U/L, N = 749). Patients in the low tertile had higher tricuspid pressure gradient, greater inferior vena cava diameter, and higher brain natriuretic peptide (BNP) levels than those in the high tertile. The cumulative 1-year incidence of the primary outcome measure (a composite endpoint of all-cause death and hospitalization for HF) was higher in the low and middle tertiles than in the high tertile [46.5% (low tertile) and 31.4% (middle tertile) vs. 22.1% (high tertile), P < 0.0001]. After adjustment for 26 variables, the excess risk of the low tertile relative to the high tertile for the primary outcome measure remained significant (hazard ratio 1.37, 95% confidence interval 1.10-1.70, P = 0.006). Restricted cubic spline models below the median of cholinesterase demonstrated incrementally higher hazards at low cholinesterase levels. CONCLUSIONS Low serum cholinesterase levels are associated with congestive findings on echocardiography, higher BNP, and higher risks for a composite of all-cause death and HF hospitalization in patients with AHF.