Miracle-dz/UniFAR-FTUs huggingface dataset:
Antiplatelet therapy in Acute Coronary Syndromes. Lights and shadows of platelet function tests to guide the best therapeutic approach.

The key role of platelets in pathophysiology of Acute Coronary Syndromes (ACS) has been well recognized. Platelet activation and aggregation, together with tissue factor-pathway activation, leads to acute thrombus formation in the coronary vessels at sites of plaque rupture. Thus, antiplatelet therapy with drugs able to interfere with platelet activation/aggregation represents a cornerstone of ACS treatment in intensive care units and catheterisation labs. Several observational studies have described that residual high platelet reactivity, despite antiplatelet therapy, is associated with increased risk of nonfatal Myocardial Infarction (MI), definite/probable stent thrombosis and cardiovascular mortality. Thus, assessment of platelet function with reliable and reproducible platelet function tests might be crucial to identify patients at high risk of thrombosis or not responding to ongoing antiplatelet strategies. However, despite this promising background, some randomized clinical trials have failed to demonstrate improvement in outcomes when using platelet function tests for clinical decision-making. This review, after describing platelet biology and pathophysiology of ACS, briefly considers the drugs currently approved for use in patients with ACS or treated by percutaneous coronary intervention (PCI). Finally, we provide an updated overview of the current methods to evaluate platelet reactivity in the clinical setting of ACS illustrating their potential advantages/limitations in current clinical practice.
Bronchopulmonary Dysplasia: A Continuum of Lung Disease from the Fetus to the Adult

Suzuki H, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet 2017;49:204–212. 7. Yatabe Y, Borczuk AC, Powell CA. Do all lung adenocarcinomas follow a stepwise progression? Lung Cancer 2011;74: 7–11. 8. Sivakumar S, Lucas FAS, McDowell TL, Lang W, Xu L, Fujimoto J, et al. Genomic landscape of atypical adenomatous hyperplasia reveals divergent modes to lung adenocarcinoma. Cancer Res 2017;77:6119–6130.
Stk40 deletion elevates c-JUN protein level and impairs mesoderm differentiation

Mesoderm development is a finely tuned process initiated by the differentiation of pluripotent epiblast cells. Serine/threonine kinase 40 (STK40) controls the development of several mesoderm-derived cell types, its overexpression induces differentiation of mouse embryonic stem cells (mESCs) toward the extraembryonic endoderm, and Stk40 knockout (KO) results in multiple organ failure and is lethal at the perinatal stage in mice. However, molecular mechanisms underlying the physiological functions of STK40 in mesoderm differentiation remain elusive. Here, we report that Stk40 ablation impairs mesoderm differentiation both in vitro and in vivo. Mechanistically, STK40 interacts with both the E3 ubiquitin ligase mammalian constitutive photomorphogenesis protein 1 (COP1) and the transcriptional regulator proto-oncogene c-Jun (c-JUN), promoting c-JUN protein degradation. Consequently, Stk40 knockout leads to c-JUN protein accumulation, which, in turn, apparently suppresses WNT signaling activity and impairs the mesoderm differentiation process. Overall, this study reveals that STK40, together with COP1, represents a previously unknown regulatory axis that modulates the c-JUN protein level within an appropriate range during mesoderm differentiation from mESCs. Our findings provide critical insights into the molecular mechanisms regulating the c-JUN protein level and may have potential implications for managing cellular disorders arising from c-JUN dysfunction.
Physical and Physiologic Determinants of Rock Climbing.

PURPOSE Rock climbing performance relies on many characteristics. Here, we identified the physical and physiologic determinants of peak performance in rock climbing across the range from lower-grade to elite. METHODS 44 male and 33 female climbers with onsight maximal climbing grades 5a-8a and 5a-7b+, respectively, were tested for physical, physiologic and psychologic characteristics (independent variables) that were correlated and modelled by multiple regression and principal component analysis to identify the determinants of rock climbing ability. RESULTS In males, 23 of 47 variables correlated with climbing ability (p<0.05, Pearson's correlation coefficients 0.773-0.340), including shoulder endurance, hand and finger strength, shoulder power-endurance, hip flexibility, lower-arm grip strength, shoulder power, upper-arm strength, core-body endurance, upper-body aerobic endurance, hamstrings and lower-back flexibility, aerobic endurance, and open-hand finger strength. In females, 10 of 47 variables correlated with climbing ability (p<0.05, Pearson's correlation coefficients 0.742-0.482): shoulder endurance and power, lower-arm grip strength, balance, aerobic endurance, and arm span. Principal component analysis and univariate multiple regression identified the main explanatory variables. In both sexes, shoulder power and endurance measured as maximum pull-ups, average arm crank power, and bent-arm hang, emerged as the main determinants (p<0.01; adjusted R2=0.77 in males and 0.62 in females). In males, finger pincer (p=0.07) and grip strength also had trends (p=0.09) toward significant effects. Finally, in test-of-principle training studies, we trained to increase main determinants 42-67%; this improved climbing ability 2-3 grades. CONCLUSIONS Shoulder power and endurance majorly determines maximal climbing. Finger, hand and arm strength, core-body endurance, aerobic endurance, flexibility and balance are important secondary determinants.
The Epidemiology of Morningness/Eveningness: Influence of Age, Gender, Ethnicity, and Socioeconomic Factors in Adults (30-49 Years)

The Horne and Ostberg Morningness/Eveningness Questionnaire (MEQ) is widely used to differentiate between morning and evening types, but there is very little epidemiological evidence about the distribution of MEQ chronotypes in the general population. The purpose of the present study was to simultaneously investigate the influence of demographic, socioeconomic, and work factors on the distribution of morningness/eveningness. A New Zealand version of the MEQ was mailed to 5000 New Zealand adults, ages 30 to 49 years, who were randomly selected from the electoral rolls (55.7% response rate). A total of 2526 questionnaires were included in the analyses. According to the Horne and Ostberg classification, 49.8% of the total population was classified as morning type compared to 5.6% having an evening-type preference. However, using new cutoffs for middle-aged working adults described by Taillard et al. (2004), 24.7% of the population was morning type and 26.4% was evening type. After controlling for ethnicity, gender, and socioeconomic deprivation, participants ages 30 to 34 years were more likely to be definitely evening type (odds ratio [OR] = 1.59, p < 0.05) and less likely to be morning type (moderately morning type, OR = 0.59, p < 0.01, or definitely morning type, OR = 0.59, p < 0.05) compared to those ages 45 to 49 years. Work schedules were also important predictors of chronotype, with night workers more likely to be definitely evening type (OR = 1.49, p = 0.05) and the unemployed less likely to be moderately morning type (OR = 0.64, p < 0.05) compared to other workers. Evening types were 2.5 times more likely to report that their general health was only poor or fair compared to morning types (p < 0.01). This study confirms that the original criteria of Horne and Ostberg (1976) are not useful for classifying chronotypes in a middle-aged population. The authors conclude that morningness/eveningness preference is largely independent of ethnicity, gender, and socioeconomic position, indicating that it is a stable characteristic that may be better explained by endogenous factors.
The Plasmodium liver-specific protein 2 (LISP2) is an early marker of liver stage development

Plasmodium vivax hypnozoites persist in the liver, cause malaria relapse and represent a major challenge to malaria elimination. Our previous transcriptomic study provided a novel molecular framework to enhance our understanding of the hypnozoite biology (Voorberg-van der Wel A, et al., 2017). In this dataset, we identified and characterized the Liver-Specific Protein 2 (LISP2) protein as an early molecular marker of liver stage development. Immunofluorescence analysis of hepatocytes infected with relapsing malaria parasites, in vitro (P. cynomolgi) and in vivo (P. vivax), reveals that LISP2 expression discriminates between dormant hypnozoites and early developing parasites. We further demonstrate that prophylactic drugs selectively kill all LISP2-positive parasites, while LISP2-negative hypnozoites are only sensitive to anti-relapse drug tafenoquine. Our results provide novel biological insights in the initiation of liver stage schizogony and an early marker suitable for the development of drug discovery assays predictive of anti-relapse activity.
SSRIs and SNRIs (SRI) in Pregnancy: Effects on the Course of Pregnancy and the Offspring: How Far Are We from Having All the Answers?

Serotonin has important roles in the development of the brain and other organs. Manipulations of synaptic serotonin by drugs such as serotonin reuptake inhibitors (SRI) or serotonin norepinephrine reuptake inhibitors (SNRI) might alter their development and function. Of interest, most studies on the outcome of prenatal exposure to SRI in human have not found significant embryonic or fetal damage, except for a possible, slight increase in cardiac malformations. In up to a third of newborns exposed to SRI, exposure may induce transient neonatal behavioral changes (poor neonatal adaptation) and increased rate of persistent pulmonary hypertension. Prenatal SRI may also cause slight motor delay and language impairment but these are transient. The data on the possible association of prenatal SRIs with autism spectrum disorder (ASD) are inconsistent, and seem to be related to pre-pregnancy treatment or to maternal depression. Prenatal SRIs also appear to affect the hypothalamic hypophyseal adrenal (HPA) axis inducing epigenetic changes, but the long-term consequences of these effects on humans are as yet unknown. SRIs are metabolized in the liver by several cytochrome P450 (CYP) enzymes. Faster metabolism of most SRIs in late pregnancy leads to lower maternal concentrations, and thus potentially to decreased efficacy which is more prominent in women that are rapid metabolizers. Studies suggest that the serotonin transporter SLC6A4 promoter is associated with adverse neonatal outcomes after SRI exposure. Since maternal depression may adversely affect the child’s development, one has to consider the risk of SRI discontinuation on the fetus and the child. As with any drug treatment in pregnancy, the benefits to the mother should be considered versus the possible hazards to the developing embryo/fetus.
Evidence for insect transmission of rabbit haemorrhagic disease virus

The spread of rabbit haemorrhagic disease (RHD) virus from quarantine on Wardang Island to mainland Australia in 1995 suggested that insects could be potential vectors. Field observations and laboratory experiments were conducted to address aspects of this hypothesis. Firstly, the variation in insect populations on the island during the field trials was examined. There was approximately a 1000-fold increase in the number of bushflies, Musca vetustissima, shortly before the spread of the virus. Secondly, M. vetustissima were tested in the laboratory as potential vectors of RHD virus, and it was demonstrated that disease could be transmitted between rabbits by flies. Finally, 13 of 16 insect samples, collected from Wardang Island and from several sites on the mainland following the spread of virus off the island, were positive for the presence of RHD virus by a specific polymerase chain reaction (PCR). Only one sample contained sufficient infectious virus to kill a susceptible rabbit. These data, combined with previously published information on fly biology, suggested that flies, particularly bushflies, may be involved in the transmission of RHD virus. Other possible routes of spread were not assessed in this study.
Asymmetry between the two acidic patches dictates the direction of nucleosome sliding by the ISWI chromatin remodeler

The acidic patch is a functionally important epitope on each face of the nucleosome that affects chromatin remodeling. Although related by 2-fold symmetry of the nucleosome, each acidic patch is uniquely positioned relative to a bound remodeler. An open question is whether remodelers are distinctly responsive to each acidic patch. Previously we reported a method for homogeneously producing asymmetric nucleosomes with distinct H2A/H2B dimers (Levendosky et al., 2016). Here, we use this methodology to show that the Chd1 remodeler from Saccharomyces cerevisiae and ISWI remodelers from human and Drosophila have distinct spatial requirements for the acidic patch. Unlike Chd1, which is equally affected by entry- and exit-side mutations, ISWI remodelers strongly depend on the entry-side acidic patch. Remarkably, asymmetry in the two acidic patches stimulates ISWI to slide mononucleosomes off DNA ends, overriding the remodeler’s preference to shift the histone core toward longer flanking DNA.
Changes in Patient Activation in a Self-Management Intervention

The purpose of this study was to compare results using individual change in level of patient activation measure (PAM) scores, individual point change scores, and group means in an outcome analysis. We evaluated changes in PAM scores (increase in level or increase of ≥5 points) to mean group PAM scores on patients who completed a self-management intervention compared with usual care on health care utilization and health-related quality of life. The sample was a subset of 91 multimorbid patients with complete data at completion of a self-management intervention. Results indicated that using a change in points allowed for more refined analysis of change compared with level changes; however, both individual measures were more reflective of actual change than group means. When tailoring interventions, we should consider using individual change scores. Further research is needed to evaluate how best to use PAM scores to measure the impact on clinical and health care outcomes.
Author response to Dr. Aziz—“Statin use and delayed onset of Huntington disease”

researchers conclude that statin use is associated with a delayed age of onset. The researchers applied a propensity-score–based design, matching premanifest HD mutation carriers who used a statin to those who did not, and comparing the hazard of a motor diagnosis between the two groups during follow-up. Although baseline body mass index (BMI) was included in the propensity score calculation, it is unclear which matching procedure was used, for example, optimal or nearest neighbour matching or yet some other procedure. Moreover, looking at the table in their article, the BMI of subjects who received statin therapy was, on average, 1.24 units higher than those who did not receive statins. This is unsuprising given that the major indication for statin use is hyperlipidemia, for which, in turn, overweight and obesity are major risk factors. Recently, we showed that a higher body weight is robustly associated with a slower disease progression in HD patients. Moreover, we found that HD patients with a relatively late age of onset had a substantially better bioenergetic profile, independent of their mutant HTT CAG repeat size. Therefore, it is extremely important to try to disentagle the effects of statin therapy from the effects of the major indication for which it is prescribed (i.e., hyperlipidemia), given that the clinical implications under these two scenarios would be diametrically opposite. In case statins would indeed have neuroprotective effects as the researchers suggest, that would indicate that statin therapy should be encouraged in HD mutation carriers. Conversely, if statin use would be just a marker of hyperlipidemia, a better nutritional state, or yet some other metabolic traits or genetic modifiers, then statin therapy should be limited in HD mutation carriers. Therefore, it would be very interesting to know whether any residual confounding by body weight, which might also serve as a proxy for some other underlying, but unmeasured, metabolic factors such as hyperlipidemia, could have contributed to the researchers’ findings. Some possibilities to this end would include additional adjustment of the final analysis for BMI, a method referred to as double adjustment in propensity-score–matched analyses, or closer matching on BMI at the outset. In any case, at this stage, the findings should be interpreted with caution, especially with regard to their potential clinical implications for treating HD mutation carriers. N. Ahmad Aziz, MD, PhD*
Carotid-cavernous fistula

Carotid cavernous fistulae are an uncommon disease. They are classified as direct or indirect. In direct fistulas there is an abnormal communication between the internal carotid artery and the cavernous sinus. Indirect forms have an abnormal bypass between the meningeal branches of the internal and/or external carotid arteries and the same sinus. The purpose of this article is to provide an overview of the anatomy of the envolved area and the clinical findings, diagnostic evaluation and treatment.
Management of symptomatic florid cemento-osseous dysplasia: Literature review and a case report

Introduction Cemento-osseous dysplasia is a jaw disorder characterized by a reactive process in which normal bone is replaced by connective tissue matrix. There are different Cemento-osseous dysplasia entities. The treatment of these lesions, once diagnosed by radiology, is not required because generally they are asymptomatic. The localization is in the tooth-bearing areas of the jaws and its distribution is symmetric. Case Reports In this case report, a 57-year-old Caucasian female patient was referred to our attention complaining of painful inflammatory events localized in the right angle of the jaw. The radiographic appearance, the distribution of several lesions and the positive vitality test of the involved teeth, supported the diagnosis of Florid Cemento-osseous dysplasia. Because of the symptomatology, the patient was submitted to surgery and the lesion and the second inferior right molar were removed. The histological examination of the specimens confirmed the diagnosis. Discussion Many lesions that may exhibit a similar sclerotic appearance on conventional radiographs have to be differentiated and dental imaging can be used to discriminate between Florid COD and other lesions. Diagnosis of Florid Cemento-osseous dysplasia can be made with accurate clinical and radiographic assessment. In asymptomatic cases no treatment is required and the patient should have regular follow-up, but in this symptomatic case it was necessary to proceed with surgical intervention. The surgery treatment in the symptomatic case had a favourable prognosis and the two years follow-up has shown a complete healing. Given the abow, it is concluded that the choice of treatment must be selective according to the disease sites. Key words:Cemento-ossifying dysplasia, fibro-osseous lesions, florid cemento-osseous dysplasia, cementoma.
Genetic Transformation and Green Fluorescent Protein Labeling in Ceratocystis paradoxa from Coconut

Ceratocystis paradoxa, the causal agent of stem-bleeding disease of the coconut palm, causes great losses to the global coconut industry. As the mechanism of pathogenicity of C. paradoxa has not been determined, an exogenous gene marker was introduced into the fungus. In this study, pCT74-sGFP, which contains the green fluorescent protein (GFP) gene, and the hygromycin B resistance gene as a selective marker, was used as an expression vector. Several protoplast release buffers were compared to optimize protoplast preparation. The plasmid pCT74-sGFP was successfully transformed into the genome of C. paradoxa, which was verified using polymerase chain reaction and green fluorescence detection. The transformants did not exhibit any obvious differences from the wild-type isolates in terms of growth and morphological characteristics. Pathogenicity tests showed that the transformation process did not alter the virulence of the X-3314 C. paradoxa strain. This is the first report on the polyethylene glycol-mediated transformation of C. paradoxa carrying a ‘reporter’ gene GFP that was stably and efficiently expressed in the transformants. These findings provide a basis for future functional genomics studies of C. paradoxa and offer a novel opportunity to track the infection process of C. paradoxa.
Arthritogenic Alphaviruses: A Worldwide Emerging Threat?

Arthritogenic alphaviruses are responsible for a dengue-like syndrome associated with severe debilitating polyarthralgia that can persist for months or years and impact life quality. Chikungunya virus is the most well-known member of this family since it was responsible for two worldwide epidemics with millions of cases in the last 15 years. However, other arthritogenic alphaviruses that are as of yet restrained to specific territories are the cause of neglected tropical diseases: O’nyong’nyong virus in Sub-Saharan Africa, Mayaro virus in Latin America, and Ross River virus in Australia and the Pacific island countries and territories. This review evaluates their emerging potential in light of the current knowledge for each of them and in comparison to chikungunya virus.
Myocardial Fibrosis as a Pathway of Prediction of Ventricular Arrhythmias and Sudden Cardiac Death in Patients With Nonischemic Dilated Cardiomyopathy

The mechanism of sudden cardiac death (SCD) in patients with nonischemic dilated cardiomyopathy (NIDCM) is mostly due to sustained ventricular tachycardia and ventricular fibrillation. The clinical guidelines for the therapeutic management of this set of patients are mostly based on left ventricular ejection fraction value which has a low specificity to differentiate the risk of SCD from the risk of mortality associated with heart failure or other comorbidities. Moreover, since SCD can occur in patients with normal or mildly depressed ejection fraction, it is necessary to identify new markers to improve the prognostic stratification of SCD. Several studies that analyzed the ventricular arrhythmia substrate found that myocardial fibrosis plays an important role in the genesis of ventricular arrhythmias in patients with NIDCM. The surrounding zone of the area of fibrosis is a heterogeneous medium, where tissue with different levels of fibrosis coexists, resulting in both viable and nonviable myocardium. This myocardial fibrosis may constitute a substrate for ventricular arrhythmias, where slow and heterogeneous conduction may favor the genesis of reentry mechanism increasing the chance to develop sustained ventricular tachycardia or ventricular fibrillation. Therefore, the evaluation of ventricular fibrosis by late gadolinium enhancement (LGE) cardiac magnetic resonance imaging has been suggested as an indicator for SCD risk stratification. Indeed, LGE in patients with NIDCM is associated with increased risk of all-cause mortality, heart failure hospitalization, and SCD. Detection of myocardial fibrosis as LGE by cardiac magnetic resonance imaging can be considered as a useful pathway of prediction of malignant ventricular arrhythmias since it has excellent prognostic characteristics and may help guide risk stratification and management in patients with NIDCM.