Miracle-dz/UniFAR-FTUs huggingface dataset:
β-Amyloid, Tau, Neurodegeneration Classification and Eligibility for Anti-amyloid Treatment in a Memory Clinic Population

Background and Objectives ATN (β-amyloid [Aβ], tau, neurodegeneration) system categorizes individuals based on their core Alzheimer disease (AD) biomarkers. An important potential future use for ATN is therapeutic decision-making in clinical practice once disease-modifying treatments (e.g., anti-amyloid), become widely available. In this cross-sectional study, we applied ATN and estimated potential eligibility for anti-amyloid treatment in a real-life memory clinic with biomarker assessments integrated into the routine diagnostic procedure and all specialized resources available for the implementation of novel treatments. Methods We included all consecutive patients at the Karolinska University Hospital Memory clinic in Solna, Stockholm, Sweden, who had their first diagnostic visit in April 2018–February 2021, informed consent for the clinic research database, and available clinical and biomarker (CSF and imaging) data. ATN classification was based on CSF Aβ42 (or Aβ42/40; A), CSF phosphorylated tau (T), and medial temporal lobe atrophy (N). For CSF markers, we applied laboratory cutoffs and data-driven cutoffs for comparison (determined with Gaussian mixture modeling). Eligibility for anti-amyloid treatment was assessed following the published recommendations for aducanumab (AD dementia or mild cognitive impairment [MCI] with no evidence of non-AD etiology, appropriate level of cognition, and AD-consistent CSF profile). Results The study population consisted of 410 patients (52% subjective cognitive impairment, 23% MCI, and 25% any dementia; age 59 ± 7 years, 56% women). Regardless of biomarker cutoffs, most patients were A−T−N− (54%–57%). A+ prevalence was 17%–30% (higher with data-driven cutoffs). Up to 13% of all patients (27% of those with MCI and 28% of those with dementia) were potentially eligible for anti-amyloid treatment when AD-consistent CSF was defined as any A+ profile. When A+T+ profile was required, treatment was targeted more to the dementia than MCI stage (eligibility up to 14% in MCI and 22% in dementia). The opposite applied to earlier-stage intervention (A+T−N−; eligibility up to 12% in MCI and 2% in dementia). Discussion In a memory clinic setting with all necessary infrastructure and national guidelines in place for dementia diagnostic examination (best-case scenario), most of the patients did not meet the eligibility criteria for anti-amyloid treatment. Continuing the development of disease-modifying treatments with different mechanisms of action is a priority.
Small Sample Properties of Generalized Method of Moments Based Wald Tests

This paper assesses the small sample properties of Generalized Method of Moments (GMM) based Wald statistics. The analysis is conducted assuming that the data generating process corresponds to (i) a simple vector white noise process and (ii) an equilibrium business cycle model. Our key findings are that the small sample size of the Wald tests exceeds their asymptotic size, and that their size increases uniformly with the dimensionality of joint hypotheses. For tests involving even moderate numbers of moment restrictions, the small sample size of the tests greatly exceeds their asymptotic size. Relying on asymptotic distribution theory leads one to reject joint hypothesis tests far too often. We argue that the source of the problem is the difficulty of estimating the spectral density matrix of the GMM residuals, which is needed to conduct inference in a GMM environment. Imposing restrictions implied by the underlying economic model being investigated or the null hypothesis being tested on this spectral density matrix can lead to substantial improvements in the small sample properties of the Wald tests.
Therapeutic plasma exchange in the management of immune checkpoint inhibitor‐associated immune‐related adverse effects: A review

Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Division of Hematology/Oncology, Sibley Memorial Hospital, Sibley Memorial Hospital John Hopkins University, Washington, DC, USA Department of Medicine, Division of Medical Oncology & Hematology, University Health Network, University of Toronto, Toronto, ON, Canada Department of Medicine, University of Washington and Fred Hutchinson Cancer Center, Seattle, Washington, USA
The incidence and burden of injury in male adolescent community rugby union in Australia

ABSTRACT Objectives To describe the incidence, location, mechanism and burden of injury in community male adolescent rugby. Methods A prospective cohort injury surveillance study using sports trainers to record ‘any physical complaint’ over three seasons (2018/2019/2021) in 979 U13-U17 community male rugby union players. Results One hundred and fifty-two time-loss injuries (27.6/1000 hours) with an associated burden of 2313 days (419.7 days/1000 hours), 169 non-time loss medical attention (30.1/1000 hours) and 813 physical complaints (147.5/1000 hours) were recorded from 5511.7 exposure hours (matches 3932.5 hours, training 1579.2 hours). Time-loss injury incidence was highest in U16 (45/1000 hours) and lowest in U17 (16.6/1000 hours), with U17 significantly lower than U16 and U15 age-grades (p < 0.05). Injury burden was greatest in U13 (561.4 days/1000 hours), and significantly higher than U15 and U17 (p < 0.05). Collectively, injury incidence was greatest for the head/neck (11.8/1000 hours), bruise/contusions were most common (8.7/1000 hours) and concussion (4.5/1000 hours) accounted for the greatest injury burden (102 days/1000 hours). Being tackled was the most observed injury mechanism (10.0/1000 hours). Forwards had significantly higher incidence in mild injury (p < 0.01). The total burden (p < 0.001) associated with mild (p < 0.001) and moderate injuries (p < 0.001) was significantly higher in forwards, as was the burden of being tackled (p < 0.001), collisions (p < 0.001), trunk (p < 0.001) and lower limb (p < 0.01) injury locations. In contrast, ruck-related injury burden was greater in backs (p < 0.001). Conclusion This study showed age-grade and positional differences in incidence and burden of injury in community adolescent rugby union. The rate of non-time loss relative to time-loss injury and muscle strain injury in U13-U14s suggests further research into injury risk and maturation in rugby is needed.
SARA suppresses myofibroblast precursor transdifferentiation in fibrogenesis in a mouse model of scleroderma

We previously reported that Smad anchor for receptor activation (SARA) plays a critical role in maintaining epithelial cell phenotype. Here, we show that SARA suppressed myofibroblast precursor transdifferentiation in a mouse model of scleroderma. Mice overexpressing SARA specifically in PDGFR-β+ pericytes and pan-leukocytes (SARATg) developed significantly less skin fibrosis in response to bleomycin injection compared with wild-type littermates (SARAWT). Single-cell RNA-Seq analysis of skin PDGFR-β+ cells implicated pericyte subsets assuming myofibroblast characteristics under fibrotic stimuli, and SARA overexpression blocked the transition. In addition, a cluster that expresses molecules associated with Th2 cells and macrophage activation was enriched in SARAWT mice, but not in SARATg mice, after bleomycin treatment. Th2-specific Il-31 expression was increased in skin of the bleomycin-treated SARAWT mice and patients with scleroderma (or systemic sclerosis, SSc). Receptor-ligand analyses indicated that lymphocytes mediated pericyte transdifferentiation in SARAWT mice, while with SARA overexpression the myofibroblast activity of pericytes was suppressed. Together, these data suggest a potentially novel crosstalk between myofibroblast precursors and immune cells in the pathogenesis of SSc, in which SARA plays a critical role.
Chromatin transitions triggered by LH density as epigenetic regulators of the genome

Abstract Motivated by experiments connecting linker histone (LH) deficiency to lymphoma progression and retinal disorders, we study by mesoscale chromatin modeling how LH density (ρ) induces gradual, as well sudden, changes in chromatin architecture and how the process depends on DNA linker length, LH binding dynamics and binding mode, salt concentration, tail modifications, and combinations of ρ and linker DNA length. We show that ρ tightly regulates the overall shape and compaction of the fiber, triggering a transition from an irregular disordered state to a compact and ordered structure. Such a structural transition, resembling B to A compartment transition connected with lymphoma of B cells, appears to occur around ρ = 0.5. The associated mechanism is DNA stem formation by LH binding, which is optimal when the lengths of the DNA linker and LH C-terminal domain are similar. Chromatin internal and external parameters are key regulators, promoting or impeding the transition. The LH density thus emerges as a critical tunable variable in controlling cellular functions through structural transitions of the genome.
In-house testing for homologous recombination repair deficiency (HRD) testing in ovarian carcinoma: a feasibility study comparing AmoyDx HRD Focus panel with Myriad myChoiceCDx assay

Summary Background Homologous recombination repair (HRR) is the main mechanism of repair of DNA double-strand breaks. Its deficiency (HRD) is a common feature of epithelial ovarian cancers (EOCs). BRCA1/2 mutations and/or other aberrations in genes of HRR are well known causes of HRD and genomic instability. Poly ADP-ribose polymerase inhibitors (PARPi) have revolutionized the management of BRCA mutant EOCs and demonstrated activity in HRD tumor cells. Determining HRD status can provide informations on the magnitude of benefit for PARPi therapy. Myriad MyChoice CDx is a next generation sequencing- based in vitro diagnostic test that assesses the Genomic Instability Score (GIS) which is an algorithmic measurement of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions using DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens. However Myriad MyChoice CDx, is a centrally performed and costly assay, with no reimbursement scheduled, at least in Italy. Methods In this report, we described our experience in performing the HRD Focus AmoyDx (Amoy Diagnostics Ltd, Xiamen, Fujian, China) on the same samples of EOCs evaluated with Myriad MyChoiceCDx assay. Results The overall percent agreement between AmoyDx and Myriad was 87.8% (65 of 74 tumors tested). All the 36 AmoyDx negative cases were confirmed to be negative by Myriad (negative predictive value, 100%). Conclusions The concordance of the results with the gold standard Myriad MyChoice CDx assay suggest the feasibility and reliability of HRD testing in diagnostic laboratories with high-throughput NGS platforms and qualified personnel.
Interspecific differences in oxidative DNA damage after hydrogen peroxide exposure of sea urchin coelomocytes

Abstract Interspecific comparison of DNA damage can provide information on the relative vulnerability of marine organisms to toxicants that induce oxidative genotoxicity. Hydrogen peroxide (H2O2) is an oxidative toxicant that causes DNA strand breaks and nucleotide oxidation and is used in multiple industries including Atlantic salmon aquaculture to treat infestations of ectoparasitic sea lice. H2O2 (up to 100 mM) can be released into the water after sea lice treatment, with potential consequences of exposure in nontarget marine organisms. The objective of the current study was to measure and compare differences in levels of H2O2-induced oxidative DNA damage in coelomocytes from Scottish sea urchins Echinus esculentus, Paracentrotus lividus, and Psammechinus miliaris. Coelomocytes were exposed to H2O2 (0–50 mM) for 10 min, cell concentration and viability were quantified, and DNA damage was measured by the fast micromethod, an alkaline unwinding DNA method, and the modified fast micromethod with nucleotide-specific enzymes. Cell viability was >92% in all exposures and did not differ from controls. Psammechinus miliaris coelomocytes had the highest oxidative DNA damage with 0.07 ± 0.01, 0.08 ± 0.01, and 0.07 ± 0.01 strand scission factors (mean ± SD) after incubation with phosphate-buffered saline, formamidopyrimidine-DNA glycosylase, and endonuclease-III, respectively, at 50 mM H2O2. Exposures to 0.5 mM H2O2 (100-fold dilution from recommended lice treatment concentration) induced oxidative DNA damage in all three species of sea urchins, suggesting interspecific differences in vulnerabilities to DNA damage and/or DNA repair mechanisms. Understanding impacts of environmental genotoxicants requires understanding species-specific susceptibilities to DNA damage, which can impact long-term stability in sea urchin populations in proximity to aquaculture farms.
Rational engineering of adeno‐associated virus capsid enhances human hepatocyte tropism and reduces immunogenicity

Gene therapy based on recombinant adeno‐associated viral (rAAV) vectors has been proved to be clinically effective for genetic diseases. However, there are still some limitations, including possible safety concerns for high dose delivery and a decreasing number of target patients caused by the high prevalence of pre‐existing neutralizing antibodies, hindering its application. Herein, we explored whether there was an engineering strategy that can obtain mutants with enhanced transduction efficiency coupled with reduced immunogenicity.
Neutralizing immunity induced against the Omicron BA.1 and BA.2 variants in vaccine breakthrough infections

Abstract Background As of early 2022, the Omicron variants are the predominant circulating lineages globally. Understanding neutralizing antibody responses against Omicron BA.1 and BA.2 following vaccine breakthrough infections will provide insights into BA.2 infectivity and susceptibility to subsequent re-infection. Methods Live virus neutralization assays were used to study immunity against Delta and Omicron BA.1 and BA.2 variants in samples from 86 individuals, 24 unvaccinated (27.9%) and 63 vaccinated (72.1%), who were infected with Delta (n = 42, 48.8%) or BA.1 (n = 44, 51.2%). Among the 63 vaccinated individuals, 39 were unboosted (45.3%), while 23 were boosted (26.7%). Results In unvaccinated infections, neutralizing antibodies (nAbs) against the three variants were weak or undetectable, except against Delta for Delta-infected individuals. Both Delta and BA.1 breakthrough infections resulted in strong nAb responses against ancestral wild-type and Delta lineages, but moderate nAb responses against BA.1 and BA.2, with similar titers between unboosted and boosted individuals. Antibody titers against BA.2 were generally higher than those against BA.1 in breakthrough infections. Conclusions These results underscore the decreased immunogenicity of BA.1 as compared to BA.2, insufficient neutralizing immunity against BA.2 in unvaccinated individuals, and moderate to strong neutralizing immunity induced against BA.2 in Delta and BA.1 breakthrough infections.
The Role of Deliberative Cognitive Styles in Preventing Belief in Politicized COVID-19 Misinformation

ABSTRACT Misinformation related to COVID-19 is a threat to public health. The present study examined the potential for deliberative cognitive styles such as actively open-minded thinking and need for evidence in deterring belief in misinformation and promoting belief in true information related to COVID-19. In addition, regarding how responses to the pandemic have been politicized, the role of political orientation and motivated reasoning were also examined. We conducted a survey in South Korea (N = 1466) during May 2020. Participants answered measures related to demographics, open-minded thinking, need for evidence, and accuracy perceptions of COVID-19 misinformation and true information items. Multi-level analyses of the survey data found that while motivated reasoning was present, deliberative cognitive styles (actively open-minded thinking and need for evidence) decreased belief in misinformation without intensifying motivated reasoning tendencies. Findings also showed a political asymmetry where conservatives detected COVID-19 misinformation at a lesser rate. Overall, results suggest that health communication related to COVID-19 misinformation should pay attention to conservative populations. Results also imply that interventions that activate deliberative cognitive styles hold promise in reducing belief in COVID-19 misinformation.
Loss of TRPV2-mediated blood flow autoregulation recapitulates diabetic retinopathy in rats

Loss of retinal blood flow autoregulation is an early feature of diabetes that precedes the development of clinically recognizable diabetic retinopathy (DR). Retinal blood flow autoregulation is mediated by the myogenic response of the retinal arterial vessels, a process that is initiated by the stretch‑dependent activation of TRPV2 channels on the retinal vascular smooth muscle cells (VSMCs). Here, we show that the impaired myogenic reaction of retinal arterioles from diabetic animals is associated with a complete loss of stretch‑dependent TRPV2 current activity on the retinal VSMCs. This effect could be attributed, in part, to TRPV2 channel downregulation, a phenomenon that was also evident in human retinal VSMCs from diabetic donors. We also demonstrate that TRPV2 heterozygous rats, a nondiabetic model of impaired myogenic reactivity and blood flow autoregulation in the retina, develop a range of microvascular, glial, and neuronal lesions resembling those observed in DR, including neovascular complexes. No overt kidney pathology was observed in these animals. Our data suggest that TRPV2 dysfunction underlies the loss of retinal blood flow autoregulation in diabetes and provide strong support for the hypothesis that autoregulatory deficits are involved in the pathogenesis of DR.
Relationship between cross-linking conditions of ethylene vinyl acetate and potential induced degradation for crystalline silicon photovoltaic modules

In this study, we investigated the relationship in crystalline silicon (c-Si) photovoltaic (PV) modules between the cross-linking level of copolymer of ethylene and vinyl acetate (EVA) as the encapsulant and the degree of degradation due to potential induced degradation (PID) phenomenon. We used three methods for the determination of cross-linking level of EVA: xylene method, which is one of the solvent extraction methods (SEM), curing degree by differential scanning calorimetry (DSC), and viscoelastic properties by dynamic mechanical analysis (DMA). The results indicate that degradation of PV modules by PID test depends on the cross-linking level of EVA. The PV modules encapsulated by EVA with higher cross-linking level show lower degradation degree due to PID phenomenon. Also we showed that EVA with higher cross-linking level tended to be higher volume resistivity. This tendency is similar to that for electrical resistance value during the PID test. The PID test was also done by changing thickness of EVA between front cover glass and c-Si with the same cross-linking level. The PV modules encapsulated by thicker EVA between front cover glass and c-Si cell show lower degradation by PID. From these results, the PV modules encapsulated by EVA with higher cross-linking level, higher volume resistivity and increased thickness would be tolerant of PID phenomenon.
The Periodontal Status of Orofacial Cleft Patients: A Systematic Review and Meta-Analysis

Objective Cleft lip and/or palate is the most commonly documented orofacial anomaly and may impact the status of health and disease of adjacent teeth along with their associated supporting structures. The authors performed a systematic review and meta-analysis to assess whether the presence of clefts altered the periodontal status of patients. Design The study was registered in PROSPERO (CRD42020210178). A systematic search of literature was performed utilizing unique search strings for PubMed, Scopus, and GoogleScholar as databases including gray literature from April 28, 2020 to October 3, 2020. Setting Cross-sectional and longitudinal human studies published in the English language, providing information about periodontal disease and its association with cleft lip, alveolus, and palate. Main Outcome Measures Periodontal outcome measures such as gingival index (GI), clinical attachment level (CAL), plaque index (PI), periodontal probing depth (PPD), and bleeding on probing (BOP) were utilized as the main outcome measures. Results Patients with clefts were predisposed to poorer periodontal outcomes. Subgroup analysis revealed compromised periodontal measures for clefts as compared to control sites without cleft which were statistically significant in terms of GI [Z = 2.44, P = . 01], CAL [Z = 2.52, P = . 01], PI [Z = 2.76, P = . 006] and not statistically significant for PPD [Z = 0.27, P = . 79] and BOP [Z = 1.47, P = . 14]. Conclusion Within the limitations of the review, the authors conclude that the presence of orofacial clefts may predispose to periodontal compromise when compared to normal controls. The GRADE rating was moderate.
Stroke care and collaborative academic research in Latin America.

OBJECTIVE A narrative overview of regional academic research collaborations to address the increasing burden and gaps in care for patients at risk of, and who suffer from, stroke in Latin America (LA). MATERIALS AND METHODS A summary of experiences and knowledge of the local situation is presented. No systematic literature review was performed. RESULTS The rapidly increasing burden of stroke poses immense challenges in LA, where prevention and manage-ment strategies are highly uneven and inadequate. Clinical research is increasing through various academic consortia and networks formed to overcome structural, funding and skill barriers. However, strengthening the ability to generate, analyze and interpret randomized evidence is central to further develop effective therapies and healthcare systems in LA. CONCLUSIONS Regional networks foster the conduct of multicenter studies -particularly randomized controlled trials-, even in resource-poor regions. They also contribute to the external validity of international studies and strengthen systems of care, clinical skills, critical thinking, and international knowledge exchange.