Miracle-dz/UniFAR-FTUs huggingface dataset:
Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology

Despite guideline recommendations and available evidence, implementation of treatment in heart failure (HF) is poor. The majority of patients are not prescribed drugs at target doses that have been proven to positively impact morbidity and mortality. Among others, tolerability issues related to low blood pressure, heart rate, impaired renal function or hyperkalaemia are responsible. Chronic kidney disease plays an important role as it affects up to 50% of patients with HF. Also, dynamic changes in estimated glomerular filtration rate may occur during the course of HF, resulting in inappropriate dose reduction or even discontinuation of decongestive or neurohormonal modulating therapy in clinical practice. As patients with HF are rarely naïve to pharmacologic therapies, the challenge is to adequately prioritize or select the most appropriate up‐titration schedule according to patient profile. In this consensus document, we identified nine patient profiles that may be relevant for treatment implementation in HF patients with a reduced ejection fraction. These profiles take into account heart rate (<60 bpm or >70 bpm), the presence of atrial fibrillation, symptomatic low blood pressure, estimated glomerular filtration rate (<30 or >30 mL/min/1.73 m2) or hyperkalaemia. The pre‐discharge patient, frequently still congestive, is also addressed. A personalized approach, adjusting guideline‐directed medical therapy to patient profile, may allow to achieve a better and more comprehensive therapy for each individual patient than the more traditional, forced titration of each drug class before initiating treatment with the next.
Antinuclear antibodies in COVID 19

We appreciated very much the interesting study by Chang et al.1 on the presence of antinuclear antibodies (ANAs) in patients with moderate/critical coronavirus disease 2019 (COVID 19). Both we and Chang and collaborators described the presence and significance of ANAs in patients with COVID19. The two experiences can be compared because Chang et al. studied a number of cases only slightly larger than us. In our opinion, the most important finding is represented by the presence of the nucleolar ANA reactivity, which, in the study by Chang et al.,1 as in ours,2 is the most frequently detected among the different ANA patterns. In this regard, it is worth mentioning that the nucleolar ANA pattern is one of the several ANA pattern detectable by Indirect immunofluorescence (Figure 1), together with other patterns, such as speckled, homogenous, multiple nuclear dots, and rim like membranous; this pattern can be the serological marker of systemic sclerosis and its antigenic target is the topoisomerase I protein (or scl70). Interestingly, it is of major relevance to note that among the clinical manifestations of systemic sclerosis, it includes pulmonary involvement in the form of a restrictive syndrome secondary to interstitial pneumopathy resembling COVID19 interstitial pneumonia. In our experience,2 however, all cases of nucleolar pattern were subsequently tested for antiExtractable Nuclear Antigens (antiENAs), as previously described,3 and no one was positive for antitopoisomerase I, whereas in Chang’s study no antiENAs were tested for. The lack of positivity for the known antiENA reactivities clearly means that we are dealing with unknown target antigens that need to be identified in order to better understand the underlying pathophysiological mechanisms. It would be very interesting to verify and confirm the frequency of the nucleolar ANA pattern in this peculiar setting of patients by other multicenter studies with the aim then to characterize this reactivity and to identify the underlying molecular target F I G U R E 1 Substrate: Hep2 cells, magnification ×40. Diffuse nucleoli positivity (red arrows), presence of perichromosomal fluorescence during the mitotic phase (yellow arrow)
Characteristics and clinical outcomes in atrial fibrillation patients classified using cluster analysis: the Fushimi AF Registry.

AIMS The risk of adverse events in atrial fibrillation (AF) patients was commonly stratified by risk factors or clinical risk scores. Risk factors often do not occur in isolation and are often found in multimorbidity 'clusters' which may have prognostic implications. We aimed to perform cluster analysis in a cohort of AF patients and to assess the outcomes and prognostic implications of the identified comorbidity cluster phenotypes. METHODS AND RESULTS The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. Hierarchical cluster analysis was performed on 4304 patients (mean age: 73.6 years, female; 40.3%, mean CHA2DS2-VASc score 3.37 ± 1.69), using 42 baseline clinical characteristics. On hierarchical cluster analysis, AF patients could be categorized into six statistically driven comorbidity clusters: (i) younger ages (mean age: 48.3 years) with low prevalence of risk factors and comorbidities (n = 209); (ii) elderly (mean age: 74.0 years) with low prevalence of risk factors and comorbidities (n = 1301); (iii) those with high prevalence of atherosclerotic risk factors, but without atherosclerotic disease (n = 1411); (iv) those with atherosclerotic comorbidities (n = 440); (v) those with history of any-cause stroke (n = 681); and (vi) the very elderly (mean age: 83.4 years) (n = 262). Rates of all-cause mortality and major adverse cardiovascular or neurological events can be stratified by these six identified clusters (log-rank test; P < 0.001 and P < 0.001, respectively). CONCLUSIONS We identified six clinically relevant phenotypes of AF patients on cluster analysis. These phenotypes can be associated with various types of comorbidities and associated with the incidence of clinical outcomes. CLINICAL TRIAL REGISTRATION INFORMATION https://www.umin. ac.jp/ctr/index.htm. Unique identifier: UMIN000005834.
Nanobody Conjugates for Targeted Cancer Therapy and Imaging

Conventional antibody-based targeted cancer therapy is one of the most promising avenues of successful cancer treatment, with the potential to reduce toxic side effects to healthy cells surrounding tumor cells. However, the full potential of antibodies is severely limited due to their large size, low stability, slow clearance, and high immunogenicity. Alternatively, recently discovered nanobodies, which are the smallest naturally occurring antigen-binding format, have shown great potential for addressing these limitations. Bioconjugation of nanobodies to functional groups such as toxins, enzymes, radionucleotides, and fluorophores can improve the efficacy and potency of nanobodies, enhance their in vivo pharmacokinetics, and expand the range of potential applications. Herein, we review the superior characteristics of nanobodies in comparison to conventional antibodies and provide insight into recent developments in nanobody conjugates for targeted cancer therapy and imaging.
Development and validation of epithelial mesenchymal transition-related prognostic model for hepatocellular carcinoma

Epithelial cell transformation (EMT) plays an important role in the pathogenesis and metastasis of hepatocellular carcinoma (HCC). We aimed to establish a genetic risk model to evaluate HCC prognosis based on the expression levels of EMT-related genes. The data of HCC patients were collected from TCGA and ICGC databases. Gene expression differential analysis, univariate analysis, and lasso combined with stepwise Cox regression were used to construct the prognostic model. Kaplan–Meier curve, receiver operating characteristic (ROC) curve, calibration analysis, Harrell’s concordance index (C-index), and decision curve analysis (DCA) were used to evaluate the predictive ability of the risk model or nomogram. GO and KEGG were used to analyze differently expressed EMT genes, or genes that directly or indirectly interact with the risk-associated genes. A 10-gene signature, including TSC2, ACTA2, SLC2A1, PGF, MYCN, PIK3R1, EOMES, BDNF, ZNF746, and TFDP3, was identified. Kaplan–Meier survival analysis showed a significant prognostic difference between high- and low-risk groups of patients. ROC curve analysis showed that the risk score model could effectively predict the 1-, 3-, and 5-year overall survival rates of patients with HCC. The nomogram showed a stronger predictive effect than clinical indicators. C-index, DCA, and calibration analysis demonstrated that the risk score and nomogram had high accuracy. The single sample gene set enrichment analysis results confirmed significant differences in the types of infiltrating immune cells between patients in the high- and low-risk groups. This study established a new prediction model of risk gene signature for predicting prognosis in patients with HCC, and provides a new molecular tool for the clinical evaluation of HCC prognosis.
Comparing Botulinum Toxin Injections with Extraocular Muscle Surgery in Toddlers with Esotropia: A Retrospective Analysis

Abstract Background In toddlers with esotropia, early alignment of the visual axes either with extraocular muscle surgery (EOMS) or botulinum toxin injections (BTIs) into both medial rectus muscles may result in improved depth perception. We compared the outcome of BTIs with EOMS in toddlers in order to gain further insight into the advantages and disadvantages of either method. Patients and Methods In this retrospective study, our encrypted database was searched for toddlers with esotropia aged 35 months or younger at the time of initial treatment with either BTIs or EOMS and who had a follow-up of at least 2 years. We analyzed the angle of deviation, dose effect (DE), and binocularity as well as the number of interventions. Results We identified 26 toddlers who received their first treatment for esotropia within the first 35 months of life: 16 with BTIs (9 males, 7 females) and 10 with EOMS (3 males, 7 females). Mean follow-up was considerably longer in the EOMS (87.7 months) than in the BTI group (35.7 months). Age at first intervention was 22.8 months in the BTI and 24.1 months in the EOMS group, and each toddler wore its full cycloplegic refraction. Mean angle at treatment was 41.25 prism diopters (PD) in the BTI compared to 52.9 PD in the EOMS group. The BTI group received an average of 1.68 BTIs, with a mean dosage of 14.5 IU Botox and a mean DE (mDE) of 1.8 PD/IU. In the EOMS group, the average number of surgeries was 1.4, with a mean dosage of 16.85 mm and a mDE of 3.14 PD/mm surgery. Some degree of binocularity could be observed in 9 (56%) of the BTI (5 × Bagolini positive, 2 × 550″, 2 × 220″) and in 4 (40%) of the EOMS group (2 × 3600″, 1 × 550″, 1 × 300″). By the end of the BTI group follow-up, four toddlers electively underwent EOMS rather than a 3rd BTI (followed by a 3rd BTI in 1), which resulted in the appearance of measurable binocularity in all four (1 × Bagolini positive, 1 × 220″, 1 × 200″, 1 × 60″). Conclusions Our results show that BTIs are a viable treatment alternative in early esotropia. Even if EOMS is ultimately required, some binocularity may develop as the visual axes are aligned for some time in the sensitive phase owing to the effects of Botox. Moreover, less surgical dosage is needed than would have otherwise been necessary to treat the original angle of deviation. BTIs are faster, less invasive, and present as an effective alternative when patient compliance is too low to reliably measure the angle of deviation, which is essential for the planning of EOMS.
SYSTEMATIC REVIEW A systematic review of pharmacoeconomic evaluations on oral diarylquinoline-based treatment for drug-resistant tuberculosis: from high to low burden countries

ABSTRACT Introduction: There is a rising global interest in the pharmacoeconomic evaluations of bedaquiline (BDQ), a novel oral diarylquinoline, for treatment of drug-resistant tuberculosis (DR-TB). Areas covered: This article systematically reviewed publications retrieved from Medline, American Psychological Association-Psychology information, Web of Science, Embase, Scopus, Science direct, Center for Reviews and Dissemination, and CINAHL Complete during 2010–2020 on pharmacoeconomic studies on BDQ for DR-TB treatment. Ten Markov model-based cost-effectiveness analyses identified were conducted in high (n = 4), intermediate (n = 2), and low (n = 4) TB burden countries. Expert opinion: The paucity of model-based health economic analyses on BDQ-containing regimens for DR-TB indicated that further pharmacoeconomic research of BDQ-based regimens, on the aspects of duration of BDQ treatment, types of DR-TB indicated, and settings of regions and health-systems, is highly warranted to inform global cost-effective use of BDQ-based regimens for DR-TB treatment. ARTICLE HISTORY Received 22 January 2021 Accepted 28 April 2021
The Lucerne Protocol for the Production of Autologous Serum Eyedrops

Abstract Background There are a variety of protocols for manufacturing autologous serum (AS) eye drops. The Lucerne protocol for the production of AS eye drops uses a slightly reduced gravitational (g)-force and time for the centrifugation process (2500 × g for 10 minutes), compared to previously published optimised protocols, to obtain high levels of epitheliotropic growth factors (3000 × g for 15 minutes). The goal of this study was to compare the concentrations of growth factors, albumin and lysozyme in autologous serum eye drops manufactured with these protocols. Material and Methods Blood from 5 healthy volunteers was placed in plastic tubes without an anticoagulant. Tubes from each donor were left in a vertical position for 2 hours at room temperature to facilitate coagulation, followed by centrifugation at either 2500 × g for 10 minutes or at 3000 × g for 15 minutes at room temperature. The serum levels of beta nerve growth factor (β-NGF), transforming growth factor β1 (TGF-β1), epidermal growth factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor BB (PDGF-BB) and vascular endothelial growth factor A (VEGF-A) were measured in triplicate with a multi-analyte Simple Plex platform. The Simple Plex cartridge allows each sample to be run in triplicate for each analyte and prevents any interaction between the antibody components for each biomarker. The serum level of albumin was measured by turbidimetric immunoassay Tina-quant and of lysozyme by single radial immunodiffusion assay. Results For all analytes, the reduced g-force and centrifugation time did not result in a significant difference in serum levels. Conclusions The Lucerne protocol for the production of autologous serum eye drops with reduced g-force and a shorter centrifugation time does not affect the concentrations of the main epitheliotropic growth factors, albumin and lysozyme, in AS eye drops.
Combination of human papillomaviruses L1 and L2 multiepitope constructs protects mice against tumor cells

Different types of cancer including cervical (>90%), anal (~88%), vaginal (~40%), and penile (~40%) cancers are associated with human papillomaviruse (HPV) infections. Three prophylactic vaccines (Cervarix, Gardasil, and Gardasil‐9) were approved to provide immuno‐protection against certain types of HPVs. Currently, next‐generation HPV vaccines such as L1/L2‐based vaccines are being developed to provide broad‐type HPV protection. In this study, we introduced a comprehensive framework for design of L1/L2 polyepitope‐based HPV vaccine candidate. This framework started with protein sequence retrieval and followed by conservancy analysis between high‐risk HPVs, MHC‐I and MHC‐II epitope mapping, and B‐cell and T‐cell epitope mapping. Subsequently, we performed Tap transport and proteasomal cleavage, population coverage, antigenicity, allergenicity and cross‐reactivity. After that, peptide‐MHCI/II flexible docking and comprehensive conservancy analysis against all HPV types were carried out. The next steps were prediction of interferon‐gamma and interleukin‐10 inducing epitopes, epitope selection and construct design, tertiary structure prediction, refinement and validation, discontinuous B‐cell epitope prediction, vaccine‐TLR4 molecular docking, and codon optimization. Our data showed that two designed vaccine constructs harboring 8 L1 peptides or 7 L2 peptides, individually were highly conserved between all well‐known HPV types. In addition, the combination of in silico/in vivo approaches indicated the potential ability of L1 and L2 polyepitope constructs for development of next generation prophylactic/therapeutic HPV vaccine.
An investigation of smoking habits and mental well‐being in healthcare personnel during COVID‐19

Abstract Aim This study aimed to the smoking levels of the healthcare personnel (n = 761) in Turkey, the changes in their smoking levels, and their mental well‐being levels. Design and Methods Data were collected via social networks from various cities in Turkey using a personal information form, the Fagerstrom test for nicotine dependence, the Warwick–Edinburgh mental well‐being scale. Findings Their mean nicotine dependence score was 3.50 ± 2.57 and mental well‐being score was 25.01 ± 5.44. The frequency of smoking during the pandemic was increased in 22.4% of the participants and was the same as that before the pandemic in 57.4% of the smokers. Practice Implications It is an introductory study of the current situation for healthcare professionals and researchers. It suggests protecting mental well‐being and reducing smoking.
Platycodin D inhibits autophagy and increases glioblastoma cell death via LDLR upregulation

Targeting autophagy is a promising therapeutic approach in cancer therapy. Here, we screened 30 traditional herbal medicines to identify novel autophagy regulators and found that Platycodon grandiflorus (PG) and platycodin D (PD), a triterpenoid saponin from PG, inhibited autophagy in glioblastoma multiforme (GBM) cells. Mechanistically, PD prevented lysosomal degradation and the fusion between autophagosomes and lysosomes by inducing sequestration of free cholesterol in lysosomes. The autophagy inhibitory effect of PD was mimicked by both genetic and pharmacological inhibition of Niemann‐Pick C1 (NPC1), which exports low‐density lipoprotein (LDL)‐derived cholesterol from lysosomes. Moreover, PD promoted the uptake of exogenous LDL cholesterol via upregulation of LDL receptor (LDLR), leading to further accumulation of cholesterol within lysosomes and GBM cell death. Importantly, these phenomena were more pronounced in LDLR‐overexpressing GBM cells than in normal astrocytes. Finally, blockade of cholesterol uptake by LDLR knockdown reversed the PD‐induced inhibition of autophagy and GBM cell growth. Our study proposes that PD could be a potent anti‐GBM drug by disrupting cholesterol trafficking and autophagy.
Primary results of long‐term outcomes in the MOMENTUM 3 pivotal trial and continued access protocol study phase: a study of 2200 HeartMate 3 left ventricular assist device implants

The MOMENTUM 3 pivotal trial established superiority of the HeartMate 3 (HM3) left ventricular assist device (LVAD), a fully magnetically levitated centrifugal‐flow pump, over the HeartMate II axial‐flow pump. We now evaluate HM3 LVAD outcomes in a single‐arm prospective continuous access protocol (CAP) post‐pivotal trial study.
Physician awareness, preparedness, and opinions toward consumer‐initiated genetic testing in Thailand: Views from a changing landscape

Consumer‐initiated genetic tests have captured public interest in recent years, including in low‐to‐middle‐income countries (LMICs) such as Thailand. Due to limited resources and personnel, physicians will most likely bear the burden of increasing service needs from the public as consumer‐initiated genetic tests become popularized. The primary objective of this study was to describe (a) awareness, (b) preparedness to provide counseling about the consumer‐initiated genetic test, and (c) opinions on the usefulness of consumer‐initiated genetic tests among physicians at an academic hospital in Bangkok, Thailand. The secondary objective was to describe factors that were associated with the awareness, preparedness, and opinion of the participants. Paper questionnaires were sent out to participants which included internal medicine residents, fellows, and faculty staff members. The questionnaires assessed awareness, preparedness to discuss consumer‐initiated genetic test results, and opinion on the usefulness of consumer‐initiated genetic tests and included both closed‐ and open‐ended questions. Responses were anonymous. Among 308 participants, there were 223 (72.4%) residents, 14 (4.5%) fellows, and 71 (23.1%) staff members. Only 15% of participants were aware of consumer‐initiated genetic tests, mostly from the internet, and only 7% were prepared to provide counseling regarding consumer‐initiated genetic tests. However, 60% agreed that consumer‐initiated genetic tests may be clinically useful. Many participants, including trainees, expressed concerns about the interpretation of consumer‐initiated genetic test results, application into clinical practice, appropriate counseling, and patient referral to geneticists. Multivariate logistic regression revealed that years of work experience was independently associated with awareness of consumer‐initiated genetic tests, while male gender and less work experience were independently associated with favorable opinion toward the usefulness of consumer‐initiated genetic tests. Our results pointed to an urgent need for genetic counselors in Thailand. Also, physicians, particularly trainees, need appropriate training to prepare them for a rapidly evolving environment where consumer‐initiated genetic tests become commonplace.
Parvalbumin interneuron inhibition onto anterior insula neurons projecting to the basolateral amygdala drives aversive taste memory retrieval

Memory retrieval refers to the fundamental ability of organisms to make use of acquired, sometimes inconsistent, information about the world. While memory acquisition has been studied extensively, the neurobiological mechanisms underlying memory retrieval remain largely unknown. The anterior insula (aIC) is indispensable in the ability of mammals to retrieve associative information regarding tastants that have been previously linked with gastric malaise. Here, we show that aversive taste memory retrieval promotes cell-type-specific activation in the aIC. Aversive, but not appetitive taste memory retrieval, relies on specific changes in activity and connectivity at parvalbumin (PV) inhibitory synapses onto aIC pyramidal neurons projecting to the basolateral amygdala. PV aIC interneurons, coordinate aversive taste memory retrieval, and are necessary for its dominance when conflicting internal representations are encountered. This newly described interaction of PV and a subset of excitatory neurons can explain the coherency of aversive memory retrieval, an evolutionary pre-requisite for animal survival. Graphical Abstract Retrieval of Conditioned Taste Aversion (CTA) memories at the anterior insular cortex activates Parvalbumin (PV) interneurons and increases synaptic inhibition onto activated pyramidal neurons projecting to the basolateral amygdala (aIC-BLA). Unlike innately appetitive taste memory retrieval, CTA retrieval increases the amplitude and frequency of synaptic inhibition onto aIC-BLA projecting neurons, that is dependent on activity in aIC PV interneurons. Activation of aIC PV interneurons is necessary for the expression of learned taste avoidance, in both sexes, regardless of stimulus identity. Extinction of aversive taste memories suppresses the frequency, but not the amplitude of synaptic inhibition on aIC-BLA projecting neurons. The reinstatement of aversive taste memories following extinction is dependent upon activation of aIC PV interneurons and increases in the frequency of inhibition on aIC-BLA projecting neurons.