Miracle-dz/UniFAR-FTUs huggingface dataset:
The ‘Surprise question’ in heart failure: a prospective cohort study

Objective The Surprise Question (SQ) is a prognostic screening tool used to identify patients with limited life expectancy. We assessed the SQ’s performance predicting 1-year mortality among patients in ambulatory heart failure (HF) clinics. We determined that the SQ’s performance changes according to sex and other demographic (age) and clinical characteristics, mainly left ventricular ejection fraction (LVEF) and the New York Heart Association (NYHA) functional classifications. Methods We conducted a prospective cohort study in two HF clinics. To assess the performance of the SQ in predicting 1-year mortality, we calculated the sensitivity, specificity, positive and negative likelihood ratios, and the positive and negative predictive values. To illustrate if the results of the SQ changes the probability that a patient dies within 1 year, we created Fagan’s nomograms. We report the results from the overall sample and for subgroups according to sex, age, LVEF and NYHA functional class. Results We observed that the SQ showed a sensitivity of 85% identifying ambulatory patients with HF who are in the last year of life. We determined that the SQ’s performance predicting 1-year mortality was similar among women and men. The SQ performed better for patients aged under 70 years, for patients with reduced or mildly reduced ejection fraction, and for patients NYHA class III/IV. Conclusions We consider the tool an easy and fast first step to identify patients with HF who might benefit from an advance care planning discussion or a referral to palliative care due to limited life expectancy.
Clan genomics: From OMIM phenotypic traits to genes and biology

Clinical characterization of a patient phenotype has been the quintessential approach for elucidating a differential diagnosis and a hypothesis to explore a potential clinical diagnosis. This has resulted in a language of medicine and a semantic ontology, with both specialty‐ and subspecialty‐specific lexicons, that can be challenging to translate and interpret. There is no ‘Rosetta Stone’ of clinical medicine such as the genetic code that can assist translation and interpretation of the language of genetics. Nevertheless, the information content embodied within a clinical diagnosis can guide management, therapeutic intervention, and potentially prognostic outlook of disease enabling anticipatory guidance for patients and families. Clinical genomics is now established firmly in medical practice. The granularity and informative content of a personal genome is immense. Yet, we are limited in our utility of much of that personal genome information by the lack of functional characterization of the overwhelming majority of computationally annotated genes in the haploid human reference genome sequence. Whereas DNA and the genetic code have provided a ‘Rosetta Stone’ to translate genetic variant information, clinical medicine, and clinical genomics provide the context to understand human biology and disease. A path forward will integrate deep phenotyping, such as available in a clinical synopsis in the Online Mendelian Inheritance in Man (OMIM) entries, with personal genome analyses.
Weight loss and exercise differentially affect insulin sensitivity, body composition, cardiorespiratory fitness and muscle strength in older adults with obesity; a randomized controlled trial.

BACKGROUND Aging-related disease risk is exacerbated by obesity and physical inactivity. It is unclear how weight loss and increased activity improve risk in older adults. We aimed to determine the effects of diet-induced weight loss with and without exercise on insulin sensitivity, VO2peak, body composition, and physical function in older obese adults. METHODS Physically inactive older (68.6 ± 4.5 years) obese (BMI 37.4 ± 4.9 kg/m 2) adults were randomized to: Health education control (HEC; n=25); Diet-induced weight loss (WL; n=31); or Weight loss and exercise (WLEX; n=28) for 6 months. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp, body composition by DXA and MRI, strength by isokinetic dynamometry, and VO2peak by graded exercise test. RESULTS WLEX improved (p<0.05) peripheral insulin sensitivity (+75 ± 103%) vs. HEC (+12 ± 67%); WL (+36 ± 47%) vs. HEC did not reach statistical significance. WLEX increased VO2peak (+7 ± 12%) vs. WL (-2 ± 24%), and prevented reductions in strength and lean mass induced by WL (p<0.05). WLEX decreased abdominal adipose tissue (-16 ± 9%) vs. HEC (-3 ± 8%) and intermuscular adipose tissue (-15 ± 13 %) vs. both HEC (+9 ± 15%) and WL (+2 ± 11%) (p<0.01). CONCLUSIONS Exercise with weight loss improved insulin sensitivity and VO2peak, decreased ectopic fat, and preserved lean mass and strength. Weight loss alone decreased lean mass and strength. Older adults intending to lose weight should perform regular exercise to promote cardiometabolic and functional benefits, which may not occur with calorie restriction-induced weight loss alone.
Prognostic significance of TIM-3 expression pattern at diagnosis in patients with t(8;21) acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease and needs to be stratified. Both, cancer cells and immune cells participate in tumor initiation, growth and progression and might affect clinical outcomes. TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3), an immune checkpoint molecule, is expressed not only on immune cells but also on leukemic stem cells (LSCs) in AML. This prompted us to investigate the prognostic significance of TIM-3 in t(8;21) AML. A total of 47 t(8;21) AML patients were tested for TIM-3 expression by multi-parameter flow cytometry at diagnosis. 35 of these, who received chemotherapy alone or along with allogeneic hematopoietic stem cell transplantation were followed up. The expression pattern of TIM-3 on T-cells and NK (natural killer) cells as a whole (T + NK) and LSCs were evaluated independently. High percentage of T + NK − TIM-3+ and CD34+CD38−TIM-3+ cells were significantly associated with a high 2-year cumulative incidence of relapse (CIR) (p = 0.028, 0.016). Further, concurrent high frequencies of T + NK-TIM-3+ and CD34+CD38-TIM-3+ cells at diagnosis were significantly associated with a high 2-year CIR (p < 0.0001) and this together with c-KIT D816 mutation were the independent adverse prognostic factors for relapse (hazard ratio (HR)=2.5, [95% confidence interval (CI), 1.1–6.0], p = 0.04; HR = 46.5, [95% CI, 2.7–811.5], p = 0.009). In conclusion, the expression pattern of TIM-3 on both T and NK cells and LSCs at diagnosis had prognostic significance in t (8;21) AML.
A Semi-Mechanistic Model of the Bactericidal Activity of High-Dose Isoniazid Against Multi-Drug-Resistant Tuberculosis: Results from a Randomized Clinical Trial.

RATIONALE There is accumulating evidence that higher-than-standard doses of isoniazid are effective against low-to-intermediate-level isoniazid-resistant strains of Mycobacterium tuberculosis, but the optimal dose remains unknown. OBJECTIVE Characterizing the association between isoniazid pharmacokinetics (standard or high-dose) and early bactericidal activity against M. tuberculosis (drug-sensitive and inhA-mutated) and N-acetyltransferase 2 status. METHODS ACTG A5312/INHindsight is 7-day early bactericidal activity study with isoniazid at normal dose (5 mg/kg) for patients with drug-sensitive bacteria and 5, 10, and 15 mg/kg doses for patients with inhA mutants. Participants with pulmonary TB received daily isoniazid monotherapy and collected sputum daily. Colony-forming units (CFU) on solid culture and time-to-positivity (TTP) in liquid culture were jointly analyzed using nonlinear mixed-effects modeling. RESULTS Fifty-nine adults were included in this analysis. Decline in sputum CFU was described by a one-compartment model, while an exponential bacterial growth model was used to interpret TTP data. The model found bacterial kill is modulated by isoniazid concentration using an effect compartment and a sigmoidal Emax relationship. The model predicted lower potency but similar maximum-kill of isoniazid against inhA-mutated isolates compared to drug-sensitive. Based on simulations from the PK/PD model, to achieve a drop in bacterial load comparable to 5mg/kg against drug-sensitive TB, 10- and 15-mg/kg doses are necessary against inhA-mutated isolates in slow and intermediate N-acetyltransferase 2 acetylators, respectively. Fast acetylators underperformed even at 15 mg/kg. CONCLUSIONS Dosing of isoniazid based on N-acetyltransferase 2 acetylator status may help patients attain effective exposures against inhA-mutated isolates while mitigating toxicity risks associated with higher doses. Clinical trial registration available at www.clinicaltrials. gov, ID: NCT01936831.
Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues

Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients’ TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients’ native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with 13C6-Glc/13C5,15N2-Gln, multiplex immunofluorescence, and digital spatial profiling (DSP) were employed to interrogate metabolic and functional responses to Pembrolizumab and/or WGP. Primary and BM PD-1+ lung cancer OTC responded to Pembrolizumab and Pembrolizumab + WGP treatments, respectively. Pembrolizumab activated innate immune metabolism and functions in primary OTC, which were accompanied by tissue damage. DSP analysis indicated an overall decrease in immunosuppressive macrophages and T cells but revealed microheterogeneity in immune responses and tissue damage. Two TMEs with altered cancer cell properties showed resistance. Pembrolizumab or WGP alone had negligible effects on BM-lung cancer OTC but Pembrolizumab + WGP blocked central metabolism with increased pro-inflammatory effector release and tissue damage. In-depth metabolic analysis and multiplex TME imaging of lung cancer OTC demonstrated overall innate immune activation by Pembrolizumab but heterogeneous responses in the native TME of a patient with primary NSCLC. Metabolic and functional analysis also revealed synergistic action of Pembrolizumab and WGP in OTC of metastatic NSCLC.
A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes.

ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. We herein detected a de novo heterozygous point mutation in ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally or soon after birth with signs of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamic simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of phospholipids altered cell characteristics, including cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. MALDI-imaging mass-spectrometry showed a marked increase of SM levels in the brains of Q84E knock-in mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.
Molecular autopsy by proxy in preconception counseling

Monogenic diseases that result in early pregnancy loss or neonatal death are genetically and phenotypically highly variable. This often poses significant challenges in arriving at a molecular diagnosis for reproductive planning. Molecular autopsy by proxy (MABP) refers to the genetic testing of relatives of deceased individuals to deduce the cause of death. Here, we specifically tested couples who lost one or more children/pregnancies with no available DNA. We developed our testing strategy using whole exome sequencing data from 83 consanguineous Saudi couples. We detected the shared carrier state of 50 pathogenic variants/likely pathogenic variants in 43 families and of 28 variants of uncertain significance in 24 families. Negative results were seen in 16 couples after variant reclassification. In 10 families, the risk of more than one genetic disease was documented. Secondary findings were seen in 10 families: either genetic variants with potential clinical consequences for the tested individual or a female carrier for X‐linked conditions. This couple‐based approach has enabled molecularly informed genetic counseling for 52% (43/83 families). Given the predominance of autosomal recessive causes of pregnancy and child death in consanguineous populations, MABP can be a helpful approach to consanguineous couples who seek counseling but lack molecular data on their deceased offspring.
Do cancer incidence and mortality rates differ among ethnicities in Canada?

BACKGROUND Cancer incidence rates have been shown to vary by ethnicity, and the increasing awareness of and interest in reporting ethnic health inequalities have been growing internationally. The objective of this study was to assess cancer incidence and mortality rates by ethnicity in Canada. DATA AND METHODS The study used the 2006 Canadian Census Health and Environment Cohort, linked to the Canadian Cancer Registry and the Canadian Vital Statistics-Death Database, to determine cancer cases and mortality from 2006 to 2016. Ethnicity was categorized as non-Indigenous North American (NINA); European; Caribbean; Latin, Central and South American (LCSA); African; East Asian; South Asian; and West Central Asian and Middle Eastern. RESULTS Europeans had the highest standardized incidence rates, while NINA had the highest mortality rates. Rates varied substantially by ethnicity and immigrant status. The top three cancers accounted for 46.5% to 61.9% of all new cancers, while the top three cancer deaths accounted for 36.1% to 61.9% of all deaths. The distribution of cancers within the top 10 cancers and the top 10 cancer deaths also differed; e.g., stomach cancer was found to be more prevalent in the East Asian, LCSA, African and Caribbean groups. Non-immigrant African males had the highest cancer incidence rates, and non-immigrant South Asian females had the highest mortality rates. DISCUSSION There is considerable variability in cancer incidence and cancer mortality rates by ethnicity, and this study addresses the knowledge gap in Canada in this area. Establishing baseline indicators, such as cancer rates by ethnicity, is essential to understanding the differences within the diverse Canadian population and to informing targeted interventions that may help reduce health inequalities.
Disentangling water sources in a gypsum plant community. Gypsum crystallization water is a key source of water for shallow-rooted plants

Abstract Background and Aims Gypsum drylands are widespread worldwide. In these arid ecosystems, the ability of different species to access different water sources during drought is a key determining factor of the composition of plant communities. Gypsum crystallization water could be a relevant source of water for shallow-rooted plants, but the segregation in the use of this source of water among plants remains unexplored. We analysed the principal water sources used by 20 species living in a gypsum hilltop, the effect of rooting depth and gypsum affinity, and the interaction of the plants with the soil beneath them. Methods We characterized the water stable isotope composition, δ 2H and δ 18O, of plant xylem water and related it to the free and gypsum crystallization water extracted from different depths throughout the soil profile and the groundwater, in both spring and summer. Bayesian isotope mixing models were used to estimate the contribution of water sources to plant xylem sap. Key Results In spring, all species used free water from the top soil as the main source. In summer, there was segregation in water sources used by different species depending on their rooting depth, but not on their gypsum affinity. Gypsum crystallization water was the main source for most shallow-rooted species, whereas free water from 50 to 100 cm depth was the main source for deep-rooted species. We detected plant–soil interactions in spring, and indirect evidence of possible hydraulic lift by deep-rooted species in summer. Conclusions Plants coexisting in gypsum communities segregate their hydrological niches according to their rooting depth. Crystallization water of gypsum represents an unaccounted for, vital source for most of the shallow-rooted species growing on gypsum drylands. Thus, crystallization water helps shallow-rooted species to endure arid conditions, which eventually accounts for the maintenance of high biodiversity in these specialized ecosystems.
A comprehensive program of cognitive stimulation with digital inclusion, physical activity and social interaction can modify BDNF levels and improve cognition in adults over 50: a randomized controlled pilot study

Abstract Objectives To analyze the effect of a comprehensive program of cognitive stimulation with digital inclusion, physical activity and social interaction, called "Oficina da Lembrança" (OL), on the cognitive status and concentration of biomarkers of neuroplasticity, neurodegeneration in adults aged 50 years and over attending a Memory Clinic. Methods In this pilot randomized controlled study, 64 patients without dementia aged 45 to 79 years, seen at a University Memory Clinic in Southern Brazil, were randomly allocated to the intervention and control groups. The intervention consisted of participation in OL for 12 weeks. Serum biomarkers (brain-derived neurotrophic factor [BDNF], S100β, and neuron-specific enolase [NSE]) and cognitive status were analyzed as primary and secondary outcomes. The Wilcoxon test and Generalized Estimating Equations (GEE) were applied. Results Of the 64 patients invited to participate in the study, 33 (intervention: 17, control: 16) completed the study with all data. Improvement of cognitive status was significant in the intervention group (22.6 to 24.5) but not in the control group (20.1 to 21.1). There was a significant reduction of BDNF in OL participants, but no significant change was observed in the neurodegenerative biomarkers S100β or NSE. The concentration of BDNF decreased significantly post-OL in the intervention group (-288.1, 95%CI −362.1 to −94.1), even after adjusting for sex, age, and educational level. Cognitive status was significantly improved in OL participants. Conclusion The OL program improved cognitive status, reduced serum BDNF levels, and empowered digitally excluded older adults. There was no effect of this intervention on S100β or NSE. Clinical trial registration This study has a Universal Trial Number (UTN) U1111-1195-2642 and was registered in the Brazilian Clinical Trials Registry (ReBEC), number RBR-38X665.
Public perceptions and behavioural responses to the first COVID-19 pandemic wave in Italy: Results from the iCARE study

Abstract Background Italy was the first European country to be affected by COVID-19. Considering that many countries are currently battling the 2nd wave of the pandemic, understanding people’s perceptions and responses to government policies remains critical for informing on-going mitigation strategies. We assessed attitudes towards COVID-19 policies, levels of adherence to preventive behaviours, and the association between COVID-19 related concerns and adherence levels. Methods We recruited a convenience sample of Italian individuals from an international cross-sectional survey (www.icarestudy.com) from March 27th to May 5th 2020. Multivariate regression models were used to test the association between concerns and the adoption of preventive measures. Results The survey included 1,332 participants (female (68%), younger than 25 (57%)) that reported high awareness (over 96%) and perceived importance (88%) of policies. We observed varied levels of adherence to: hand washing (96%), avoiding social gatherings (96%), self-isolation if suspected or COVID-19 positive (77%). Significantly lower adherence to self-isolation was reported by individuals with current employment. High levels of concerns regarding health of other individuals and country economy were reported. Only health concerns for others were significantly associated with higher adherence to hand washing behaviour. Conclusions In order to inform current/future government strategies, we provide insights about population’s responses to the initial pandemic phase in Italy. Communication approaches should consider addressing people’s concerns regarding the health of other individuals to motivate adherence to prevention measures. Provision of social and economic support is warranted to avoid unequal impacts of governmental policies and allow effective adherence to self-isolating measures.
The Stability Effect of Atomic Layer Deposition (ALD) of Al2O3 on CH3NH3PbI3 Perovskite Solar Cell Fabricated by Vapor Deposition

The perovskite solar cells (PSCs) with Al2O3 passivation layer were fabricated and characterized. The PSC have some advantages of easier and cheaper fabrication process than that of conventional Si solar cells, III-V compound semiconductor solar cells, and organic solar cells. The perovskite light harvester, CH3NH3PbI3, was deposited by vapor deposition on [compact TiO2 / F-doped tin oxide (FTO) / glass]. The advantage of vapor deposition over solution process is expected to be able to offer the thin film with smoother surface over larger area. Then, Al2O3 passivation layer was deposited by atomic layer deposition (ALD) on the CH3NH3PbI3 light harvester. Al2O3 passivation layer was expected to prevent the CH3NH3PbI3 light harvester from oxidation and improve the solar cell efficiency, and ALD has been one of the most effective methods to deposit Al2O3 thin film for last 25 years. The atomic layer deposited Al2O3 layer thickness was optimized from the solar cell characterization. The optimized power conversion efficiency (PCE) and Al2O3 thickness were ~8.0 % and ~10.0 nm, respectively.
A Longitudinal Study of the Impact of Schwartz Center Rounds on Moral Distress

Moral distress occurs when moral integrity is compromised and can affect any healthcare professional. This study examined the impact of Schwartz Center Rounds (SCRs) on moral distress using a longitudinal, quasi-experimental design to examine SCR attendees from 2015 to 2019. Data were collected via a 2-part survey composed of demographics and Moral Distress Thermometer (MDT) readings before rounds and immediately after rounds. Most participants experienced either no change in moral distress (50.6%) or a decrease in moral distress (33.7%) after attending one of the SCRs. Participants who worked with adult populations had higher moral distress after participation for most topics. An increase in moral distress was associated with a longer time in the current position. Fifty percent of the physicians had a decrease in their moral distress immediately after the rounds. Schwartz Center Rounds is a promising approach to foster high-functioning teams while promoting wellness and mitigating moral distress among employees.