Miracle-dz/UniFAR-FTUs huggingface dataset:
Cardiac Fibroblasts Mediate a Sexually Dimorphic Fibrotic Response to β‐Adrenergic Stimulation

Background Biological sex is an important modifier of cardiovascular disease and women generally have better outcomes compared with men. However, the contribution of cardiac fibroblasts (CFs) to this sexual dimorphism is relatively unexplored. Methods and Results Isoproterenol (ISO) was administered to rats as a model for chronic β‐adrenergic receptor (β‐AR)‐mediated cardiovascular disease. ISO‐treated males had higher mortality than females and also developed fibrosis whereas females did not. Gonadectomy did not abrogate this sex difference. To determine the cellular contribution to this phenotype, CFs were studied. CFs from both sexes had increased proliferation in vivo in response to ISO, but CFs from female hearts proliferated more than male cells. In addition, male CFs were significantly more activated to myofibroblasts by ISO. To investigate potential regulatory mechanisms for the sexually dimorphic fibrotic response, β‐AR mRNA and PKA (protein kinase A) activity were measured. In response to ISO treatment, male CFs increased expression of β1‐ and β2‐ARs, whereas expression of both receptors decreased in female CFs. Moreover, ISO‐treated male CFs had higher PKA activity relative to vehicle controls, whereas ISO did not activate PKA in female CFs. Conclusions Chronic in vivo β‐AR stimulation causes fibrosis in male but not female rat hearts. Male CFs are more activated than female CFs, consistent with elevated fibrosis in male rat hearts and may be caused by higher β‐AR expression and PKA activation in male CFs. Taken together, our data suggest that CFs play a substantial role in mediating sex differences observed after cardiac injury.
Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA)

Supplemental Digital Content is available in the text. Background: Adjuvant breast cancer therapy containing anthracyclines with or without anti–human epidermal growth factor receptor–2 antibodies and radiotherapy is associated with cancer treatment–related cardiac dysfunction. In the PRADA trial (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy), concomitant treatment with the angiotensin receptor blocker candesartan attenuated the reduction in left ventricular ejection fraction (LVEF) in women receiving treatment for breast cancer, whereas the β-blocker metoprolol attenuated the increase in cardiac troponins. This study aimed to assess the long-term effects of candesartan and metoprolol or their combination to prevent a reduction in cardiac function and myocardial injury. Methods: In this 2×2 factorial, randomized, placebo-controlled, double-blind, single-center trial, patients with early breast cancer were assigned to concomitant treatment with candesartan cilexetil, metoprolol succinate, or matching placebos. Target doses were 32 and 100 mg, respectively. Study drugs were discontinued after adjuvant therapy. All 120 validly randomized patients were included in the intention-to-treat analysis. The primary outcome measure was change in LVEF assessed by cardiovascular magnetic resonance imaging from baseline to extended follow-up. Secondary outcome measures included changes in left ventricular volumes, echocardiographic peak global longitudinal strain, and circulating cardiac troponin concentrations. Results: A small decline in LVEF but no significant between-group differences were observed from baseline to extended follow-up, at a median of 23 months (interquartile range, 21 to 28 months) after randomization (candesartan, 1.7% [95% CI, 0.5 to 2.8]; no candesartan, 1.8% [95% CI, 0.6 to 3.0]; metoprolol, 1.6% [95% CI, 0.4 to 2.7]; no metoprolol, 1.9% [95% CI, 0.7 to 3.0]). Candesartan treatment during adjuvant therapy was associated with a significant reduction in left ventricular end-diastolic volume compared with the noncandesartan group (P=0.021) and attenuated decline in global longitudinal strain (P=0.046) at 2 years. No between-group differences in change in cardiac troponin I and T concentrations were observed. Conclusions: Anthracycline-containing adjuvant therapy for early breast cancer was associated with a decline in LVEF during extended follow-up. Candesartan during adjuvant therapy did not prevent reduction in LVEF at 2 years, but was associated with modest reduction in left ventricular end-diastolic volume and preserved global longitudinal strain. These results suggest that a broadly administered cardioprotective approach may not be required in most patients with early breast cancer without preexisting cardiovascular disease. Registration: URL: https://www.clinicaltrials. gov; Unique identifier: NCT01434134.
Duration of antibiotic treatment using procalcitonin-guided treatment algorithms in older patients: a patient-level meta-analysis from randomized controlled trials

Abstract Background Older patients have a less pronounced immune response to infection, which may also influence infection biomarkers. There is currently insufficient data regarding clinical effects of procalcitonin (PCT) to guide antibiotic treatment in older patients. Objective and design We performed an individual patient data meta-analysis to investigate the association of age on effects of PCT-guided antibiotic stewardship regarding antibiotic use and outcome. Subjects and methods We had access to 9,421 individual infection patients from 28 randomized controlled trials comparing PCT-guided antibiotic therapy (intervention group) or standard care. We stratified patients according to age in four groups (<75 years [n = 7,079], 75–80 years [n = 1,034], 81–85 years [n = 803] and >85 years [n = 505]). The primary endpoint was the duration of antibiotic treatment and the secondary endpoints were 30-day mortality and length of stay. Results Compared to control patients, mean duration of antibiotic therapy in PCT-guided patients was significantly reduced by 24, 22, 26 and 24% in the four age groups corresponding to adjusted differences in antibiotic days of −1.99 (95% confidence interval [CI] −2.36 to −1.62), −1.98 (95% CI −2.94 to −1.02), −2.20 (95% CI −3.15 to −1.25) and − 2.10 (95% CI −3.29 to −0.91) with no differences among age groups. There was no increase in the risk for mortality in any of the age groups. Effects were similar in subgroups by infection type, blood culture result and clinical setting (P interaction >0.05). Conclusions This large individual patient data meta-analysis confirms that, similar to younger patients, PCT-guided antibiotic treatment in older patients is associated with significantly reduced antibiotic exposures and no increase in mortality.
Predictors of worker mental health in intellectual disability services during COVID-19.

BACKGROUND Workers supporting adults with intellectual disabilities experience significant stress in their essential role during COVID-19. The purpose of this study was to describe the experience of these workers and determine predictors of emotional distress. METHODS Eight hundred and thirty-eight workers supporting adults with intellectual disabilities completed an online survey about their work during COVID-19 and their mental health in July 2020. RESULTS One in four workers reported moderate to severe emotional distress. Being older and more experienced, having counselling services available through one's agency, and engaging in regular exercise or hobbies outside work were associated with less distress. Workers who reported increased stress in the workplace, stigma towards their families because of their job, personal fears about spreading COVID-19, and receipt of medications for mental health conditions or therapy reported greater distress. CONCLUSIONS More attention is needed to address the mental health of workers supporting adults with intellectual disabilities as they continue their essential work during the pandemic.
Chromosome 20q11.21 Amplifications in Colorectal Cancer.

BACKGROUND Colorectal cancer is the most common gastrointestinal carcinoma in western countries. Prognosis of metastatic colorectal cancer has improved in the last decades, but the disease continues to carry an adverse outcome in most cases. An improved understanding of molecular pathogenesis has provided incremental benefits in survival outcomes with the introduction of targeted therapies for specific sub-types and gives hope for further improvements. MATERIALS AND METHODS Publicly available data from genomic series of colorectal cancer published by the TCGA were analyzed with the aim of characterizing the sub-set of colorectal cancers carrying amplifications of chromosome 20q11.21, compared with cancers with no amplifications in this locus. Associations of 20q11.21-amplified cancers with other molecular lesions commonly observed in colorectal cancer were explored. mRNA expression of genes from the locus in amplified cases was analyzed. An exploratory survival analysis was also performed. RESULTS Amplifications of genes at chromosome arm 20q are observed in 7% to 9% of colorectal cancers, representing the most commonly amplified loci in this type of cancer. The 20q11.21 presents the highest amplification rate in the 20q arm. 20q11.21 amplified cancers display concomitant mutations in the KRAS pathway and SMAD4 less often than non-amplified cancers. Mutations in DNA repair genes are also less often encountered in 20q11.21 amplified colorectal cancers than non-amplified ones. CONCLUSION Amplification of genes at locus 20q11.21, representing the most frequently amplified locus in colorectal cancers, is associated with specific molecular characteristics and may have therapeutic implications.
Men's willingness to support HPV vaccination and cervical cancer screening in Nigeria.

Cervical cancer is the second most common female cancer in Nigeria, even though it can be prevented by vaccination and screening. The uptake of these preventive services is extremely low due to lack of spousal support and cost. Human papilloma virus (HPV) vaccines and cervical screening require finance as health services are mostly paid out of pocket. This study explored Nigerian men's willingness to encourage and pay for family member to obtain HPV vaccine and cervical screening. This is a cross-sectional study of 352 men aged 18-65 years living in 12 communities in the 6-geopolitical region. We found poor perception of HPV risk, and believed their family was not susceptible to cervical cancer. However, the majority (>80%) believed HPV vaccine and cervical screenings are important. Additionally, a good number (>58%) would encourage and pay for their family member to receive HPV vaccine and cervical screening. Residency, educational level and monthly income were significantly associated with willingness to encourage their family to receive HPV vaccine and cervical screening. Also, age group, marital status, residency, educational level and monthly income were significantly associated with the willingness to pay for HPV vaccine and cervical cancer screening. Majority were willing to encourage and pay for their family member to get vaccinated and receive cervical screening. This supports the findings that lack of male involvement may be an overlooked obstacle to cervical cancer prevention in developing countries.
Long‐term declines and recovery of meadow area across the world’s seagrass bioregions

As human impacts increase in coastal regions, there is concern that critical habitats that provide the foundation of entire ecosystems are in decline. Seagrass meadows face growing threats such as poor water quality and coastal development. To determine the status of seagrass meadows over time, we reconstructed time series of meadow area from 175 studies that surveyed 547 sites around the world. We found an overall trajectory of decline in all seven bioregions with a global net loss of 5602 km2 (19.1% of surveyed meadow area) occurring since 1880. Declines have typically been non‐linear, with rapid and historical losses observed in several bioregions. The greatest net losses of area occurred in four bioregions (Tropical Atlantic, Temperate North Atlantic East, Temperate Southern Oceans and Tropical Indo‐Pacific), with declining trends being the slowest and most consistent in the latter two bioregions. In some bioregions, trends have recently stabilised or reversed. Losses, however, still outweigh gains. Despite consistent global declines, meadows show high variability in trajectories, within and across bioregions, highlighting the importance of local context. Studies identified 12 different drivers of meadow area change, with coastal development and water quality as the most commonly cited. Overall, however, attributions were primarily descriptive and only 10% of studies used inferential attributions. Although ours is the most comprehensive dataset to date, it still represents only one‐tenth of known global seagrass extent, with conspicuous historical and geographic biases in sampling. It therefore remains unclear whether the bioregional patterns of change documented here reflect changes in the world's unmonitored seagrass meadows. The variability in seagrass meadow trajectories, and the attribution of change to numerous drivers, suggest we urgently need to improve understanding of the causes of seagrass meadow loss if we are to improve local‐scale management.
Fluoride-Induced Changes in In Vivo Papillary Cyclic AMP

Two separate experiments were designed to measure urinary cyclic AMP and renal papillary cyclic AMP, respectively, Results suggest that urinary cyclic AMP excretion rate is unchanged and cannot be used as an index of tubular sensitivity to either vasopressin or fluoride. However, renal papillary tissue cyclic AMP increased significantly (p<0.05) at plasma fluoride concentrations which result in polyuric renal failure. Further, it appears that fluoride independently stimulates cyclic AMP in the papilla, demonstrated by the additive effect with vasopressin. It was postulated that the defect in water reabsorption induced by fluoride must be at a step subsequent to the generation of cyclic AMP, because one would expect to see an antidiuresis, not a diuresis with increased tissue cyclic AMP.
Translating a Theory of Active Learning: An Attempt to Close the Research-Practice Gap in Education

Despite decades of research related to teaching and learning, the findings have made little impact on classroom teaching and learning. This paper briefly describes the four existing methods to close this gap, with more extensive analyses of the limitations of one of the four methods, which is to consolidate and distill robust laboratory findings reported over the past decades and attempt to translate them for classroom practice. An alternative method is proposed, which is to translate a theory of how students learn, called Interactive, Constructive, Active, Passive (ICAP), so that teachers and practitioners can translate their understanding of such a theory into practice themselves, thereby giving teachers autonomy, flexibility, generalizability, and ownership of their own designed interventions based on ICAP. The paper proposes that in order to close the research-practice gap, a multi-step empirical translation research framework is needed.
Platelet autoantibody specificity and response to rhTPO treatment in patients with primary immune thrombocytopenia

This retrospective study aimed to evaluate the relationship between plasma autoantibody species and rhTPO response in adult ITP patients who failed the first‐line treatments. Plasma anti‐glycoprotein (GP) IIb/IIIa and anti‐GPIb/IX autoantibodies were detected in 47·2% and 40·6% of the 123 patients, respectively. Overall response rate to rhTPO treatment in patients without anti‐GPIb/IX autoantibodies was significantly higher than patients with anti‐GPIb/IX autoantibodies (82·2% vs. 60·0%, P = 0·006). By contrast, no statistical difference in response rate was observed between patients with or without anti‐GPIIb/IIIa autoantibodies (74·1% vs. 72·3%, P = 0·819). Therefore, the presence of anti‐GPIb/IX autoantibodies might serve as a predictive factor for poor response to rhTPO treatment in ITP.
Investigational immunotherapy targeting CD19 for the treatment of acute lymphoblastic leukemia

ABSTRACT Introduction The anti-CD19 immunotherapy for the treatment of B-precursor acute lymphoblastic leukemia (B-ALL) underwent an expansion in the last decade. CD19 is widely expressed on B-ALL and nearly ideal for immunotherapy because of strong ‘on target’ ─ but manageable ‘off target’ effects. Areas covered We review the major advances in the field, including data on CD19 monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engaging antibodies and adoptive cellular therapies such as chimeric antigen receptor T cells (CAR-Ts). We discuss novel strategies on approved anti-CD19 immunotherapies. The focus is on experimental anti-CD19 antibodies or CAR-Ts, which might overcome the limitations of toxicity, rapid clearance or resistance. Expert Opinion The potential of new anti-CD19 antibodies in ALL is limited. The most promising results were achieved with novel cellular constructs. Bi- or multi-specific CAR-Ts might overcome the immune escape by antigen loss. Modified constructs with lower peak expansion or longer persistence provide better control of the toxicity and might improve the efficacy. Finally, the allogeneic ‘off the shelf’ constructs from healthy donors avoid the time-consuming preparation and the exhaustion of immune cells.
Multidisciplinary intensive outpatient rehabilitation program for patients with moderate-to-advanced Parkinson's disease.

BACKGROUND Intensive, multi-disciplinary, rehabilitation programs for patients with Parkinson's disease (PWPs) have shown to be effective. However, most programs are based on in-patient service, which is expensive. OBJECTIVE To demonstrate the feasibility of a multidisciplinary, intensive, outpatient rehabilitation program (MIOR) for moderate to advanced Parkinson's Disease (H&Y≥2). METHOD The MIOR program takes place at a community rehabilitation center ('Ezra Le'Marpe'), 3 times a week, 5 hours, 8 weeks, and includes 20 PWPs in each cycle. The multi-disciplinary team includes physical, occupational, speech and hydro therapists. Additional activities include, social work groups, boxing, dancing and bridge. RESULTS Data was collected retroactively for the first two years. Data analysis includes 158 patient files who completed the program (mean disease duration 10.1±6 and mean H&Y stage 2.8±0.67). Assessments were performed at the beginning and end of the intervention. Positive results were collected: improvement in number of falls (p < 0.0001), Functional Independence Measure (p < 0.0001), quality of life (p < 0.01), balance (p < 0.0001), upper limb function (p < 0.0001) and paragraph reading vocal intensity (p < 0.01). CONCLUSIONS MIOR is a feasible program, showing positive results in moderate to advanced PWP's, improving quality of life, daily function, and motor performance. The current outcomes demonstrate feasibility of MIOR in addition to medical treatment.
Gene expression analysis of subchondral bone, cartilage, and synovium in naturally occurring equine palmar/plantar osteochondral disease

Osteoarthritis (OA) is a disease of the entire joint but the relationship between pathological events in various joint tissues is poorly understood. We examined concurrent changes in bone, cartilage, and synovium in a naturally occurring equine model of joint degeneration. Joints (n = 64) were grossly assessed for palmar/plantar osteochondral disease (POD) in racehorses that required euthanasia for unrelated reasons and assigned a grade of 0 (n = 34), 1 (n = 17), 2 or 3 (n = 13) using a recognized grading scheme. Synovium, cartilage, and subchondral bone were collected for histological and gene expression analysis. Relations between POD grade, cartilage histological score, and gene expression levels were examined using one‐way analysis of variance or Kruskal–Wallis test and Spearman's correlation coefficient with corrections for multiple comparisons. Cartilage histological score increased in joints with POD grade 1 (p = 0.002) and 2 or 3 (p < 0.001) compared to 0. At grade 1, expression of COL1A1, COL2A1, and MMP1 increased and BGN decreased in subchondral bone while expression of BGN and ACAN decreased in cartilage. These changes further progressed at grades 2 and 3. POD grades 2 and 3 were associated with decreased expression of osteoclast inhibitor OPG and increased markers of cartilage degeneration (MMP13, COL1A1). Expression of the vascular endothelial growth factor decreased with POD grade and negatively correlated with cartilage histological score. Synovium showed no histological or transcriptomic changes related to pathology grade. Cartilage degeneration in POD is likely to be secondary to remodeling of the subchondral bone. Limited activation of proinflammatory and catabolic genes and moderate synovial pathology suggests distinct molecular phenotype of POD compared with OA.
Combined haploidentical and cord blood transplantation for refractory severe aplastic anaemia and hypoplastic myelodysplastic syndrome

Umbilical cord blood (UCB) transplantation is a potentially curative treatment for patients with refractory severe aplastic anaemia (SAA), but has historically been associated with delayed engraftment and high graft failure and mortality rates. We conducted a prospective phase 2 trial to assess outcome of an allogeneic transplant regimen that co‐infused a single UCB unit with CD34+‐selected cells from a haploidentical relative. Among 29 SAA patients [including 10 evolved to myelodysplastic syndrome (MDS)] who underwent the haplo cord transplantation (median age 20 years), 97% had neutrophil recovery (median 10 days), and 93% had platelet recovery (median 32 days). Early myeloid engraftment was from the haplo donor and was gradually replaced by durable engraftment from UCB in most patients. The cumulative incidences of grade II–IV acute and chronic graft‐versus‐host disease (GVHD) were 21% and 41%, respectively. With a median follow‐up of 7·5 years, overall survival was 83% and GVHD/relapse‐free survival was 69%. Patient‐ and transplant‐related factors had no impact on engraftment and survival although transplants with haplo‐versus‐cord killer‐cell immunoglobulin‐like receptor (KIR) ligand incompatibility had delayed cord engraftment. Our study shows haplo cord transplantation is associated with excellent engraftment and long‐term outcome, providing an alternative option for patients with refractory SAA and hypoplastic MDS who lack human leucocyte antigen (HLA)‐matched donors.
Personality Traits Relate to Chronotype at Both the Phenotypic and Genetic Level.

INTRODUCTION Diurnal preferences have been linked to personality but often with mixed results. The present study examines the relationships between sleep timing (chronotype), diurnal preferences and the Five-Factor Model of personality traits at the phenotypic and genetic level. METHODS Self- and informant-reports of the NEO Personality Inventory-3, self-reports of the Munich Chronotype Questionnaire, and DNA samples were available for 2,515 Estonian adults (Mage = 45.76 years; 59% females). Genetic correlations were obtained through summary statistics of genome-wide association studies. RESULTS Results showed that higher Conscientiousness and lower Openness to Experience were significant predictors of earlier chronotype. At the level of facets, we found that more straightforward (A2) and excitement-seeking (E5), yet less self-disciplined (C5) people were more likely to have later chronotypes. The nuance-level Polypersonality score was correlated with chronotype at r = . 28 (p < .001). Conscientiousness and Openness were genetically related with diurnal preferences. The polygenic score for morningness-eveningness significantly predicted the Polypersonality score. CONCLUSION Phenotypic measures of chronotype and personality showed significant associations at all three of levels of the personality hierarchy. Our findings indicate that the relationship between personality and morningness-eveningness is partly due to genetic factors. Future studies are necessary to further refine the relationship.