Miracle-dz/UniFAR-FTUs huggingface dataset:
Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

Significance We found that cancer-associated fibroblasts, the most abundant noncancer cell type in esophageal cancer tissue, contribute to the resistance of tumors against currently applicable treatments. These cancer-associated fibroblasts do so by producing and secreting IL-6. IL-6 induces a mesenchymal, resistant tumor cell state. Inhibition of IL-6 reverted the mesenchymal cell state and resensitized tumor cells to therapy. Serum-borne proxies for the presence of IL-6–producing fibroblasts were identified and found to be predictive for the response to neoadjuvant therapy. Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.
Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia

Phenylalanine hydroxylase (PAH) deficiency is responsible for most cases of phenylketonuria (PKU). Furthermore, numerous studies on BH4-sensitive PAH deficiency have been conducted. To date, BH4, a cofactor of PAH, has not been used to treat PKU in Russia.Genotype data of patients with PKU can be used to predict their sensitivity to BH4 therapy. A cohort of 2579 patients with PKU from Russia was analyzed for 25 common PAH gene mutations using custom allele-specific multiplex ligation-dependent probe amplification-based technology. A mutation detection rate of 84.1% chromosomes was accomplished. Both pathogenic alleles were identified in 73.1% of patients. The most frequent pathogenic variants were p.Arg408Trp (50.9%), p.Arg261Gln (5.3%), p.Pro281Leu (3.5%), IVS12+1G>A (3.1%), IVS10-11G>A (2.6%), and p.Arg158Leu (2.4%). The exact boundaries of a PAH exon 5 deletion were defined as EX5del4154ins268 (c.442-2913_509+1173del4154ins268). Severe phenotypes prevailed in the cohort, and classical PKU was observed in 71.8% cases. Due to the genotype-based prediction, 55.9% of the probands were non-responders to the BH4-treatment, and 20.2% were potential responders. Analysis of genotype data is useful to predict BH4 response in PKU patients. The high rate of non-responders among Russian patients was due to the high allele frequency of severe PAH mutations.
irRECIST for the Evaluation of Candidate Biomarkers of Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: Analysis of a Phase II Prospective Clinical Trial

Purpose: Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared with standard clinical endpoints (RECISTv1.1). Experimental Design: Endpoints based on RECISTv1.1 [objective response rate (ORR)/progression-free survival (PFS)] or irRECIST [immune-related ORR (irORR)/immune-related PFS (irPFS)] were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 IHC, and by multiplex immunofluorescence for CD8, PD-1, TIM-3, and LAG-3. T-cell activation signatures were assessed by RNA sequencing. Results: Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR, but immune-related progressive disease (irPD) rate was significantly lower than progressive disease (PD) rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR, but patients with TC PD-L1 ≥1% had longer median irPFS and higher irORR. High percentage of CD8+ tumor-infiltrating cells (TIC) that are PD-1+TIM-3−LAG-3− (% CD8+PD-1+TIM-3−LAG-3− TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8+PD-1+TIM-3−LAG-3− TIC identified three groups of patients for which irPFS and irORR were significantly different. Conclusions: Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared with RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8+ TIC may predict outcome on nivolumab in mccRCC.
Burden of Respiratory Syncytial Virus Disease and Mortality Risk Factors in Argentina: 18 Years of Active Surveillance in a Children's Hospital.

BACKGROUND Respiratory syncytial virus is the leading cause of acute lower respiratory infection in children. We aimed to describe the clinical-epidemiologic pattern and risk factors for mortality associated with RSV infection. METHODS This is a prospective, cross-sectional study of acute lower respiratory infection in children admitted to the Children's Hospital during 2000 to 2017. Viral diagnosis was made by fluorescent antibody techniques or real-time-polymerase chain reaction. We compared clinical-epidemiologic characteristics of RSV infection in nonfatal versus fatal cases. Multiple logistic regression was used to identify independent predictors of mortality. RESULTS Of 15,451 patients with acute lower respiratory infection, 13,033 were tested for respiratory viruses and 5831 (45%) were positive: RSV 81.3% (4738), influenza 7.6% (440), parainfluenza 6.9% (402) and adenovirus 4.3% (251). RSV had a seasonal epidemic pattern coinciding with months of lowest average temperature. RSV cases show a case fatality rate of 1.7% (82/4687). Fatal cases had a higher proportion of prematurity (P < 0.01), perinatal respiratory history (P < 0.01), malnourishment (P < 0.01), congenital heart disease (P < 0.01), chronic neurologic disease (P < 0.01) and pneumonia at clinical presentation (P = 0.014). No significant difference between genders was observed. Most deaths occurred among children who had complications: respiratory distress (80.5%), nosocomial infections (45.7%), sepsis (31.7%) and atelectasis (13.4%). Independent predictors of RSV mortality were moderate-to-severe malnourishment, odds ratio (OR): 3.69 [95% confidence interval (CI): 1.98-6.87; P < 0.0001]; chronic neurologic disease, OR: 4.14 (95% CI: 2.12-8.08; P < 0.0001); congenital heart disease, OR: 4.18 (95% CI: 2.39-7.32; P< 0.0001); and the age less than 6 months, OR: 1.99 (95% CI: 1.24-3.18; P = 0.004). CONCLUSIONS RSV showed an epidemic pattern affecting mostly young children. Malnourishment, chronic neurologic disease, congenital heart disease and the age less than 6 months were the independent risk factors for RSV mortality.
A hybrid 4-item Krousel-Wood Medication Adherence Scale predicts cardiovascular events in older hypertensive adults.

BACKGROUND There is a need for a brief, open access, self-report medication adherence scale that overcomes challenges of existing adherence tools, is associated with incident cardiovascular disease (CVD), and identifies low 'implementation' adherers to antihypertensive medications to facilitate blood pressure management. METHODS AND RESULTS Antihypertensive medication adherence was assessed in a cohort of 1532 older hypertensive adults without prior CVD using the self-report 4-item Krousel-Wood Medication Adherence Scale (K-Wood-MAS-4), a hybrid tool developed to predict pharmacy refill and which captures four domains of adherence behavior: self-efficacy, physical function, intentional medication-taking, and forgetfulness. The 4-item scale categorized participants as low and high adherers using scores at least 1 and less than 1, respectively. Participants were followed after K-Wood-MAS-4 assessment to identify incident CVD events (stroke, myocardial infarction, congestive heart failure, or CVD death). The prevalence of low adherence was 38.7%. During a median follow-up of 2.8 years (maximum 3.8 years), 136 (8.9%) participants had an incident CVD event; 12.8 and 6.4% in low and high adherers, respectively. The adjusted hazard ratio (aHR) for incident CVD associated with low versus high adherence was 2.29 [95% confidence interval (CI): 1.61, 3.26]. Results were similar when stratified by age [<75 years - aHR 3.53 (95% CI: 1.65, 7.56); ≥75 years - aHR 1.98 (95% CI: 1.32, 2.97)], sex [women - aHR 1.90 (95% CI: 1.16, 3.12); men - aHR 2.80 (95% CI: 1.68, 4.65)], and race [black - aHR 2.22 (95% CI: 0.93, 5.31); white - aHR 2.26 (95% CI: 1.54, 3.34)]. CONCLUSION Low medication adherence using the 'hybrid' K-Wood-MAS-4 predicts incident CVD in a cohort of older adults with established hypertension.
Systematic Use of Music as an Environmental Intervention and Quality of Care in Nursing Homes: A Qualitative Case Study in Norway

Background: The systematic use of music as an environmental intervention in nursing homes shows beneficial effects on patients’ health, safety, and quality of life in a care-related perspective. A county in Norway and a Nursing Education Department in a region of Norway collaborated on the project “systematic use of music as environmental intervention and quality of care in nursing homes” for nursing students. Methods: This study from Norway (2017) had a qualitative and explorative approach. The sample (n = 33) was strategically and conveniently selected. Seven different focus group interviews consisted of nursing students, practice counselors, teachers, and project leaders, representing three nursing homes and healthcare centers. Passive observation lasting two days in each of the six departments was executed in order to observe environmental treatment in practice. Results: The beneficial aspects of using music as an environmental intervention in nursing homes increased among the students, and contributed to improved interaction, communication, and development of care with the patients. Students who participated actively in musical interaction such as improvisation, singing, and music listening with the patients were committed and motivated. The staff and management showed varied enthusiasm for the project. Conclusions: If the systematic use of music as environmental therapy and quality of care in elderly care is to be successful, it seems vital to include this theme early in nursing education. By creating early involvement among nurses, it might influence, inspire, and encourage involvement among employees and management.
The prevalence, incidence, and associated factors of pressure injuries among immobile inpatients: A multicentre, cross‐sectional, exploratory descriptive study in China

The aim of this study was to assess the prevalence, incidence, and the associated factors of pressure injuries (PIs) among immobile hospitalised patients in China. Being immobile during hospitalisation put these patients at a higher risk of PIs. There is little literature about pressure injury (PI) prevalence or PI incidence in immobile hospitalised patients in hospitals in China. This was a multicentre, cross‐sectional, exploratory descriptive study. A total of 23 985 immobile patients were recruited from 25 general hospitals in six provinces of China from November 1, 2015 to March 18, 2016. Information was collected on demographic characteristics, physical assessment information, and treatment and nursing care measures. The PI period prevalence was 3.38%, and the PI cumulative incidence was 1.23%. Most PIs (84.03%) were Stage 1 or Stage 2. A total of 48.22% of PIs occurred in the sacrum or heel region. In the multivariate analysis, the following factors were associated with higher PI prevalence: age, gender, length of immobility, type of hospital, modified Braden Scale score, urinary incontinence, faecal incontinence, low serum albumin, the usage of fixation or restraint devices, and patient's discharge diagnosis (lower limb fracture, malnutrition, and spinal cord injury). PI prevalence for immobile hospitalised patients in the study was lower than those reported in literature. However, because of the large population in China, the number of patients who suffer with PIs can be very high. The relating factors of higher PI prevalence identified in this study were consistent with current literature. Patients with a higher number of these associated factors should be monitored more closely, and preventative measures should be taken to prevent PI occurrence in high‐risk populations.
Intersession Reliability and Within-Session Stability of a Novel Perception-Action Coupling Task.

BACKGROUND: The perception-action coupling task (PACT) was designed as a more ecologically valid measure of alertness/reaction times compared to currently used measures by aerospace researchers. The purpose of this study was to assess the reliability, within-subject variability, and systematic bias associated with the PACT.METHODS: There were 16 subjects (men/women = 9 / 7; age = 27.8 ± 3.6 yr) who completed 4 identical testing sessions. The PACT requires subjects to make judgements on whether a virtual ball could fit into an aperture. For each session, subjects completed nine cycles of the PACT, with each cycle lasting 5 min. Judgement accuracy and reaction time parameters were calculated for each cycle. Systematic bias was assessed with repeated-measures ANOVA, reliability with intraclass correlation coefficients (ICC), and within-subject variability with coefficients of variation (CVTE). RESULTS: Initiation time (Mean = 0.1065 s) showed the largest systematic bias, requiring the elimination of three cycles to reduce bias, with all other variables requiring, at the most, one. All variables showed acceptable reliability (ICC > 0.70) and within-subject variability (CVTE < 20%) with only one cycle after elimination of the first three cycles.CONCLUSIONS: With a three-cycle familiarization period, the PACT was found to be reliable and stable.Connaboy C, Johnson CD, LaGoy AD, Pepping G-J, Simpson RJ, Deng Z, Ma L, Bower JL, Eagle SR, Flanagan SD, Alfano CA. Intersession reliability and within-session stability of a novel perception-action coupling task. Aerosp Med Hum Perform. 2019; 90(2):77-83.
Intermediate-term outcome of Aurolab aqueous drainage implant

Purpose: To report the intermediate-term safety and efficacy of Aurolab aqueous drainage implant (AADI) in patients with glaucoma. Methods: Retrospective review of patients who underwent AADI between January 2013 and December 2016. Patients aged >16 years and with a minimum follow-up of 6 months were included. Success was defined as complete when the intraocular pressure was ≥6 and ≤21 mmHg without antiglaucoma medication and as qualified if those requiring additional antiglaucoma medications were included. Results: The study included 55 patients (55 eyes) with a mean age ± standard deviation (SD) of 47.3 ± 18.1 years with a mean follow-up of 16.7 ± 11.4 months. Mean intraocular pressure reduced from 30.8 ± 11.1 mmHg to 13.1 ± 4.7, 14.1 ± 4.8, 15.7 ± 2.5 (P < 0.001) mmHg at 6 months, 1 year, and 2 years, respectively. The mean number of antiglaucoma medications reduced from 3.4 ± 1 to 0.8 ± 1.2, 0.7 ± 1.1, 0.8 ± 1 (P < 0.001) at 6 months, 1 year, and 2 years, respectively. The cumulative probability of complete and qualified success was 62% and 100% at 6 months, 54% and 92% at 1 year, and 43% and 88% at 2 years, respectively. Four patients failed during the follow-up period. Postoperative complication occurred in 28 eyes (51%), of which 17 eyes (31%) required intervention. Conclusion: AADI is a safe and effective treatment for the control of intraocular pressure in patients with glaucoma.
Restorative Effects of Classroom Soundscapes on Children’s Cognitive Performance

Previous studies have examined the restorative benefits of soundscapes on adults’ cognitive performance, but it was unclear whether those benefits would be possible for children. In this paper, two experiments applied a before–after design to explore the restorative effects of different soundscapes on children’s sustained attention and short-term memory, respectively, in a simulated classroom situation. In Experiment 1, 46 children aged 8–12 were first mentally fatigued by performing an oral arithmetic task and then were asked to conduct a sustained attention to response test (SART), in order to assess their attention fatigue. After that, a period of 3-min soundscape was presented, and SART was conducted again to examine their attention recovery. In Experiment 2, 45 children participated and the experiment procedure was the same as in Experiment 1, except that a digit span test (DST) was used instead to measure short-term memory. The results showed that music, birdsong, fountain sound, and stream sound facilitated greater recovery than other sounds in reaction time. Participants also showed better performance in short-term memory after exposure to fountain sound and stream sound, followed by music and birdsong. Those results confirmed the actual restorative effects of perceived restorative soundscapes on children’s cognitive performance.
The use of analytic hierarchy process for measuring the complexity of medical diagnosis

Diagnostic complexity is an important contextual factor affecting a variety of medical outcomes. Existing measurements of diagnosis complexity either rely on crude proxies or use fine-grained measures that employ indicators from proprietary data that are not readily available. Hence, the study of this important construct in fields such as medical informatics has been hampered by the difficulty of measuring diagnostic complexity. This article presents a novel approach for conceptualizing and operationalizing diagnostic task complexity as a multi-dimensional construct, which employs the readily available International Classification of Diseases codes from medical encounters in hospitals and uses Analytic Hierarchical Process methodology. We demonstrate the reliability of the proposed approach and show that despite using a relatively simple procedure, it is able to predict readmission rates just as well as (or even better) than some of the sophisticated measures that have been used in recent studies (namely, the LaCE score index).
A cytosolic chaperone complex controls folding and degradation of type III CD38

Cluster of differentiation 38 (CD38) is the best-studied enzyme catalyzing the synthesis of the Ca2+ messenger cyclic ADP-ribose. It is a single-pass transmembrane protein, but possesses dual orientations. We have documented the natural existence of type III CD38 in cells and shown that it is regulated by a cytosolic activator, calcium- and integrin-binding 1 (CIB1). However, how type III CD38 can be folded correctly in the reductive cytosol has not been addressed. Using the yeast two-hybrid technique with CD38's catalytic domain (sCD38) as bait, here we identified a chaperone, Hsp70-interacting protein (Hip), that specifically interacts with both the type III CD38 and sCD38. Immunoprecipitation coupled with MS identified a chaperone complex associated specifically with sCD38. Pharmacological and siRNA-mediated knockdown of Hsp90 chaperones decreased the expression levels of both sCD38 and type III CD38, suggesting that these chaperones facilitate their folding. Moreover, knockdown of Hsc70 or DNAJA2 increased the levels of both CD38 types, consistent with the roles of these proteins in mediating CD38 degradation. Notably, Hip knockdown decreased type III CD38 substantially, but only marginally affected sCD38, indicating that Hip was selective for the former. More remarkably, DNAJA1 knockdown decreased sCD38 but increased type III CD38 levels. Mechanistically, we show that Hsc70 mediates lysosomal degradation of type III CD38, requiring the lysosomal receptor Lamp2A and the C19-motif in the C terminus of CD38. Our results indicate that folding and degradation of type III CD38 is effectively controlled in cells, providing further strong support of its physiological relevance.
Lectin Sequence Distribution in QTLs from Rice (Oryza sativa) Suggest a Role in Morphological Traits and Stress Responses

Rice (Oryza sativa) is one of the main staple crops worldwide but suffers from important yield losses due to different abiotic and biotic stresses. Analysis of quantitative trait loci (QTL) is a classical genetic method which enables the creation of more resistant cultivars but does not yield information on the genes directly involved or responsible for the desired traits. Lectins are known as proteins with diverse functions in plants. Some of them are abundant proteins in seeds and are considered as storage/defense proteins while other lectins are known as stress-inducible proteins, implicated in stress perception and signal transduction as part of plant innate immunity. We investigated the distribution of lectin sequences in different QTL related to stress tolerance/resistance, morphology, and physiology through mapping of the lectin sequences and QTL regions on the chromosomes and subsequent statistical analysis. Furthermore, the domain structure and evolutionary relationships of the lectins in O. sativa spp. indica and japonica were investigated. Our results revealed that lectin sequences are statistically overrepresented in QTLs for (a)biotic resistance/tolerance as well as in QTLs related to economically important traits such as eating quality and sterility. These findings contribute to the characterization of the QTL sequences and can provide valuable information to the breeders.
Bortezomib Maintenance for the Treatment of Monoclonal Gammopathy of Renal Significance

Monoclonal gammopathy of renal significance (MGRS) defines renal diseases resulting from the nephrotoxic effects of monoclonal proteins secreted from non-malignant clonal B cells or plasma cells, that do not meet criteria for multiple myeloma, Waldenstrom’s macroglobulinemia, chronic lymphocytic leukemia, or lymphomas. Renal disease in MGRS can result from monoclonal immunoglobulin deposition to different parts of the kidney and includes a wide spectrum of glomerular, tubulointerstitial and vascular renal diseases. Recognizing MGRS is important because renal outcomes are poor and treatments targeting the underlying clonal disease have been associated with improved renal survival. In this case report, we present a case of a patient with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) subtype of MGRS who underwent a phased clone directed treatment of induction and extended maintenance therapy to achieve renal response.