Miracle-dz/UniFAR-FTUs huggingface dataset:
Contributions on Clinical Decision Support from the 2018 Literature

Summary Objectives: To summarize recent research and select the best papers published in 2018 in the field of computerized clinical decision support for the Decision Support section of the International Medical Informatics Association (IMIA) yearbook. Methods: A literature review was performed by searching two bibliographic databases for papers referring to clinical decision support systems (CDSSs). The aim was to identify a list of candidate best papers from the retrieved bibliographic records, which were then peer-reviewed by external reviewers. A consensus meeting of the IMIA editorial team finally selected the best papers on the basis of all reviews and the section editors' evaluation. Results: Among 1,148 retrieved articles, 15 best paper candidates were selected, the review of which resulted in the selection of four best papers. The first paper introduces a deep learning model for estimating short-term life expectancy (>3 months) of metastatic cancer patients by analyzing free-text clinical notes in electronic medical records, while maintaining the temporal visit sequence. The second paper takes note that CDSSs become routinely integrated in health information systems and compares statistical anomaly detection models to identify CDSS malfunctions which, if remain unnoticed, may have a negative impact on care delivery. The third paper fairly reports on lessons learnt from the development of an oncology CDSS using artificial intelligence techniques and from its assessment in a large US cancer center. The fourth paper implements a preference learning methodology for detecting inconsistencies in clinical practice guidelines and illustrates the applicability of the proposed methodology to antibiotherapy. Conclusions: Three of the four best papers rely on data-driven methods, and one builds on a knowledge-based approach. While there is currently a trend for data-driven decision support, the promising results of such approaches still need to be confirmed by the adoption of these systems and their routine use.
Dexmedetomidine for the prevention of postoperative delirium in elderly patients undergoing noncardiac surgery: A meta-analysis of randomized controlled trials

Background Postoperative delirium (POD) among the elderly population that undergoes noncardiac surgery is significantly associated with adverse clinical outcomes. We conducted this meta-analysis to evaluate the effectiveness and safety of dexmedetomidine for the prophylaxis of POD among the elderly population after noncardiac surgery. Methods We searched Embase, PubMed, and the Cochrane Library from inception date to March 2019 for randomized controlled trials (RCTs) that compared dexmedetomidine and placebo for the prevention of POD and evaluated the major cardiovascular outcomes among elderly people after noncardiac surgery. Two authors independently screened the studies and extracted data from the published articles. The main outcome was the incidence of POD. The secondary outcomes included the occurrence of bradycardia, hypotension, hypertension, tachycardia, myocardial infarction, stroke, hypoxaemia, and all-cause mortality. Results A total of 6 RCTs with 2102 participants were included. Compared with placebo, dexmedetomidine significantly reduced the prevalence of POD (RR = 0.61, 95% CI 0.34–0.76, P = 0.001, I2 = 66%), and the risk of tachycardia (RR = 0.48, 95% CI 0.30–0.76, P = 0.002, I2 = 0%), hypertension (RR = 0.59, 95% CI 0.44–0.79, P < 0.001, I2 = 20%), stroke (RR = 0.22, 95% CI 0.06–0.76, P = 0.02, I2 = 0%), and hypoxaemia (RR = 0.50, 95% CI 0.32–0.78, P = 0.002, I2 = 0%) in elderly patients who underwent noncardiac surgery. However, dexmedetomidine accelerated the occurrence of bradycardia (RR = 1.36, 95% CI 1.11–1.67, P = 0.003, I2 = 0%). Furthermore, no significant differences were observed in the incidence of hypotension, myocardial infarction, and all-cause mortality between the dexmedetomidine and placebo groups. Conclusions Among elderly patients after noncardiac surgery, the prophylactic use of dexmedetomidine, compared with the use of placebo, was related to a decline in the incidence of POD.
The macromolecular composition of noncalcified marine macroalgae

The macromolecular composition of macroalgae influences nutrient flow and food quality in aquatic ecosystems and the value of macroalgae species for human consumption, aquaculture, biofuels, and other applications. We used literature data (125 publications, 1,117 observations) and a hierarchal Bayesian statistical model to estimate the average macromolecular composition, protein, lipid, and carbohydrate of macroalgae as a whole and at the phylum level. Our focus was on marine, noncalcified macroalgae sampled from wild‐grown populations in the field. We found that the median macromolecular composition is 9.98% protein, 2.7% lipid, 48.5% carbohydrate, and 31.8% ash as percent dry weight. We compared the median macromolecular content of macroalgae to microalgae and herbaceous plants and test for differences in macromolecular content across macroalgal phyla. Macroalgae were much more enriched in carbohydrate and minerals than the microalgae and lower in protein and lipid than many herbaceous plants. Rhodophyte macroalgae have significantly less lipid and more protein and the Ochrophyte macroalgae have significantly less protein than the average.
Adaptation of Syntenic Xyloglucan Utilization Loci of Human Gut Bacteroidetes to Polysaccharide Side Chain Diversity

The catabolism of complex carbohydrates that otherwise escape the endogenous digestive enzymes of humans and other animals drives the composition and function of the gut microbiota. Thus, detailed molecular characterization of dietary glycan utilization systems is essential both to understand the ecology of these complex communities and to manipulate their compositions, e.g., to benefit human health. Our research reveals new insight into how ubiquitous members of the human gut microbiota have evolved a set of microheterogeneous gene clusters to efficiently respond to the structural variations of plant xyloglucans. The data here will enable refined functional prediction of xyloglucan utilization among diverse environmental taxa in animal guts and beyond. ABSTRACT Genome sequencing has revealed substantial variation in the predicted abilities of individual species within animal gut microbiota to metabolize the complex carbohydrates comprising dietary fiber. At the same time, a currently limited body of functional studies precludes a richer understanding of how dietary glycan structures affect the gut microbiota composition and community dynamics. Here, using biochemical and biophysical techniques, we identified and characterized differences among recombinant proteins from syntenic xyloglucan utilization loci (XyGUL) of three Bacteroides and one Dysgonomonas species from the human gut, which drive substrate specificity and access to distinct polysaccharide side chains. Enzymology of four syntenic glycoside hydrolase family 5 subfamily 4 (GH5_4) endo-xyloglucanases revealed surprising differences in xyloglucan (XyG) backbone cleavage specificity, including the ability of some homologs to hydrolyze congested branched positions. Further, differences in the complement of GH43 alpha-l-arabinofuranosidases and GH95 alpha-l-fucosidases among syntenic XyGUL confer distinct abilities to fully saccharify plant species-specific arabinogalactoxyloglucan and/or fucogalactoxyloglucan. Finally, characterization of highly sequence-divergent cell surface glycan-binding proteins (SGBPs) across syntenic XyGUL revealed a novel group of XyG oligosaccharide-specific SGBPs encoded within select Bacteroides. IMPORTANCE The catabolism of complex carbohydrates that otherwise escape the endogenous digestive enzymes of humans and other animals drives the composition and function of the gut microbiota. Thus, detailed molecular characterization of dietary glycan utilization systems is essential both to understand the ecology of these complex communities and to manipulate their compositions, e.g., to benefit human health. Our research reveals new insight into how ubiquitous members of the human gut microbiota have evolved a set of microheterogeneous gene clusters to efficiently respond to the structural variations of plant xyloglucans. The data here will enable refined functional prediction of xyloglucan utilization among diverse environmental taxa in animal guts and beyond.
Knowledge acquisition and retention following Saving Children’s Lives course for healthcare providers in Botswana: a longitudinal cohort study

Objectives Millions of children die every year from serious childhood illnesses. Most deaths are avertable with access to quality care. Saving Children’s Lives (SCL) includes an abbreviated high-intensity training (SCL-aHIT) for providers who treat serious childhood illnesses. The objective of this study was to examine the impact of SCL-aHIT on knowledge acquisition and retention of providers. Setting 76 participating centres who provide primary and secondary care in Kweneng District, Botswana. Participants Doctors and nurses expected by the District Health Management Team to provide initial care to seriously ill children, completed SCL-aHIT between January 2014 and December 2016, submitted demographic data, course characteristics and at least one knowledge assessment. Methods Retrospective, cohort study. Planned and actual primary outcome was adjusted acquisition (change in total knowledge score immediately after training) and retention (change in score at 1, 3 and 6 months), secondary outcomes were pneumonia and dehydration subscores. Descriptive statistics and linear mixed models with random intercept and slope were conducted. Relevant institutional review boards approved this study. Results 211 providers had data for analysis. Cohort was 91% nurses, 61% clinic/health postbased and 45% pretrained in Integrated Management of Childhood Illness (IMCI). A strong effect of SCL-aHIT was seen with knowledge acquisition (+24.56±1.94, p<0.0001), and loss of retention was observed (−1.60±0.67/month, p=0.018). IMCI training demonstrated no significant effect on acquisition (+3.58±2.84, p=0.211 or retention (+0.20±0.91/month, p=0.824) of knowledge. On average, nurses scored lower than physicians (−19.39±3.30, p<0.0001). Lost to follow-up had a significant impact on knowledge retention (−3.03±0.88/month, p=0.0007). Conclusions aHIT for care of the seriously ill child significantly increased provider knowledge and loss of knowledge occurred over time. IMCI training did not significantly impact overall knowledge acquisition nor retention, while professional status impacted overall score and lost to follow-up impacted retention.
TRUST: Trial of Radical Upfront Surgical Therapy in advanced ovarian cancer (ENGOT ov33/AGO‐OVAR OP7)

Background Primary cytoreductive surgery followed by chemotherapy has been considered standard management for patients with advanced ovarian cancer over decades. An alternative approach of interval debulking surgery following neoadjuvant chemotherapy was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS), which were criticized owing to important limitations, especially regarding the rate of complete resection. Primary Objective To clarify the optimal timing of surgical therapy in advanced ovarian cancer. Study Hypothesis Primary cytoreductive surgery is superior to interval cytoreductive surgery following neoadjuvant chemotherapy for overall survival in patients with advanced ovarian cancer. Trial Design TRUST is an international open, randomized, controlled multi-center trial investigating overall survival after primary cytoreductive surgery versus neoadjuvant chemotherapy and subsequent interval cytoreductive surgery in patients with FIGO stage IIIB–IVB ovarian, tubal, and peritoneal carcinoma. To guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (eg, ≥50% complete resection rate in upfront surgery for FIGO IIIB–IVB patients, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST quality committee delegates. Patients in the primary cytoreductive surgery arm undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas patients in the interval cytoreductive surgery arm undergo 3 cycles of neoadjuvant chemotherapy after histologic confirmation of the disease, followed by interval cytoreductive surgery and subsequently, 3 cycles of platinum-based chemotherapy. The intention of surgery for both groups is complete tumor resection according to guideline recommendations. Major Inclusion/Exclusion Criteria Major inclusion criteria are suspected or histologically confirmed, newly diagnosed invasive epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma FIGO stage IIIB–IVB (IV only if resectable metastasis). Major exclusion criteria are non-epithelial ovarian malignancies and borderline tumors; prior chemotherapy for ovarian cancer; or abdominal/pelvic radiotherapy. Primary Endpoint Overall survival. Sample Size 772 patients. Estimated Dates for Completing Accrual and Presenting Results Accrual completion approximately mid-2019, results are expected after 5 years' follow-up in 2024. Trial Registration NCT02828618.
Assessment of the impact of sex in intensity, skin flares and central processing of histaminergic itch—A pilot study

Itch is the commonest skin‐related symptom, and sex differences are increasingly recognised as important determinants in stratified medicine, but only little is known about sex differences in itch. Questionnaire‐based studies indicated that women perceive itch as more intensive and bothersome in comparison with men. However, data of studies using standardised itch models to objectify sex differences are scarce and inconsistent. To determine sex differences in intensity, skin flares and central processing of histaminergic itch, we compared 15 female and 15 male healthy subjects in a double‐blinded, within‐subject, placebo‐controlled study using a histamine skin prick itch model (histamine 1% applied onto the volar forearm) and functional MRI. We found trends in higher mean itch intensity (0.58 VAS, CI 95% 0.004‐1.19, P = .056) and maximum itch intensity (men 3.93 VAS ± 0.39 SD at 3 minutes, women 4.73 VAS ± 0.31 SD at 4 minutes, P = .073) in women paralleled by a trend in a stronger positive correlation between itch intensity and blood oxygen level–dependent (BOLD) activity in brain structures identified during itch in comparison with men (rs in women: .46, P = .08, rs in men: .07, P = .79). The erythema and wheal following histamine skin pricking were (non‐significantly) larger in men, indicating that higher mean itch intensities on the right volar forearm in women may not be explained by more intense flares. The comparison of the activation patterns between the sexes revealed increased activity in men compared to women in the left middle temporal gyrus (temporooccipital part)/lateral occipital cortex. Thus, our findings indicate that histaminergic itch perception and central itch processing differ between the sexes under standardised conditions.
Pregnancy after bariatric surgery: Consensus recommendations for periconception, antenatal and postnatal care

The objective of the study is to provide evidence‐based guidance on nutritional management and optimal care for pregnancy after bariatric surgery. A consensus meeting of international and multidisciplinary experts was held to identify relevant research questions in relation to pregnancy after bariatric surgery. A systematic search of available literature was performed, and the ADAPTE protocol for guideline development followed. All available evidence was graded and further discussed during group meetings to formulate recommendations. Where evidence of sufficient quality was lacking, the group made consensus recommendations based on expert clinical experience. The main outcome measures are timing of pregnancy, contraceptive choice, nutritional advice and supplementation, clinical follow‐up of pregnancy, and breastfeeding. We provide recommendations for periconception, antenatal, and postnatal care for women following surgery. These recommendations are summarized in a table and print‐friendly format. Women of reproductive age with a history of bariatric surgery should receive specialized care regarding their reproductive health. Many recommendations are not supported by high‐quality evidence and warrant further research. These areas are highlighted in the paper.
Large-effect flowering time mutations reveal conditionally adaptive paths through fitness landscapes in Arabidopsis thaliana

Significance Mutations are often assumed to be largely detrimental to fitness, but they may also be beneficial, and mutations with large phenotypic effects can persist in nature. One explanation for these observations is that mutations may be beneficial in specific environments because these conditions shift trait expression toward higher fitness. This hypothesis is rarely tested due to the difficulty of replicating mutants in multiple natural environments and measuring their phenotypes. We did so by planting Arabidopsis thaliana genotypes with large-effect flowering time mutations in field sites across the species’ European climate range. We quantified the adaptive value of mutant traits, finding that certain mutations increased fitness in some environments but not in others. Contrary to previous assumptions that most mutations are deleterious, there is increasing evidence for persistence of large-effect mutations in natural populations. A possible explanation for these observations is that mutant phenotypes and fitness may depend upon the specific environmental conditions to which a mutant is exposed. Here, we tested this hypothesis by growing large-effect flowering time mutants of Arabidopsis thaliana in multiple field sites and seasons to quantify their fitness effects in realistic natural conditions. By constructing environment-specific fitness landscapes based on flowering time and branching architecture, we observed that a subset of mutations increased fitness, but only in specific environments. These mutations increased fitness via different paths: through shifting flowering time, branching, or both. Branching was under stronger selection, but flowering time was more genetically variable, pointing to the importance of indirect selection on mutations through their pleiotropic effects on multiple phenotypes. Finally, mutations in hub genes with greater connectedness in their regulatory networks had greater effects on both phenotypes and fitness. Together, these findings indicate that large-effect mutations may persist in populations because they influence traits that are adaptive only under specific environmental conditions. Understanding their evolutionary dynamics therefore requires measuring their effects in multiple natural environments.
Ischemic preconditioning induces cortical microglial proliferation and a transcriptomic program of robust cell cycle activation

Ischemic preconditioning (IPC) is an experimental phenomenon in which a subthreshold ischemic insult applied to the brain reduces damage caused by a subsequent more severe ischemic episode. Identifying key molecular and cellular mediators of IPC will provide critical information needed to develop novel therapies for stroke. Here we report that the transcriptomic response of acutely isolated preconditioned cortical microglia is dominated by marked upregulation of genes involved in cell cycle activation and cellular proliferation. Notably, this transcriptional response occurs in the absence of cortical infarction. We employed ex vivo flow cytometry, immunofluorescent microscopy, and quantitative stereology methods on brain tissue to evaluate microglia proliferation following IPC. Using cellular colocalization of microglial (Iba1) and proliferation (Ki67 and BrdU) markers, we observed a localized increase in the number of microglia and proliferating microglia within the preconditioned hemicortex at 72, but not 24, hours post‐IPC. Our quantification demonstrated that the IPC‐induced increase in total microglia was due entirely to proliferation. Furthermore, microglia in the preconditioned hemisphere had altered morphology and increased soma volumes, indicative of an activated phenotype. Using transgenic mouse models with either fractalkine receptor (CX3CR1)‐haploinsufficiency or systemic type I interferon signaling loss, we determined that microglial proliferation after IPC is dependent on fractalkine signaling but independent of type I interferon signaling. These findings suggest there are multiple distinct targetable signaling pathways in microglia, including CX3CR1‐dependent proliferation that may be involved in IPC‐mediated protection.
A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229).

BACKGROUND Immune checkpoint inhibitors are active in a broad range of cancers, including programmed death ligand 1 (PD-L1)-positive, triple-negative, metastatic breast cancer (MBC). Antibody-dependent cell-mediated cytotoxicity is a mechanism of action of trastuzumab. We performed a phase Ib trial of durvalumab and trastuzumab in HER2-positive MBC previously treated with chemotherapy and anti-HER2 antibodies to assess safety, efficacy, and correlative endpoints. PATIENTS AND METHODS Patients with HER2-positive MBC were enrolled on a standard 3 + 3 design. Dose level 1 was durvalumab (1,125 mg intravenously day 1) and trastuzumab (8 mg/kg intravenously loading, then 6 mg/kg day 1) on a q3 weekly cycle. An expansion cohort at the recommended phase II dose (RP2D) performed tumor biopsies at baseline and after cycle 1. The primary endpoint was to establish the RP2D. RESULTS Fifteen patients were accrued from April to December 2016, of which 14 were evaluable for response. Median age was 54 years (range 40-86); the majority had visceral disease (87%) and at least three prior (adjuvant and/or metastatic) lines of chemotherapy (73%), including trastuzumab (93%), pertuzumab (60%), and trastuzumab-emtansine (93%) for MBC. No dose-limiting toxicities were observed at dose level 1 (n = 6) or dose expansion (n = 9) during cycle 1. One patient developed a grade ≥3 immune-related adverse event (grade 4 diabetes mellitus). No responses by RECIST were seen, with 4 of 14 patients (29%) demonstrating stable disease as best response at week 6 (median duration, 2.7 months). All patients had <1% PD-L1 expression on either archival tissue (7/15) or prestudy biopsy (8/15). In the dose expansion cohort, evaluable pretreatment and on-treatment tumor biopsies (n = 5) showed minimal CD8 cell infiltration. CONCLUSION The RP2D of durvalumab and trastuzumab is standard full doses of both agents. No significant clinical activity was observed in patients with heavily pretreated HER2-positive PD-L1-negative MBC. IMPLICATIONS FOR PRACTICE This phase Ib trial with associated correlative endpoints provides insights into the lack of activity of the combination of durvalumab and trastuzumab in heavily pretreated HER2-positive metastatic breast cancer (MBC). No significant clinical activity was observed in patients with heavily pretreated HER2-positive programmed death ligand 1 (PD-L1)-negative MBC with evidence of cytotoxic T-cell exhaustion. Furthermore, all patients had no expression of PD-L1 in the tumor cells. These data support the importance of PD-L1 as an important selection biomarker and the need to assess the tumor microenvironment for immune regulatory cells. Further work is needed to understand how to activate the "cold" tumors to be able to combine current immune-oncology agents.