Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting Tumor-Associated Macrophages to Increase the Efficacy of Immune Checkpoint Inhibitors: A Glimpse into Novel Therapeutic Approaches for Metastatic Melanoma

Simple Summary Stimulation of the host immune responses, through the use of biotech drugs that remove a brake on the immune system (immune checkpoint inhibitors), is a current widely used strategy to treat a variety of advanced-stage tumors with impressive outcomes also in patients refractory to standard chemotherapy. However, as in the case of metastatic melanoma, many patients fail to achieve a long-lasting clinical benefit. The aim of this article is to provide an overview of the current scientific evidence concerning the role played by cells of the tumor micro-environment, and in particular tumor-associated M2 macrophages, on the innate or acquired resistance of melanoma to immune checkpoint inhibitors. A special focus will be given to potential therapeutic interventions capable of counteracting tumor ability to evade the control of the immune system in order to enhance the efficacy of immune checkpoint inhibitors. Abstract Immune checkpoint inhibitors (ICIs) represent a promising therapeutic intervention for a variety of advanced/metastatic solid tumors, including melanoma, but in a large number of cases, patients fail to establish a sustained anti-tumor immunity and to achieve a long-lasting clinical benefit. Cells of the tumor micro-environment such as tumor-associated M2 macrophages (M2-TAMs) have been reported to limit the efficacy of immunotherapy, promoting tumor immune evasion and progression. Thus, strategies targeting M2-TAMs have been suggested to synergize with immune checkpoint blockade. This review recapitulates the molecular mechanisms by which M2-TAMs promote cancer immune evasion, with focus on the potential cross-talk between pharmacological interventions targeting M2-TAMs and ICIs for melanoma treatment.
Duodenal Metatranscriptomics to Define Human and Microbial Functional Alterations Associated with Severe Obesity: A Pilot Study

Obesity is a multifactorial disorder, and the gut microbiome has been suggested to contribute to its onset. In order to better clarify the role of the microbiome in obesity, we evaluated the metatranscriptome in duodenal biopsies from a cohort of 23 adult severely obese and lean control subjects using next generation sequencing. Our aim was to provide a general picture of the duodenal metatranscriptome associated with severe obesity. We found altered expressions of human and microbial genes in the obese compared to lean subjects, with most of the gene alterations being present in the carbohydrate, protein, and lipid metabolic pathways. Defects were also present in several human genes involved in epithelial intestinal cells differentiation and function, as well as in the immunity/inflammation pathways. Moreover, the microbial taxa abundance inferred by our transcriptomic data differed in part from the data that we previously evaluated by 16S rRNA in 13/23 individuals of our cohort, particularly concerning the Firmicutes and Proteobacteria phyla abundances. In conclusion, our pilot study provides the first taxonomic and functional characterization of duodenal microbiota in severely obese subjects and lean controls. Our findings suggest that duodenal microbiome and human genes both play a role in deregulating metabolic pathways, likely affecting energy metabolism and thus contributing to the obese phenotype.
Morpheme Analysis Associated with German Noun Plural Endings among Second Language (L2) Learners Using Event-Related Potentials (ERPs)

This paper aims to examine the morpho-syntactic process of noun plural endings, “-n” and “-s”, in adult second language (L2) learners using event-related potentials (ERPs). German noun plural endings consist of many inflectional forms. They are one of the difficulties faced by German L2 learners. We recorded an electroencephalogram (EEG) study of German L2 learners by dividing study subjects into low and high L2 learners according to the learning level. We examined what ERP components were associated with L2 language processing. All participants were Korean German L2 learners who had achieved varying levels of proficiency. As a result of our analysis, we confirmed different morpho-syntactic processing between the two groups. First, N400 was detected at any learning level. It confirmed language processing supportive of the Full-Listing Model for irregular endings. Second, we confirmed left anterior negativity (LAN), as detected in both low and high proficiency L2 learners. LAN is supportive of a Full-Parsing Model for regular endings, as it was detected in both low and high proficiency L2 learners. However, P600 was detected in highly proficient L2 learners only. It implies that high proficiency learners differ from low proficiency L2 learners. P600 is processed in a reparsing process after recognition of grammatical errors. Based on this result, more active use of a Dual Mechanism Model is possible as learning levels improve. It confirms that improvement in L2 learners results in an approach to cognitive processing similar to that of German first language (L1) speakers.
The Difference of Suicidal Ideation Between Shift Workers and Day Workers by Gender

Abstract Shift work does not synchronize with the 24-hour human circadian rhythm, so shift workers experience various problems related to this disruption. This study investigated the relationship between suicidal risk and emotional difficulties such as depression and anxiety in shift workers according to gender. We analyzed data collected from 79,009 health checkup recipients. We checked psychosocial factors for different genders using the Chi-square test and t-tests. To examine the relationship between shift work and suicidal ideation, we estimated an odds ratio after adjustment for age, depression, and insomnia. There was no difference in terms of the risk of suicidal ideation between shift workers and day workers among women (adjusted odds ratio [AOR], 0.957; 95% confidence interval [CI], 0.826–1.109), whereas the risk of suicidal ideation was significantly higher for shift workers than for day workers among men (AOR, 1.157; 95% CI, 1.021–1.310). This study confirmed that associated factors of shift work-related suicidal ideation could act differently by gender. Shift work for women is generally associated with emotional difficulties such as depression and anxiety, whereas maladaptation to shift work may be related to suicidal ideation among men. A gender-specific suicide prevention approaches will be needed for shift workers.
Egocentric and Allocentric Spatial Memory in Mild Cognitive Impairment with Real-World and Virtual Navigation Tasks: A Systematic Review

Background: Spatial navigation is the ability to estimate one’s position on the basis of environmental and self-motion cues. Spatial memory is the cognitive substrate underlying navigation and relies on two different reference frames: egocentric and allocentric. These spatial frames are prone to decline with aging and impairment is even more pronounced in Alzheimer’s disease (AD) or in mild cognitive impairment (MCI). Objective: To conduct a systematic review of experimental studies investigating which MCI population and tasks are used to evaluate spatial memory and how allocentric and egocentric deficits are impaired in MCI after navigation. Methods: PRISMA and PICO guidelines were applied to carry out the systematic search. Down and Black checklist was used to assess methodological quality. Results: Our results showed that amnestic MCI and AD pathology are the most investigated typologies; both egocentric and allocentric memory are impaired in MCI individuals, and MCI due to AD biomarkers has specific encoding and retrieval impairments; secondly, spatial navigation is principally investigated with the hidden goal task (virtual and real-world version), and among studies involving virtual reality, the privileged setting consists of non-immersive technology; thirdly, despite subtle differences, real-world and virtual versions showed good overlap for the assessment of MCI spatial memory. Conclusion: Considering that MCI is a subclinical entity with potential risk for conversion to dementia, investigating spatial memory deficits with navigation tasks might be crucial to make accurate diagnosis and rehabilitation.
Rates and Predictors of Deterioration in a Trial of Internet-Delivered Cognitive Behavioral Therapy for Reducing Suicidal Thoughts

Abstract Objective It is necessary for suicide prevention interventions to demonstrate safety. One important aspect of safety is evidence that deterioration rates are low. No studies have examined deterioration of suicidal ideation in the context of an internet-based cognitive behavioral therapy (CBT) intervention to reduce suicidal ideation. A secondary analysis of the outcomes of an online trial was conducted to determine rates of deterioration in a CBT intervention called Living with Deadly Thoughts, relative to an attention control condition, and to identify factors associated with deterioration. Method The randomized controlled trial included 418 adults with suicidal ideation at baseline (77% females, mean age 40.6 years). Deterioration was defined in two ways: a reliable increase in Suicidal Ideation Attributes Scale (SIDAS score) of ≥6.0 units; or triggering the safety protocol during the trial as determined by high levels of suicidality. Analyses were repeated with multiply imputed data. Predictors of deterioration were identified using logistic regression analysis. Results 30 (14%) participants in the control group and 15 (7%) in the intervention group met criteria for reliable deterioration (Fisher’s exact p = 0.027). In a fully adjusted logistic regression model, greater initial severity of suicidal thinking was associated with lower odds of deterioration, while intervention condition, demographics, psychological factors and mental health factors had no significant association with deterioration. Conclusions Participation in an online suicide prevention intervention was associated with lower prevalence of reliable deterioration than participation in an attention-control intervention, providing further evidence that internet-based CBT interventions do not cause harm. Highlights First study to assess deterioration in an internet suicide prevention intervention Rates of reliable deterioration were higher in control (14%) than intervention (7%) No psychological or demographic factors were robustly associated with deterioration Findings provide further evidence that internet based CBT programs are not harmful
Individualized, Intraoperative Dosing of Fibrinogen Concentrate for the Prevention of Bleeding in Neonatal and Infant Cardiac Surgery Using Cardiopulmonary Bypass (FIBCON)

Supplemental Digital Content is available in the text. Background: Mediastinal bleeding is common following pediatric cardiopulmonary bypass surgery for congenital heart disease. Fibrinogen concentrate (FC) represents a potential therapy for preventing bleeding. Methods: We performed a single-center, phase 1b/2a, randomized controlled trial on infants 2.5 to 12 kg undergoing cardiopulmonary bypass surgery, aimed at (1) demonstrating the feasibility of an intraoperative point-of-care test, rotational thromboelastometry, to screen out patients at low risk of postoperative bleeding and then guide individualized FC dosing in high-risk patients and (2) determining the dose, safety, and efficacy of intraoperative FC supplementation. Screening occurred intraoperatively 1-hour before bypass separation using the rotational thromboelastometry variable fibrinogen thromboelastometry maximum clot firmness (FibTEM-MCF; fibrinogen contribution to clot firmness). If FibTEM-MCF ≥7 mm, patients entered the monitoring cohort. If FibTEM-MCF ≤6 mm, patients were randomized to receive FC/placebo (2:1 ratio). Individualized FC dose calculation included weight, bypass circuit volume, hematocrit, and intraoperative measured and desired FibTEM-MCF. The coprimary outcomes, measured 5 minutes post-FC administration were FibTEM-MCF (desired range, 8–13 mm) and fibrinogen levels (desired range, 1.5–2.5 g/L). Secondary outcomes were thrombosis and thrombosis-related major complications and postoperative 24-hour mediastinal blood loss. Results: We enrolled 111 patients (cohort, n=21; FC, n=60; placebo, n=30); mean (SD) age, 6.4 months (5.8); weight, 5.9 kg (2.0). Intraoperative rotational thromboelastometry screening effectively excluded low-risk patients, in that none in the cohort arm (FibTEM-MCF, ≥7 mm) demonstrated clinically significant early postoperative bleeding (>10 mL/kg per 4 hours). Among randomized patients, the median (range) FC administered dose was 114 mg/kg (51–218). Fibrinogen levels increased from a mean (SD) of 0.91 (0.22) to 1.7 g/L (0.41). The postdose fibrinogen range was 1.2 to 3.3 g/L (72% within the desired range). The corresponding FibTEM-MCF values were as follows: pre-dose, 5.3 mm (1.9); post-dose, 13 mm (3.2). Ten patients (8 FC and 2 placebo) exhibited 12 possible thromboses; none were clearly related to FC. There was an overall difference in mean (SD) 24-hour mediastinal drain loss: cohort, 12.6 mL/kg (6.4); FC, 11.6 mL/kg (5.2); placebo, 17.1 mL/kg (14.3; ANOVA P=0.02). Conclusions: Intraoperative, individualized dosing of FC appears feasible. The need for individualized dosing is supported by the finding that a 4-fold variation in FC dose is required to achieve therapeutic fibrinogen levels. Registration: URL: https://eudract.ema. europa.eu/; Unique identifier: 2013-003532-68. URL: https://www.isrctn. com/; Unique identifier: 50553029.
Rating the seriousness of maternal and child health outcomes linked with pregnancy weight gain.

BACKGROUND Current pregnancy weight gain guidelines were developed based on implicit assumptions of a small group of experts about the relative seriousness of adverse health outcomes. Therefore, they will not necessarily reflect the values of women. OBJECTIVE To estimate the seriousness of 11 maternal and child health outcomes that have been consistently associated with pregnancy weight gain by engaging patients and health professionals. METHODS We collected data using an online panel approach with a modified Delphi structure. We selected a purposeful sample of maternal and child health professionals (n = 84) and women who were pregnant or recently postpartum (patients) (n = 82) in the United States as panellists. We conducted three concurrent panels: professionals only, patients only, and patients and professionals. During a 3-round online modified Delphi process, participants rated the seriousness of health outcomes (Round 1), reviewed and discussed the initial results (Round 2), and revised their original ratings (Round 3). Panellists assigned seriousness ratings (0, [not serious] to 100 [most serious]) for infant death, stillbirth, preterm birth, gestational diabetes, preeclampsia, small-for-gestational-age (SGA) birth, large-for-gestational-age (LGA) birth, unplanned caesarean delivery, maternal obesity, childhood obesity, and maternal metabolic syndrome. RESULTS Each panel individually came to a consensus on all seriousness ratings. The final median seriousness ratings combined across all panels were highest for infant death (100), stillbirth (95), preterm birth (80), and preeclampsia (80). Obesity in children, metabolic syndrome in women, obesity in women, and gestational diabetes had median seriousness ratings ranging from 55 to 65. The lowest seriousness ratings were for SGA birth, LGA birth, and unplanned caesarean delivery (30-40). CONCLUSION Professionals and women rate some adverse outcomes as being more serious than others. These ratings can be used to establish the range of pregnancy weight gain associated with the lowest risk of a broad range of maternal and child health outcomes.
Alpha-1 blocker use increased risk of subsequent renal cell carcinoma: A nationwide population-based study in Taiwan

Elevated Renal cell carcinoma (RCC) risk has been associated with the use of several antihypertensive medications but has not yet been elucidated in the populations prescribed alpha-1 blockers that are commonly used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS-BPH). The aim of the present study was to investigate the association between alpha-1 blocker use and the risk of developing RCC using a nationwide population-based database in Taiwan. Patients who were treated with alpha-1 blockers for at least 28 days were identified through the Taiwan National Health Insurance Research Database from 2000 to 2010. The unexposed participants were matched with the exposed cases according to age, sex, and index year at a ratio of 3:1. Cox proportional hazards regression, stratified by sex and comorbidities and adjusted for age, was performed to estimate hazard ratios (HRs) for the risk of subsequent RCC. Among 2,232,092 subjects, patients who received alpha-1 blocker treatment had a higher risk of RCC than the unexposed group. Taking into account hypertension and BPH, the adjusted HR was significantly higher in male alpha-1 blocker users who had no BPH and either the presence (HR: 1.63, 95% confidence interval [CI] = 1.22–2.18) or absence (HR: 2.31, 95% CI = 1.40–3.81) of hypertension than in men not receiving these drugs. Taken together, male alpha-1 blocker users who had no comorbidity of BPH exhibited an increased risk for developing RCC independent of hypertension. Further study is warranted to elucidate the underlying mechanisms of this association.
Anti-biofilm Activity of Oral Health-care Products Containing Chlorhexidine Digluconate and Citrox.

PURPOSE To analyze in vitro new formulations with Citrox and chlorhexidine digluconate (CHX) regarding their antibacterial activity against planktonic bacteria and their potential to inhibit biofilm formation or to act on existing biofilms. MATERIALS AND METHODS Five oral health care products with 0.05%-0.5% CHX formulations (four rinses and one gel) were compared with Citrox preparations and additive-free CHX solutions. The minimal inhibitory concentrations (MIC) were determined against 13 oral bacteria associated with caries or periodontitis. Further, the activity on retarding biofilm formation and on existing biofilms was analyzed; both a 'cariogenic' (5 species) and a 'periodontal' (12 species) biofilm were included. RESULTS The MIC values did not differ between the CHX mouthrinse/gel formulations and the respective additive-free CHX solutions. Citrox was active against selected periodontopathogens (e.g. Porphyromonas gingivalis). The CHX formulations more effectively retarded biofilm formation than did solutions with the same concentration of CHX but without additives. The anti-biofilm activities depended on the CHX concentration in the formulations. Both CHX solutions and formulations (rinse and gel) were only slightly active on an already formed biofilm. Citrox did not exert any anti-biofilm effect. CONCLUSION The present in vitro data support the anti-biofilm activity of the novel CHX, Citrox, poly-L-lysine and xylitol oral health-care formulations. Further studies are warranted to confirm the present findings in various clinical settings.
Prophylactic dressings in the prevention of pressure ulcer related to the use of personal protective equipment by health professionals facing the COVID‐19 pandemic: A randomized clinical trial

Device‐related pressure injury (DRPI) is a serious problem that is affecting professionals working on the front lines against COVID‐19 due to the prolonged use of personal protective equipment (PPE). In addition to the physical and psychological integrity of professionals, these injuries can compromise the quality of care. Therefore, using technologies to prevent this adverse effect is an urgent matter. This is a parallel two‐arm randomized clinical trial without the use of a control group to compare the use of foam and extra‐thin hydrocolloid in preventing DRPI associated with the use of PPE by health professionals working on the front lines against coronavirus. In total, 88 professionals were divided into two groups: foam and hydrocolloid. Data were collected using two instruments and related to demographic and professional characteristics and skin evaluation. Each volunteer received one of the dressings, both with the same dimensions and arranged over similar regions, and data were gathered at baseline and after 6 or 12 hours. Descriptive and inferential analytic statistical methods were used; the significance level adopted was 5%. No participant developed DRPI, but four areas with hyperemia were observed in the foam group (two in the forehead, one in the cheeks, and one in the nose bridge), as well as four areas with hyperemia in the hydrocolloid group (two in the nose bridge, one in the right ear, and one in the left ear). There was no difference between the groups regarding skin conditions and discomfort (P > .05). The average cost obtained was $ 5.8/person and $ 4.4/person in the foam group and the hydrocolloid group, respectively, considering the dressing measurements. The results show that foam and extra‐thin hydrocolloid were effective in preventing DRPI associated with the use of PPE.
Comment on: Pancreatectomy With Arterial Resection for Pancreatic Adenocarcinoma: How Can It Be Done Safely and With Which Outcomes?

Reply: We would like to thank Dr Robertson et al and Dr Zhang et al for their interest in our study reporting the short and long-term outcomes of pancreatectomy with arterial resection for adenocarcinoma. As reported recently, there has been a growing debate around the role of surgery in patients with locally advanced pancreatic cancers because the therapeutic armamentarium for this category of patients has not classically included resection. The extensive use of FOLFIRINOX chemotherapy has been associated to an objective pathological response. This therapy—along with the technical advances achieved in pancreatic surgery—has led surgeons to perform more extensive resections in an attempt to provide care to patients with locally advanced disease. Several institutions are now reporting series of combined arterial and venous resections with encouraging pathologic, postoperative, and survival rates. Our study confirmed that in a specialized setting, these extended pancreatectomies, while initially abandoned, are now feasible and could eventually be included into the treatment of patients with locally advanced pancreatic adenocarcinomas. Once the safety of this surgery has been proven, the question remains of how to select the best candidates. Patient selection remains the foremost factor for achieving optimal results. In surgical oncology, an optimal result is the best compromise between a proven survival benefit, good long-term quality-of-life, and an acceptable risk of operative mortality. Pancreatic surgeons can play an important part of this equation by providing the highest technical expertise while striving for the lowest
Emergence of carbapenem-resistant ST131 Escherichia coli carrying bla OXA-244 in Germany, 2019 to 2020

The dissemination of carbapenem-producing Gram-negative bacteria is a major public health concern. We report the first detection of OXA-244-producing ST131 O16:H5 Escherichia coli in three patients from two tertiary hospitals in the south-west of Germany. OXA-244 is emerging in Europe. Because of detection challenges, OXA-244-producing E. coli may be under-reported. The emergence of carbapenem resistance in a globally circulating high-risk clone, such as ST131 E. coli is of clinical relevance and should be monitored closely.