Miracle-dz/UniFAR-FTUs huggingface dataset:
Intravenous fosfomycin for the treatment of patients with bone and joint infections: a review

ABSTRACT Introduction Fosfomycin is a wide spectrum bactericidal antibiotic with a unique mode of action, low toxicity, and good penetration in tissues with deep-seated infections, including bone and joint infections. Areas covered Data were extracted from 19 published articles. Three hundred and sixty-five patients, with broad age range, received intravenous fosfomycin for the treatment of bone and joint infections (including arthritis, acute and chronic osteomyelitis, discitis, periprosthetic joint infection). Fosfomycin was given as part of a combination antimicrobial therapy in the majority of patients (93.7%). The dosage of fosfomycin ranged from 4 g/day (in one case) to 24 g/day. The dosage of fosfomycin, in some cases, mostly pediatric, was calculated based on body weight, ranging from 50 mg/kg/day to 250 mg/kg/day. The duration of fosfomycin treatment ranged from a couple of days up to 3 months. The most common isolated pathogen was Staphylococcus aureus (38.9%). Three hundred patients (82.2%) were successfully treated. Fosfomycin was well tolerated, as few patients developed mild adverse events, mostly gastrointestinal discomfort, hypernatremia, skin rash, and neutropenia. Expert opinion The available data suggests that intravenous fosfomycin may be beneficial for the treatment of patients with bone and joint infections, especially when used as part of a combination antibiotic regimen.
Protocol of a randomized controlled trial investigating the effectiveness of Recovery-focused Community support to Avoid readmissions and improve Participation after Stroke (ReCAPS)

Rationale To address unmet needs, electronic messages to support person-centered goal attainment and secondary prevention may avoid hospital presentations/readmissions after stroke, but evidence is limited. Hypothesis Compared to control participants, there will be a 10% lower proportion of intervention participants who represent to hospital (emergency/admission) within 90 days of randomization. Methods and design Multicenter, double-blind, randomized controlled trial with intention-to-treat analysis. The intervention group receives 12 weeks of personalized, goal-centered, and administrative electronic messages, while the control group only receive administrative messages. The trial includes a process evaluation, assessment of treatment fidelity, and an economic evaluation. Participants: Confirmed stroke (modified Rankin Score: 0-4), aged ≥18 years with internet/mobile phone access, discharged directly home from hospital. Randomization: 1:1 computer-generated, stratified by age and baseline disability. Outcomes assessments: Collected at 90 days and 12 months following randomization. Outcomes Primary outcomes include hospital emergency presentations/admissions within 90 days of randomization. Secondary outcomes include goal attainment, self-efficacy, mood, unmet needs, disability, quality-of-life, recurrent stroke/cardiovascular events/deaths at 90 days and 12 months, and death and cost-effectiveness at 12 months. Sample size: To test our primary hypothesis, we estimated a sample size of 890 participants (445 per group) with 80% power and two-tailed significance threshold of α = 0.05. Given uncertainty for the effect size of this novel intervention, the sample size will be adaptively re-estimated when outcomes for n = 668 are obtained, with maximum sample capped at 1100. Discussion We will provide new evidence on the potential effectiveness, implementation, and cost-effectiveness of a tailored eHealth intervention for survivors of stroke.
Evidence for a gradient within the medial temporal lobes for flexible retrieval under hierarchical task rules

A fundamental question in memory research is how the hippocampus processes contextual cues to retrieve distinct mnemonic associations. Prior research has emphasized the importance of hippocampal–prefrontal interactions for context‐dependent memory. Our fMRI study examined the human medial temporal lobes (MTL) and their prefrontal interactions when retrieving memories associated with hierarchically organized task contexts. Participants learned virtual object‐location associations governed by subordinate and superordinate task rules, which could be independently cued to change. On each fMRI trial, participants retrieved the correct object for convergent rule and location contextual information. Results demonstrated that hippocampal activity and hippocampal–prefrontal functional interconnectivity distinguished retrieval under different levels of hierarchically organized task rules. In explicit contrast to the hippocampal tail, anterior (body and head) regions were recruited specifically for superordinate changes in the contextual hierarchy. The hippocampal body also differed in its functional connectivity with the prefrontal cortex for superordinate versus subordinate changes. Our findings demonstrate a gradient in MTL for associative retrieval under changing task rules, and advance understanding of hippocampal–prefrontal interactions that support flexible contextual memory.
Dexmedetomidine inhibits unstable motor network in patients with primary motor area gliomas

Background: Sedative agents such as dexmedetomidine have been found to transiently exacerbate or unmask limb motor dysfunction in patients with eloquent area brain gliomas. The present study aims to investigate whether dexmedetomidine can inhibit motor plasticity in patients with glioma via fMRI. Methods: 21 patients with brain glioma were prospectively recruited between September 2017 and December 2018. Patients were classified into pre-M1 (primary motor cortex) group (n=9), post-M1 group (n=6), and non-eloquent group (control group) (n=6) according to the tumor position related to M1. The hand movement task-fMRI and resting state fMRI (rs-fMRI) were performed before and after sedation using dexmedetomidine. The lateralization index (LI) of activation voxels and magnitude and the functional connectivity (FC) of motor network were compared before and after sedation and among different groups. Results: Permanent postoperative motor deficit of the upper limb was found in 5 of 6 patients in the pre-M1 group, and none in other groups (P < .01). Task-fMRI showed the LI of activation volume and activation magnitude at M1 significantly increased only in the pre-M1 group after sedation (P < .05). Rs-fMRI showed 60.0% (27 of 45) FCs of motor network decreased in pre-M1 group after sedation (p[FDR] < .05); whereas there was no FC reduction in post-M1 and control groups (p[FDR] > .05). Conclusions: In patients with eloquent area gliomas, dexmedetomidine can inhibit the unstable compensative motor plasticity on both task- and rs-fMRI. fMRI may be a promising method for elucidating the effect of sedative agents on motor plasticity.
A chemical screen for modulators of mRNA translation identifies a distinct mechanism of toxicity for sphingosine kinase inhibitors

We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs.
Preventive use of a topical anti-inflammatory glucocorticoid in atopic dogs without clinical sign of otitis does not affect ear canal microbiota and mycobiota.

BACKGROUND Otitis externa is associated with a lack of bacterial/fungal diversity in atopic dermatitis. Clinical experience has shown that use of topical corticosteroids in the ear canal (EC) can prevent otitis. No data are available on the impact of this treatment on the EC microbiota. HYPOTHESIS/OBJECTIVES To observe the bacterial/fungal diversity in the EC and the clinical effect of topical corticosteroids administered over a four week period in atopic dogs without active otitis. ANIMALS Ten atopic dogs without active otitis. METHODS AND MATERIALS Mometasone was applied in the right EC, while the left was used as control. A clinical and cytological evaluation of the EC was performed. Swabs of each EC were analysed using next-generation sequencing methods. RESULTS At the beginning of the trial, variations in microbiota and mycobiota were observed between dogs and also within individuals. Statistically, no significant difference was observed in alpha and beta diversity between the treated and the untreated group over time. Clinically, right and left EC diversities were no different at Day (D)28 (P = 0.28). A significant difference was noted between D0 and D28 for the treated ears (P = 0.012) and not for the untreated ears (P = 0.63). No cytological evidence of microbes was found for treated ECs at D28. CONCLUSIONS AND CLINICAL RELEVANCE These data suggest that the use of topical corticosteroids as proactive treatment is unlikely to increase the risk of secondary microbial overgrowth. The positive clinical effect of this proactive treatment seems to be supported through cytological and otoscopic improvement.
The understanding of the immunopathology in COVID-19 infection

Abstract Coronaviruses belonging to the Coronaviridae family are single-stranded RNA viruses. The entry of SARS-CoV-2 is accomplished via ACE-2 receptors. SARS-CoV-2 infection coactivates both innate and adaptive immune responses. Although SARS-CoV-2 stimulates antibody production with a typical pattern of IgM/IgG, cellular immunity is also impaired. In severe cases, low CD4 + and CD8 + T cell counts are associated with impaired immune functions, and high neutrophil/lymphocyte ratios accompanying low lymphocyte subsets have been demonstrated. Recently, high IFN -α/γ ratios with impaired T cell responses, and increased IL-1, IL-6, TNF-α, MCP-1, IP-10, IL-4, IL-10 have been reported in COVID-19 infection. Increased proinflammatory cytokines and chemokines in patients with severe COVID-19 may cause the suppression of CD4 + and CD8 + T cells and regulatory T cells, causing excessive inflammatory responses and fatal cytokine storm with tissue and organ damage. Consequently, novel therapeutics to be developed against host immune system, including blockade of cytokines (IL-6, IL-1, IFN) themselves, their receptors or signaling pathways- JAK inhibitors- could be effective as potential therapeutics.
First open-label, single-arm, prospective study of real-world use of FIX replacement therapy in a predominantly pediatric hemophilia B population in China

Supplemental Digital Content is available in the text Abstract Background: Nonacog alfa (recombinant factor IX [FIX]) is approved in China for the control and prevention of bleeding events in patients with hemophilia B. This was the first study to assess prophylaxis and on-demand therapy with recombinant FIX replacement in a real-world setting in China. This study aimed to evaluate the safety and efficacy of nonacog alfa in Chinese patients with hemophilia B. Methods: In this open-label, multicenter study (clinicaltrials.gov identifier NCT02336178), patients received on-demand or prophylactic treatment with intravenous nonacog alfa for approximately 6 months or 50 exposure days, whichever occurred first. The primary safety outcome was medically important events (i.e., development of FIX inhibitors, allergic reactions, and thrombotic events). Key secondary efficacy outcomes included the annualized bleeding rate for on-demand treatment and prophylaxis, response to on-demand treatment, the number of infusions per bleeding event, and the number of breakthrough bleeding events within 48 hours of prophylaxis. Results: Seventy male patients (mean [standard deviation] age 7.8 [7.2] years) were enrolled (on-demand, n = 37; prophylaxis, n = 57 [24 patients were included in both groups]). Thirty-eight (54%) patients had up to 50 FIX exposure days before the study. The only medically important event was a transient low-titer FIX inhibitor (incidence 1.4%, 95% confidence interval, 0–7.7). The mean annualized bleeding rate was 26.3 for on-demand treatment and 6.5 for prophylaxis. A mean (standard deviation) of 1.5 (1.7) nonacog alfa infusions were given per bleeding episode; 78.8% of episodes resolved with 1 infusion. Response was “excellent” or “good” for 88% of the on-demand infusions. Twenty-three bleeding events (n = 11 patients) occurred within 48 hours of 2032 prophylaxis doses (1.13%). Conclusion: In the real-world setting, nonacog alfa is safe and effective for on-demand treatment and for prophylaxis for patients with hemophilia B in China.
Outcomes of excessive alcohol drinkers without baseline evidence of chronic liver disease after 15 years follow-up: Heavy burden of cancer and liver disease mortality

Background Most long-term heavy drinkers do not have clinically evident chronic liver disease (CLD). However, at any time-point, their risk of developing CLD remains unknown. We aimed to evaluate the long-term outcomes of a group of heavy drinkers, without evidence of CLD at baseline. Methods A cohort of 123 long-term heavy drinkers without CLD were prospectively recruited in 2002 and retrospectively followed until 2018. Results At baseline (2002), median alcohol consumption was 271±203g/day during 21.5±20 years, 65% being abstinent during the previous 1.75±5 months. Patients were followed for 14±3 years. During follow-up, 53% reported any alcohol intake. Alcohol consumption during follow-up associated weakly with either 1- or 6-months previous abstinence at baseline. Until 2018, progression to CLD occurred in 6%, associating with years of alcohol intake during follow-up (OR 1.15 [1.01–1.31]) and baseline alkaline-phosphatase (OR 1.05 [1.01–1.10]). During follow-up, being abstinent for at least 1 year positively associated with CLD-free survival. 27% died (55% of cancer–mostly oropharyngeal cancer, 27% of cardiovascular disease, and 9% of liver disease), with a mean age of 71 years [69–74] (10 years less than the expected in the Portuguese population). Achieving abstinence for at least 1 year positively associated with overall survival, while smoking, and hepatic steatosis at baseline associated negatively. Conclusion Long-term heavy drinkers seemed to have a decreased life expectancy compared with the overall Portuguese population. Cancer was the main cause of death. Our results suggest that progression to CLD depends mostly on continued alcohol intake. Alcohol abstinence, even if temporary, seems to decrease the risks of CLD and mortality.
Collective states and their transitions in football

Movement, positioning and coordination of player formations is a key aspect for the performance of teams within field-based sports. The increased availability of player tracking data has given rise to numerous studies that focus on the relationship between simple descriptive statistics surrounding team formation and performance. While these existing approaches have provided a high-level a view of team-based spatial formations, there is limited research on the nature of collective movement across players within teams and the establishment of stable collective states within game play. This study draws inspiration from the analysis of collective movement in nature, such as that observed within schools of fish and flocking birds, to explore the existence of collective states within the phases of play in soccer. Order parameters and metrics describing group motion and shape are derived from player movement tracks to uncover the nature of the team’s collective states and transitions. This represents a unique addition to the current body of work around the analysis of player movement in team sports. The results from this study demonstrate that sequences of ordered collective behaviours exist with relatively rapid transitions between highly aligned polar and un-ordered swarm behaviours (and vice-versa). Defensive phases of play have a higher proportion of ordered team movement than attacking phases, indicating that movements linked with attacking tactics, such as player dispersion to generate passing and shooting opportunities leads to lower overall collective order. Exploration within this study suggests that defensive tactics, such as reducing the depth or width to close passing opportunities, allows for higher team movement speeds and increased levels of collective order. This study provides a novel view of player movement by visualising the collective states present across the phases of play in football.
LSD1 and Aberrant DNA Methylation Mediate Persistence of Enteroendocrine Progenitors That Support BRAF-Mutant Colorectal Cancer

This study establishes enteroendocrine progenitors as a targetable population that promotes BRAF-mutant colorectal cancer and can be blocked by LSD1 inhibition to suppress tumor growth. Despite the connection of secretory cells, including goblet and enteroendocrine (EEC) cells, to distinct mucus-containing colorectal cancer histologic subtypes, their role in colorectal cancer progression has been underexplored. Here, our analysis of The Cancer Genome Atlas (TCGA) and single-cell RNA-sequencing data demonstrates that EEC progenitor cells are enriched in BRAF-mutant colorectal cancer patient tumors, cell lines, and patient-derived organoids. In BRAF-mutant colorectal cancer, EEC progenitors were blocked from differentiating further by DNA methylation and silencing of NEUROD1, a key gene required for differentiation of intermediate EECs. Mechanistically, secretory cells and the factors they secrete, such as trefoil factor 3, promoted colony formation and activation of cell survival pathways in the entire cell population. Lysine-specific demethylase 1 (LSD1) was identified as a critical regulator of secretory cell specification in vitro and in a colon orthotopic xenograft model, where LSD1 loss blocks formation of EEC progenitors and reduces tumor growth and metastasis. These findings reveal an important role for EEC progenitors in supporting colorectal cancer. Significance: This study establishes enteroendocrine progenitors as a targetable population that promotes BRAF-mutant colorectal cancer and can be blocked by LSD1 inhibition to suppress tumor growth.
Construction and validation of educational material on promoting breastfeeding in schools.

OBJECTIVE to build and validate an educational technology on the promotion of breastfeeding for schoolchildren. METHODS a methodological study was developed through a bibliographic survey, situational diagnosis, creation of illustrations, layout, design and texts, validation of the material with the help of expert judges and target audience. RESULTS the content judges enabled the validation of the material with an overall Content Validity Index of 90%, the judges of the design Suitability Assessment of Materials of 90.4% and the target audience with a 95.6% agreement. The readability percentage proved to be excellent, with an overall score of 100%. CONCLUSION the educational technology proved to be a valid and reliable instrument to promote a breastfeeding culture among schoolchildren.
Seroprevalence of SARS-CoV-2 Among Skilled Nursing Facility Residents and Staff Members — Los Angeles County, August–September 2020

Abstract Background The prevalence of current/past coronavirus disease 2019 (COVID-19) in skilled nursing facility (SNF) residents is unknown because of asymptomatic infection and constrained testing capacity early in the pandemic. We conducted a seroprevalence survey (SPS) to determine a more comprehensive prevalence of past COVID-19 in Los Angeles County SNF residents and staff members. Methods We recruited participants from 24 facilities; participants were requested to submit a nasopharyngeal (NP) swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR testing and serum for detection of SARS-CoV-2 antibodies. All participants were cross-referenced with our surveillance database to identify persons with prior positive SARS-CoV-2 results. Results From August 18 to September 24, 2020, we enrolled 3,305 participants (1,340 residents and 1,965 staff members). Among 856 residents providing serum, 362 (42%) had current/past SARS-CoV-2 infection. Of the 346 serology positive residents, 199 (58%) did not have a documented prior positive SARS-CoV-2 PCR result. Among 1,806 staff members providing serum, 454 (25%) had current/past SARS-CoV-2 infection. Of the 447 serology positive staff members, 353 (79%) did not have a documented prior positive SARS-CoV-2 PCR result. Conclusions Past testing practices and policies missed a substantial number of SARS-CoV-2 infections in SNF residents and staff members.
Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.

BACKGROUND Weeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called Multisystem Inflammatory Syndrome in Children (MIS-C). Gastrointestinal symptoms are common in MIS-C patients and severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not previously been identified. METHODS Here, we analyzed biospecimens from 100 children: 19 children with MIS-C, 26 with acute COVID-19, and 55 controls. Stool was assessed for SARS-CoV-2 by RT-PCR and plasma was assessed for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As proof of concept, we treated a MIS-C patient with larazotide, a zonulin antagonist, and monitored impact on antigenemia and clinical response. RESULTS We showed that in MIS-C, prolonged presence of SARS-CoV-2 in the GI tract leads to release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The MIS-C patient treated with larazotide displayed a coinciding decrease in plasma SARS-CoV-2 Spike antigen levels, inflammatory markers, and a resultant clinical improvement above that achieved with currently available treatments. CONCLUSION These mechanistic data of MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.