Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinico-Haematologic association and prognostic relevance of NPM1 and FLT3-ITD mutations in acute Myeloid Leukaemia

Background & Objectives: Molecular genetic abnormalities have a significant role not only in diagnosis but also in determining the clinical course and prognosis. Nucleophosmin-1 (NPM-1) is associated with good prognosis while internal tandem duplication of the fms-like tyrosine kinase-3 gene (FLT3-ITD) confers a poor prognosis. Knowledge of the status of these mutations in AML patients not only guides treatment decisions but also helps in predicting response to frontline induction and consolidation chemotherapy as well as the risk of relapse and overall survival. Our objectives were to determine the prevalence, clinico-haematological features and immunophenotypic characteristics of AML patients with FLT3-ITD and NPM1 mutation and to evaluate the response to induction therapy (CR) and disease free survival (DFS) in this cohort of patients. Methods: Patients diagnosed as AML from March 2015 to March 2017 at Armed Forces Institute of Pathology Rawalpindi were included in the study. Clinico-haematologic and immunophenotypic parameters were noted and molecular analysis for FLT3-ITD and NPM1 mutation was performed. Any correlation with cytogenetics or other molecular markers was also studied. Response to standard induction chemotherapy and disease-free survival were assessed. Results: A total of 108 cases of AML were analyzed. Median age was 35 years and 64.8% were males. The median age of the study group was 35 years. Of these, 70 (64.8%) were males while 38 (35.2%) were females. Twenty-nine (26.9%) patients were NPM1 positive, twelve (11.1%) were FLT3-ITD positive while eight (7.4%) were positive for both mutations. Patients with NPM1 mutations were associated with female gender, higher haemoglobin level and platelet counts while those with FLT3-ITD mutations were predominantly seen in male patients and had significantly higher WBC counts, bone marrow blasts, biopsy cellularity and LDH levels. CR rates of NPM1 positive, FLT3-ITD positive and both mutation positive groups were 72%, 60% and 71%, respectively. The median disease-free survival was significantly lower in the FLT3-ITD positive group (7.1 months) as compared to the NPM1 positive group (16.1 months). The median disease-free survival was 12 months and 11.9 months in the NPM1 positive/FLT3-ITD positive and the NPM1 negative/FLT3-ITD negative groups, respectively. Conclusion: AML patients harbouring NPM1 and FLT3-ITD mutations have distinct clinical and haematological characteristics. NPM1 mutations have a better CR and DFS as compared to FLT3-ITD group.
Antibacterial activity and mechanism of silver nanoparticles against multidrug-resistant Pseudomonas aeruginosa

Background The threat of drug-resistant Pseudomonas aeruginosa requires great efforts to develop highly effective and safe bactericide. Objective This study aimed to investigate the antibacterial activity and mechanism of silver nanoparticles (AgNPs) against multidrug-resistant P. aeruginosa. Methods The antimicrobial effect of AgNPs on clinical isolates of resistant P. aeruginosa was assessed by minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). In multidrug-resistant P. aeruginosa, the alterations of morphology and structure were observed by the transmission electron microscopy (TEM); the differentially expressed proteins were analyzed by quantitative proteomics; the production of reactive oxygen species (ROS) was assayed by H2DCF-DA staining; the activity of superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) was chemically measured and the apoptosis-like effect was determined by flow cytometry. Results Antimicrobial tests revealed that AgNPs had highly bactericidal effect on the drug-resistant or multidrug-resistant P. aeruginosa with the MIC range of 1.406–5.625 µg/mL and the MBC range of 2.813–5.625 µg/mL. TEM showed that AgNPs could enter the multidrug-resistant bacteria and impair their morphology and structure. The proteomics quantified that, in the AgNP-treated bacteria, the levels of SOD, CAT, and POD, such as alkyl hydroperoxide reductase and organic hydroperoxide resistance protein, were obviously high, as well as the significant upregulation of low oxygen regulatory oxidases, including cbb3-type cytochrome c oxidase subunit P2, N2, and O2. Further results confirmed the excessive production of ROS. The antioxidants, reduced glutathione and ascorbic acid, partially antagonized the antibacterial action of AgNPs. The apoptosis-like rate of AgNP-treated bacteria was remarkably higher than that of the untreated bacteria (P<0.01). Conclusion This study proved that AgNPs could play antimicrobial roles on the multidrug-resistant P. aeruginosa in a concentration- and time-dependent manner. The main mechanism involves the disequilibrium of oxidation and antioxidation processes and the failure to eliminate the excessive ROS.
Does an increased number of cesarean sections result in greater risk for mother and baby in low-risk, late preterm and term deliveries?

Objective: To compare surgical complications and maternal and neonatal outcomes of low-risk, late preterm and term pregnant women who have had one or two previous cesarean sections (CSs) with those who have had three or more CSs. Methods: We conducted a retrospective study of 850 patients undergoing repeat CS at a tertiary level maternity hospital in Ankara, Turkey. Of those, 380 had previously undergone one or two CSs (Group-I: second or third CS) and 470 had previously undergone three or four CSs (Group-II: fourth or fifth CS). Outcomes and complications were compared between the groups. Results: The two groups were statistically significantly different in terms of maternal age, parity, body mass index, maternal weight gain during pregnancy, and length of hospital stay (all p<0.001). Although the prevalence of intraperitoneal adhesions and placenta previa was higher in Group-II than in Group-I (p<0.001), there was no statistically significant difference in terms of cesarean hysterectomy and adjacent organ injuries (p>0.05). There were also no significant differences between the groups in terms of neonatal outcomes (p>0.05). Conclusion: Although the increase in the number of CSs appears to be associated with intraperitoneal adhesions and placenta previa, adverse maternal and neonatal outcomes were not observed in those women with low-risk pregnancies who underwent CS for the fourth or fifth time. Therefore, fourth and fifth CSs may be considered relatively safe surgical procedures in this cohort.
Preparation and optimization of lidocaine transferosomal gel containing permeation enhancers: a promising approach for enhancement of skin permeation

Aim To develop the topical gel containing transferosomal lidocaine as alternative to painful local anesthetic injection. Materials and methods The transfersomes were prepared by film hydration technique using soybean phosphatidylcholine and cholesterol. The prepared transfersomes were evaluated for the morphology, drug loading, %EE, particle size and in vitro release. The transferosomal gel of lidocaine was prepared using HPMC k15 as gelling agent and propylene glycol, dimethyl sulfoxide (DMSO), and polyamidoamine dendrimer third generation (PAMAM G3) solutions were used as permeation enhancer. The formulated gels were evaluated for pH, viscosity, drug content and ex-vivo permeation of the gel. The analgesic effect of the formulation was tested using tail flick test. Results The transfersomes showed that transfersomes (F4) had the highest entrapment efficiency (%EE) approaching 79.87±2.35, low particle size 179.5 nm, and zeta potential of −43.5±4.74 mV. According to the rat tail flick test, the AUC0–90 minutes of the control formulation (lidocaine solution, A) was 352.32±5.87 seconds minutes. While the maximum AUC0–90 minutes value was found to be 570.5±6.81 seconds minutes for gel formulation (F) containing transfersomal lidocaine with PAMAM G3 dendrimer as permeation enhancer. In this case, the local anesthetic efficacy was increased by 1.62-folds as compared to control formulation. Conclusion From the present study, it can be concluded that the topical gel loaded with transfersomal lidocaine shows enhanced skin permeation effect along with increase in local anesthetic action of lidocaine.
Extensively drug-resistant Gram-negative bacterial bloodstream infection in hematological disease

Background Extensively drug-resistant Gram-negative bacterial (XDR-GNB) bloodstream infection (BSI) is difficult to treat and is associated with a high mortality rate in patients with hematological diseases. The aim of this study is to investigate the predisposing risk factors and the efficacy of the antibiotic treatment in these patients, including exploration of efficacy and adverse effects of high-dose tigecycline. Methods Between January 2013 and December 2017, 27 XDR-GNB BSI patients with hematological diseases were diagnosed and retrospectively reviewed in the current study. Results Clinical response in patients with severe complications (such as severe neutropenia >10 days, grade III–IV acute graft-versus-host disease (aGVHD), and concurrent pneumonia) was significantly lower than in patients without or with only mild complications (P=0.033). The efficacy rate was 62.5% (10/16) in patients with tigecycline-based combination therapy regimen, 77.8% (7/9) with a high-dose tigecycline regimen, and 42.9% (3/7) with a standard-dose tigecycline regimen (P=0.36). The 30-day survival rates of patients undergoing high-dose or standard-dose tigecycline treatment were 66.7% (95% CI: 28.2–87.8) and 57.1% (95% CI: 17.2–83.7), respectively, (P=0.603). Patients with mild complications were associated with superior 30-day survival rates than patients with severe complications (93.8% vs 36.4%, P=0.001), >10 days of neutropenia (90.9% vs 33.3%, P=0.012), severe aGVHD (100% vs 40%, P=0.049), and concurrent pneumonia (84.6% vs 57.1%, P=0.048). Conclusion Our study indicated that XDR-GNB BSI in patients of hematological diseases with severe complications, such as long duration of neutropenia (>10 days) and severe aGVHD were associated with poor clinical response and short survival. We first indicated that these patients undergoing high-dose tigecycline treatment had an improved clinical response and an increased 30-day survival rate compared with the standard-dose group, although the differences were not statistically significant. This might be due to more severe complicated patients enrolled in high-dose group and the limited number size in our study.
F-box/WD-40 repeat-containing protein 7: A potential target in the progression and treatment of gastrointestinal malignancy

Cancer is a principal cause of human morbidity and mortality, with gastrointestinal malignancies, in particular, resulting in a marked number of tumor-associated mortalities. The progression of gastrointestinal malignancy is regulated by a variety of aberrantly expressed proteins, a number of which facilitate tumor progression, whereas, others function as tumor suppressors. The detection of such proteins not only contributes to the early diagnosis of cancer, they may additionally serve as potential therapeutic targets. In normal tissues, numerous proteins encoded by proto-oncoproteins are degraded by ubiquitylation enzymes, consisting of F-box/WD-40 repeat-containing protein 7 (Fbw7) and other proteins, thus avoiding tumorigenesis and maintaining homeostasis. In tumor tissues, the downregulation of Fbw7, caused by various factors, leads to disorders in ubiquitinase synthesis, which may induce tumor progression and chemoresistance, particularly in gastrointestinal malignancy. Therefore, an in-depth study of the regulatory mechanisms involved in disorders of Fbw7 expression and the role of Fbw7 in chemoresistance of gastrointestinal tumors may suggest improvements for early diagnostic screening and targeted therapy.
Reemergence of Classical Swine Fever, Japan, 2018

In September 2018, classical swine fever reemerged in Japan after 26 years, affecting domestic pigs and wild boars. The causative virus belongs to the 2.1 subgenotype, which caused repeated outbreaks in eastern and Southeast Asia. Intensive surveillance of swine and vaccination of wild boars will help control and eradicate this disease in Japan.
Pediatric Bilateral Cochlear Implantation: Simultaneous Versus Sequential Surgery.

OBJECTIVE To compare outcomes of bilateral cochlear implantation between simultaneous and sequential surgeries. STUDY DESIGN Retrospective study of surgical outcome for 54 children who received bilateral cochlear implants (CIs) over a five-year period. SETTING Tertiary health care PATIENTS:: We analyze surgical outcomes for 54 children who received two CIs over a five-year period. Thirty-two of these children received these implants simultaneously and 22 of these children received their implants sequentially (76 CI operations and 108 CI). INTERVENTION One hundred and eight CIs; Group A-bilateral simultaneous CI; Group B- bilateral sequential CI. MAIN OUTCOME MEASURES Measurement of body temperature; recording drug administration measurement of the total length of hospital stay, surgery time, and total operating room utilization; recording complications. RESULTS Simultaneous bilateral CI-implantation is associated with a significantly reduced cumulative surgical time and cumulative operating room time. It shortens the total in-patient stay for children in comparison to sequential implantations. There were no clinically significant, adverse consequences of simultaneous implant surgery. Further information include medical history including cochlear malformations as well as complications after the surgery, use of analgesic and antiemetic medication and length of hospital stay. CONCLUSIONS Simultaneous bilateral surgery is a safe option of pediatric cochlear implantation.
Coincidence time resolution of 30 ps FWHM using a pair of Cherenkov-radiator-integrated MCP-PMTs

Radiation detectors dedicated to time-of-flight positron emission tomography (PET) have been developed, and coincidence time resolution (CTR) of sub-100 ps full width at half maximum (FWHM) has been achieved by carefully optimizing scintillators and photodetectors. Achieving a CTR of 30 ps FWHM by using a pair of annihilation γ-rays would allow us to directly localize the annihilation point within an accuracy of 4.5 mm. Such direct localization can potentially eliminate the requirement of image reconstruction processes in clinical PET systems, which would have a huge impact on clinical protocols and molecular imaging. To obtain such a high CTR, researchers have investigated the use of prompt emissions such as Cherenkov radiation and hot-intra band luminescence. Although it is still challenging to achieve a CTR of 30 ps FWHM even with a Cherenkov-based detector, the experimentally measured CTR is approaching the goal. In this work, we developed a Cherenkov-radiator-integrated micro-channel plate photomultiplier tube (CRI-MCP-PMT), where there are no optical boundaries between the radiator and photocathode, and its timing performance was investigated. By removing the optical boundaries, reflections are eliminated and transmission to the photocathode is improved, resulting in high timing capability. As a result, a CTR of 30.1 ± 2.4 ps FWHM, which is equivalent to a position resolution of 4.5 ± 0.3 mm along a line of response (LOR), was obtained by using a pair of CRI-MCP-PMTs.
Regular transient limb ischemia prevents atherosclerosis progression in hypercholesterolemic rabbits

Background: Endothelial dysfunction, the initial pathogenic factor in atherosclerosis, can be alleviated via transient limb ischemia. We observed the effects of regular transient limb ischemia (RTLI) on atherosclerosis in hypercholesterolemic rabbits. Methods: Twenty-eight rabbits were randomized to control, cholesterol, sham, ischemia groups (n = 7 each) between October 2010 and March 2011. They were fed a normal diet in the control group and hypercholesterolemic diet in other groups for 12 weeks. Six cycles of RTLI were performed once per day on the ischemia group. Serum samples were prepared to measure the total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) before the experiment (W0), at the end of weeks 4, 8, 12 (W4, W8, W12). The whole aorta was harvested at W12 and stained using Sudan IV to identify the plaque. The plaque area was measured using Image J. Results were analyzed by analysis of variance or rank sum test. Results: Concentrations of TC in the cholesterol group were higher than those in the control group at W4 (29.60 [23.75, 39.30] vs. 1.00 [0.80, 1.55], Z = –2.745, P = 0.006), W8 (41.78 [28.08, 47.37] vs. 0.35 [0.10, 0.68], Z = –2.739, P = 0.006), W12 (48.32 [40.04, 48.95] vs. 0.61 [0.50, 0.86], Z = –2.739, P = 0.006). Similar results were obtained for HDL-C and LDL-C. Serum concentrations of TC, HDL-C, and LDL-C in the hypercholesterolemic groups had no differences (all P > 0.05). The percentage of plaque area in the cholesterol group was higher than that in the control group (47.22 ± 23.89% vs. 0, Z = –2.986, P = 0.003). Square root of the percentage of plaque area was smaller in the ischemia group than that in the cholesterol (0.44 ± 0.13 vs. 0.67 ± 0.18, P = 0.014) or sham groups (0.44 ± 0.13 vs. 0.61 ± 0.12, P = 0.049). Conclusion: In hypercholesterolemic rabbits, RTLI might prevent atherosclerosis progression by reducing the percentage of plaque area.
Short-Term Exposure to Ambient Air Pollution and Asthma Mortality.

RATIONALE Short-term exposure to air pollution has been associated with asthma exacerbation and increased health-care use due to asthma, but its effect on asthma mortality remains largely unknown. OBJECTIVES To quantitatively assess the association between short-term exposure to air pollution and asthma mortality. METHODS We investigated 4,454 individuals who lived in Hubei province, China and died from asthma between 2013 and 2018. A case-crossover design and conditional logistic regression models were applied for data analyses. Exposures to particulate matter ≤ 2.5 µm in aerodynamic diameter (PM2.5), PM10, sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO) and ozone (O3) were estimated by inverse distance weighted averages of all monitoring stations within 50 km from each case's home address. MEASUREMENTS AND MAIN RESULTS Each interquartile range (IQR) increase of PM2.5 (lag 3; IQR: 47.1 µg/m3), NO2 (lag 03; IQR: 26.3 µg/m3) and O3 (lag 3; IQR: 52.9 µg/m3) were positively associated with asthma mortality, with odds ratios (ORs) of 1.07 (95% confidence interval [CI]: 1.01-1.12), 1.11 (95% CI: 1.01-1.22) and 1.09 (95% CI: 1.01-1.18), respectively. There was no evidence of departure from linearity for these associations. Further adjustment for other pollutants did not change the associations materially. We did not observe significant associations between PM10, SO2, CO exposures and asthma mortality. Overall, the estimates remained consistent in various sensitivity analyses. CONCLUSIONS Our results provide new evidence that short-term exposures to PM2.5, NO2 and O3 may increase asthma mortality risk. Further studies are needed to confirm our findings in other populations.
Reviewers' comments: Reviewer #1 (Remarks to the Author): The manuscript by Liu et al describes the identification and detailed characterisation of a here-to unrecognised pathway that regulates sterol biosynthesis. After providing evidence that Fusarium homologues of known sterol regulatory pathways

The manuscript by Liu et al describes the identification and detailed characterisation of a here-to unrecognised pathway that regulates sterol biosynthesis. After providing evidence that Fusarium homologues of known sterol regulatory pathways from other organisms did not have this role in F. graminearum, the authors undertook an elegant loss-of-function genetic screen to find transcription factors that contribute to basal tolerance to sterol biosynthesis inhibitors. The authors went on to characterise how the protein functions and the signalling and chromatin remodelling complexes involved in its regulation of sterol biosynthesis. Although the bulk of the paper (and title) focuses on the role of the identified transcription factor and signalling pathways in sterol biosynthesis regulation the work provides tantalising evidence that the transcription factor has a broader role in regulation of transcription associated with the pathogenesis process. For this reason the title could be made slightly broader.
A non‐coding RNA from the intercellular adhesion (ica) locus of Staphylococcus epidermidis controls polysaccharide intercellular adhesion (PIA)‐mediated biofilm formation

Polysaccharide intercellular adhesin (PIA)‐associated biofilm formation is mediated by the intercellular adhesin (ica) locus and represents a major pathomechanism of Staphylococcus epidermidis. Here, we report on a novel long non‐coding (nc)RNA, named IcaZ, which is approximately 400 nucleotides in size. icaZ is located downstream of the ica repressor gene icaR and partially overlaps with the icaR 3ʹ UTR. icaZ exclusively exists in ica‐positive S. epidermidis, but not in S. aureus or other staphylococci. Inactivation of the gene completely abolishes PIA production. IcaZ is transcribed as a primary transcript from its own promoter during early‐ and mid‐exponential growth and its transcription is induced by low temperature, ethanol and salt stress. IcaZ targets the icaR 5ʹ UTR and hampers icaR mRNA translation, which alleviates repression of icaADBC operon transcription and results in PIA production. Interestingly, other than in S. aureus, posttranscriptional control of icaR mRNA in S. epidermidis does not involve icaR mRNA 5ʹ/3ʹ UTR base pairing. This suggests major structural and functional differences in icaADBC operon regulation between the two species that also involve the recruitment of ncRNAs. Together, the IcaZ ncRNA represents an unprecedented novel species‐specific player involved in the control of PIA production in NBSP S. epidermidis.
Active Monitoring and Feedback to Improve Blood Culture Fill Volumes and Positivity across a Large Integrated Health System.

BACKGROUND The sensitivity of blood cultures increases with the volume of blood collected. However, hospitals face challenges in collecting adequate fill volume and under-filled blood bottles are ubiquitous. METHODS Blood bottle fill volumes were measured using an automated monitoring system across multiples sites (10 hospitals, 3 laboratories) within a large suburban/urban health system. Baseline fill volumes were measured for 4 months. A quality improvement program was then implemented over 36 months. Strategies to improve fill volume included education, standardized data collection, novel and unblinded information cascades, targeted communication, and bottle markings for blood collectors. RESULTS A total of 516,201 blood cultures were evaluated over 40 months. In the pre-implementation period no hospitals collected the recommended 8-10 ml/bottle, and the average system fill volume was 2.3 ml. At the end of the post-implementation period, 7 of 10 hospitals achieved ≥8 ml/bottle and the system-average increased to 8.6 ml (p<0.0001). The positivity rate increased 20%, from 7.39% to 8.85% (p <0.01). Compared to the pre-implementation period, the proportion of positive cultures with potential contaminants (such as coagulase negative staphylococci) decreased, while the proportion of potential pathogens (such as Gram negative rods) increased (p < 0.05). CONCLUSIONS Here we show that under-filled blood cultures are extremely common but that certain operational and educational strategies can result in sustained improvements across a large and complex network of hospitals and laboratories. This leads to increased detection of pathogens which can have tremendous impact on the management of bloodstream infections and sepsis.