Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of a five gene signature to predict time to biochemical recurrence after radical prostatectomy

Identification of novel biomarkers associated with high‐risk prostate cancer or biochemical recurrence can drive improvement in detection, prognosis, and treatment. However, studies can be limited by small sample sizes and sparse clinical follow‐up data. We utilized a large sample of prostate specimens to identify a predictive model of biochemical recurrence following radical prostatectomy and we validated this model in two external data sets.
Prevalence of Substandard Amoxicillin Oral Dosage Forms in the National Capital District of Papua New Guinea

Abstract. Antibiotics are commonly reported as being substandard or falsified in low- to middle-income countries, having potential to contribute to the development of antimicrobial resistance and drug-resistant infections. Amoxicillin, used to treat a number of infections and listed by the WHO as an essential medicine, presented as a good drug candidate for this study. We aimed to measure the prevalence of substandard and falsified amoxicillin oral products (tablets, capsules, and suspensions) in the National Capital District of Papua New Guinea (PNG). These oral products were surveyed in 2018 and 2019 from retail pharmacies, private and public health facilities, and the Area Medical Store, representing more than 90% of licensed medicine outlets. The product packaging was visually inspected, and the samples were analyzed for amoxicillin content using a validated high-performance liquid chromatography method. Although no falsified products were identified, 15% of the 190 products analyzed contained substandard amounts of amoxicillin. Quality varied with the dosage form (P = 0.002), with capsules exhibiting the lowest incidence of substandard content (4% in 2019) and tablets collected in 2018 experiencing the highest failure rate (50%). Suspension (40%) quality was compromised by failure to achieve homogeneity on reconstitution. A higher incidence of substandard content (P = 0.002) was associated with one major retail group. Routine testing of medicines by resource-poor countries is often unachievable, leading to the circulation of poor quality drugs, which is a global public health concern. Our study highlighted that substandard amoxicillin oral products are indeed prevalent in the NCD of PNG.
Impact of COVID-19 on Outcomes for Patients With Cervical Cancer in India

PURPOSE The COVID-19 pandemic has placed unprecedented demands on the health system. This led to delays in the initiation and completion of cancer treatment. We assessed the long-term health consequences because of the delay in diagnosis and treatment for cervical cancer due to COVID-19 in India. METHODS We used a Markov-model–based analysis assessing the lifetime health outcomes of the cohort of women population at risk from cervical cancer in India. The decrease in survival for those with the treatment interruption was calculated based on the number of days the treatment was extended beyond the standard duration. Furthermore, to model the impact of late diagnosis and delayed treatment initiation, the patients were assumed to have upstaged during the delay period, as per natural progression of disease. RESULTS We estimate 2.52% (n = 795) to 3.80% (n = 2,160) lifetime increase in the deaths caused by cervical cancer with treatment restrictions ranging from 9 weeks to 6 months, respectively, as compared to no delay. On the contrary, 88-238 deaths because of COVID-19 disease are estimated to be saved during this restriction period among the patients with cervical cancer. Overall, the excess mortality because of cervical cancer led to 18,159-53,626 life-years being lost and an increase of 16,808-50,035 disability-adjusted life-years. CONCLUSION Delays in diagnosis and treatment are likely to lead to more cervical cancer deaths as compared to COVID-19 mortality averted among the patients with cervical cancer. Health systems must reorganize in terms of priority setting for provision of care, starting with prioritizing the treatment of patients with early-stage cervical cancer, increasing use of teleconsultation, and strengthening the role of primary care physicians in provision of cancer care.
Evaluation of honey authenticity in Lebanon by analysis of carbon stable isotope ratio using elemental analyzer and liquid chromatography coupled to isotope ratio mass spectrometry

Abstract Honey is one of the most valuable sweeteners consumed by humans all over the world. Consequently, it is often a target for adulteration through the addition of different sugar syrups during or after honey production, resulting in a reduction in its nutritive value. For the first time, this study analyzes honey samples of various botanical species collected from different Lebanese regions using element analyzer (EA) and liquid chromatography (LC) coupled with isotope ratio mass spectrometry (IRMS). The δ13C of bulk honey, its protein fraction, and the main individual sugars (glucose, fructose, disaccharides, and trisaccharide) were determined, in order to characterize and evaluate the authenticity of honey consumed in Lebanon. The results showed that the δ13C values for bulk honey and its protein range from −26.5‰ to −24.5‰ and from −26.4‰ to −24.7‰, respectively, for authentic samples. δ13C values for samples adulterated with sugar syrups range from −11.2‰ to −25.1‰ for bulk honey and from −26.6‰ to −23.7‰ for its proteins, with a difference between bulk and protein values between −1 and −8.7‰. Using LC‐C‐IRMS techniques, the δ13C of individual sugars provides additional information on the presence of undeclared sugars. We found that all authentic samples had Δδ13Cf‐g and Δδ13C max values within the naturally occurring range of ±1‰ and ±2.1‰, respectively, while the adulterated samples fall outside the Δδ13C ranges. The oligosaccharide peak was detected in most adulterated samples.
Effectiveness of statin intensive therapy in type 2 diabetes mellitus with high visit-to-visit blood pressure variability

Supplemental Digital Content is available in the text Background: Intensive lipid-lowering therapy is recommended in type 2 diabetes mellitus (T2DM) patients with target organ damage. However, the evidence is insufficient to stratify the patients who will benefit from the intensive therapy among them. High visit-to-visit variability in systolic blood pressure (SBP) is associated with increased risk of cardiovascular events. We investigated the effectiveness of intensive versus standard statin therapy in the primary prevention of cardiovascular events among T2DM patients with retinopathy stratified by visit-to-visit SBP variability. Methods: The standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy study was the first trial comparing statin intensive therapy targeting low-density lipoprotein cholesterol (LDL-C) <70 mg/dl and standard therapy targeting LDL-C ≥100 to <120 mg/dl in T2DM patients with retinopathy without known cardiovascular disease. Using this dataset, we divided the patients into two subpopulations based on standard deviation (SD) and average real variability (ARV) of clinic SBP within the initial 6 months. Results: In a total of 4899 patients, 240 composite cardiovascular events were observed during a median follow-up of 37.3 months. In multivariable-adjusted model comparing intensive versus standard therapy, the hazard ratios for composite cardiovascular events were 0.64 (95% CI 0.45–0.90) and 1.21 (95% CI 0.82–1.80) in patients with high and low SBP variability as defined by SD, respectively. Interaction between SBP variability and statin therapy was significant (P = 0.018). The analysis using ARV of SBP showed similar results. Conclusion: Statin intensive therapy targeting LDL-C <70 mg/dl had benefits in primary prevention of cardiovascular events compared with standard therapy among T2DM patients with retinopathy having high, but not low, visit-to-visit SBP variability.
Traditional Chinese medicine Bu-Shen-Jian-Pi-Fang attenuates glycolysis and immune escape in clear cell renal cell carcinoma: results based on network pharmacology

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common malignant type of kidney cancer. The present study aims to explore the underlying mechanism and potential targets of the traditional Chinese medicine Bu-Shen-Jian-Pi-Fang (BSJPF) in the treatment of ccRCC based on network pharmacology. After obtaining the complete composition information for BSJPF from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, we analyzed its chemical composition and molecular targets and then established a pharmacological interaction network. Twenty-four significantly differentially expressed genes and nine pathways mainly related to tumor proliferation were identified and screened. Functional enrichment analysis indicated that the potential targets might be significantly involved in glycolysis and the HIF-1 signaling pathway. To further confirm the effect of BSJPF on ccRCC cell proliferation, a BALB/c xenograft mouse model was constructed. Potential targets involved in regulating glycolysis and the tumor immune microenvironment were evaluated using RT-qPCR. VEGF-A expression levels were markedly decreased, and heparin binding-EGF expression was increased in the BSJPF group. BSJPF also inhibited tumor proliferation by enhancing GLUT1- and LDHA-related glycolysis and the expression of the immune checkpoint molecules PD-L1 and CTLA-4, thereby altering the immune-rejection status of the tumor microenvironment. In summary, the present study demonstrated that the mechanism of BSJPF involves multiple targets and signaling pathways related to tumorigenesis and glycolysis metabolism in ccRCC. Our research provides a novel theoretical basis for the treatment of tumors with traditional Chinese medicine and new strategies for immunotherapy in ccRCC patients.
Impact of the coronavirus disease 2019 pandemic on healthcare workers: systematic comparison between nurses and medical doctors

Supplemental Digital Content is available in the text Purpose of review The COVID-19 outbreak has had major impact on individual's psychological health and overall well being worldwide. Evidence shows that these psychological challenges are especially prominent in healthcare workers (HCW); especially in nurses. Indeed, several studies report that nurses suffer more psychologically because of the consequences of the pandemic compared with medical doctors. To further look into this, we systematically review the recent literature to see whether the psychological impact of the COVID-19 pandemic differs between medical doctors and nurses across studies and which aspects of mental health are especially affected in nurses. Recent findings Across studies, there is solid evidence that nurses show poorer mental health outcomes compared with medical doctors during the COVID-19 pandemic. This is especially true for symptoms of depression, anxiety and posttraumatic stress disorder (PTSD). Here, prevalence rates in nurses are often higher than 50%. In contrast, general stress levels and burnout seem to be comparable between nurses and medical doctors. Summary Given that nurses suffer more from depression, anxiety and PTSD symptoms during the COVID-19 pandemic, special programs addressing their needs are required.
Spontaneous slow oscillation—slow spindle features predict induced overnight memory retention

Abstract Study Objectives Synchronization of neural activity within local networks and between brain regions is a major contributor to rhythmic field potentials such as the EEG. On the other hand, dynamic changes in microstructure and activity are reflected in the EEG, for instance slow oscillation (SO) slope can reflect synaptic strength. SO-spindle coupling is a measure for neural communication. It was previously associated with memory consolidation, but also shown to reveal strong interindividual differences. In studies, weak electric current stimulation has modulated brain rhythms and memory retention. Here, we investigate whether SO-spindle coupling and SO slope during baseline sleep are associated with (predictive of) stimulation efficacy on retention performance. Methods Twenty-five healthy subjects participated in three experimental sessions. Sleep-associated memory consolidation was measured in two sessions, in one anodal transcranial direct current stimulation oscillating at subjects individual SO frequency (so-tDCS) was applied during nocturnal sleep. The third session was without a learning task (baseline sleep). The dependence on SO-spindle coupling and SO-slope during baseline sleep of so-tDCS efficacy on retention performance were investigated. Results Stimulation efficacy on overnight retention of declarative memories was associated with nesting of slow spindles to SO trough in deep nonrapid eye movement baseline sleep. Steepness and direction of SO slope in baseline sleep were features indicative for stimulation efficacy. Conclusions Findings underscore a functional relevance of activity during the SO up-to-down state transition for memory consolidation and provide support for distinct consolidation mechanisms for types of declarative memories.
A Machine Learning Approach for Mortality Prediction in COVID-19 Pneumonia: Development and Evaluation of the Piacenza Score

Background Several models have been developed to predict mortality in patients with COVID-19 pneumonia, but only a few have demonstrated enough discriminatory capacity. Machine learning algorithms represent a novel approach for the data-driven prediction of clinical outcomes with advantages over statistical modeling. Objective We aimed to develop a machine learning–based score—the Piacenza score—for 30-day mortality prediction in patients with COVID-19 pneumonia. Methods The study comprised 852 patients with COVID-19 pneumonia, admitted to the Guglielmo da Saliceto Hospital in Italy from February to November 2020. Patients’ medical history, demographics, and clinical data were collected using an electronic health record. The overall patient data set was randomly split into derivation and test cohorts. The score was obtained through the naïve Bayes classifier and externally validated on 86 patients admitted to Centro Cardiologico Monzino (Italy) in February 2020. Using a forward-search algorithm, 6 features were identified: age, mean corpuscular hemoglobin concentration, PaO2/FiO2 ratio, temperature, previous stroke, and gender. The Brier index was used to evaluate the ability of the machine learning model to stratify and predict the observed outcomes. A user-friendly website was designed and developed to enable fast and easy use of the tool by physicians. Regarding the customization properties of the Piacenza score, we added a tailored version of the algorithm to the website, which enables an optimized computation of the mortality risk score for a patient when some of the variables used by the Piacenza score are not available. In this case, the naïve Bayes classifier is retrained over the same derivation cohort but using a different set of patient characteristics. We also compared the Piacenza score with the 4C score and with a naïve Bayes algorithm with 14 features chosen a priori. Results The Piacenza score exhibited an area under the receiver operating characteristic curve (AUC) of 0.78 (95% CI 0.74-0.84, Brier score=0.19) in the internal validation cohort and 0.79 (95% CI 0.68-0.89, Brier score=0.16) in the external validation cohort, showing a comparable accuracy with respect to the 4C score and to the naïve Bayes model with a priori chosen features; this achieved an AUC of 0.78 (95% CI 0.73-0.83, Brier score=0.26) and 0.80 (95% CI 0.75-0.86, Brier score=0.17), respectively. Conclusions Our findings demonstrated that a customizable machine learning–based score with a purely data-driven selection of features is feasible and effective for the prediction of mortality among patients with COVID-19 pneumonia.
Disciplinary Responsibility in Prison

Correctional mental health clinicians are sometimes asked to assess disciplinary responsibility, that is, to ascertain whether an inmate is culpable for violating prison rules. This assessment of disciplinary responsibility is akin to insanity determinations in criminal proceedings. In this article, I review the moral, legal, and practical aspects of disciplinary responsibility. I use California's test of responsibility for prison misconduct, which is similar to the Durham rule, to illustrate some of the dilemmas involved in creating and implementing a test of disciplinary responsibility.
Dilated main pancreatic duct can be a negative predictor of pancreatitis related to biliary SEMS insertion across the papilla

Abstract Objectives Post-ERCP pancreatitis (PEP) after self-expandable metallic stent (SEMS) insertion across the papilla of Vater is an important adverse event that affects the patient’s quality of life (QOL). We examined the predictive factors of PEP after SEMS insertion to treat obstructive jaundice due to malignancy. Methods Ninety patients who underwent biliary SEMS insertion for biliary obstruction due to malignancy at Iwata City Hospital between 2010 and 2018 were reviewed. We evaluated the relationship between the incidence of PEP after biliary SEMS insertion and clinical factors. We measured the thickness of the pancreatic parenchyma and diameter of the main pancreatic duct (MPD) at the left side of the corpus vertebrae. Results Mild and severe PEP were diagnosed in 10 (11.1%) and 1 (1.1%) patients, respectively. Only the thickness of the pancreatic parenchyma and diameter of MPD significantly differed between the PEP and non-PEP groups. The incidence of PEP among patients whose thickness of the pancreatic parenchyma at the left side of the corpus vertebrae was less than 9.5 mm (0%) on computed tomography was lower than that in patients whose thickness was 9.5 mm or greater (34.4%). Similarly, a wider (5 mm or more) diameter of MPD (4.3%) reduced the incidence of PEP compared with a narrower diameter (40.0%). Logistic regression analysis revealed that the probability of PEP decreases 3.91 times for every 1-mm increase in MPD diameter (95% CI 1.23–12.4, p = .02). Conclusion Based on our study, a dilated MPD is a negative predictive factor of pancreatitis related to biliary SEMS insertion.
Exchange transfusion in the management of critical pertussis in young infants: a case series

It is proposed that severe leucocytosis mainly contributes to pulmonary hypertension by blocking pulmonary capillaries and restricting blood flow. Exchange transfusion (ET) in pertussis has been demonstrated as a safe and useful technique for depleting the leucocyte mass. We aim to discuss four cases of pertussis‐induced respiratory distress and the effectiveness of ET in such a setting.
Isotopic analyses of Ordovician–Silurian siliceous skeletons indicate silica‐depleted Paleozoic oceans

The Phanerozoic Eon marked a major transition from marine silica deposition exclusively via abiotic pathways to a system dominated by biogenic silica sedimentation. For decades, prevailing ideas predicted this abiotic‐to‐biogenic transition were marked by a significant decrease in the concentration of dissolved silica in seawater; however, due to the lower perceived abundance and uptake affinity of sponges and radiolarians relative to diatoms, marine dissolved silica is thought to have remained elevated above modern values until the Cenozoic radiation of diatoms. Studies of modern marine silica biomineralizers demonstrated that the Si isotope ratios (δ30Si) of sponge spicules and planktonic silica biominerals produced by diatoms or radiolarians can be applied as quantitative proxies for past seawater dissolved silica concentrations due to differences in Si isotope fractionations among these organisms. We undertook 446 ion microprobe analyses of δ30Si and δ18O of sponge spicules and radiolarians from Ordovician–Silurian chert deposits of the Mount Hare Formation in Yukon, Canada. These isotopic data showed that sponges living in marine slope and basinal environments displayed small Si isotope fractionations relative to coeval radiolarians. By constructing a mathematical model of the major fluxes and reservoirs in the marine silica cycle and the physiology of silica biomineralization, we found that the concentration of dissolved silica in seawater was less than ~150 μM during early Paleozoic time—a value that is significantly lower than previous estimates. We posit that the topology of the early Paleozoic marine silica cycle resembled that of modern oceans much more closely than previously assumed.
Persistence Alters the Interaction between Chlamydia trachomatis and Its Host Cell

In response to stress, the obligate intracellular pathogen Chlamydia trachomatis stops dividing and halts its biphasic developmental cycle. The infectious, extracellular form of this bacterium is highly susceptible to killing by the host immune response, and by pausing development, Chlamydia can survive in an intracellular, “aberrant” state for extended periods of time. ABSTRACT In response to stress, the obligate intracellular pathogen Chlamydia trachomatis stops dividing and halts its biphasic developmental cycle. The infectious, extracellular form of this bacterium is highly susceptible to killing by the host immune response, and by pausing development, Chlamydia can survive in an intracellular, “aberrant” state for extended periods of time. The relevance of these aberrant forms has long been debated, and many questions remain concerning how they contribute to the persistence and pathogenesis of the organism. Using reporter cell lines, fluorescence microscopy, and a dipeptide labeling strategy, we measured the ability of C. trachomatis to synthesize, assemble, and degrade peptidoglycan under various aberrance-inducing conditions. We found that all aberrance-inducing conditions affect chlamydial peptidoglycan and that some actually halt the biosynthesis pathway early enough to prevent the release of an immunostimulatory peptidoglycan component, muramyl tripeptide. In addition, utilizing immunofluorescence and electron microscopy, we determined that the induction of aberrance can detrimentally affect the development of the microbe’s pathogenic vacuole (the inclusion). Taken together, our data indicate that aberrant forms of Chlamydia generated by different environmental stressors can be sorted into two broad categories based on their ability to continue releasing peptidoglycan-derived, immunostimulatory muropeptides and their ability to secrete effector proteins that are normally expressed at the mid- and late stages of the microbe’s developmental cycle. Our findings reveal a novel, immunoevasive feature inherent to a subset of aberrant chlamydial forms and provide clarity and context to the numerous persistence mechanisms employed by these ancient, genetically reduced microbes.
Profiling beneficial and potential adverse effects of MeCP2 overexpression in a hypomorphic Rett syndrome mouse model

De novo loss‐of‐function mutations in methyl‐CpG‐binding protein 2 (MeCP2) lead to the neurodevelopmental disorder Rett syndrome (RTT). Despite promising results from strategies aimed at increasing MeCP2 levels, additional studies exploring how hypomorphic MeCP2 mutations impact the therapeutic window are needed. Here, we investigated the consequences of genetically introducing a wild‐type MECP2 transgene in the Mecp2 R133C mouse model of RTT. The MECP2 transgene reversed the majority of RTT‐like phenotypes exhibited by male and female Mecp2 R133C mice. However, three core symptom domains were adversely affected in female Mecp2R133C/+ animals; these phenotypes resemble those observed in disease contexts of excess MeCP2. Parallel control experiments in Mecp2Null/+ mice linked these adverse effects to the hypomorphic R133C mutation. Collectively, these data provide evidence regarding the safety and efficacy of genetically overexpressing functional MeCP2 in Mecp2 R133C mice and suggest that personalized approaches may warrant consideration for the clinical assessment of MeCP2‐targeted therapies.