Miracle-dz/UniFAR-FTUs huggingface dataset:
Encoding sound in the cochlea: from receptor potential to afferent discharge

Ribbon‐class synapses in the ear achieve analog to digital transformation of a continuously graded membrane potential to all‐or‐none spikes. In mammals, several auditory nerve fibres (ANFs) carry information from each inner hair cell (IHC) to the brain in parallel. Heterogeneity of transmission among synapses contributes to the diversity of ANF sound‐response properties. In addition to the place code for sound frequency and the rate code for sound level, there is also a temporal code. In series with cochlear amplification and frequency tuning, neural representation of temporal cues over a broad range of sound levels enables auditory comprehension in noisy multi‐speaker settings. The IHC membrane time constant introduces a low‐pass filter that attenuates fluctuations of the receptor potential above 1–2 kHz. The ANF spike generator adds a high‐pass filter via its depolarization‐rate threshold that rejects slow changes in the postsynaptic potential and its phasic response property that ensures one spike per depolarization. Synaptic transmission involves several stochastic subcellular processes between IHC depolarization and ANF spike generation, introducing delay and jitter that limits the speed and precision of spike timing. ANFs spike at a preferred phase of periodic sounds in a process called phase‐locking that is limited to frequencies below a few kilohertz by both the IHC receptor potential and the jitter in synaptic transmission. During phase‐locking to periodic sounds of increasing intensity, faster and facilitated activation of synaptic transmission and spike generation may be offset by presynaptic depletion of synaptic vesicles, resulting in relatively small changes in response phase. Here we review encoding of spike‐timing at cochlear ribbon synapses.
Durvalumab: an investigational anti-PD-L1 antibody for the treatment of biliary tract cancer

ABSTRACT Introduction: The prognosis of patients with advanced biliary tract cancer (BTC) remains dismal, with a 5-year overall survival rate of less than 10%. Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several hematological and solid tumors, controversial results have been reported in BTC. In this setting, the anti-PD-L1 inhibitor durvalumab is currently under investigation in several clinical trials as monotherapy, or in combination with other pharmacological agents. Areas covered: We offer an overview of immunotherapies for BTC, discuss recently published or presented data on durvalumab pharmacology, safety, and efficacy in the treatment of BTC and consider future research directions for the agent in this setting. Expert opinion: The promising antitumor activity shown by durvalumab in early trials warrants further investigation because it may provide more effective, much needed treatment options. The results of clinical trials of this PD-L1 inhibitor, as a monotherapy or in combination, are eagerly awaited. Future efforts should focus on the identification and development of reliable biomarkers of response to durvalumab in BTC, clarifying the role of PD-L1 expression, microsatellite instability (MSI), mismatch repair (MMR), tumor mutational burden (TMB) and other emerging predictors.
Reduction of neuroinflammation alleviated mouse post bone fracture and stroke memory dysfunction

Tibia fracture (BF) enhances stroke injury and post-stroke memory dysfunction in mouse. Reduction of neuroinflammation by activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) reduced acute neuronal injury and sensorimotor dysfunction in mice with BF 1-day after stroke. We hypothesize that reduction of neuroinflammation by activation of α-7 nAchR improves long-term memory function of mice with BF 6-h before stroke. The mice were randomly assigned to saline, PHA-568487 (α-7 nAchR agonist) and methyllycaconitine (antagonist) treatment groups. The sensorimotor function was tested by adhesive removal and corner tests at 3 days, the memory function was tested by Y-maze test weekly for 8 weeks and novel objective recognition test at 8 weeks post-injuries. We found PHA-568487 treatment reduced, methyllycaconitine increased the number of CD68+ cells in the peri-infarct and hippocampal regions, neuronal injury in the infarct region, sensorimotor and long-term memory dysfunctions. PHA-568487 treatment also reduced, while methyllycaconitine treatment increased atrophy of hippocampal granule cell layer and white matter damage in the striatum. In addition, PHA-568487 treatment increased neuron proliferation in granule cell layer. Our data indicated that reduction of neuroinflammation through activation of α-7 nAchR decreased neuronal damage, sensorimotor and long-term memory dysfunction of mice with BF shortly before stroke.
Covid‐19 and oral diseases: Crosstalk, synergy or association?

The coronavirus disease 2019 (Covid‐19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that clinically affects multiple organs of the human body. Cells in the oral cavity express viral entry receptor angiotensin‐converting enzyme 2 that allows viral replication and may cause tissue inflammation and destruction. Recent studies have reported that Covid‐19 patients present oral manifestations with multiple clinical aspects. In this review, we aim to summarise main signs and symptoms of Covid‐19 in the oral cavity, its possible association with oral diseases, and the plausible underlying mechanisms of hyperinflammation reflecting crosstalk between Covid‐19 and oral diseases. Ulcers, blisters, necrotising gingivitis, opportunistic coinfections, salivary gland alterations, white and erythematous plaques and gustatory dysfunction were the most reported clinical oral manifestations in patients with Covid‐19. In general, the lesions appear concomitant with the loss of smell and taste. Multiple reports show evidences of necrotic/ulcerative gingiva, oral blisters and hypergrowth of opportunistic oral pathogens. SARS‐CoV‐2 exhibits tropism for endothelial cells and Covid‐19‐mediated endotheliitis can not only promote inflammation in oral tissues but can also facilitate virus spread. In addition, elevated levels of proinflammatory mediators in patients with Covid‐19 and oral infectious disease can impair tissue homeostasis and cause delayed disease resolution. This suggests potential crosstalk of immune‐mediated pathways underlying pathogenesis. Interestingly, few reports suggest recurrent herpetic lesions and higher bacterial growth in Covid‐19 subjects, indicating SARS‐CoV‐2 and oral virus/bacteria interaction. Larger cohort studies comparing SARS‐CoV‐2 negative and positive subjects will reveal oral manifestation of the virus on oral health and its role in exacerbating oral infection.
Predictors of postpartum depression among an obstetric population in South-Western Nigeria

ABSTRACT Background Perinatal maternal depression is the most common mood disturbance associated with pregnancy. It has grave consequences on both maternal health and wellbeing of offsprings, albeit usually neglected in low- and middle-income countries. Objective To evaluate the relationship between antenatal depression(APD) and postpartum depression(PPD) and predictors of postpartum depression among an obstetric population in South-western Nigeria. Methods This was a prospective longitudinal cohort study involving272 pregnant women recruited between 34 and 36 weeks of pregnancy and followed up to till 6 weeks after delivery. Edinburgh Postnatal Depression Scale (EPDS) questionnaires were administered to collect data. Data were analysed with SPSS version 23.A p-value < 0.05 was taken as statistically significant. Results The prevalences of antepartum and postpartum depression were 6.3%, (95% CI 3.4%-9.2%) and 8.8% (95% CI 5.4%-12.1%) respectively. The Spearman correlation coefficient for antepartum EPDS and postpartum EPDS scores was 0.52, p < 0.001. The predictors of postpartum depression were antepartum depression (adjusted OR 10.6, 95% CI 8.33–48.60, p < 0.001), puerperal sepsis (adjusted OR 4.33, 95% CI 3.89–8.69, p = 0.03), domestic violence (adjusted OR 3.40, 95% CI 1.94–15.67, p = 0.01) and age group 25–34 years (adjusted OR 0.11, 95% CI 0.02–0.75, p = 0.02), and household income $1671-$3330 (adjusted OR 0.10, 95% CI 0.02–0.56, p = 0.01). Conclusion There was a positive association between the antenatal EPDS and postnatal EPDS scores. Screening for maternal depression should be considered in prenatal period. Further studies are necessary to explore the novel finding of predictive role of puerperal sepsis in PPD.
Propriedades físicas de um Latossolo Vermelho distrófico cultivado e sob mata nativa

The understanding and quantification of the impact caused by soil use and management on the physical soil quality are fundamental for the development of sustainable agricultural systems. The objective of this research was to quantify some physical soil properties to evaluate the physical quality of a dystrophic Red Latosol (Rhodic Ferralsol) in the northwest of the State of Parana, Brazil. Undisturbed soil samples were collected from two contiguous areas on an Experimental Farm of the State University of Maringa. One area was cultivated with annual crops under conventional tillage (disk plow and harrowing) and the other under native forest (semidecidual seasonal forest). The evaluated physical soil attributes were soil porosity and bulk density, soil water retention curve, soil resistance curve, and the least limiting water range. Results indicated significantly higher values of bulk density and lower values of soil porosity in the cultivated area. The soil water retention curve was not influenced by the soil use system, but was negatively influenced by bulk density. The soil resistance curve was influenced by the soil use system, evidenced by high values of soil resistance to root penetration under increasing drought in the cultivated soil. The least limiting water range was significantly smaller in the cultivated soil owing to the soil resistance to root penetration and air-filled porosity, which determined the lower and upper limits of soil water availability with bulk density increase. In the soil under native forest, the least limiting water range was equal to the water availability determined by the field capacity and the permanent wilting point. Soil compaction in the cultivated soil induced changes in the soil porous system, which were described by lower values of the least limiting water range than in virgin soil.
Oxygen diffusion in sanidine feldspar and a critical appraisal of oxygen isotope-mass-effect measurements in non-cubic materials

Abstract Oxygen exchange experiments have been performed between single crystals of sanidine feldspar and water enriched in 17O and 18O; temperatures were in the range 550–850°C and total pressure 1 kbar. Oxygen isotope diffusion profiles in a direction perpendicular to (001) were determined with an ion microprobe. The diffusion data for both isotopes followed a single Arrhenius relationship described by D = 3·95 × 10−12 exp(−109·7 ± 4kJ mol−1/RT)m2s−1. Combining concentration-distance data for 17O and 18O simultaneously for each profile in the form of a double ‘inverse error function plot’ enabled the ratio D 17/D 18 of diffusion coefficients to be obtained directly, and the isotope mass effect E α β to be estimated. At 550 and 650°C E α β values were in the range 0·83–1·03, suggesting an interstitial mechanism for oxygen diffusion in sanidine feldspar, although the uncertainties (±0·10) do not preclude a vacancy mechanism. A methodology and mathematical analysis has been developed for isotope-mass-effec.
Shared Genetic Background Between Cerebrospinal Fluid Biomarkers and Risk for Alzheimer's Disease: A Two-Sample Mendelian Randomization Study.

BACKGROUND Whether the epidemiological association of amyloid-β (Aβ) and tau pathology in late-onset Alzheimer's disease (LOAD) is causal remains unclear. OBJECTIVE We aimed to investigate the shared genetic background between the cerebrospinal fluid (CSF) biomarkers for Aβ and tau pathology and the risk of LOAD. METHODS We conducted a two-sample Mendelian randomization (MR) analysis. We used summary statistics of genome-wide association studies for CSF biomarkers (Aβ 1-42 [Aβ], phosphorylated tau181 [p-tau], and total tau [t-tau]) in 3,146 individuals and for LOAD in 21,982 cases and 41,944 controls. We tested the association between changes in the genetically predicted CSF biomarkers and LOAD risk. RESULTS We found a decrease in LOAD risk per one-standard-deviation (SD) increase in the genetically predicted CSF Aβ (odds ratio [OR], 2.87×10-3 for AD; 95%confidence interval [CI], 1.54×10-4 -0.05; p = 8.91×10-5). Conversely, we observed an increase in LOAD risk per one-SD increase in the genetically predicted CSF p-tau (OR, 19.46; 95%CI, 1.50-2.52×102; p = 0.02) and t-tau (OR, 33.80; 95%CI, 1.57-7.29×102; p = 0.02). However, only the association between p-tau and the risk for LOAD remained significant after the exclusion of the APOE variant (rs769449). CONCLUSION We found the causal association between CSF biomarkers and the risk for LOAD. Our results suggest that the etiology of LOAD involves multiple biological processes, including the pathways of Aβ and tau proteins. Further MR studies using large-scale data of multiple candidate biomarkers are needed to elucidate the pathophysiology of LOAD.
Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib (MLN9708) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant.

LESSONS LEARNED Fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. BACKGROUND Fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. METHODS This is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses. RESULTS Among nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) Cmax of 155 (122-171) ng/mL; Tmax of 1 (1-1.5) h; terminal elimination half-life of 66.6 (57.3-102.6) hr after initial dose; AUC of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51 days (range 47-137). CONCLUSION This drug combination has a favorable safety profile and anti-tumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing.
Key Elements of the Critical Care Work Environment Associated With Burnout and Compassion Satisfaction.

BACKGROUND As the role of a health care system's influence on nurse burnout becomes better understood, an under-standing of the impact of a nurses' work environment on burnout and well-being is also imperative. OBJECTIVE To identify the key elements of a healthy work environment associated with burnout, secondary trauma, and compassion satisfaction, as well as the effect of burnout and the work environment on nurse turnover. METHODS A total of 779 nurses in 24 critical care units at 13 hospitals completed a survey measuring burnout and quality of the work environment. Actual unit-level data for nurse turnover during a 5-month period were queried and compared with the survey results. RESULTS Among nurses in the sample, 61% experience moderate burnout. In models controlling for key nurse characteristics including age, level of education, and professional recognition, 3 key elements of the work environment emerged as significant predictors of burnout: staffing, meaningful recognition, and effective decision-making. The latter 2 elements also predicted more compassion satisfaction among critical care nurses. In line with previous research, these findings affirm that younger age is associated with more burnout and less compassion satisfaction. CONCLUSIONS Efforts are recommended on these 3 elements of the work environment (staffing, meaningful recognition, effective decision-making) as part of a holistic, systems-based approach to addressing burnout and well-being. Such efforts, in addition to supporting personal resilience-building activities, should be undertaken especially with younger members of the workforce in order to begin to address the crisis of burnout in health care.
Evaluation of the chest computed tomography and hemogram data in patients with COVID-19: the importance of thymus

Background/aim To investigate the relationship between imaging findings and peripheral blood cell counts of COVID-19 patients and the degree of thymus fat involution of these patients. Materials and methods Computed tomography (CT) images of 87 patients with COVID-19 positive through RT-PCR testing were evaluated retrospectively by two radiologists. Ground glass densities and other signs of viral pneumonia were recorded, lung involvement was scored quantitatively. The patients thymus fat involution was graded on CT. Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratios (PLR), lymphocyte and platelet counts were calculated. Imaging findings and degrees of thymus fat involution were compared with laboratory data. Results Quantitative scoring of lung involvement was calculated at mean 6.63 ± 4.70 (1–23) for observer 1 and mean 6.55 ± 4.65 (1–23) for observer 2 ( K = 0.824–1.000). Statistical significance was determined between the increase in age and the increase in scores of lung findings ( p = 0.003). Lymphocyte count ( p = 0.0001) and PLR ( p = 0.001) were significantly lower in patients with severe CT involvement. A statistically significantcorrelation was found between increased thymus fat component and presence of COVID-19 lung involvement in CT ( r = 0.461). Conclusion The severity of imaging findings for COVID-19 patients significantly correlates with the degree of fat involution in patients’ thymus tissue.
Association of Inflammatory Markers with Mortality in Patients Hospitalized with Non-massive Pulmonary Embolism.

OBJECTIVE Pulmonary embolism (PE) is a serious pathology with high rates of morbidity and mortality. Studies regarding the efficacy of new inflammatory markers as a predictor of mortality in PE have thus far been limited. This study aimed to evaluate the predictive value of platelet/lymphocyte ratio (PLR), neutrophil/lymphocyte ratio (NLR), platelet/mean platelet volume (PLT/MPV), and C-reactive protein (CRP) on short-term and long-term mortality in patients with PE. MATERIAL AND METHODS A retrospective, observational cohort study was carried out in a tertiary teaching hospital. Patients with PE hospitalized in the pulmonology ward were enrolled. Their characteristics, hemogram parameters, PLR, NLR, CRP levels, PLT/MPV on admission, and mortality were recorded. The predictive accuracies of inflammatory markers were determined through receiver operating characteristic curves. The risk factors for mortality were further analyzed with Cox regression analysis. RESULTS A total of 828 patients with PE were included in the study. The 1-month mortality was 1%, and the 1-year mortality was 8.5%. An NLR value above 6 was associated with an almost 13-fold increase in short-term (30-day) mortality. We found that an NLR above 3.15 and age were independent risk factors for long-term (1-year) mortality. The other inflammatory markers, namely PLR and CRP, were not found to be associated with long-term mortality. CONCLUSION PE is a serious condition in the elderly. Elevated NLR values appear to be a good and feasible predictor of inflammation, which can be correlated with higher mortality over both the short-term and long-term periods.
Association of Eviction With Adverse Birth Outcomes Among Women in Georgia, 2000 to 2016

Key Points Question Is eviction during pregnancy associated with adverse birth outcomes, an important determinant of health across the life course? Findings In this case-control study of 88 862 births in Georgia, eviction during pregnancy, particularly during the second and third trimester, was associated with reductions in infants’ weight and gestational age at birth compared with maternal eviction at any other time. Meaning These findings suggest that housing, social, and medical assistance to pregnant women at risk for eviction might improve birth outcomes and health across the life course.
Otological manifestation of temporomandibular joint disorder in Ekiti, a sub-Saharan African country

Objective To determine the prevalence, sociodemographic features, and clinical presentation of temporomandibular joint disorder in otorhinolaryngological practice. Methods This prospective hospital-based study involved patients diagnosed with temporomandibular joint disorder in our institution’s ear, nose, and throat department. Data for this study were obtained from the patients using pretested interviewer-assisted questionnaires. Results The prevalence of temporomandibular joint disorder in this study was 1.3%. The study population included 17 (26.2%) male patients with a male:female ratio of 1.0:2.8. Joint disorder accounted for 75.4% of all disorders, while both mastication muscle and joint disorder accounted for 21.5%. A majority of the patients (47.7%) presented between weeks 1 and 13 of the illness. Unilateral temporomandibular joint disorder accounted for 98.5% of all disorders. The main otologic clinical features were earache and a dull tympanic membrane in 100% and 35.4% of patients, respectively. Middle ear assessment revealed type A in 73.8% of patients and type B in 20.0% according to Jerger’s classification system of tympanometry. Most patients (81.5%) were referred by their family physician. All patients had undergone prehospital treatment prior to presentation. Conclusion Temporomandibular joint disorder is a common presentation in medical practice. Common clinical features include ear, joint, and mastication muscle disorders.
The dynamic phase transition in the spin-1/2 Ising system within the path probability method

We study the dynamic phase transitions and present the dynamic phase diagrams of the spin-1/2 Ising system under the presence of a time-varying (sinusoidal) external magnetic field within the path probability method (PPM) of Kikuchi and we observe that the PPM gives exactly the same result as with the Glauber-type stochastic dynamics based on the mean-field theory (DMFT). We also investigate the influence of the rate constant on the dynamic phase diagrams in detail and five new and interesting dynamic phase diagrams are found. We notice that the derivation of the dynamic equations by using the PPM is more clear and easier than within the DMFT and the Glauber-type stochastic dynamics based on the effective-field theory (DEFT). The advantages and disadvantages of the PPM over the DMFT and DEFT are also discussed.
Fluorescence microscopy studies of a peripheral-benzodiazepine-receptor-targeted molecular probe for brain tumor imaging

This study investigates the potential of a new multi-modal lanthanide chelate complex for specifically targeting brain tumor cells. We report here results from ongoing studies of up-take, sub-cellular localization and binding specificity of this new molecular imaging probe. Fluorescence microscopy investigations in living rat C6 glioma tumor cells demonstrate that the new imaging agent has affinity for glioma cells and binds to mitochondria.