Miracle-dz/UniFAR-FTUs huggingface dataset:
Temporal Contrast Sensitivity Increases despite Photoreceptor Degeneration in a Mouse Model of Retinitis Pigmentosa

Abstract The detection of temporal variations in amplitude of light intensity, or temporal contrast sensitivity (TCS), depends on the kinetics of rod photoresponse recovery. Uncharacteristically fast rod recovery kinetics are facets of both human patients and transgenic animal models with a P23H rhodopsin mutation, a prevalent cause of retinitis pigmentosa (RP). Here, we show that mice with this mutation (RhoP23H/+) exhibit an age-dependent and illumination-dependent enhancement in TCS compared with controls. At retinal illumination levels producing ≥1000 R*/rod/s or more, postnatal day 30 (P30) RhoP23H/+ mice exhibit a 1.2-fold to 2-fold increase in retinal and optomotor TCS relative to controls in response to flicker frequencies of 3, 6, and 12 Hz despite significant photoreceptor degeneration and loss of flash electroretinogram (ERG) b-wave amplitude. Surprisingly, the TCS of RhoP23H/+ mice further increases as degeneration advances. Enhanced TCS is also observed in a second model (rhodopsin heterozygous mice, Rho+/−) with fast rod recovery kinetics and no apparent retinal degeneration. In both mouse models, enhanced TCS is explained quantitatively by a comprehensive model that includes photoresponse recovery kinetics, density and collecting area of degenerating rods. Measurement of TCS may be a non-invasive early diagnostic tool indicative of rod dysfunction in some forms of retinal degenerative disease.
The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt

BACKGROUND The efficacy of rifaximin in the secondary prevention of overt hepatic encephalopathy (HE) is well documented, but its effectiveness in preventing a first episode in patients after transjugular intrahepatic portosystemic shunt (TIPS) has not been established. OBJECTIVE To determine whether rifaximin prevents overt HE after TIPS compared with placebo. DESIGN Randomized, double-blind, multicenter, placebo-controlled trial. (ClinicalTrials.gov: NCT02016196). PARTICIPANTS 197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding. INTERVENTION Patients were randomly assigned to receive rifaximin (600 mg twice daily) or placebo, beginning 14 days before TIPS and continuing for 168 days after the procedure. MEASUREMENTS The primary efficacy end point was incidence of overt HE within 168 days after the TIPS procedure. RESULTS An episode of overt HE occurred in 34% (95% CI, 25% to 44%) of patients in the rifaximin group (n = 93) and 53% (CI, 43% to 63%) in the placebo group (n = 93) during the postprocedure period (odds ratio, 0.48 [CI, 0.27 to 0.87]). Neither the incidence of adverse events nor transplant-free survival was significantly different between the 2 groups. LIMITATIONS The study's conclusion applies mainly to patients with alcoholic cirrhosis, who made up the study population. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated. CONCLUSION In patients with cirrhosis treated with TIPS, rifaximin was well tolerated and reduced the risk for overt HE. Rifaximin should therefore be considered for prophylaxis of post-TIPS HE. PRIMARY FUNDING SOURCE French Public Health Ministry.
Quality of inpatient antimicrobial use in hematology and oncology patients

Abstract Objectives: To compare antimicrobial prescribing practices in Australian hematology and oncology patients to noncancer acute inpatients and to identify targets for stewardship interventions. Design: Retrospective comparative analysis of a national prospectively collected database. Methods: Using data from the 2014–2018 annual Australian point-prevalence surveys of antimicrobial prescribing in hospitalized patients (ie, Hospital National Antimicrobial Prescribing Survey called Hospital NAPS), the most frequently used antimicrobials, their appropriateness, and guideline concordance were compared among hematology/bone marrow transplant (hemBMT), oncology, and noncancer inpatients in the setting of treatment of neutropenic fever and antibacterial and antifungal prophylaxis. Results: In 454 facilities, 94,226 antibiotic prescriptions for 62,607 adult inpatients (2,230 hemBMT, 1,824 oncology, and 58,553 noncancer) were analyzed. Appropriateness was high for neutropenic fever management across groups (83.4%–90.4%); however, hemBMT patients had high rates of carbapenem use (111 of 746 prescriptions, 14.9%), and 20.2% of these prescriptions were deemed inappropriate. Logistic regression demonstrated that hemBMT patients were more likely to receive appropriate antifungal prophylaxis compared to oncology and noncancer patients (adjusted OR, 5.3; P < .001 for hemBMT compared to noncancer patients). Oncology had a low rate of antifungal prophylaxis guideline compliance (67.2%), and incorrect dosage and frequency were key factors. Compared to oncology patients, hemBMT patients were more likely to receive appropriate nonsurgical antibacterial prophylaxis (aOR, 8.4; 95% CI, 5.3–13.3; P < .001). HemBMT patients were also more likely to receive appropriate nonsurgical antibacterial prophylaxis compared to noncancer patients (OR, 3.1; 95% CI, 1.9–5.0; P < .001). However, in the Australian context, the hemBMT group had higher than expected use of fluoroquinolone prophylaxis (66 of 831 prescriptions, 8%). Conclusions: This study demonstrates why separate analysis of hemBMT and oncology populations is necessary to identify specific opportunities for quality improvement in each patient group.
Self-Transcendence Mediates the Relationship between Early Trauma and Fatal Methods of Suicide Attempts

Background Early trauma is known to be a risk factor of suicide-related behavior. On the other hand, people who attempt suicide using a fatal method are reported to be more likely to complete suicide. In this study, we assumed that early trauma affects an individual's temperament and character and thereby increases the risk of a fatal method of suicide attempts. Methods We analyzed 92 people with a history of previous suicide attempts. We compared the Temperament and Character Inventory-Revised scores between the groups with and without early trauma, and between the groups with and without a history of suicide attempt using fatal methods through an analysis of covariance with age, sex, and presence of a psychiatric history as covariates. A mediation analysis was conducted of the relationship between early trauma and fatal methods of suicide attempt with self-transcendence as a mediator. Results Higher self-transcendence was reported in the fatal group (27.71 ± 13.78 vs. 20.97 ± 12.27, P = 0.010) and the early trauma group (28.05 ± 14.30 vs. 19.43 ± 10.73, P = 0.001), respectively. The mediation model showed that self-transcendence mediates the relationship between early trauma and fatal methods of suicide attempt. The 95% confidence intervals for the direct and indirect effect were (−0.559, 1.390) and (0.026, 0.947), respectively. Conclusion Self-transcendence may mediate the relationship between early trauma and fatal methods of suicide attempt. Self-transcendence may be associated with unhealthy defenses and suicidal behavior for self-punishment and may constitute a marker of higher suicide risk.
High-resolution imaging reveals compartmentalization of mitochondrial protein synthesis in cultured human cells

Significance In mitochondria from various species, the OXPHOS complexes reside mainly in the invaginated cristae membranes, as opposed to the inner boundary membrane (IBM) that parallels the mitochondrial outer membrane. However, the IBM contains dynamic contact sites enriched for translocases that import proteins from the cytosol. As the majority of OXPHOS components are imported and need to be integrated in assembly with the mtDNA-encoded components, where does intramitochondrial translation occur? Here we report: 1) a method for visualizing protein synthesis in human mitochondria at super resolution; 2) that synthesis is enriched at cristae membranes, in preference to the IBM; and 3) that sites of translation are spatially separated from RNA granules where RNA processing, maturation, and mitoribosomal assembly occur. Human mitochondria contain their own genome, mitochondrial DNA, that is expressed in the mitochondrial matrix. This genome encodes 13 vital polypeptides that are components of the multisubunit complexes that couple oxidative phosphorylation (OXPHOS). The inner mitochondrial membrane that houses these complexes comprises the inner boundary membrane that runs parallel to the outer membrane, infoldings that form the cristae membranes, and the cristae junctions that separate the two. It is in these cristae membranes that the OXPHOS complexes have been shown to reside in various species. The majority of the OXPHOS subunits are nuclear-encoded and must therefore be imported from the cytosol through the outer membrane at contact sites with the inner boundary membrane. As the mitochondrially encoded components are also integral members of these complexes, where does protein synthesis occur? As transcription, mRNA processing, maturation, and at least part of the mitoribosome assembly process occur at the nucleoid and the spatially juxtaposed mitochondrial RNA granules, is protein synthesis also performed at the RNA granules close to these entities, or does it occur distal to these sites? We have adapted a click chemistry-based method coupled with stimulated emission depletion nanoscopy to address these questions. We report that, in human cells in culture, within the limits of our methodology, the majority of mitochondrial protein synthesis is detected at the cristae membranes and is spatially separated from the sites of RNA processing and maturation.
Neural correlates of recursive thinking during interpersonal strategic interactions

To navigate the complex social world, individuals need to represent others' mental states to think strategically and predict their next move. Strategic mentalizing can be classified into different levels of theory of mind according to its order of mental state attribution of other people's beliefs, desires, intentions, and so forth. For example, reasoning people's beliefs about simple world facts is the first‐order attribution while going further to reason people's beliefs about the minds of others is the second‐order attribution. The neural substrates that support such high‐order recursive reasoning in strategic interpersonal interactions are still unclear. Here, using a sequential‐move interactional game together with functional magnetic resonance imaging (fMRI), we showed that recursive reasoning engaged the frontal‐subcortical regions. At the stimulus stage, the ventral striatum was more activated in high‐order reasoning as compared with low‐order reasoning. At the decision stage, high‐order reasoning activated the medial prefrontal cortex (mPFC) and other mentalizing regions. Moreover, functional connectivity between the dorsomedial prefrontal cortex (dmPFC) and the insula/hippocampus was positively correlated with individual differences in high‐order social reasoning. This work delineates the neural correlates of high‐order recursive thinking in strategic games and highlights the key role of the interplay between mPFC and subcortical regions in advanced social decision‐making.
Safety and efficacy analysis of pembrolizumab dosing patterns in patients with advanced melanoma and non-small cell lung cancer

Aim To evaluate the impact of discrepancy between prescribed and recommended fixed 200 mg dose (P-F discrepancy) on immune-related adverse events (irAEs) and treatment efficacy in patients with advanced melanoma and NSCLC. Methods This retrospective study included 177 patients with advanced melanoma or non-small cell lung cancer (NSCLC) who received at least one cycle of single-agent pembrolizumab. We defined P-F discrepancy as the differences between prescribed pembrolizumab dose and 200 mg recommended dose, expressed in percentages. Our primary outcome was immune-related adverse events (irAEs), and our secondary outcomes included overall survival (OS) and progression free survival (PFS). Results The median P-F discrepancy was –21.5%, with the 25th and 75th percentile at –32% and –5.0% respectively. ROC curve analyses did not show any optimal cutoffs to prognosticate irAEs (AUC = 0.558 for all patients) or cancer mortality (AUC = 0.583 for melanoma; AUC = 0.539 for NSCLC) in either cancer type. Separate multivariable Cox analyses suggested no statistically significant association between P-F discrepancy and overall survival in patients with melanoma (HR 1.012, 95%CI 0.987–1.038, P = 0.362) or NSCLC (HR 0.998, 95%CI 0.978–1.019, P = 0.876). Conclusion There was no optimal pembrolizumab cut-off point to predict irAEs or treatment efficacy. We supported the use of weight-based pembrolizumab dosing, given the potential cost-saving and no differences in terms of irAEs or treatment efficacy in patients with advanced melanoma or NSCLC. Future studies on province- or national-level would be important to validate our findings.
Energy Supplementation during the Last Third of Gestation Improves Mother–Young Bonding in Goats

Simple Summary The last third of gestation is a period of high energy demand for the dam, because she needs to support the growth of fetuses and the newborn. Moreover, towards the end of gestation, maternal feed intake is reduced as the mass of the fetoplacental unit increases. The maternal diet often cannot meet nutritional requirements, compromising thermoregulatory capacity, wellbeing, and viability, and the survival of the newborn. We have shown that energy supplementation of the mother during the last third of gestation does not affect progeny birth weight but enhances mother–young bonding. Abstract We tested whether maternal energy supplementation during the last third of gestation improves birth weight, neonatal wellbeing, and mother–young bonding. Thirty-six pregnant French Alpine goats were randomly allocated among three nutritional treatments for the last third of pregnancy: (i) Control, fed alfalfa (T-0; n = 12); (ii) alfalfa + 150 g/head daily energy concentrate (T-150; n = 12); (iii) alfalfa + 300 g/head daily energy concentrate (T-300; n = 12). At birth, we collected progeny data on birth weight, birth type, sex, rectal temperature, heart rate, respiratory rate, time to standing, time to udder connection, and time to first feeding. For the dams, we collected data on the duration of labor, time to clean the progeny, and time to allow first suckling. At birth, body weight, rectal temperature, heart rate, and the respiratory rate did not differ among treatments (p > 0.05). In the dams, labor duration was not affected by the treatments (p > 0.05). The T-150 dams were faster to clean the newborn and allow first suckling (p < 0.05). The T-150 progeny were faster to stand and the T-300 progeny were faster to connect to the udder (p < 0.05). We conclude that energy supplementation of the dam during the last third of gestation does not affect the birth weight of the progeny, but enhances the mother–young bonding.
Seroprevalence, Risk Factors and Molecular Identification of Bovine Leukemia Virus in Egyptian Cattle

Simple Summary Bovine leukemia virus (BLV) is distributed worldwide and affects dairy cattle causing significant economic losses. This study’s objective was to assess the risk factors associated with BLV infection and identify the Egyptian BLV strain’s genetic diversity. The overall seroprevalence of BLV infection in Egyptian dairy cattle was 18.2%, and the grazing cattle in the losing house system had a higher probability of getting BLV infection. The sequencing and phylogenetic analysis for one Egyptian BLV strain was performed, and the obtained results confirmed the clustering of Egyptian BLV strain into genotype-1. Abstract Bovine leukemia virus (BLV) is distributed worldwide and affects dairy cattle causing severe economic losses. The BLV has been serologically reported in Egypt, but few studies have evaluated its associated risk factors and genetic classification. Therefore, this study assessed risk factors associated with BLV infection and identified the genetic diversity of the Egyptian strain. The study was conducted on 500 dairy cattle distributed in four Governorates located in Northern Egypt. Overall, the seroprevalence of BLV infection among Egyptian dairy cattle was 18.2%. The grazing cattle in the losing house system had higher odds for BLV seropositivity, and bad practice such as the use of a single needle or one plastic glove for more than one animal was considered a significant risk factor for BLV infection. Besides, the sequencing and phylogenetic analysis for one Egyptian BLV strain was performed, and the obtained results confirmed the clustering of Egyptian BLV strain into genotype-1. The assessment of associated risk factors for BLV infection and determination of its genetic classification are essential to implement an effective control program.
Impact of preoperative echocardiography on surgical delays and outcomes among adults with hip fracture.

AIMS Echocardiography is commonly used in hip fracture patients to evaluate perioperative cardiac risk. However, echocardiography that delays surgical repair may be harmful. The objective of this study was to compare surgical wait times, mortality, length of stay (LOS), and healthcare costs for similar hip fracture patients evaluated with and without preoperative echocardiograms. METHODS A population-based, matched cohort study of all hip fracture patients (aged over 45 years) in Ontario, Canada between 2009 and 2014 was conducted. The primary exposure was preoperative echocardiography (occurring between hospital admission and surgery). Mortality rates, surgical wait times, postoperative LOS, and medical costs (expressed as 2013$ CAN) up to one year postoperatively were assessed after propensity-score matching. RESULTS A total of 2,354 of 42,230 (5.6%) eligible hip fracture patients received a preoperative echocardiogram during the study period. Echocardiography ordering practices varied among hospitals, ranging from 0% to 23.0% of hip fracture patients at different hospital sites. After successfully matching 2,298 (97.6%) patients, echocardiography was associated with significantly increased risks of mortality at 90 days (20.1% vs 16.8%; p = 0.004) and one year (32.9% vs 27.8%; p < 0.001), but not at 30 days (11.4% vs 9.8%; p = 0.084). Patients with echocardiography also had a mean increased delay from presentation to surgery (68.80 hours (SD 44.23) vs 39.69 hours (SD 27.09); p < 0.001), total LOS (19.49 days (SD 25.39) vs 15.94 days (SD 22.48); p < 0.001), and total healthcare costs at one year ($51,714.69 (SD 54,675.28) vs $41,861.47 (SD 50,854.12); p < 0.001). CONCLUSION Preoperative echocardiography for hip fracture patients is associated with increased postoperative mortality at 90 days and one year but not at 30 days. Preoperative echocardiography is also associated with increased surgical delay, postoperative LOS, and total healthcare costs at one year. Echocardiography should be considered an urgent test when ordered to prevent additional surgical delay. Cite this article: Bone Joint J 2021;103-B(2):271-278.
DSPE-PEG polymers for improving pulmonary absorption of poorly absorbed macromolecules in rats and relative mechanism

Abstract Objective This study aims to investigate the potential of DSPE-PEG polymers (DSPE-PEG-OH and DSPE-PEG-SH) on improving absorption of poorly absorbable macromolecules via intrapulmonary administration and underlying mechanism. Methods In situ pulmonary absorption experiments were performed to investigate the absorption of model compounds after intrapulmonary administration to rats. The local membrane damage induced by these DSPE-PEG polymers were evaluated based on morphological observation of lung tissues and measurement of biological toxic markers in bronchoalveolar lavage fluid (BALF) postintrapulmonary delivery of DSPE-PEG polymers to rats. The underlying enhancement mechanism of these polymers was explored by investigating their effects on the pulmonary membrane fluidity and gene expression of tight junction associated proteins with fluorescence polarization and western blotting, respectively. Results Intrapulmonary delivery of these DSPE-PEG polymers significantly enhanced absorptions of poorly absorbed model drugs and did not induce serious damage to the pulmonary membranes of rats. Mechanistic studies demonstrated unaffected pulmonary membrane fluidity and up-regulated expression levels of tight junction-associated proteins by DSPE-PEG polymers, thus indicating that paracellular pathways might be included in the underlying mechanisms by which DSPE-PEG polymers exerted their enhancing actions on drug absorption. Conclusions These findings suggested that these DSPE-PEG polymers are potential for promoting absorptions of poorly absorbable macromolecules with no evidence of damage to the local pulmonary membranes of rats. Novelty statement In this study, DSPE-PEG-OH and DSPE-PEG-SH polymers, two DSPE-PEG2000 conjugates with different terminal groups demonstrated significant promoting effects on the absorption of poorly absorbed macromolecular drugs after intrapulmonary delivery to rats, and did not induce serious damage to the pulmonary membranes of rats. These DSPE-PEG polymers could statistically downregulate expression levels of tight junction-associated proteins (ZO-1 and occludin), indicating the underlying mechanism by which these polymers exerted their absorption enhancing actions through pulmonary epithelial paracellular pathways. Thus, this study exhibited prospective potential of these DSPE-PEG polymers in developing into dosage forms with the aim to improve the poor bioavailability of some poorly absorbed macromolecular drugs.
A Concept Evaluation Study of a New Combination Bictegravir plus Tenofovir Alafenamide Nanoformulation with Prolonged Sustained-Drug-Release Potency for HIV-1 Preexposure Prophylaxis

The antiretroviral treatment (ART) approach is the best-prescribed approach to date for preexposure prophylaxis (PrEP) for high-risk individuals. However, the daily combination antiretroviral (cARV) regimen has become cumbersome for healthy individuals, leading to nonadherence. ABSTRACT The antiretroviral treatment (ART) approach is the best-prescribed approach to date for preexposure prophylaxis (PrEP) for high-risk individuals. However, the daily combination antiretroviral (cARV) regimen has become cumbersome for healthy individuals, leading to nonadherence. Recent surveys showed high acceptance of parenteral sustained-release ART enhancing PrEP adherence. Our approach is to design a parenteral nanoparticle (NP)-based cARV sustained-release (cARV-SR) system as long-acting HIV PrEP. Here, we report a new combination of two potent ARVs (tenofovir alafenamide fumarate [TAF] and bictegravir [BIC]) loaded as a nanoformulation intended as a cARV-SR for PrEP. The BIC+TAF NPs were fabricated by using a standardized in-house methodology. In vitro intracellular kinetics, cytotoxicity, and HIV-1 protection studies demonstrated that BIC+TAF encapsulation prolonged drug retention, reduced drug-associated cytotoxicity, and enhanced HIV protection. In human peripheral blood mononuclear cells, nanoformulated BIC+TAF demonstrated significant (P < 0.05) improvement in the drug’s selectivity index by 472 times compared to the BIC+TAF in solution. In vivo pharmacokinetic study of BIC, TAF, and respective drug metabolites in female BALB/c mice after single subcutaneous doses of BIC+TAF NPs demonstrated plasma drug concentrations of BIC and tenofovir above the intracellular 50% inhibitory concentration during the entire 30-day study period and prolonged persistence of both active drugs in the HIV target organs, including the vagina, colon, spleen, and lymph nodes. This report demonstrates that the encapsulation of BIC+TAF in a nanoformulation improved its therapeutic selectivity and the in vivo pharmacokinetics of free drugs. Based on these preliminary studies, we hypothesize that cARV-SR has potential as an innovative once-monthly delivery treatment for PrEP.