Miracle-dz/UniFAR-FTUs huggingface dataset:
Incidence and characteristics of neurotoxicity in immune checkpoint inhibitors with focus on neuromuscular events: Experience beyond the clinical trials

Immune checkpoint inhibitors (ICIs) are associated with various neurological adverse events (NAEs). We herein explored the incidence and clinical phenotype of immune‐related NAEs in cancer patients. Medical records of ICI‐treated cancer patients were reviewed between the years 2010 and 2018, with an aim to characterize immuno‐related NAEs. A total of 1185 ICIs‐treated patients were identified, 63.7% of which were males and 36.3% were females, with a mean age of 63.4 ± 7.3 years. Twenty‐four from the overall ICIs‐treated patients (2%) developed NAEs. No differences were identified in terms of age, sex, tumor type and class of ICIs between the patients who developed NAEs and those who did not. The median number of cycles of ICI treatment before NAEs onset were 4.5 (1‐10), and the median time was 102 days. Peripheral nervous system (PNS) involvement was present in 14 patients (58.4%) and central nervous system (CNS) involvement in 10 (33.3%), including 2 patients with aseptic meningitis and polyradicular involvement. Amongst PNS complications, there were five (20.8%) with axonal sensory neuropathies, four (16.7%) with Guillain‐Barre‐like syndromes, and four (16.7%) with myositis and/or myasthenic syndromes. The majority of patients with PNS‐related NAEs (n = 11; 78.6%) improved after ICIs discontinuation and treatment with immune‐modulating therapies. The time to neuromuscular toxicities onset was significantly shorter, compared to CNS NAEs (median 70 vs 119 days, P = .037). Immune‐related NAEs mostly present with neuromuscular complications. Discontinuation of ICIs and appropriate treatment should be commenced early throughout the process, in order to maximize a favorable outcome.
Mortality Prediction in Rural Kenya: A Cohort Study of Mechanical Ventilation in Critically Ill Patients

Importance: Critical care is expanding in low- and middle-income countries. Yet, due to factors such as missing data and different disease patterns, predictive scores often fail to adequately predict the high rates of mortality observed. Objectives: We evaluated multiple prognostic models for the outcome of mortality in critically ill, mechanically ventilated patients in rural Kenya and examined factors contributing to mortality in our setting. Design, Setting, and Participants: A prospective cohort study was conducted on mechanically ventilated patients in rural Kenya. Consecutive patients 16 years old and older initiated on mechanical ventilation between January 1, 2016, and April 30, 2017, at Tenwek Hospital were included. Demographic data, clinical characteristics, and patient outcomes were collected during routine clinical care. Main Outcomes and Measures: We assessed the discrimination and calibration of multiple previously-described models for mortality: Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, quick Sequential Organ Failure Assessment, Simplified Acute Physiology Score II, Modified Early Warning Score, Tropical Intensive Care Score, Rwanda-Mortality Predictive Model, Vitals score (validated in Tanzania), and Vitals score for sepsis (validated in Uganda). Factors most associated with mortality were analyzed in our cohort utilizing stepwise regression. Results: Among the final cohort of 300 patients, the overall mortality rate was 60.7%, the average age was 39.9 years, 65% were male, and 33% were seen at an outside facility prior to admission to the critical care unit. Missing variables occurred in patients for numerous models but were complete in most adapted to resource-limited settings. Models displayed moderate prediction of mortality and variable discrimination area under the receiver operating characteristic curves (and Hosmer-Lemeshow chi-square statistic) of 0.77 (22.4) for Acute Physiology and Chronic Health Evaluation II, 0.70 (3.4) for Modified Early Warning Score, 0.65 (0.16) for quick Sequential Organ Failure Assessment, 0.55 (18.4) for Simplified Acute Physiology Score II and 0.74 (9.2) for Rwanda-Mortality Predictive Model, 0.72 (0.12) for Vitals Tanzania, 0.68 (14.7) for Vitals Uganda, and 0.65 (13.9) for Tropical Intensive Care Score. Variables associated with increased mortality in our population were hypotension, infection, traumatic brain injury, and hematocrit. Conclusions and Relevance: Overall, survival for critically ill patients in rural Kenya was poor, but predictable with contributing factors. Models designed for resource-constrained settings had favorable discrimination and better calibration for mortality prediction than high-resource models in our population of mechanically ventilated, critically ill patients in rural Kenya.
Ultrasound-responsive highly biocompatible nanodroplets loaded with doxorubicin for tumor imaging and treatment in vivo

Abstract As an injectable anticancer drug delivery system, the biological safety of nanocarriers is the most important prerequisite for their clinical application. The objective of our study was to synthesize special ultrasound-responsive highly biocompatible chitosan nanodroplets (BCNDs), observe their spatiotemporally control the delivery of doxorubicin (DOX) in vivo. The experimental results showed that the BCNDs were successfully prepared with high biosafety in vivo and great ultrasound imaging ability. DOX-BCNDs promoted the anticancer effects of DOX in vivo and inhibited the development of tumors. They also reduced the side effects to the heart and kidneys. In conclusion, BCNDs are a new type of smart nanocarrier with high biocompatibility and efficacy have great potential to be used in the clinic.
Understanding the Genetic Domestication History of the Jianchang Duck by Genotyping and Sequencing of Genomic Genes Under Selection

The Jianchang duck is mainly distributed in Southwest China, and has the characteristics of fast growth rate and strong abilities in lipid deposition in the liver. In order to investigate the effects of domestication process on formation of the unique characteristics of Jianchang duck, the whole genome of sixteen individuals and three pooling of Jianchang duck were re-sequenced, and genome data of 70 mallards and 83 domestic ducks from thirteen different places in China were obtained from NCBI. The population stratification and evolution analysis showed gene exchanges existed between the Jianchang and other domestic duck populations, as well as Jianchang ducks and mallards. Genomic comparison between mallards and Jianchang ducks showed genes, including CNTN1, CHRNA9, and SHANK2, which is involved in brain and nerve development, experienced strong positive selection in the process of Jianchang duck domestication. The genomic comparison between Jianchang and domestic duck populations showed that HSD17B12 and ESM1, which affect lipid metabolism, experienced strong positive selection during the domestication process. FST analysis among populations of Jianchang duck with different plumage colors indicated that MITF was related to the phenotype of a white feather, while MC1R was related to the phenotype of hemp feather. Our results provided a base for the domestication process of Jianchang duck and the genomic genes for unique traits.
Preserved capacity for satellite cell proliferation, regeneration, and hypertrophy in the skeletal muscle of healthy elderly men

Blunted muscle hypertrophy and impaired regeneration with aging have been partly attributed to satellite cell (SC) dysfunction. However, true muscle regeneration has not yet been studied in elderly individuals. To investigate this, muscle injury was induced by 200 electrically stimulated (ES) eccentric contractions of the vastus lateralis (VL) of one leg in seven young (20‐31 years) and 19 elderly men (60‐73 years). This was followed by 13 weeks of resistance training (RT) for both legs to investigate the capacity for hypertrophy. Muscle biopsies were collected Pre‐ and Post‐RT, and 9 days after ES, for immunohistochemistry and RT‐PCR. Hypertrophy was assessed by MRI, DEXA, and immunohistochemistry. Overall, surprisingly comparable responses were observed between the young and elderly. Nine days after ES, Pax7+ SC number had doubled (P < .05), alongside necrosis and substantial changes in expression of genes related to matrix, myogenesis, and innervation (P < .05). Post‐RT, VL cross‐sectional area had increased in both legs (~15%, P < .05) and SCs/type II fiber had increased ~2‐4 times more with ES+RT vs RT alone (P < .001). Together these novel findings demonstrate “youthful” regeneration and hypertrophy responses in human elderly muscle. Furthermore, boosting SC availability in healthy elderly men does not enhance the subsequent muscle hypertrophy response to RT.
Coexistence of autosomal dominant polycystic kidney disease type 1 and hereditary renal hypouricemia type 2: A model of early‐onset and fast cyst progression

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid‐filled cyst development leading to end‐stage renal disease. The rate of disease progression in ADPKD exhibits high inter‐ and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD). However, the two disorders have distinct and well‐delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24‐year‐old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next‐generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan.
A novel miniature hexagonal shape switched pattern and frequency reconfigurable antenna

This proposed work introduces the structure of frequency and pattern reconfigurable patch antenna. This proposed design comprises of a hexagon patch antenna with four oblique slits, two longitudinal and two latitudinal slits. Four PIN diodes are used to enable frequency and pattern reconfiguration in the longitudinal and latitudinal slits. The operating frequencies of the proposed reconfigurable antenna are 4.25, 5.65, 6.8, and 8.2 GHz and have a pattern slope of −30°, 0°, +30°, and 180°. The pattern is reconfigurable in four directions without any servo system. The designed antenna is fabricated, and its performance is proved using quantifications. Experimental results have less than 15% error with the simulated results. This antenna is used for C‐band applications.
Saddle pulmonary embolism with fluorouracil: A case report

Introduction As a single agent, fluorouracil has been documented to have a small but present chance of causing extravasation of the port when not properly administered. It has also been shown that cancer patients receiving chemotherapy are at increased risk of deep vein thrombosis, symptomatic or silent. Case report A 43-year-old male patient with stage III colon cancer receiving FOLFOX developed a saddle pulmonary embolism involving possible extravasation that was discovered following cycle 3 of chemotherapy. CT scan and lower extremity Doppler confirmed non-occlusive deep vein thrombosis along with saddle pulmonary embolism. Management and outcome: For acute management, patient underwent bilateral pulmonary artery thrombolysis. Following this, the patient was initiated on rivaroxaban indefinitely. The right subclavian port was removed, and a new port was placed in the left subclavian. Patient went on to receive three more cycles of chemotherapy. Discussion Fluorouracil, an inflammitant, has been shown to have damaging potential, especially in terms of the integrity of the endothelium. Over time, this can lead to serious complications such as cardiotoxicity, including deep vein thrombosis formation. Based on how and when the thrombi were discovered, it is not possible to deduce whether the port, the 5-FU, extravasation or other factors were the precipitators of the formation of the thrombi. The combination of chemotherapy treatment along with CVC placement appears to have an additive risk to the formation of a thrombus. Practitioners should take caution when evaluating for extravasation and CVC integrity and note other potential differentials for causes, including deep vein thrombosis/saddle pulmonary embolism formation.
Both BRCA1-wild type and -mutant triple-negative breast cancers show sensitivity to the NAE inhibitor MLN4924 which is enhanced upon MLN4924 and cisplatin combination treatment

Triple-negative breast cancer (TNBC) shows limited therapeutic efficacy. PARP inhibitor has been approved to treat advanced BRCA-mutant breast cancer but shows high resistance. Therefore, the development of new therapeutics that sensitize TNBC irrespective of BRCA status is urgently needed. The neddylation pathway plays a critical role in many physiological processes by regulating the degradation of proteins. MLN4924, a selective inhibitor of the key neddylation enzyme NEDD8 Activation Enzyme (NAE1), shows higher sensitivity to both BRCA1-wild type and -mutant TNBCs compared to other breast cancer subtypes. MLN4924 induced re-replication with >4N DNA content leading to robust DNA damage. Accumulation of unrepaired DNA damage resulted in S and G2/M arrest causing apoptosis and senescence, due to the stabilization of the replication initiation protein CDT1 and the accumulation of cell cycle proteins upon MLN4924 treatment. Moreover, adding MLN4924 to the standard TNBC chemotherapeutic agent cisplatin increased the DNA damage level, further enhancing the sensitivity. In vivo, MLN4924 reduced tumor growth in a NOD-SCID mouse xenograft model by inducing DNA damage which was further augmented with the MLN4924 and cisplatin cotreatment. NAE1 is overexpressed in TNBC cell lines and in patients compared to other breast cancer subtypes suggesting that NAE1 status is prognostic of MLN4924 treatment response and outcome. Taken together, we demonstrated the mechanism of TNBC sensitization by the MLN4924 and MLN4924/cisplatin treatments irrespective of BRCA1 status, provided a strong justification for using MLN4924 alone or in combination with cisplatin, and identified a genetic background in which this combination will be particularly effective.
The evolution of African swine fever virus in Sardinia (1978 to 2014) as revealed by whole genome sequencing and comparative analysis.

African swine fever (ASF) is a highly contagious and lethal viral disease of pigs and wild boars, which is enzootic in many African countries and on the Italian island of Sardinia, where it has been present since 1978. Previous genetic analyses of Sardinian ASF virus (ASFV) isolates have revealed that they all belong to p72 genotype I, with only minor sequence variations. However, these studies examined only a few selected genes. To distinguish between these closely related isolates and better investigate ASFV evolution in Sardinia, we sequenced the complete genomes of 12 Sardinian ASFV isolates collected between 1978 and 2012, and compared them with 47/Ss/2008 and 26544/OG10. Most of the observed changes occurred in a time-dependent manner; however, their biological significance remains unclear. As a whole, our results demonstrate the remarkable genetic stability of these strains, supporting a single source introduction of the virus.
Cultivation Effects of Medical Television Viewing on Aspiring Doctors

ii Acknowledgments. iii List of Tables . v Chapter 1Introduction . 1 Chapter 2Literature Review . 3 Cultivation Theory . 3 Criticisms of Cultivation Theory . 5 Uses and Gratifications Theory . 7 Portrayals of Careers on Television . 9 Television and Health Perceptions. 11 Medical Television. 17 Anticipatory Socialization . 21 Television and Anticipatory Socialization . 25 Medical Drama Viewing and Aspiring Doctors . 28 Chapter 3Method . 31 Justification . 31 Sample and Survey Design . 33 Chapter 4Results . 34 Medical Drama Viewing and Perceptions of Health Conditions . 35 Experience in the Medical Field and Perceptions of Health Conditions . 37
Salient Features of Monomeric Alpha-Synuclein Revealed by NMR Spectroscopy

Elucidating the structural details of proteins is highly valuable and important for the proper understanding of protein function. In the case of intrinsically disordered proteins (IDPs), however, obtaining the structural details is quite challenging, as the traditional structural biology tools have only limited use. Nuclear magnetic resonance (NMR) is a unique experimental tool that provides ensemble conformations of IDPs at atomic resolution, and when studying IDPs, a slightly different experimental strategy needs to be employed than the one used for globular proteins. We address this point by reviewing many NMR investigations carried out on the α-synuclein protein, the aggregation of which is strongly correlated with Parkinson’s disease.
High Specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG Positive Ewing Sarcoma

Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for EWSR1-FLI1-positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including EWSR1-ERG-positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by EWSR1-ERG-positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available.
Timing of hip hemiarthroplasty and the influence on prosthetic joint infection

Introduction Previous research suggested that patients have increased risk of infection with increased time from presentation with a femoral neck fracture to treatment with a hip hemiarthroplasty (HHA). The purpose of this study was to determine if rates of prosthetic joint infections within 3 months of surgery was affected by the time from patient presentation with a femoral neck fracture to the time of treatment with HHA. Materials and methods Acute hip fractures treated with HHA between 2005 and 2017 at three centres in Norway were enrolled in the study. Multi-trauma patients were excluded. Univariable analysis was performed to determine any significant effect of pre-operative waiting time on infection rate. Two pre-planned analyses dichotomizing pre-operative waiting time cut-offs were performed. Results There were 2300 patients with an average age of 82 (range, 48–100) years included of which 3.4% experienced a prosthetic joint infection within 3 months. The primary analysis found no significant difference in infection rate depending on time to surgery (OR = 1.06 (95% CI 0.94–1.20, p = 0.33)). The secondary analyses showed no significant differences in infection rates when comparing pre-operative waiting time of <24 hours vs ≥24 hours (OR = 0.92 (95% CI 0.58–1.46, p = 0.73)) and <48 hours vs ≥48 hours (OR = 1.39 (95% CI 0.81–2.38, p = 0.23)). Conclusion Based off of a large retrospective Norwegian database of hip fractures there did not appear to be a significant difference in infection rate based on pre-operative wait time to surgery.
The effect of simulated circumferential soft exoskeleton compression at the knee on discomfort and pain

Abstract There is a lack of data and guidance on soft exoskeleton pressure contact with the body. The purpose of this research was to study the relationship between circumferential loading at the knee and discomfort/pain, to inform the design of soft exoskeletons/exosuits. The development of discomfort and pain was studied during standing and walking with circumferential compression using a pneumatic cuff. Our results show higher tolerance for intermittent than continuous compression during standing. Discomfort was triggered at pressures ranging from 13.7 kPa (continuous compression) to 30.4 kPa (intermittent compression), and pain at 52.9 kPa (continuous compression) to 60.6 kPa (intermittent compression). During walking, cyclic compression caused an increase in discomfort with time. Higher cuff inflation pressures caused an earlier onset and higher end intensities of discomfort than lower pressures. Cyclic cuff inflation of 10 kPa and 20 kPa was reasonably well tolerated. Practitioner summary Soft exoskeleton compression of the knee was simulated during static and dynamic compression cycles. The results can be used to understand how users tolerate pressure at the knee, and also to understand the levels at which discomfort and pain are experienced. Abbreviations: BMI: body mass index; DDT: discomfort detection threshold; EndVAS: end of experiment rating on visual analog discomfort scale; PDT: pain detection threshold; SD: standard deviation; SE: standard error; TSP: temporal summation of pain; VAS: visual analogue scale
Association of TP53 rs1042522 C>G and miR‐34b/c rs4938723 T>C polymorphisms with hepatoblastoma susceptibility: A seven‐center case–control study

Hepatoblastoma is a rare malignancy originating from pluripotent stem cells with unknown etiology. An understanding of the etiology in pediatric hepatoblastoma has been hampered by the unavailability of sufficient patient samples. To date, only a few epidemiological studies with small sample sizes have been performed investigating risk factors for hepatoblastoma. TP53 and pri‐miR‐34b/c genes are implicated in the tumorigenesis, yet the role of their polymorphisms in hepatoblastoma susceptibility remains unknown.