Miracle-dz/UniFAR-FTUs huggingface dataset:
The surface area effect: How the intermediate dose spill depends on the PTV surface area in SRS

Abstract Purpose Stereotactic radiosurgery (SRS) is rapidly becoming the standard of care for many intracranial targets. The characteristics of the planning target volume (PTV) can affect the intermediate dose spill and thus normal brain volume dose which is correlated with brain toxicity. R50% (volume receiving 50% of prescription dose divided by PTV volume) is a useful metric to quantify the intermediate dose spill. We propose a novel understanding of how the PTV surface area (SAPTV) affects the intermediate dose spill of SRS treatments. Methods Using a phantom model provided by a computed tomography (CT) of the IROC Head Phantom® and Eclipse® Treatment Planning System, we investigate the relationship of R50% and SAPTV in single‐target SRS treatments. The planning studies are conducted for SRS treatments on a Varian TrueBeam® linear accelerator with high‐definition MLC and a 6 MVFFF beam mode. These data are analyzed to ascertain trends in R50% related to SAPTV. Since SAPTV is not available as a structure property in the Eclipse RTPS, we introduce an Eclipse script to extract PTV surface area of arbitrary‐shaped PTVs. We compare a physically reasonable theoretical prediction of R50%, R50%Analytic, to the R50% achieved in treatment planning studies. Results The SRS phantom study indicates good correlation between the plan R50% and SAPTV. A near‐linear relationship of plan R50% vs SAPTV is observed as predicted by the R50%Analytic model. Agreement between plan R50% values and R50%Analytic predictions is good for all but the very smallest PTV volumes. Conclusions We demonstrate dependence of the intermediate dose spill measured by R50% on the SAPTV. We call that dependence the surface area effect. This dependence is explicit in the R50%Analytic prediction model. The predicted value of R50%Analytic for a given PTV could be used for guidance during SRS treatment plan optimization, and plan evaluation for that PTV.
The effect of myxomatous mitral valve disease severity on packed cell volume in dogs.

OBJECTIVES The aim of this study was to examine whether associations between disease severity and packed cell volume exist in dogs with myxomatous mitral valve disease. MATERIALS AND METHODS Data were selected from 289 dogs that had been examined at a research clinic (2004-2017) on multiple occasions (n=1465). American College of Veterinary Internal Medicine stage and echocardiographic measurements were entered in separate multivariable linear mixed effects models with packed cell volume as the dependent variable. Age, breed, sex, weight and blood urea nitrogen concentrations were additionally tested in these analyses to control for patient characteristics. RESULTS Packed cell volume (% whole blood) in stages B1 and B2 (B1: 42.62 ±0.27, P=0.001; B2: 41.77± 0.42, P < 0.001) was lower than stage A (44.57 ±0.53). In stage C, packed cell volume was greater than both preclinical stages (C: 43.84 ±0.46). When the administration of loop diuretics was included in statistical models, packed cell volume was inversely related to normalised left ventricular internal diameters (β: -2.37; 95% confidence intervals: -3.49, -1.25; P < 0.001). CLINICAL SIGNIFICANCE Dogs with myxomatous mitral valve disease may develop reductions in packed cell volume as their disease progresses. Although this finding was statistically significant at a population level, it should be noted that the differences described are relatively small. This, along with other causes of variation in packed cell volume, means that changes would be challenging to appreciate within individual patients. Plasma volume depletion following diuretic administration may explain why findings differed in stage C.
Chapman–Enskog Method in Chemical Kinetics

Nonequilibrium effects in gas‐phase reactions associated with the perturbation of the Maxwell speed distribution by the reaction have been investigated by Prigogine and others using the Chapman–Enskog method in the lowest‐order approximation. We have extended these calculations to the second order in the Burnett expansion of the perturbation in a series of Sonine polynomials. In the case of the reaction A + A→B + C in which the products B and C are removed and no inert gas is present, the appropriate elastic collision integrals have been evaluated for the model of rigid elastic spheres and the reactive collision integrals have been evaluated for two reaction cross sections, one corresponding to the simple collision theory of bimolecular reactions with activation energy e* and the other to the “centrifugal barrier” theory of free‐radical recombinations. For the activated reactions the detailed results show that the Chapman–Enskog method is useless when the reaction is fast (e* / kT ≲ 5) because the perturb.
Impact of COVID-19 pandemic on the utilization of routine immunization services in Lebanon

Introduction The global abrupt progression of the COVID-19 pandemic may disrupt critical life-saving services such as routine immunization (RI), thus increasing the susceptibility of countries to outbreaks of vaccine-preventable diseases (VPDs). Being endemic to several infectious diseases, Lebanon might be at increased risk of outbreaks as the utilization of RI services might have deteriorated due to the pandemic and the country’s political unrest following the October 2019 uprising. The aim of this study was to assess the changes in the utilization of RI services in both the public and private sectors following the COVID-19 pandemic. Methods A self-administered cross-sectional survey was completed electronically, in April 2020, by 345 private pediatricians who are registered in professional associations of physicians in Lebanon and provide immunization services at their clinics. Means of the reported percentages of decrease in the utilization of vaccination services by pediatricians were calculated. As for the public sector, an examination of the monthly differences in the number of administered vaccine doses in addition to their respective percentages of change was performed. Adjustment for the distribution of RI services between the sectors was performed to calculate the national decrease rate. Results The utilization of vaccination services at the national level decreased by 31%. In the private sector, immunization services provision diminished by 46.9% mainly between February and April 2020. The highest decrease rates were observed for oral poliovirus vaccine (OPV) and hepatitis A, followed by measles and pneumococcal conjugate vaccines. The number of vaccine doses administered in the public sector decreased by 20%. The most prominent reductions were detected for the OPV and measles vaccines, and during October 2019 and March 2020. Conclusion The substantial decrease in the utilization of RI as a result of the COVID-19 pandemic requires public health interventions to prevent future outbreaks of VPDs.
High‐throughput genotyping of HLA‐G, HLA‐F, MICA, and MICB and analysis of frequency distributions in healthy blood donors from Catalonia

Similarly to HLA class I molecules, certain non‐classical HLA class I genes and MHC class I polypeptide‐related sequences A and B (MICA and MICB) act as ligands for KIR and NKG2D natural killer receptors. Although these genes are less polymorphic than HLA class I, few studies have analyzed their association with diseases. Information on allele frequencies in healthy donors is needed to map their distribution worldwide. This study is the first to analyze high‐resolution HLA‐G, HLA‐F, MICA, and MICB allele frequencies using a novel high‐throughput next generation‐sequencing method. We analyzed DNA samples from 96 unrelated blood donors resident in Catalonia, Spain, and registered in the Barcelona Blood and Tissue Bank. Using the first two fields of the HLA nomenclature, we detected six HLA‐G and two HLA‐F alleles. The most frequent alleles were HLA‐G*01:01 (77.08%) and HLA‐F*01:01(84.90%). When the four fields were analyzed, we detected 16 and 10 alleles, respectively. Nineteen alleles were detected for MICA and 10 for MICB. The most frequent alleles in these cases were MICA*008:01 (16.15%) and MICB*005:02 (46.84%). All frequencies were in Hardy Weinberg equilibrium except MICA. We also estimated maximum‐likelihood haplotype frequencies and calculated corresponding linkage disequilibrium (LD) values and found that few allele pairs were in disequilibrium. Strong LD between MICA and HLA‐B (using data from a previous study) was observed. Our findings will be useful for guiding further research evaluating the functional role of these genes in different diseases and populations.
Investigation of the relationship between immune checkpoints and mismatch repair deficiency in recurrent and nonrecurrent glioblastoma

Background/aim Microsatellite instability tests and programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) in the immune checkpoint pathway are the tests that determine who will benefit from immune checkpoint inhibitor therapy. We aimed to show the expression of DNA mismatch repair proteins and PD-1/PD-L1 molecules that inhibit immune checkpoints, to explain the relationship between them, and to demonstrate their predictive role in recurrent and nonrecurrent glioblastoma. Materials and methods We analyzed 27 recurrent and 47 nonrecurrent cases at our archive. We performed immunohistochemical analysis to determine expressions of PD-1, PD-L1, and mismatch repair proteins in glioblastoma. We evaluated the relationship between these two group and compared the results with the clinicopathological features. Results The mean age of diagnosis was significantly lower in recurrent glioblastoma patients. Median survival was longer in this group. We found that PD-L1 expression was reduced in recurrent cases. Additionally, recurrent cases had a significantly higher rate of microsatellite instability. Loss of PMS2 was high in both group but was substantially higher in recurrent cases. Conclusion The presence of microsatellite instability and low PD-L1 levels, which are among the causes of treatment resistance in glioblastoma, were found to be compatible with the literature in our study, with higher rates in recurrent cases. In recurrent cases with higher mutations and where immunotherapy resistance is expected less, low PD-L1 levels thought that different combinations with other immune checkpoint inhibitors can be tried as predictive and prognostic marker in GBM patients.
Gene expression barcode values reveal a potential link between Parkinson’s disease and gastric cancer

Gastric cancer is a disease that develops from the lining of the stomach, whereas Parkinson’s disease is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. Although these two diseases seem to be distinct from each other, increasing evidence suggests that they might be linked. To explore the linkage between these two diseases, differentially expressed genes between the diseased people and their normal controls were identified using the barcode algorithm. This algorithm transforms actual gene expression values into barcode values comprised of 1’s (expressed genes) and 0’s (silenced genes). Once the overlapped differentially expressed genes were identified, their biological relevance was investigated. Thus, using the gene expression profiles and bioinformatics methods, we demonstrate that Parkinson’s disease and gastric cancer are indeed linked. This research may serve as a pilot study, and it will stimulate more research to investigate the relationship between gastric cancer and Parkinson’s disease from the perspective of gene profiles and their functions.
Basal Rachis Internode Injection (BRII): A novel inoculation method to evaluate wheat resistance to Fusarium head blight.

Fusarium head blight (FHB) is one of the most destructive fungal diseases of wheat. Difficulties in reliably phenotyping of this disease, however, greatly hindered the understanding of the mechanism of wheat-pathogen interaction and genetic improvement of FHB resistance. Here we report a novel inoculation method called "Basal Rachis Internode Injection" (BRII), which is implemented by injecting inoculum into the basal internode of a rachis instead of a floret as done in single floret inoculation (SFI). One of the prominent advantages of BRII over SFI and other traditional methods lies in its independence of moisture-maintaining system that is required for all existing methods, thus being insensitive to environmental humidity and cost-effective. Another unique feature for BRII is that this method produces nearly clear-cut reaction types, by which FHB resistance could be treated as a qualitative trait because generally no FHB symptom appeared on the spikelets of resistant genotypes. In addition, BRII outperformed SFI by higher infection rate and better goodness-of-fit with known FHB resistance and QTL components in a panel of 15 genotypes, as well as two populations of recombinant inbred lines (RILs) segregating in Fhb1. To be noteworthy, BRII and SFI methods are not mutually replaceable but rather complimentary to each other since each method has its own advantage in differentiating FHB resistance among genotypes. Combining these two methods would significantly improve the reliability and consistency of FHB phenotyping in wheat.
The master regulator MAT1-1-1 of fungal mating binds to its targets via a conserved motif in the human pathogen Aspergillus fumigatus

Abstract Mating-type transcription factors are master regulators of sexually related signal transduction pathways in fungi; however, their recognition of specific DNA sequences from target genes is widely undetermined. Here, we identified and characterized the DNA-binding sequence of the MAT1-1-1 alpha-box domain transcription factor from the human pathogen Aspergillus fumigatus. In order to explore MAT1-1-1 DNA-binding targets, we used the previously reported MAT1-1-1 binding motif from Penicillium chrysogenum, in a bioinformatics approach. We identified 18 A. fumigatus genes carrying the MAT1.1 sequence in their upstream region, among them genes for the α-pheromone precursor (PpgA), G-protein-coupled pheromone receptor (PreA), and for TomA, an unidentified protein. To validate our prediction further, quantification of transcript levels showed a decrease in expression of ppgA, tomA, and others in a MAT1-1 deletion strain. For a functional analysis of the binding sites, truncated variants of the A. fumigatus MAT1-1-1 gene were introduced into Escherichia coli for heterologous expression. The yield of recombinant protein was further optimized for the AfMAT1-1-178–235 variant that harbors an extended alpha-box domain. AfMAT1-1-178–235 bound to a subset of the most strongly upregulated genes: ppgA, preA, and tomA. The DNA-binding specificity was confirmed by testing mutated binding sequences, as well as performing competition experiments with specific and non-specific sequences. Finally, equilibrium dissociation constants of 1.83 ± 0.1 and 1.45 ± 0.26 µM were determined for AfMAT1-1-178–235 and fusion protein GST-AfMAT1-1-178–235. Collectively, these findings provide further insights into AfMAT1-1-1-mediated gene expression and imply that alpha-box domain regulators from other members of Eurotiales control fungal development in a conserved manner.
The Yin and Yang of traditional Chinese and Western medicine

The success of Western Scientific approaches to medicine, over the last 150 years, can be measured by substantial increases in life expectancy, reductions in infant mortality and the virtual elimination of many infectious diseases accompanied by development of effective management practices for noncommunicable diseases. However, major challenges remain in the form of infectious diseases that evolve resistance to pharmaceuticals rapidly, new diseases, particularly those caused by viruses and effective long‐term treatments for chronic, noncommunicable diseases. Traditional Chinese Medicine (TCM) can offer complementary treatments based on personalised interventions, informed by knowledge accumulated from empirical observations gathered over centuries of practice, that address the impact of disease on the whole body.
Long‐term corticosteroid use, adrenal insufficiency and the need for steroid‐sparing treatment in adult severe asthma

Secondary adrenal insufficiency (AI) occurs as the result of any process that disrupts normal hypothalamic and/or anterior pituitary function and causes a decrease in the secretion of steroid hormones from the adrenal cortex. The most common cause of secondary AI is exogenous corticosteroid therapy administered at supraphysiologic dosages for ≥ 1 month. AI caused by oral corticosteroids (OCS) is not well‐recognized or commonly diagnosed but is often associated with reduced well‐being and can be life‐threatening in the event of an adrenal crisis. Corticosteroid use is common in respiratory diseases, and asthma is a representative condition that illustrates the potential challenges and opportunities related to corticosteroid‐sparing therapies. For individuals with severe asthma (approximately 5%–10% of all cases), reduction or elimination of maintenance OCS without loss of control can now be accomplished with biologic therapies targeting inflammatory mediators. However, the optimal strategy to ensure early identification and treatment of AI and safe OCS withdrawal in routine clinical practice remains to be defined. Many studies with biologics have involved short evaluation periods and small sample sizes; in addition, cautious approaches to OCS tapering in studies with a placebo arm, coupled with inconsistent monitoring for AI, have contributed to the lack of clarity. If the goal is to greatly reduce and, where possible, eliminate long‐term OCS use in severe asthma through the increasing adoption of biologic treatments, there is an urgent need for clinical trials that address both the speed of OCS withdrawal and how to monitor for AI.
Curtailing Unnecessary Waste Among Operating Room Personnel: Evaluating the Cost Awareness of Commonly Used Surgical Items

Background Operating rooms (ORs) generate 70% of hospital waste, leading to increased costs for the hospital, patient, and the environment. The lack of cost awareness among physicians has been well documented; however, there is little information on anesthesiologists or ancillary OR staff. This study aimed to evaluate the cost awareness of commonly used items at an academic medical center among OR personnel. Methods Anonymous surveys were distributed to OR personnel (nurses, surgical technicians (STs), nurse anesthetists, anesthesiologists, surgeons, and residents), asking for the estimated costs of ten commonly used items. These costs were then compared against actual costs to evaluate the accuracy of participants’ estimates. Responders were clustered by job, highest level of education, and years of experience for comparison. Results 167 surveys were collected, and overall only 16.4% of estimates were accurate within 50% of actual price. No significant differences in accuracy between groups were identified overall (P = .2), but both surgical and anesthesia attendings had significantly higher rates of correct responses than their respective residents. No difference was seen in accuracy when all attendings (surgeons and anesthesiologists) were compared with either nurses or STs. Linear regression demonstrated no correlation between number of years at current position or years at institution and number of correct responses (R2 = .0025 and R2 = .005, respectively). Discussion Addressing the knowledge deficit around item costs via global education of all OR personnel (surgeons, anesthesia providers, and ancillary staff) could be a viable pathway to reduce waste, and thus cost, for our healthcare system.
Stability testing in monoclonal antibodies

Abstract Monoclonal antibodies are proteinaceous in nature and are subject to instability issues. Stability testing of monoclonal antibodies is a critical regulatory requirement in their development and commercialization as therapeutic biological molecules. This article reviews the numerous drug manufacturing processes such as: upstream processing, downstream purification and aseptic filling along with physical and chemical factors such as protein concentration, structure, pH, temperature, light, agitation, deamidation, oxidation, glycation leading to instabilities in monoclonal antibodies and it spotlights the variety of analytical techniques employed to investigate and generate information on stability studies and henceforth, helps in developing the stability-indicating methods. In addition, this paper aims to discuss the ICH regulatory guideline (s) for the stability assessment of biological products (Drug Substance and Drug Product).
Sonic hedgehog signals hinder the transcriptional network necessary for pancreatic endoderm formation from human embryonic stem cells

Hedgehog morphogens govern multiple aspects of pancreas organogenesis and functioning with diverse outcomes across species. Although most current differentiation protocols repress Sonic hedgehog (SHH) signals during in vitro endocrine specification, the role and mechanisms through which the SHH pathway antagonizes pancreas development during in vitro human embryonic stem (hES) cell differentiation remain unclear. We modulated SHH signaling at transitory stages of hES cell‐derived pancreatic progenitors and analyzed the effect on cellular fate decisions. We identify the Hedgehog pathway as a negative regulator of pancreatic endoderm formation through up‐regulation of a set of pancreatobiliary markers required for ductal specification, including SOX17, FOXA2, HNF1β, HNF6, PDX1, and SOX9. Surprisingly, active Hedgehog signals impeded a group of pancreatic epithelium markers, including HNF4α, HHEX, PAX6, and PTF1α. To understand how SHH signals repress the transcription of these specific markers, we analyzed Polycomb group proteins. We found differential expression of Polycomb Repressive Complex 1 subunit, BMI1 upon Shh pathway modulation in the pancreatic progenitors. Ectopic activation of Sonic hedgehog results in over‐expression of BMI1 and its associated repressive histone mark, H2AK119Ub1, in the multipotent progenitors. Our data suggest that Sonic hedgehog restricts the pancreatic differentiation program by limiting progenitor cells acquiring pancreatic epithelial fates and instead promotes pancreatobiliary differentiation. We further provide mechanistic cues of an association between Hedgehog signaling and epigenetic silencers during pancreatic lineage decisions.
Membrane voltage as a dynamic platform for spatiotemporal signaling, physiological, and developmental regulation

Abstract Membrane voltage arises from the transport of ions through ion-translocating ATPases, ion-coupled transport of solutes, and ion channels, and is an integral part of the bioenergetic “currency” of the membrane. The dynamics of membrane voltage—so-called action, systemic, and variation potentials—have also led to a recognition of their contributions to signal transduction, both within cells and across tissues. Here, we review the origins of our understanding of membrane voltage and its place as a central element in regulating transport and signal transmission. We stress the importance of understanding voltage as a common intermediate that acts both as a driving force for transport—an electrical “substrate”—and as a product of charge flux across the membrane, thereby interconnecting all charge-carrying transport across the membrane. The voltage interconnection is vital to signaling via second messengers that rely on ion flux, including cytosolic free Ca2+, H+, and the synthesis of reactive oxygen species generated by integral membrane, respiratory burst oxidases. These characteristics inform on the ways in which long-distance voltage signals and voltage oscillations give rise to unique gene expression patterns and influence physiological, developmental, and adaptive responses such as systemic acquired resistance to pathogens and to insect herbivory.