Miracle-dz/UniFAR-FTUs huggingface dataset:
The Nobel Prize for Medicine awarded for cancer therapy by inhibition of negative immune regulation

As haematologists, it is with pleasure to see that the 2018 Nobel Prize for Medicine has been awarded to two people who have both published in the British Journal of Haematology. We may also be puzzled that the Nobel Prize Committee has not yet seen fit to award one of the people involved in the string of events that lead from Janet Rowley0s realization of balanced translocations in leukaemia as a model for cancer in general, over the cloning of the BCR-ABL1 gene, leading to the hugely successful results with Imatinib in chronic myeloid leukaemia (CML). However, we doubt that anyone would dispute that the prize to James Allison (Fig 1) and Tasuku Honjo (Fig 2) was richly deserved and has much relevance to our speciality as well as the broader field of cancer (www.nobel prize.org/prizes/medicine/2018/summary). For myself (FC: Outgoing Editor in Chief), as I come to the end of many years in the role as Editor, it is of particular pleasure to see two contributors, who have been of great importance to the field of lymphoma, awarded this prestigious prize. It is perhaps appropriate to take a look back beyond the quarter century of cancer immunotherapy and the first introduction of antibodies interfering with the second signal of T-cell activation, which subsequently defined the field of checkpoint inhibition. Indeed, it has been a chequered history, beginning with the Coleys toxin (that, by coincidence, was developed at the same institution that Jim Allison produced anti-CTLA4), which was the result of a serendipitous observation of the short-lived suppression of tumours in patients who had severe bacterial infections. This somewhat spurious reagent had a couple of revivals in recent decades, but it is highly doubtful that it will ever enter mainstay therapy. A similar fate applies to Corynebacterium parvum and a range of other
Compound Fracture

The melancholy terminations of those cases of compound fracture which the young practitioner has witnessed under the usual hospital treatment, naturally induce him to form the general resolution of amputating almost indiscriminately. He knows well that, whenever a case is presented to him, instant decision becomes necessary, that he has it not in his power to watch the first symptoms of approaching gangrene, and then to arrest its progress by the knife; but that, before replacing the torn integuments, or adj usting the shattered ends of the bone, he must fix, and irrevocably fix, amputate now or never. When, added to this, there crowd upon his mind the dreadful
Extraintestinal infections caused by nontyphoidal Salmonella from a tertiary care center in India

BACKGROUND: Infection with Salmonella has become an increasing problem worldwide. Recently, nontyphoid Salmonella (NTS) has become a global concern causing threat to the health of human. It causes gastrointestinal infection which may be self-limiting, but invasive infections may be fatal, requiring appropriate therapy. This study was done to analyze the spectrum of NTS infections causing extraintestinal infections and its susceptibility pattern from a tertiary care center in India. MATERIALS AND METHODS: The medical records of 27 patients whose cultures were positive for NTS between the years 2013–2016 were included in this retrospective study. The relevant demographic, clinical, and laboratory data were analyzed. RESULTS: Among the 27 patients, predominant patients were in the age group of 20–30 years. The male to female ratio is 1.7:1. Salmonella typhimurium was the predominant NTS isolated among 15/27 (55.5%), followed by Salmonella enteritidis 4/27 (14.8%). 18/27 (66.6%) of NTS were isolated from blood. Nalidixic acid was sensitive in 2/15 of S. typhimurium, 2/4 of S. enteritidis and 1/3 of Salmonella weltevreden, while others are nalidixic acid-resistant implying resistance to quinolones. They were sensitive to other antibiotics reported. CONCLUSION: This study highlights the spectrum of NTS causing extraintestinal infections which is an emerging infection occurring mostly in immunosuppressed individuals. There should be a high degree of clinical suspicion which would help in the early diagnosis and management of patients.
Response to Bayliss et al: “Re: Propranolol Treatment for Hemangioma of Infancy: Risks and Recommendations”>

To the Editor: I read with interest the recent publication of Garcovich et al (1) reporting an interesting case of vulvar pyoderma gangrenosum. Indeed, vulvar pyoderma gangreosum is an uncommon cause of spontaneous vulvar ulceration (2). However, it is important to keep in mind that this finding can be associated with gastrointestinal disease, particularly Crohn disease (3), and is sometimes the presenting manifestation of Crohn disease. In cases of vulvar PG, a complete investigation to look for Crohn disease should be performed.
Oral Administration of a Chemically Modified Curcumin, TRB-N0224, Reduced Inflammatory Cytokines and Cartilage Erosion in a Rabbit ACL Transection Injury Model

Objective To evaluate the effects of TRB-N0224, a chemically modified curcumin (CMC) with zinc binding properties and improved pharmacokinetics, in a rabbit anterior cruciate ligament (ACL) transection injury–induced model of osteoarthritis (OA). Design Thirty-eight skeletally mature New Zealand white rabbits were studied in 4 groups: a sham with arthrotomy (n = 6), control with ACL transection (n = 6), and 2 treatment groups with ACL transection and administration of TRB-N0224 at low (25 mg/kg/day) (n = 13) and high (50 mg/kg/day) (n = 13) doses. After euthanization at 12 weeks, outcomes were measured by post-necropsy gross morphology, biomechanics, and cartilage and synovium histology. Rabbit blood ELISA quantified cytokine and matrix metalloproteinase (MMP) concentrations at 0, 4, 8, and 12 weeks. Results Both treatment doses had fewer distal femoral condyle erosive defects than the control; the low dose demonstrated a mean 78% decrease (P < 0.01). Histologically, the low- and high-dose treatment groups had fewer cartilage pathologic changes and less severe synovitis than the control. CMC alone did not have a major effect on the biomechanics of healthy cartilage or cartilage in the ACL transection model, as demonstrated in 5 of the 6 measured properties/regions (P < 0.05). ELISA results suggested that the key mediators of OA, (interleukin) IL-1β, IL-6, TNFα (tumor necrosis factor-α), MMP-9, and MMP-13, had decreased concentrations with TRB-N0224 treatment at different time points between weeks 4 to 12 (P < 0.05). Conclusions In the pathogenesis of OA, an imbalance exists between catabolic and anabolic mediators. These results suggest the potential of TRB-N0224 to modulate MMP and cytokine levels, slowing the macroscopic and histopathological progression of OA.
Surveys still teach vital non‐technical lessons in General Surgery

In general surgery, observational studies are disregarded and often seen as non‐noteworthy research. We intend to defend the use of surveys in general surgery and colorectal surgery. This review highlights the historical importance and contemporary utility of surveys internationally and in our region, thus reminding Australasian surgeons and clinicians in numerous disciplines of the usefulness of this research tool. Well‐constructed surveys often successfully capture qualitative data otherwise impossible to collect through randomized controlled trial. The results of these surveys may advise national policies and medical registration agencies thus having a direct influence on individuals and their public health. Samples from contemporary survey‐based research publications from international and Australasian authors are used to illustrate some of the vital non‐technical lessons learned in recent times.
Distribution of diabetes, hypertension and non-communicable disease risk factors among adults in rural Bangladesh: a cross-sectional survey

Background Non-communicable diseases (NCDs) are increasing in low-income settings. We conducted a survey of risk factors, blood pressure and blood glucose in rural Bangladesh and assessed variations by age, sex and wealth. Methods We surveyed a random sample of 12 280 adults aged >30 years in 96 villages in rural Bangladesh. Fieldworkers measured blood glucose and conducted an glucose tolerance test with a repeat blood test 120 min post glucose ingestion. Blood pressure, anthropometric, socioeconomic, lifestyle and behavioural risk factors data were also collected. Data were analysed to describe the prevalence of diabetes, intermediate hyperglycaemia, hypertension and NCD risk factors by age, sex and wealth. Results Women had higher levels of overweight or obesity and lower levels of physical activity and fruit and vegetable consumption than men; 63% of men used tobacco compared with 41.3% of women. Overweight or obesity and abdominal obesity (waist to hip ratio) increased with socioeconomic status (least poor vs most poor: OR (95% CI) 3.21 (2.51 to 4.11) for men and 2.83 (2.28 to 3.52) for women). Tobacco use, passive smoke exposure and salt consumption fell with increasing socioeconomic status in both sexes. Clustering of risk factors showed more than 70% of men and women reported at least three risk factors. Women in the least poor group were 33% more likely to have three or more risk factors compared with women in the most poor group (1.33 (95% CI 1.17 to 1.58)). The combined prevalence of impaired fasting glucose, impaired glucose tolerance and diabetes was 26.1% among men and 34.9% among women, and increased with age. The prevalence of prehypertension and hypertension was 30.7% and 15.9% among men and 27.2% and 22.5% among women, with similar rising prevalence with age. Conclusion NCD risk factors, hyperglycaemia and raised blood pressure are an immediate health threat in rural Bangladesh. Initiatives to improve detection, treatment and prevention strategies are needed.
Effect of continuous cooking on cooking water properties and pasta quality.

Professional pasta cookers are filled with fresh water. The solids leached from the cooked pasta make pasta less firm and stickier while leading to changes in water properties and overflow. Added fresh water then has to be reheated. The effect of continuous cooking on cooked pasta quality and water properties was investigated for the first time by simulating professional pasta cooking on a laboratory scale. Continuous cooking procedure of 12 batches led to a solid content of cooking water of 37 g kg−1 , resulting in an increase in shear-thinning behaviour and consistency index. Pasta cooking loss decreased from 52.7 to 35.7 g kg−1 due to the lower water concentration gradient through the pasta. This was confirmed by a decrease in swelling index from 2.0 × 10−3 to 1.6 × 10−3 g kg−1 during the optimal cooking time (13 min 45 s). Surprisingly, continuous cooking made the pasta firmer while stickiness did not differ significantly (P > 0.05). Taking batch number 7 as the acceptability threshold, further studies are required to find an optimal solution for retaining cooking water properties highly affecting daily cooking procedures in food service kitchens.
Neutrophil and Granulocytic Myeloid-Derived Suppressor Cell–Mediated T Cell Suppression Significantly Contributes to Immune Dysregulation in Common Variable Immunodeficiency Disorders

Common variable immunodeficiency disorders (CVID) represent a group of primary immunodeficiency diseases characterized by hypogammaglobulinemia and impaired specific Ab response, resulting in recurrent infections due to dysfunctional immune response. The specific mechanisms mediating immune deficiency in CVID remain to be determined. Previous studies indicated that immune dysregulation in CVID patients is associated with chronic microbial translocation, systemic immune activation, and altered homeostasis of lymphocytic and myeloid lineages. A detailed phenotypic, functional characterization of plasma markers and immune cell populations was performed in 46 CVID patients and 44 healthy donors. CVID patients displayed significantly elevated plasma levels of a marker of neutrophil activation neutrophil gelatinase–associated lipocalin. Neutrophils from CVID patients exhibited elevated surface levels of CD11b and PD-L1 and decreased levels of CD62L, CD16, and CD80, consistent with a phenotype of activated neutrophils with suppressive properties. Neutrophils from CVID patients actively suppressed T cell activation and release of IFN-γ via the production of reactive oxygen species. Furthermore, CVID was associated with an increased frequency of low-density neutrophils (LDNs)/granulocytic myeloid-derived suppressor cells. LDN/granulocytic myeloid-derived suppressor cell frequency in CVID patients correlated with reduced T cell responsiveness. Exogenous stimulation of whole blood with bacterial LPS emulated some but not all of the phenotypic changes observed on neutrophils from CVID patients and induced neutrophil population with LDN phenotype. The presented data demonstrate that neutrophils in the blood of CVID patients acquire an activated phenotype and exert potent T cell suppressive activity. Specific targeting of myeloid cell–derived suppressor activity represents a novel potential therapeutic strategy for CVID.
Effect of high uric acid on the disposition of metformin: in vivo and in vitro studies

Metformin is always used as the baseline antidiabetic therapy for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia. Metformin is excreted into urine through active secretion mediated by rOCTs and rMATE1.The aim of this study was to identify the effects of high uric acid on the disposition and its mechanism. For the in vivo study, a hyperuricemic animal model was induced by intraperitoneal injection of potassium oxonate (250 mg/kg) in rats. Metformin (100 mg/kg) was administered orally to investigate the pharmacokinetics in control and hyperuricemic rats, respectively. For the in vitro study, HEK293 and HepaRG cells were used to investigate the effect of uric acid (15 mg/dl) on the expression of OCT1, OCT2 and MATE1 and the disposition of metformin, respectively. The in vivo study showed that the AUC0 → 600 of metformin was significantly decreased by 33.3%, whereas the cumulative urinary excretion of metformin was increased by 25.4% in hyperuricemic rats compared with that in control rats. The renal rOCT1, rOCT2 and rMATE1 and hepatic rMATE1 levels were increased in hyperuricemic rats compared with those in control rats, respectively. The in vitro study showed that uric acid could upregulate the expression of OCT2 and MATE1 in HEK293 cells and MATE1 in HepaRG cells and increase the intracellular metformin concentration in these two cell lines. These results demonstrated that a high uric acid level promoted urinary metformin excretion and decreased the plasma metformin concentration; the in vivo and in vitro studies provided a possible explanation being that high uric acid could upregulate the expression of renal metformin transporters OCTs and MATE1.
Preliminary studies on antiinflammatory and analgesic activities of Spilanthes acmella in experimental animal models

OBJECTIVE: To evaluate the antiinflammatory and analgesic activities of the aqueous extract of Spilanthes acmella (SPA) in experimental animal models. MATERIAL AND METHODS: SPA was evaluated for antiinflammatory action by carrageenan-induced rat paw edema. The analgesic activity was tested by acetic acid-induced writhing response in albino mice and tail flick method in albino rats. RESULTS: The aqueous extract of SPA in doses of 100, 200 and 400 mg/kg showed 52.6, 54.4 and 56.1% inhibition of paw edema respectively at the end of three hours and the percentage of protection from writhing was 46.9, 51.0 and 65.6 respectively. In the tail flick model, the aqueous extract of SPA in the above doses increased the pain threshold significantly after 30 min, 1, 2 and 4 h of administration. SPA showed dose-dependent action in all the experimental models. CONCLUSION: The present study indicates that SPA has significant antiinflammatory and analgesic properties.
Parallel computation: models and methods

1. Introduction2. Models of Computation3. Combinational Circuits4. Parallel Prefix Computation5. Divide and Conquer6. Pointer-Based Data Structures7. Linear Arrays8. Meshes and Related Models9. Hypercubes and Stars10. Models Using Buses11. Broadcasting with Selective Reduction12. Parallel SynergyBibliographyIndex
Identification of Linear Systems: A Practical Guideline to Accurate Modeling

Chapter headings and selected topics: Preface. A General Introduction to Parameter Estimation. Steps in the identification process. Parameter estimation, an example: measurement of a resistor. The ideal estimator. A Review of Estimation Methods and their Applications. Motives in focusing on the least squares technique. Parametric models. Time domain versus frequency domain. Errors due to noise on the independent variables. A Maximum Likelihood Estimator for Linear Time Invariant Systems. Measurement of a resistance. Estimation of transfer functions: a practical approach. Estimation of transfer functions: a theoretical approach. Numerical considerations. Extensions of the model. Application of ELiS to experimental data. Conclusions. Design of Excitation Signals. Optimization of the time domain behaviour of excitation signals. Optimizing the frequency domain behaviour of excitation signals: design of optimized power spectra. Model Selection. Verification of model validity. Introduction of the model complexity in the cost function. Study of the influence of model errors on the behaviour of the cost function. Optimal experiment strategy. Examples. Estimation of Linear Time Invariant Systems with Delay. The estimation algorithm and its properties. Simulations. Phase Correction of Linear Time Invariant Systems with Digital Allpass Filters. Phase distortion. Optimization strategy. Noise sensitivity. Application of ELiS to Measurement Problems. Modal analysis. Flight flutter data analysis. A Guideline for Transfer Function Estimation. Accurate modeling of a linear analog system. References. Author index. Subject index.
Assessment of Mars Pathfinder landing site predictions

Remote sensing data at scales of kilometers and an Earth analog were used to accurately predict the characteristics of the Mars Pathfinder landing site at a scale of meters. The surface surrounding the Mars Pathfinder lander in Ares Vallis appears consistent with orbital interpretations, namely, that it would be a rocky plain composed of materials deposited by catastrophic floods. The surface and observed maximum clast size appears similar to predictions based on an analogous surface of the Ephrata Fan in the Channeled Scabland of Washington state. The elevation of the site measured by relatively small footprint delay-Doppler radar is within 100 m of that determined by two-way ranging and Doppler tracking of the spacecraft. The nearly equal elevations of the Mars Pathfinder and Viking Lander 1 sites allowed a prediction of the atmospheric conditions with altitude (pressure, temperature, and winds) that were well within the entry, descent, and landing design margins. High-resolution (∼38 m/pixel) Viking Orbiter 1 images showed a sparsely cratered surface with small knobs with relatively low slopes, consistent with observations of these features from the lander. Measured rock abundance is within 10% of that expected from Viking orbiter thermal observations and models. The fractional area covered by large, potentially hazardous rocks observed is similar to that estimated from model rock distributions based on data from the Viking landing sites, Earth analog sites, and total rock abundance. The bulk and fine-component thermal inertias measured from orbit are similar to those calculated from the observed rock size-frequency distribution. A simple radar echo model based on the reflectivity of the soil (estimated from its bulk density), and the measured fraction of area covered by rocks was used to approximate the quasi-specular and diffuse components of the Earth-based radar echos. Color and albedo orbiter data were used to predict the relatively dust free or unweathered surface around the Pathfinder lander compared to the Viking landing sites. Comparisons with the experiences of selecting the Viking landing sites demonstrate the enormous benefit the Viking data and its analyses and models had on the successful predictions of the Pathfinder site. The Pathfinder experience demonstrates that, in certain locations, geologic processes observed in orbiter data can be used to infer surface characteristics where those processes dominate over other processes affecting the Martian surface layer.
Evolutionary divergence of the nuclear pore complex from fungi to metazoans

Nuclear pore complex (NPC) is the largest multimeric protein assembly of the eukaryotic cell, which mediates the nucleocytoplasmic transport. The constituent proteins of this assembly (nucleoporins) are present in varying copy numbers to give a size from ~ 60 MDa (yeast) to 112 MDa (human) and share common ancestry with other membrane‐associated complexes such as COPI/COPII and thus share the same structural folds. However, the nucleoporins across species exhibit very low percentage sequence similarity and this reflects in their distinct secondary structure and domain organization. We employed thorough sequence and phylogenetic analysis guided from structure‐based alignments of all the nucleoporins from fungi to metazoans to understand the evolution of NPC. Through evolutionary pressure analysis on various nucleoporins, we deduced that these proteins are under differential selection pressure and hence the homologous interacting partners do not complement each other in the in vitro pull‐down assay. The super tree analysis of all nucleoporins taken together illustrates divergent evolution of nucleoporins and notably, the degree of divergence is more apparent in higher order organisms as compared to lower species. Overall, our results support the hypothesis that the protein–protein interactions in such large multimeric assemblies are species specific in nature and hence their structure and function should also be studied in an organism‐specific manner.
Explaining user adoption of virtual worlds: Towards a multipurpose motivational model

: This study reports on an attempt to enhance our understanding of the reasons behind virtual world usage. By providing a mixture of utilitarian and hedonic value, virtual worlds represent an emerging class of multipurpose information systems (MPIS). Previous research seems to fall short in explaining MPIS adoption, especially since key extrinsic and intrinsic motivators are left out of consideration. Drawing upon IT adoption research, motivation theory and the consumer behavior literature, this research extends available works and provides insight into the influence and roles of extrinsic and intrinsic motivation. Hypotheses are postulated and tested using a sample of 1627 users of the virtual world Second Life. The results confirm the majority of the hypotheses and support the comprehensive model. The findings indicate instantaneous effects of extrinsic and intrinsic motivation, and highlight reinforcing effects of intrinsic motivation. Implications for research and practice are discussed.