Miracle-dz/UniFAR-FTUs huggingface dataset:
Supramolecular PEGylation of biopharmaceuticals

Significance Pharmaceutical practice has transitioned away from small-molecule drugs to the use of biomolecules (peptides, proteins, and antibodies). Where formulation of small molecules focused primarily on solubility, biopharmaceuticals introduced an array of complications due to their more complex secondary and tertiary structures, contributing to concerns surrounding aggregation and denaturation over time in formulation. Here, we outline an approach using noncovalent supramolecular affinity to endow biopharmaceuticals with a polymer known to inhibit protein aggregation and improve solubility. This method stands in contrast to similar approaches to covalently graft the same polymer onto the protein, instead offering a broadly useful and modular formulation excipient that can be combined with authentic unmodified protein drugs to extend shelf life. The covalent modification of therapeutic biomolecules has been broadly explored, leading to a number of clinically approved modified protein drugs. These modifications are typically intended to address challenges arising in biopharmaceutical practice by promoting improved stability and shelf life of therapeutic proteins in formulation, or modifying pharmacokinetics in the body. Toward these objectives, covalent modification with poly(ethylene glycol) (PEG) has been a common direction. Here, a platform approach to biopharmaceutical modification is described that relies on noncovalent, supramolecular host–guest interactions to endow proteins with prosthetic functionality. Specifically, a series of cucurbit[7]uril (CB[7])–PEG conjugates are shown to substantially increase the stability of three distinct protein drugs in formulation. Leveraging the known and high-affinity interaction between CB[7] and an N-terminal aromatic residue on one specific protein drug, insulin, further results in altering of its pharmacological properties in vivo by extending activity in a manner dependent on molecular weight of the attached PEG chain. Supramolecular modification of therapeutic proteins affords a noncovalent route to modify its properties, improving protein stability and activity as a formulation excipient. Furthermore, this offers a modular approach to append functionality to biopharmaceuticals by noncovalent modification with other molecules or polymers, for applications in formulation or therapy.
Measurement of Typhi Vi antibodies can be used to assess adaptive immunity in patients with immunodeficiency

Vaccine‐specific antibody responses are essential in the diagnosis of antibody deficiencies. Responses to Pneumovax II are used to assess the response to polysaccharide antigens, but interpretation may be complicated. Typhim Vi®, a polysaccharide vaccine for Salmonella typhoid fever, may be an additional option for assessing humoral responses in patients suspected of having an immunodeficiency. Here we report a UK multi‐centre study describing the analytical and clinical performance of a Typhi Vi immunoglobulin (Ig)G enzyme‐linked immunosorbent assay (ELISA) calibrated to an affinity‐purified Typhi Vi IgG preparation. Intra‐ and interassay imprecision was low and the assay was linear, between 7·4 and 574 U/ml (slope = 0·99–1·00; R2 > 0·99); 71% of blood donors had undetectable Typhi Vi IgG antibody concentrations. Of those with antibody concentrations > 7·4 U/ml, the concentration range was 7·7–167 U/ml. In antibody‐deficient patients receiving antibody replacement therapy the median Typhi Vi IgG antibody concentrations were < 25 U/ml. In vaccinated normal healthy volunteers, the median concentration post‐vaccination was 107 U/ml (range 31–542 U/ml). Eight of eight patients (100%) had post‐vaccination concentration increases of at least threefold and six of eight (75%) of at least 10‐fold. In an antibody‐deficient population (n = 23), only 30% had post‐vaccination concentration increases of at least threefold and 10% of at least 10‐fold. The antibody responses to Pneumovax II and Typhim Vi® correlated. We conclude that IgG responses to Typhim Vi® vaccination can be measured using the VaccZyme Salmonella typhi Vi IgG ELISA, and that measurement of these antibodies maybe a useful additional test to accompany Pneumovax II responses for the assessment of antibody deficiencies.
Massive transfusion protocols: current best practice

Massive transfusion protocols (MTPs) are established to provide rapid blood replacement in a setting of severe hemorrhage. Early optimal blood transfusion is essential to sustain organ perfusion and oxygenation. There are many variables to consider when establishing an MTP, and studies have prospectively evaluated different scenarios and patient populations to establish the best practices to attain improved patient outcomes. The establishment and utilization of an optimal MTP is challenging given the ever-changing patient status during resuscitation efforts. Much of the MTP literature comes from the trauma population, due to the fact that massive hemorrhage is the leading cause of preventable trauma-related death. As we come to further understand the positive and negative clinical impacts of transfusion-related factors, massive transfusion practice can be further refined. This article will first discuss specific MTPs targeting different patient populations and current relevant international guidelines. Then, we will examine a wide selection of therapeutic products to support MTPs, including newly available products and the most suitable of the traditional products. Lastly, we will discuss the best design for an MTP, including ratio-based MTPs and MTPs based on the use of point-of- care coagulation diagnostic tools.
Utility of Neck, Height, and Tonsillar Size to Screen for Obstructive Sleep Apnea among Obese Youth

Objectives To determine whether neck:height ratio combined with adenoid and tonsillar size is a good predictive tool for obstructive sleep apnea in obese youth. Study Design Cross-sectional study. Setting Sleep clinics at the Hospital for Sick Children, Toronto, Canada. Subjects and Methods Consented obese individuals aged 8 to 18 years were recruited between 2013 and 2015. Anthropometric measures were obtained by a trained research coordinator in a standardized manner. Otolaryngologists evaluated adenoid and tonsil sizes. Obstructive sleep apnea was diagnosed with an overnight polysomnogram as an obstructive apnea-hypopnea index ≥2. Multivariable logistic regressions investigated the relationship between potential predictors and obstructive sleep apnea. The C-statistic measured the predictive ability. Results Of the 53 subjects (median age, 13 years; 55% males), 28 (53%) were diagnosed with obstructive sleep apnea, with a median index of 10.6 per hour. In a logistic regression controlling for adenoid size, enlarged tonsils were significantly associated with the presence of obstructive sleep apnea (P < .01). Adding neck:height ratio into the model improved the model predictive ability (C-index increased from 0.73 to 0.84). Controlling for tonsil and adenoid sizes, an increase in neck:height ratio was significantly associated with the presence of obstructive sleep apnea (P = .01). Conclusion Our study suggests that neck:height ratio combined with tonsillar hypertrophy may have a strong predictive ability for obstructive sleep apnea and may be useful in an ambulatory setting to screen obese youth at high risk. These findings should be confirmed in a larger study.
Endocrine function and oocyte retrieval after autologous transplantation of ovarian cortical strips to the forearm.

CONTEXT In reproductive-age women, one of the common adverse effects of chemotherapy and radiotherapy is premature ovarian failure. In addition, a significant number of women experience early menopause due to oophorectomy performed for benign indications. OBJECTIVE To develop an ovarian transplantation technique to preserve endocrine function in women undergoing sterilizing radiotherapy and/or chemotherapy, or oophorectomy. DESIGN AND SETTING Case study of 2 patients in New York who received autologous ovarian transplantation (patient A, November 1999; patient B, April 2000) to the forearm prior to pelvic radiotherapy or after oophorectomy. PARTICIPANTS Patient A is a 35-year-old woman with stage IIIB squamous cell cervical carcinoma and patient B is a 37-year-old woman with recurrent benign ovarian serous cysts. MAIN OUTCOME MEASURES Follicular development evident by ultrasound examination; cyclical production of estradiol and progesterone; restoration of serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels to nonmenopausal range; and disappearance of menopausal symptoms. RESULTS Menopause was confirmed immediately after the transplantation in both patients by serum follicle-stimulating hormone measurements (patient A, 47 mIU/mL; patient B, 50.7 mIU/mL). In patient A, follicle development was noted by physical and ultrasound examinations approximately 10 weeks after the transplantation. The mean (SE) follicle-stimulating hormone and luteinizing hormone levels decreased to 8.6 (0.4) mIU/mL and 12.8 (0.8) mIU/mL, respectively. The peripheral estradiol levels showed cyclical variation (mean [SE], 115 [9.2] pg/mL [422 (33.8) pmol/L), and during the 18-month follow-up, a dominant follicle developed each month. The estradiol levels from the right cubital vein were consistent with ovarian vein measurements (mean [SE], 1069 [269] pg/mL [3924 (987.5) pmol/L]). Percutaneous oocyte aspirations yielded a mature oocyte. In patient B, ovarian function was demonstrated by ultrasound visualization of a 9-mm follicle by 6 months after transplantation. Thereafter, the patient had spontaneous menstruation every 25 to 28 days. Ovulation was further confirmed by midluteal progesterone measurements (range, 7-10.1 ng/mL; mean [SE], 8.5 [0.9] ng/mL). Patient B's ovarian graft was still functional 10 months after the transplantation. CONCLUSIONS Subcutaneous ovarian transplantation appears to be a relatively simple, novel technique to preserve endocrine function in women undergoing sterilizing cancer therapy or surgery.
Blood pressure variability in individuals with and without (pre)diabetes: The Maastricht Study

Objective: The mechanisms associating (pre)diabetes and cardiovascular disease (CVD) are incompletely understood. We hypothesize that greater blood pressure variability (BPV) may underlie this association, due to its association with (incident) CVD. Therefore, we investigated the association between (pre)diabetes and very short-term to mid-term BPV, that is within-visit, 24-h and 7-day BPV. Methods: Cross-sectional data from The Maastricht Study [normal glucose metabolism (NGM), n = 1924; prediabetes, n = 511; type 2 diabetes mellitus (T2DM), n = 975; 51% men, aged 60 ± 8 years]. We determined SD for within-visit BPV (n = 3244), average real variability for 24-h BPV (n = 2699) day (0900–2100 h) and night (0100–0600 h) separately, and SD for 7-day BPV (n = 2259). Differences in BPV as compared with NGM were assessed by multiple linear regressions with adjustment for potential confounders. Results: In T2DM, the average systolic/diastolic values of within-visit, 24-h and 7-day BPV were 4.8/2.6, 10.5/7.3 and 10.4/6.5 mmHg, respectively, and in prediabetes 4.9/2.6, 10.3/7.0 and 9.4/5.9 mmHg, respectively. T2DM was associated with greater nocturnal systolic BPV [0.42 mmHg (95% confidence interval: 0.05–0.80)], and greater 7-day systolic [0.76 mmHg (0.32–1.19)] and diastolic BPV [0.65 mmHg (0.29–1.01)], whereas prediabetes was associated with greater within-visit systolic BPV only [0.35 mmHg (0.06–0.65)], as compared with NGM. Conclusion: Both T2DM and prediabetes are associated with slightly greater very short-term to mid-term BPV, which may, according to previous literature, explain a small part of the increased CVD risk seen in (pre)diabetes. Nevertheless, these findings do not detract from the fact that very short-term to mid-term BPV is substantial and important in individuals with and without (pre)diabetes.
Detecting shapes in noise: tuning characteristics of global shape mechanisms

The proportion of signal elements embedded in noise needed to detect a signal is a standard tool for investigating motion perception. This paradigm was applied to the shape domain to determine how local information is pooled into a global percept. Stimulus arrays consisted of oriented Gabor elements that sampled the circumference of concentric radial frequency (RF) patterns. Individual Gabors were oriented tangentially to the shape (signal) or randomly (noise). In different conditions, signal elements were located randomly within the entire array or constrained to fall along one of the concentric contours. Coherence thresholds were measured for RF patterns with various frequencies (number of corners) and amplitudes (“sharpness” of corners). Coherence thresholds (about 10% = 15 elements) were lowest for circular shapes. Manipulating shape frequency or amplitude showed a range where thresholds remain unaffected (frequency ≤ RF4; amplitude ≤ 0.05). Increasing either parameter caused thresholds to rise. Compared to circles, thresholds increased by approximately four times for RF13 and five times for amplitudes of 0.3. Confining the signals to individual contours significantly reduced the number of elements needed to reach threshold (between 4 and 6), independent of the total number of elements on the contour or contour shape. Finally, adding external noise to the orientation of the elements had a greater effect on detection thresholds than adding noise to their position. These results provide evidence for a series of highly sensitive, shape-specific analysers which sum information globally but only from within specific annuli. These global mechanisms are tuned to position and orientation of local elements from which they pool information. The overall performance for arrays of elements can be explained by the sensitivity of multiple, independent concentric shape detectors rather than a single detector integrating information widely across space (e.g. Glass pattern detector).
Bark and Ambrosia Beetle (Curculionidae: Scolytinae) Diversity Found in Agricultural and Fragmented Forests in Piracicaba-SP, Brazil

Abstract Land use changes and forest fragmentation result in biodiversity loss and displacement, with insects among the most affected groups. Among these, bark beetles (Curculionidae: Scolytinae) occupy a prominent position due to their close ties to food resources, i.e., trees, and importance as primary decomposers in forest ecosystems. Therefore, our study aimed to document scolytine biodiversity associated with landscape components that vary based on their physical or botanical composition. Bark beetle diversity was sampled monthly for 12 mo in an Atlantic forest remnant and five adjacent vegetation plots (mixed Agroforestry System—AFS, of native trees and fruit species; AFS of rubber trees and coffee plants; coffee monoculture; rubber monoculture; and pasture). In total, 1,833 individuals were sampled from 38 species of which 24 (63%) were detected in very low abundance. The remaining 14 species were more abundant and widespread almost in all areas. Hypothenemus hampei (Westwood), Premnobius cavipennis (Eichhoff), Hypothenemus sp1. , and Xyleborus volvulus (Fabricius) were the most abundant. The greatest abundance and richness of bark beetles were found in the dry and cold season. The varied microclimatic conditions of the vegetation plots greatly affected the diversity of the Scolytinae. Solar radiation presented a significant negative effect on abundance in almost all the studied areas. The greatest scolytine diversity was found in anthropic areas with tree canopy structure. Open areas (pasture and coffee monocrop) had a lower species diversity. Similarly, a lower abundance and species richness were found for the Atlantic forest remnant.
An analytic behavior model for disk drives with readahead caches and request reordering

Modern disk drives read-ahead data and reorder incoming requests in a workload-dependent fashion. This improves their performance, but makes simple analytical models of them inadequate for performance prediction, capacity planning, workload balancing, and so on. To address this problem we have developed a new analytic model for disk drives that do readahead and request reordering. We did so by developing performance models of the disk drive components (queues, caches, and the disk mechanism) and a workload transformation technique for composing them. Our model includes the effects of workload-specific parameters such as request size and spatial locality. The result is capable of predicting the behavior of a variety of real-world devices to within 17% across a variety of workloads and disk drives.
What's the Story? A New Perspective on the Value of Economic Forecasts

We apply textual analysis tools to measure the degree of optimism versus pessimism of the text that describes Federal Reserve Board forecasts published in the Greenbook. The resulting measure of Greenbook text sentiment, ? Tonality,? is found to be strongly correlated, in the intuitive direction, with the Greenbook point forecast for key economic variables such as unemployment and inflation. We then examine whether Tonality has incremental power for predicting unemployment, GDP growth, and inflation up to four quarters ahead. We find it to have significant and substantive predictive power for both GDP growth and unemployment, particularly since 1991: higher (more optimistic) Tonality presages higher GDP growth and lower unemployment, relative to the Greenbook point forecasts. We then test whether Tonality helps predict monetary policy and stock returns. Higher Tonality has some power to predict tighter than forecasted monetary policy, while it has substantial power fo r predicting higher 3-month, 6-month, and 12-month stock market returns.
On the Efficiency of Individualized Theta/Beta Ratio Neurofeedback Combined with Forehead EMG Training in ADHD Children

Background: Neurofeedback training (NFT) to decrease the theta/beta ratio (TBR) has been used for treating hyperactivity and impulsivity in attention deficit hyperactivity disorder (ADHD); however, often with low efficiency. Individual variance in EEG profile can confound NFT, because it may lead to influencing non-relevant activity, if ignored. More importantly, it may lead to influencing ADHD-related activities adversely, which may even result in worsening ADHD symptoms. Electromyogenic (EMG) signal resulted from forehead muscles can also explain the low efficiency of the NFT in ADHD from both practical and psychological point-of-view. The first aim of this study was to determine EEG and EMG biomarkers most related to the main ADHD characteristics, such as impulsivity and hyperactivity. The second aim was to confirm our hypothesis that the efficiency of the TBR NFT can be increased by individual adjustment of the frequency bands and simultaneous training on forehead muscle tension. Methods: We recruited 94 children diagnosed with ADHD (ADHD) and 23 healthy controls (HC). All participants were male and aged between six and nine. Impulsivity and attention were assessed with Go/no-Go task and delayed gratification task, respectively; and 19-channel EEG and forehead EMG were recorded. Then, the ADHD group was randomly subdivided into (1) standard, (2) individualized, (3) individualized+EMG, and (4) sham NFT (control) groups. The groups were compared based on TBR and EEG alpha activity, as well as hyperactivity and impulsivity three times: pre-NFT, post-NFT and 6 months after the NFT (follow-up). Results: ADHD children were characterized with decreased individual alpha peak frequency, alpha bandwidth and alpha amplitude suppression magnitude, as well as with increased alpha1/alpha2 (a1/a2) ratio and scalp muscle tension when c (η2 ≥ 0.212). All contingent TBR NFT groups exhibited significant NFT-related decrease in TBR not evident in the control group. Moreover, we detected a higher overall alpha activity in the individualized but not in the standard NFT group. Mixed MANOVA considering between-subject factor GROUP and within-subject factor TIME showed that the individualized+EMG group exhibited the highest level of clinical improvement, which was associated with increase in the individual alpha activity at the 6 months follow-up when comparing with the other approaches (post hoc t = 3.456, p = 0.011). Conclusions: This study identified various (adjusted) alpha activity metrics as biomarkers with close relationship with ADHD symptoms, and demonstrated that TBR NFT individually adjusted for variances in alpha activity is more successful and clinically more efficient than standard, non-individualized NFT. Moreover, these training effects of the individualized TBR NFT lasted longer when combined with EMG.
Evaluation of Scoring Systems and Prognostic Factors in Patients With Spinal Metastases From Lung Cancer

Study Design. A retrospective study of 180 patients with lung cancer spinal metastases, wherein prognostic score-predicted survival was compared with actual survival. Objective. To evaluate and compare the accuracy of prognostic scoring systems in lung cancer spinal metastases. Summary Of Background Data. The modified Tokuhashi, Tomita, modified Bauer, and Oswestry scores are currently used to guide decisions regarding operative treatment of patients with spinal metastases. The best system for predicting survival in patients with lung cancer spinal metastases remains undetermined. The high incidence of spinal metastases from lung cancer and improved survival of patients treated with systemic therapy warrants evaluation of these scoring systems in this particular context. Methods. Patients with lung cancer spinal metastases treated at our institution between May 2001 and August 2012 were studied. Fifty-one patients were treated surgically. The primary outcome measure was survival from the time of diagnosis. Scoring-predicted survival was compared with actual survival. Potential prognostic factors were investigated using Cox regression analyses. Predictive values of each scoring system for 3- and 6-month survival were measured via receiver operating characteristic (ROC) curves. Results. Histological subtype (P = 0.015), sex (P = 0.001), Karnofsky performance scale (P = 0.001), extent of neurological palsy (P = 0.002), and visceral metastases (P = 0.037) are significant predictors of survival. Besides the Oswestry spinal risk index, no significant differences were found between different prognostic subgroups within the individual scoring systems. Although the modified Bauer score was most accurate, all four scoring systems had areas under the ROC curve 0.5 or less. Conclusion. Although better prognostic scores correlated with longer survival, all four scoring systems are inaccurate in prognosticating patients with lung cancer spinal metastases. Specific lung cancer histology appears prognostic and should be considered, especially given the increased survival of patients receiving new targeted therapies appropriate to their disease. Level of Evidence: 3