LLukas22/scidocs huggingface dataset:
Statistical and regulatory considerations in assessments of interchangeability of biological drug products

When the patent of a brand-name, marketed drug expires, new, generic products are usually offered. Small-molecule generic and originator drug products are expected to be chemically identical. Their pharmaceutical similarity can be typically assessed by simple regulatory criteria such as the expectation that the 90 % confidence interval for the ratio of geometric means of some pharmacokinetic parameters be between 0.80 and 1.25. When such criteria are satisfied, the drug products are generally considered to exhibit therapeutic equivalence. They are then usually interchanged freely within individual patients. Biological drugs are complex proteins, for instance, because of their large size, intricate structure, sensitivity to environmental conditions, difficult manufacturing procedures, and the possibility of immunogenicity. Generic and brand-name biologic products can be expected to show only similarity but not identity in their various features and clinical effects. Consequently, the determination of biosimilarity is also a complicated process which involves assessment of the totality of the evidence for the close similarity of the two products. Moreover, even when biosimilarity has been established, it may not be assumed that the two biosimilar products can be automatically substituted by pharmacists. This generally requires additional, careful considerations. Without declaring interchangeability, a new product could be prescribed, i.e. it is prescribable. However, two products can be automatically substituted only if they are interchangeable. Interchangeability is a statistical term and it means that products can be used in any order in the same patient without considering the treatment history. The concepts of interchangeability and prescribability have been widely discussed in the past but only in relation to small molecule generics. In this paper we apply these concepts to biosimilars and we discuss: definitions of prescribability and interchangeability and their statistical implementation; the relation between bioequivalence and interchangeability for small-molecule drug products; regulatory requirements and expectations of biosimilar products in various jurisdictions; possible statistical approaches to establish the similarity and interchangeability of biologic drug products; definition of other technical terms such as switchability and automatic substitution. The paper will be concluded with a discussion of the anticipated future use of interchangeability of biological drug products.
Antecedents and maternal health outcomes of unintended pregnancy: a systematic review

Background: While concerns about adverse health outcomes of unintended pregnancies for the mother have been expressed, there has only been limited research on the outcomes of unintended pregnancies. This review provides an overview of antecedents and maternal health outcomes of unintended pregnancies (UIPs) carried to term live
Improved survival with MEK inhibition in BRAF-mutated melanoma.

BACKGROUND
Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.


METHODS
In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.


RESULTS
Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.


CONCLUSIONS
Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).
Spontaneous cholecystocutaneous fistula: a rare complication of gallbladder disease.

CONTEXT
Spontaneous cholecystocutaneous abscess or fistula is an extremely uncommon complication secondary to cholecystitis. Over the past 50 years fewer than 20 cases of spontaneous cholecystocutaneous fistulas have been described in the medical literature. We here report a case of subcutaneous gallstone as a rare clinical presentation of the already uncommon cholecystocutaneous fistula.


CASE REPORT
An 81-year-old man presented with a large subcutaneous abscess in the right subcostal area with surrounding cellulitis and crepitus. An abdominal computed tomography scan showed two subcutaneous gallstones and communication between the abscess and the gallbladder. Cholecystectomy was performed and the abdominal wall abscess was drained externally. This case report demonstrates that maintaining a high degree of suspicion of this rare entity is helpful in achieving correct preoperative diagnosis, and that computed tomography scan should be performed in all cases of unexplained abdominal wall suppuration or cellulitis.
DREADDS: Use and application in behavioral neuroscience.

Technological advances over the last decade are changing the face of behavioral neuroscience research. Here we review recent work on the use of one such transformative tool in behavioral neuroscience research, chemogenetics (or Designer Receptors Exclusively Activated by Designer Drugs, DREADDS). As transformative technologies such as DREADDs are introduced, applied, and refined, their utility in addressing complex questions about behavior and cognition becomes clear and exciting. In the behavioral neuroscience field, remarkable new findings now regularly appear as a result of the ability to monitor and intervene in neural processes with high anatomical precision as animals behave in complex task environments. As these new tools are applied to behavioral questions, individualized procedures for their use find their way into diverse labs. Thus, "tips of the trade" become important for wide dissemination not only for laboratories that are using the tools but also for those who are interested in incorporating them into their own work. Our aim is to provide an up-to-date perspective on how the DREADD technique is being used for research on learning and memory, decision making, and goal-directed behavior, as well as to provide suggestions and considerations for current and future users based on our collective experience. (PsycINFO Database Record
Applying artificial intelligence to disease staging: Deep learning for improved staging of diabetic retinopathy

PURPOSE
Disease staging involves the assessment of disease severity or progression and is used for treatment selection. In diabetic retinopathy, disease staging using a wide area is more desirable than that using a limited area. We investigated if deep learning artificial intelligence (AI) could be used to grade diabetic retinopathy and determine treatment and prognosis.


METHODS
The retrospective study analyzed 9,939 posterior pole photographs of 2,740 patients with diabetes. Nonmydriatic 45° field color fundus photographs were taken of four fields in each eye annually at Jichi Medical University between May 2011 and June 2015. A modified fully randomly initialized GoogLeNet deep learning neural network was trained on 95% of the photographs using manual modified Davis grading of three additional adjacent photographs. We graded 4,709 of the 9,939 posterior pole fundus photographs using real prognoses. In addition, 95% of the photographs were learned by the modified GoogLeNet. Main outcome measures were prevalence and bias-adjusted Fleiss' kappa (PABAK) of AI staging of the remaining 5% of the photographs.


RESULTS
The PABAK to modified Davis grading was 0.64 (accuracy, 81%; correct answer in 402 of 496 photographs). The PABAK to real prognosis grading was 0.37 (accuracy, 96%).


CONCLUSIONS
We propose a novel AI disease-staging system for grading diabetic retinopathy that involves a retinal area not typically visualized on fundoscopy and another AI that directly suggests treatments and determines prognoses.
Single stage grid connected solar micro-inverter with two level fuzzy logic MPPT controller

This paper presents a single stage grid connected three phase micro inverter for transfer of power from a solar array to grid controlled by a two level fuzzy logic controller. The system utilizes a line commutated inverter, thus the need for synchronization modules are eliminated. A fuzzy logic controller is designed and developed to track the maximum power from the PV panel and generate an appropriate control variable which is compatible for the switching of thyristorised converter. A two level logic is chosen for faster convergence with variable correction steps for the fuzzy logic controller. The maximum power point voltage window is identified from the PV array characteristics and the rule base for the two levels is developed. The system is tested for two array ratings of 5.8 kW and 8.7 kW to bring out the generic nature of the proposed fuzzy controller for power tracking. The micro inverter system is executed in MATLAB/Simulink for varying ambient conditions of the PV panel and the power balance is verified as proof of theory.
Psychometric evaluation of the Serbian version of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31)

PURPOSE
To evaluate the psychometric properties of the Serbian-language version of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31).


METHODS
After undergoing a translation and cultural adaptation of its items in order to create a Serbian-language version of QOLIE-31, we assessed its psychometric properties-reliability, construct validity and criterion validity. The sample consisted of 203 adults with epilepsy. Reliability was tested both by assessing the internal consistency and by the test-retest method. Construct validity was assessed by factor analysis, multitrait-scaling analysis and method of known-groups validation. This was achieved by assessing the relationship between scales and external measures (socio-demographic characteristics, seizure severity and etiology of epilepsy). Criterion validity was assessed by correlation analysis between QOLIE-31 and Short form 36 health survey (SF-36) and Neurotoxicity scale-II.


RESULTS
The domains showed high internal consistency (Cronbach's α 0.94). Test-retest reliability for Overall test score was 0.83 (Pearson's coefficient) indicating temporal stability. Seizure severity and etiology of epilepsy significantly influenced all QOLIE-31 domains except the Medication effect domain, with lowest scores in high seizure severity and symptomatic etiology groups. Employment status significantly influenced Overall quality of life, Emotional well-being, Social function and Overall score. Educational level was related to the Emotional well-being domain, with highest scores for students. The QOLIE-31 was highly positively correlated with SF-36 (rho=0.898) and strongly negatively correlated with Neurotoxicity scale-II (rho=-0.783).


CONCLUSION
Serbian adaptation of the QOLIE-31 questionnaire is reliable and valid for assessing the quality of life in patients with epilepsy.
Use of levonorgestrel intrauterine system for medical indications in adolescents.

The levonorgestrel intrauterine system (LNG-IUS) is an underused contraceptive method in adolescent populations. In addition to being a highly effective, reversible, long-acting contraception, the LNG-IUS has many noncontraceptive health benefits including reduced menstrual bleeding, decreased dysmenorrhea and pelvic pain related to endometriosis, and menstruation suppression in teens with physical or developmental disabilities. The LNG-IUS can also provide endometrial protection in teens with chronic anovulation, and may be used to treat endometrial hyperplasia and cancer. This review examines the evidence supporting the use of the LNG-IUS in adolescents for these noncontraceptive benefits.
Placental cord drainage after vaginal delivery as part of the management of the third stage of labour.

BACKGROUND
Cord drainage in the third stage of labour involves unclamping the previously clamped and divided umbilical cord and allowing the blood from the placenta to drain freely into an appropriate receptacle.


OBJECTIVES
The objective of this review was to assess the specific effects of placental cord drainage on the third stage of labour following vaginal birth, with or without prophylactic use of uterotonics in the management of the third stage of labour.


SEARCH STRATEGY
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (February 2010).


SELECTION CRITERIA
Randomised controlled trials comparing placental cord draining with no placental cord drainage as part of the management of the third stage of labour.


DATA COLLECTION AND ANALYSIS
Two review authors independently assessed the quality of trials and extracted data. This was then verified by the third review author who then entered the agreed outcomes to the review.


MAIN RESULTS
Three studies involving 1257 women met our inclusion criteria. Cord drainage reduced the length of the third stage of labour (mean difference (MD) -2.85 minutes, 95% confidence interval (CI) -4.04 to -1.66; three trials, 1257 women (heterogeneity: T² = 0.87; Chi²P=17.19, I² = 88%)) and reduced the average amount of blood loss (MD -77.00 ml, 95% CI -113.73 to -40.27; one trial, 200 women).No incidence of retained placenta at 30 minutes after birth was observed in the included studies, therefore, it was not possible to compare this outcome. The differences between the cord drainage and the control group were not statistically significant for postpartum haemorrhage or manual removal of the placenta. None of the included studies reported fetomaternal transfusion outcomes and there were no data relating to maternal pain or discomfort during the third stage of labour.


AUTHORS' CONCLUSIONS
There was a small reduction in the length of the third stage of labour and also in the amount of blood loss when cord drainage was applied compared with no cord drainage. The clinical importance of such observed statistically significant reductions, is open to debate. There is no clear difference in the need for manual removal of placenta, blood transfusion or the risk of postpartum haemorrhage. Due to small trials with medium risk of bias, the results should be interpreted with caution.
Dalfampridine in chronic sensorimotor deficits after ischemic stroke: A proof of concept study.

OBJECTIVE
To evaluate the safety and tolerability of dalfampridine extended release (D-ER) in participants with chronic post-ischemic stroke deficits, and to assess for potential drug activity on sensorimotor function.


METHODS
Using a double-blind, placebo-controlled, cross-over design, participants were randomized to placebo/D-ER or D-ER/placebo sequences and given D-ER 10 mg or placebo twice daily. Key inclusion criteria were: ischemic stroke ≥ 6 months, Fugl-Meyer Assessment lower extremity motor score ≤ 28, ability to complete Timed 25-Foot Walk (T25FW). The primary outcome was safety and tolerability. The key exploratory measure was walking speed (T25FW). Other assessments were: Box and Block, and Grip and Pinch tests; Functional Independence Measure. Full-crossover data were analyzed using mixed-effects model.


RESULTS
A total of 83 participants were randomized: 70 completed and 13 discontinued the study. Adverse events were consistent with previous D-ER trials; no new safety signals were observed. Four participants experienced serious adverse events: 3 seizures (1 placebo, 2 D-ER), 1 was secondary to intentional overdose. Most common treatment-emergent adverse events were: dizziness, nausea, arthralgia and fatigue. Mixed-effects analysis showed an effect for D-ER vs. placebo in improving walking speed (0.21 vs. 0.10 ft/s; p = 0.027).


CONCLUSIONS
D-ER was generally well tolerated in participants with chronic stroke deficits. Potential drug activity on lower extremity sensorimotor function, with an improvement in walking speed, was seen.
The english romantic closet: Women theatre artists, Joanna Baillie, and Basil

While revisionist studies of English Romantic drama began to proliferate after 1966,' they nevertheless tended in several directions that reinforced traditional perceptions of the era as antitheatrical and therefore less important to theatre historians: they highlighted the poetic over the performative element (and thus the aesthetic over the historical) in their discussion of closet plays; and they ignored women's contributions to the theatre and dramatic literature of the period. Addressing the former problem, scholars have recently investigated the historical contexts of Romantic drama to show how these plays respond to the era's political, cultural, and theatrical events.8 One of these contexts is the performance history of particular closet plays, a study of which has helped undermine the closet/stage dichotomy used in the past to hinder appreciation of what Marilyn Gaull has called "the apparent necessity of theatrical experience" during the Romantic age (255). Anne K. Mellor's work is indispensable for addressing the second problem, the neglect of women theatre artists. Both. Romanticism and Feminism (1988) and Romanticism and Gender (1993) show how conceptions of the English Romantic period change when its texts are read from feminist perspectives.' The same is true for the period's theatre and drama. Once we begin to look at the issues raised by women associated with early—nineteenth-century London theatre and how their ideas were framed in relation to these writers' gendered position on public and private stages, then other scenes appear that reveal the era's astonishing theatricality. The lens of gender brings into crisp focus the contours of the Romantic stage. For instance, the closet play comes into view as a genre especially well suited for providing women with a forum for dramatic experimentation within the privacy of their homes, just as the late-eighteenth-century private theatrical underscored (and capitalized upon) the theatricality of domestic life by giving women unusually intensive experiences in playwrighting, stage management, and acting/ Read in the
Cross-sectional Analysis of AGE-CML, sRAGE, and esRAGE with Diabetes and Cardiometabolic Risk Factors in a Community-Based Cohort.

BACKGROUND
Advanced glycation end products (AGEs) and their receptors are regarded as central to the development of diabetic complications, but associations with diabetes and cardiometabolic outcomes in previous studies are mixed.


METHODS
Using ELISA assays, we measured N(6)-carboxymethyllysine (AGE-CML), soluble receptor for AGEs (sRAGE), and endogenous secreted receptor for AGEs (esRAGE) in 1874 participants from the Atherosclerosis Risk in Communities study. We conducted a cross-sectional analysis to evaluate associations of these biomarkers with demographics, diabetes, hyperglycemia, cardiometabolic measures, and genetic variants in the gene encoding RAGE, AGER (advanced glycosylation end-product specific receptor).


RESULTS
After adjustment for demographics and body mass index (BMI), there were no significant differences in AGE-CML, sRAGE, or esRAGE by diabetes or hemoglobin A1c. Black race and AGER genetic variants were strongly associated with lower sRAGE and esRAGE even after adjustment [percent difference (95% CI) in black vs whites in sRAGE: -29.17 (-34.86 to -23.48), esRAGE: -26.97 (-33.11 to -20.84); with rs2070600 in sRAGE: -30.13 (-40.98 to -19.29), and esRAGE: -30.32 (-42.42 to -18.21); with rs2071288 in sRAGE: -20.03 (-34.87 to -5.18), and esRAGE: -37.70 (-55.75 to -19.65)]. Estimated glomerular filtration rate and albuminuria significantly correlated with sRAGE and esRAGE. BMI and C-reactive protein significantly negatively correlated with AGE-CML, sRAGE, and esRAGE. AGE-CML was modestly correlated with fructosamine and glycated albumin.


CONCLUSIONS
AGE-CML, sRAGE, and esRAGE were more related to genetic, kidney, and inflammatory measures than to diabetes in this community-based population. Our results suggest that, when measured by ELISA, these biomarkers lack specificity and are of limited value in evaluating the role of these compounds in diabetes.
Learning to generate images with perceptual similarity metrics

Deep networks are increasingly being applied to problems involving image synthesis, e.g., generating images from textual descriptions and reconstructing an input image from a compact representation. Supervised training of image-synthesis networks typically uses a pixel-wise loss (PL) to indicate the mismatch between a generated image and its corresponding target image. We propose instead to use a loss function that is better calibrated to human perceptual judgments of image quality: the multiscale structural-similarity score (MS-SSIM) [1]. Because MS-SSIM is differentiable, it is easily incorporated into gradient-descent learning. We compare the consequences of using MS-SSIM versus PL loss on training autoencoders. Human observers reliably prefer images synthesized by MS-SSIM-optimized models over those synthesized by PL-optimized models, for two distinct PL measures (L1 and L2 distances). We also explore the effect of training objective on image encoding and analyze conditions under which perceptually-optimized representations yield better performance on image classification. Finally, we demonstrate the superiority of perceptually-optimized networks for super-resolution imaging. We argue that significant advances can be made in modeling images through the use of training objectives that are well aligned to characteristics of human perception.
Authentication Techniques in Cloud Computing: A Review

Authentication is an important topic in cloud computing security. That is why various authentication techniques in cloud environment are presented in this paper. This process serves as a protection against different sorts of attacks where the goal is to confirm the identity of a user and the user requests services from cloud servers. Multiple authentication technologies have been put forward so far that confirm user identity before giving the permit to access resources. Each of these technologies (username and password, multi-factor authentication, mobile trusted module, public key infrastructure, single sign-on, and biometric authentication) is at first described in here. The different techniques presented will then be compared. Keywords— Cloud computing, security, authentication, access control,