Dose selection and optimization is an important topic in drug development to maximize treatment benefits for all patients. While exposure-response (E-R) analysis is a useful method to inform dose-selection strategy, in oncology, special considerations for prognostic factors are needed due to their potential to confound the E-R analysis for monoclonal antibodies. The current review focuses on three different approaches to mitigate the confounding effects for monoclonal antibodies in oncology: (1) cox-proportional hazards modeling and case-matching, (2) tumor growth inhibition-overall survival (TGI-OS) modeling, and (3) multiple dose level study design. In the presence of confounding effects, studying multiple dose levels may be required to reveal the true E-R relationship. However, it is impractical for pivotal trials in oncology drug development programs. Therefore, the strengths and weaknesses of the other two approaches are considered, and the favorable utility of TGI-OS modeling to address confounding in E-R analyses is described. In the broader scope of oncology drug development, this review discusses the downfall of the current emphasis on E-R analyses using data from single dose level trials, and proposes that development programs be designed to study more dose levels in earlier trials.

Understanding the molecular mechanisms that correlate pathologies with missense mutations is of critical importance for disease risk estimations and for devising personalized therapies. Thus, we have performed a bioinformatic survey of ClinVar, a database of human genomic variations, to find signals that can account for missense mutation pathogenicity. Arginine resulted as the most frequently replaced amino acids both in benign and pathogenic mutations. By adding the structural dimension to this investigation to increase its resolution, we found that arginine mutations occurring at the protein-DNA interface increase pathogenicity 6.5 times with respect to benign variants. Glycine is the second amino acid among all the pathological missense mutations. Necessarily replaced by larger amino acids, glycine replacements perturb the structural stability of proteins and, therefore, their functions, being mostly located in buried protein moieties. Arginine and glycine appear as representative of missense mutations causing respectively changes in interaction processes and in protein structural features, the two main molecular mechanisms of genome-induced pathologies.

The diversity of butterflies is known to some extent in Nepal, but the study of their interactions with nectar plant sources and floral attributes is limited. This study was conducted along the periphery of Rupa Wetland, a Ramsar site, from February to November 2019 to assess butterfly species diversity and to identify the factors influencing their foraging choices at nectar plants. We assessed the number of butterfly species, their abundance, and their floral foraging behavior, from 28 linear transects (500 m long each) placed in a stratified and random manner throughout the study area. Five factors, i.e., category of plant, flower colour, corolla shape, corolla depth, and the proboscis length of butterfly species were taken into account to assess the nectar plant choices of butterfly families. Moreover, species diversity at the family level, and overall, were determined through several indices. When examining overall butterfly diversity and abundance, we recorded a total of 1,535 butterflies belonging to 138 species within six families. For our examination of butterfly-nectar plant observations, we recorded a total of 298 individuals belonging to 31 species of butterfly visiting a total of 28 nectar plant species. Among the recorded butterflies, Zemeros flegyas was found to be the most abundant (92 individuals), while only a single individual each of the species Troides helena, Gandaca herina and Belonois aurota were recorded. Of the 28 nectar host plant species, Biden pilosa was the most popular and was visited by 13 species of butterflies. Overall, total butterfly visitation was found to be significantly influenced by plant category (herbaceous preferred over woody), floral colour (yellow, white, and purple preferred over pink), and corolla shape (tubular preferred over non-tubular). Moreover, there was a significant positive correlation (r = 0.466) between the proboscis length of butterflies and the corolla tube length of flowers (p<0.001).

The purplish bifurcate mussel Mytilisepta virgata is widely distributed and represents one of the major components of the intertidal community in the northwestern Pacific (NWP). Here, we characterized population genetic structure of NWP populations throughout their whole distribution range using both mitochondrial (mtDNA cox1) and nuclear (ITS1) markers. Population genetic analyses for mtDNA cox 1 sequences revealed two monophyletic lineages (i.e., southern and northern lineages) geographically distributed according to the two different surface water temperature zones in the NWP. The timing of the lineage split is estimated at the Pliocene- mid-Pleistocene (5.49-1.61 Mya), which is consistent with the timing of the historical isolation of the East Sea/Sea of Japan from the South and East China Seas caused by sea level decline during glacial cycles. Historical sea level fluctuation during the Pliocene-Pleistocene and subsequent adaptation of mussels to different surface water temperature zones may have contributed to shaping the contemporary genetic diversity and deep divergence of the two mitochondrial lineages. Unlike mtDNA sequences, a clear lineage splitting between the two mitochondrial lineages was not found in ITS1 sequences, showing a star-like structure that is composed of a mixture of southern and northern mitochondrial lineages. Possible scenarios are proposed to explain this type of mito-nuclear discordance: stochastic divergence in the coalescent processes of the two molecular markers, or balancing selection under different marine environments. Future work is required to address whether the thermal physiology of these mussels correlates with the deep divergence of their mitochondrial genes.

Introduction: Programmed death 1 (PD-1) is a co-receptor which is located at the surface of cells like natural killer, monocytes, T and B cells. It has two ligands including programmed death ligand-1 (PD-L1) and ligand-2 (PD-L2). T cell functions are inhibited by activation of PD-1/PD-L1 pathway and this pathway is used by viruses and some tumor cells in order to escape from immune eradication. In our study we evaluated PD-L1 expression in the tissue specimens of patients with Wilms tumor, neuroblastoma and other renal tumors. Material and Methods: Totally 60 patients who were followed up at Gazi University Hospital with the diagnosis of neuroblastoma, Wilms tumor and other renal tumors were included. PD-L1 expression was examined in tumor samples of the patients. Results: Positive staining with PD-L1 was detected only in two male patients. Both of them had neuroblastoma and advanced stage disease. None of the patients with Wilms tumor and other renal tumors had positive PD-L1 staining. Conclusion: Unlike adult tumors; PD-L1 expression is not common in childhood tumors due to differences in immune system between children and adults. Further studies are needed to establish the importance and effects of PD-1/PD-L1 pathway in pediatric tumors.

Background: To assess how genomic information of the general population reflects probabilities of developing diseases and the differences in those probabilities among ethnic groups, a general population database was analyzed with an example of congenital hypothyroidism. Methods: Ten candidate genes that follow an autosomal recessive inheritance pattern in congenital hypothyroidism (SLC5A5, TPO, TG, IYD, DUOXA2, DUOX2, TSHR, TSHB, TRHR, FOXE1) in the gnomAD database (v2.1.1) were analyzed. The carrier frequency (CF) and predicted genetic prevalence (pGP) were estimated. Results: The total CF in the overall population was 2.9%. DUOX2 showed the highest CF (1.46%), followed by TG (0.47%), TPO (0.42%), TSHR (0.16%), DUOXA2 (0.15%), IYD (0.08%), TRHR (0.07%), SLC5A5 (0.07%), TSHB (0.04%), and FOXE1 (0%). The pGP in the overall population was 6.57 individuals per 100.000 births (1:15,216). The highest pGP was in the East Asian group at 44.65 per 100,000 births (1:2,240), followed by Finnish (14.21), other (5.99), Non-Finnish European (5.96), African (3.80), South Asian (3.07), Latino (2.99), and Ashkenazi Jewish (1.52) groups. Conclusion: The feasibility of genetic screening for congenital hypothyroidism may be determined by ethnicity. Comparing the pGP with the real prevalence of congenital hypothyroidism indicates that genetic screening in East Asian may be feasible.

Background: Febrile neutropenia (FN) is a frequent complication of chemotherapy treatment in children with oncological diseases. It can cause serious complications due to infections (SIC), such as severe sepsis and septic shock. In order to identify the predictors of severity for diminished survival in these patients, it is important to have a better treatment strategy, so as to reduce the rate of mortality. Procedure: Retrospective, descriptive and analytical study conducted through a review of medical records of cancer patients from 0 to 18 years old with FN episodes admitted to the Pediatric Intensive Care Unit in Brazil, from June/2013 to January/2018. Epidemiological, clinical and laboratory variables were analyzed for survival outcome. The rates of severe sepsis, septic shock, and mortality were also investigated. Results: Data from 140 FN episodes were analyzed. Most of the children had hematological diseases (80.8%), the average age was 8.5 years old, and the main microorganisms identified in cultures were Gram negative bacteria. The predictors of severity for diminished survival utilizing multivariate analyses were hematological neoplasms in relapse, abnormal capillary filling, and a serum calcium value <7 mg/dL. The rate of severe sepsis was 38.57%, the rate of septic shock was 37.85%, and the rate of mortality was 25.71%. Conclusion: Predictors of severity for diminished survival were hematological neoplasms in relapse, abnormal capillary filling time, and a serum calcium value lower than 7 mg/dL. The rate of severe sepsis was 38.57%, the rate of septic shock was 37.85%, and the rate of mortality was 25.71%.

Background: Coronavirus disease-2019 (COVID-19) could be associated with morbidity and mortality in immunocompromised children. Objective: To measure the frequency of SARS-COV-2 infection among hospitalized children with cancer and detect the associated clinical manifestations and outcomes. Methodology: A prospective non-interventional study including all hospitalized children with cancer conducted between mid-April and mid-June 2020 in Ain Shams University hospital, Egypt. Clinical, laboratory and radiological data were collected. SARS-CoV2 infection was diagnosed by RT-PCR tests in nasopharyngeal swabs. Results: Fifteen of 61 hospitalized children with cancer were diagnosed with SARS-COV-2. Their mean age was 8.3±3.5 years. Initially, 10(66.7%) were asymptomatic and 5(33.3%) were symptomatic with fever and/or cough. Baseline laboratory tests other than SARS-COV-2 RT-PCR were not diagnostic; the mean absolute lymphocyte count was 8.7±2.4 x109/L, C-reactive protein was mildly elevated in most of patients. Imaging was performed in 10(66.7%) patients with significant radiological findings detected in 4(40%) patients. Treatment was mainly supportive with antibiotics as per the febrile neutropenia protocol and local Children Hospital guidance for management of COVID-19 in children. Conclusion: Pediatric cancer patients with COVID-19 were mainly asymptomatic or with mild symptoms. A high index of suspicion and regular screening with nasopharyngeal swab in asymptomatic hospitalized cancer patients is recommended. 

Photovoltaic properties of the natural dyes of chlorophylls consist of Chl a, Chl b, Chl c2, Chl d, Phe a, Phe y and Mg-Phe a, were studied in the gas phases and water. The extension of the π-conjugated system, the substitution of the central Mg2+ and proper functional groups in the chlorophyll structures can amplify the charge transfer and photovoltaic performance. Chl a shows more favorable dynamics of charge transfer than other studied chlorophylls. Chl d, Phe a, Phe y and Mg-Phe a, have a greater rate of the exciton dissociation in comparison with Chl a, Chl b, and Chl c2 originated from a lower electronic chemical hardness, a lower exciton binding energy, and a bigger electron-hole radius. As a result, better efficiencies of the light-harvesting and energy conversion of the chlorophylls mainly appear in the Soret band. The LHE values of the chlorophylls in water show that solvent favorably affects the ability of light-harvesting of the photosensitizers. Finally, based on the energy conversion efficiency, Chl a, Phe a, and Mg-Phe a, are proposed as the best candidates for using in the dye-sensitized solar cells.

Hypoplastic left heart syndrome is a fatal congenital complex heart defect where the left side of the heart is critically undeveloped. HLHS with complex partial monosomy and partial trisomy are rare conditions that have not reported to occur together.

An 87-year-old male with expressive aphasia, weakness in the right upper extremity, and inability to write as normal. Carotid Doppler suggested a high-grade lesion of left common Carotid Artery that was confirmed by Carotid angiogram.

Cytomegalovirus (CMV) infection exists in 50-80% of the world’s population in clinically undetected form due to their immunocompetent status. Here we report a case of a 42-year-old COVID-19 patient with no past medical history, who received tocilizumab, which led to a massive lower gastrointestinal bleeding not responded to medical management.

Childhood rashes or exanthemas are common and are usually relatively benign. There are many causes of rash in children, including mainly viruses, and less often bacterial toxins, drugs, allergens, and other diseases. Viral exanthema often appears while children are taking a medication in the course of a viral infection; it can mimic drug exanthema, and is perceived as a drug allergy in 10% of cases. The drugs most commonly implicated are beta-lactams (BL) and nonsteroidal anti-inflammatory drugs (NSAIDs). Viruses, commonly Epstein Barr virus (EBV), human herpesvirus 6 (HHV6) and cytomegalovirus (CMV), and the bacterium Mycoplasma pneumoniae, may cause exanthema either from the infection itself (active or latent) or because of interaction with drugs that are taken simultaneously. Determination of the exact diagnosis requires a careful clinical history and thorough physical examination. Haematological and biochemical investigations and histology are not always helpful in differentiating between the two types of exanthema. Serology or polymerase chain reaction (PCR) can be helpful, although a concomitant acute infection does not exclude drug hypersensitivity. A drug provocation test (DPT), although considered the gold standard for the diagnosis, is not preferred by the patients. Skin tests are not well tolerated, and in vitro tests, such as the basophil activation test and lymphocyte transformation, are of low sensitivity and specificity and their relevance is debatable. Based on current evidence, we propose a systematic clinical approach for timely differential diagnosis and management of rashes in children who present a cutaneous eruption while receiving a drug.

Patient in sinus rhythm with dilated cardiomyopathy and low ejection fraction < 35% have a 4% risk of embolic event (1). This is a soft indication for therapeutic anti-coagulation(controversial) (2). Presence of excess Intra-cardiac Smoke-like Echoes increase risk of embolic event and switch the soft indication to strong one

Benchmarking the performance of generative methods for drug design is complex and multifaceted. In this report, we propose a separation of concerns for de novo drug design, categorizing the task into three main categories: generation, discrimination, and exploration. We demonstrate that changes to any of these three concerns impacts benchmark performance for drug design taks. In this report we present Deriver, an open-source Python package that acts as a modular framework for molecule generation, with a focus on integrating multiple generative methods. Using Deriver, we demonstrate that changing parameters related to each of these three concerns impacts chemical space traversal significantly, and that the freedom to independently adjust each is critical to real-world applications having conflicting priorities. We find that combining multiple generative methods can improve optimization of molecular properties, and lower the chance of becoming trapped in local minima. Additionally, filtering molecules for drug-likeness (based on physicochemical properties and SMARTS pattern matching) before they are scored can hinder exploration, but can improve the quality of the final molecules. Finally, we demonstrate that any given task has an exploration algorithm best suited to it, though in practice linear probabilistic sampling generally results in the best outcomes, when compared to Monte Carlo sampling or greedy sampling. We intend that Deriver, which is being made freely available, will be helpful to others interested in collaboratively improving existing methods in de novo drug design centered around inheritance of molecular structure, modularity, extensibility, and separation of concerns.

Abstract Background: Contact-force sensing catheters are widely used in catheter ablation. The technique of high-power ablation has gained a growing attention in recent years. Our purpose of this meta-analysis is to compare the efficacy and safety between higher-power and conventional power ablation of atrial fibrillation (AF) by contact-force sensing catheters. Methods: We identified studies through searching MEDLINE, EMBASE, the Web of Science, Scopus and the Cochrane Library from inception up until July 2020. The primary outcomes were the recurrence of atrial tachyarrhythmia and complications. The secondary outcomes were acute reconnections of pulmonary veins(PVs), ablation time, and the total procedural time. Results: We identified four nonrandomized, observational studies (nROS) involving 231 patients with high-power ablation and 239 patients with conventional power ablation. There were insignificant differences in the recurrence rate of atrial tachyarrhythmia (14.2% versus 20.5%, OR: 0.64, 95%CI: 0.39 to 1.04, Z = 1.82, P = 0.07) and clinical complications (1.7% versus 2.5%, OR: 0.72, 95%CI: 0.21 to 2.47, Z = 0.51, P = 0.61) between high-power versus conventional power ablation. The high-power group was fewer in acute PVs reconnections (P = 0.0001) , shorter in ablation time (P < 0.0001) , and the total procedural time (P < 0.0001) compared with conventional power group. Conclusion: High-power ablation of AF was safe and efficient compared with that of conventional power ablation, and reduced ablation time and the total procedural time.

The impact of the COVID-19 outbreak had devastating consequences globally with 20,675,770 affected and 749,061 dead. Despite different measures to restrict transmission, the death toll continues to rise. The SAARC group of countries comprising eight nations—Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka, where 23.75% of the world population reside, implemented containment measures at different stages of the outbreak with varying consequences. In this review, we examined the onset and transmission of the virus in each country at an early stage and critically appraised their response with respect to their medical facilities for diagnosis and management. We found that countries that succeeded to contain the spread of COVID-19 were able to do so by prioritizing non-pharmaceutical interventions (e.g. early and stricter lockdowns). Currently, the epicentre of COVID-19 appears to be shifting to India (the largest SAARC nation), the death toll is likely to steeply increase if effective and aggressive measures are not taken urgently. The authors believe that authorities of each of the SAARC countries should act decisively and cooperatively as a matter of urgency increasing the regional collaboration in an eloquent and durative way.

Type B Aortic Dissection (TBAD) occurs seldomly in pregnancy, but has disastrous consequences for both mother and fetus. The focus of immediate surgical repair of Type A Aortic Dissection due to higher mortality of patients is less clear in its counterpart, TBAD, in which management is controversial and debated. Risk factors for TBAD include: aortic wall stress due to hypertension, previous cardiac surgery, structural abnormalities (bicuspid aortic valve, aortic coarctation), and connective tissue disorders. In pregnancy, pre-eclampsia is a cause of increased aortic wall stress. Management of this condition is often conservative, but this is dependent on a number of factors, including gestation, cardiovascular stability of the patient, and symptomology. In most cases, a Caesarean section prior to intervention is carried out, unless certain indications are present. Due to a scarce number of cases across decades, it is difficult to determine which management is optimal. This article collates knowledge so far on this rare event during pregnancy.

Vegetarianism and veganism are increasingly popular. However, veganism risks development of vitamin B12 deficiency as it is not available from plant sources. Moreover, its impact may be slow to be detected because body stores of vitamin B12 can last years. There is currently no UK guidance on antenatal diagnosis and management of vitamin B12 deficiency. This paper reviews the metabolism, diagnosis and treatment of vitamin B12 in pregnancy. It concludes that prophylactic vitamin B12 supplementation should be given to high risk groups around the time of pregnancy.

The mechanisms of ruthenium-catalyzed synthesis of pyrrole from C4-olefinated isoxazole were investigated by employing the density functional theory (DFT) calculations. Three main steps are included in this reaction: N−O cleavage, 1,5-cyclization, and H-transfer steps. The H-transfer is calculated to be the rate-determining step. The role of Cu(OAc)2 employed in this reaction is to supply HOAc molecule to facilitate the H-transfer step.

Background: Risk factors for hepatitis C complication including diabetes and hypertension have seen in a many previous studies. This made the need for prompted interest in prevention through the identifying individuals at risk for these risk factors and increased investment in screening by pharmacist. Objectives: The aim of this study is to screen for several risk factors include (age, sex, BMI, Hypertension, diabetes and obesity) in HCV positive (1959) Egyptian patients. Setting: Prospective cross sectional study from September 2018 to February 2019. A total of 1959 medical records were collected. By comparing the patient characteristics, variables related to metabolic risk and body composition measured. Regression models were built to adjust for possible confounding factors. Results: The positive HCV antibody prevalence rate was 41.0 % in men and 59.0 % in women. The variables included in regression analysis are age, BMI, uncontrolled HTN were statistically significant (P < 0.001) with DM in HCV positive cases. HCV Patients with high BMI with age ≥40 (years) associated significantly with diabetes and HTN (p<0.001). Hypertensive HCV Egyptian patients were significantly associated with sex, age >40 and DM (p< 0.001). Conclusion HCV infection and metabolic disorders spin in a closed cycle relationship. Reducing the complications of DM has a promising future of limiting the complications of HCV.

CONSTANS-LIKE (COL) family members are commonly implicated in light signal transduction during early photomorphogenesis. However, some of their functions remain unclear. Here, we propose a role for COL13 in hypocotyl elongation in Arabidopsis thaliana. We found that COL13 RNA accumulates at high levels in hypocotyls and that a disruption in the COL13 function via a T-DNA insertion or RNAi led to the formation of longer hypocotyls of Arabidopsis seedlings under red light. On the contrary, overexpression of COL13 resulted in the formation of shorter hypocotyls. Using various genetic, genomic, and biochemical assays, we proved that another COL protein, COL3, directly binds to the promoter of COL13, and the promoter region of COL3 was targeted by the transcription factor LONG HYPOCOTYL 5 (HY5), to form an HY5-COL3-COL13 regulatory chain for regulating hypocotyl elongation under red light. Additionally, further study demonstrated that COL13 interacts with COL3, and COL13 promotes the interaction between COL3 and CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), suggesting a possible COP1-dependent COL3-COL13 feedback pathway. Our results provide new information regarding the gene network in mediating hypocotyl elongation.

A document by Oluwafunmibi Anjorin. Click on the document to view its contents.

Aim: To evaluate current fluconazole dosing regimens against established pharmacodynamic targets in critically ill adults. Methods: Data from critically ill adults treated with fluconazole (n=30) were used to develop a population pharmacokinetic model. Probability of target attainment (PTA) (fAUC24/MIC >100) was determined from simulations for four previously proposed dosing regimens; (i) 400 mg once daily (ii) a 800 mg loading dose followed by 400 mg once daily, (iii) 400 mg twice daily and (iv) a 12 mg/kg loading dose followed by 6 mg/kg once daily. The effect of body weight (40, 70, 120 kg) and renal function (continuous renal replacement therapy (CRRT), 20, 60, 120, 180 mL/min glomerular filtration rates) on PTA was assessed. Results: Early (0-48 h) fluconazole target attainment for patients with Minimum Inhibitory Concentrations (MIC) of 2 mg/L was highly variable. PTA was highest with an 800 mg loading dose for underweight (40 kg) patients and with a 12 mg/kg loading dose for the remainder. End-of-treatment PTA was highest with 400 mg twice daily maintenance dosing for patients who were under- or normal- weight and 6 mg/kg maintenance dosing for overweight (120 kg) patients. None of the fluconazole regimens reliably attained early targets for MICs of ≥4 mg/L. Conclusion: Current fluconazole dosing regimens do not achieve adequate early target attainment in critically ill adults, particularly in those who are overweight, have higher renal function or are undergoing CRRT. Current fluconazole dosing strategies are generally inadequate to treat organisms with an MIC of ≥4 mg/L.