Responsive Sensory Evaluation to Develop Flexible Taste-Masked Paediatric Primaquine Tablets against Malaria for Low-Resource Settings

Primaquine is an important antimalarial drug for malaria transmission blocking and radical cure, but it is not currently available in child-friendly formulations in appropriate doses. Adult-strength tablets are often crushed and dissolved in water to obtain the required dose, which exposes the drug’s bitter taste. As part of the developing paediatric primaquine (DPP) project, this study adopted a responsive sensory pharmaceutics approach by integrating real-time formulation development and pre-clinical taste assessment to develop palatable, flavour-infused primaquine tablets. A design of experiment (DoE) approach was used to screen different taste-masking agents and excipient blends with trained, expert sensory assessors, with quinine hydrochloride as a model bitter tastant. The taste-masking efficacy of selected prototype formulation blends was validated with naïve assessors using the highest 15 mg primaquine dose. The mean bitterness intensity rating, measured on a discrete 11-point scale, was halved from 7.04 for the unflavoured control to 2.74–3.70 for the formulation blends. Sucralose had the biggest impact on bitterness suppression and improving palatability. Two different flavouring systems have been developed, and their acceptability in paediatric patients will be assessed as part of upcoming validation field clinical trials in Africa

MMSE is an independent prognostic factor for survival in primary central nervous system lymphoma

Introduction: To assess the value of the Mini-Mental State Examination (MMSE)-score at baseline in predicting survival in adult primary central nervous system lymphoma (PCNSL) patients. Methods: In the HOVON 105/ ALLG NHL 24 phase III study patients with newly-diagnosed PCNSL were randomized between high-dose methotrexate-based chemotherapy with or without rituximab. Data on potential (MMSE-score), and known baseline prognostic factors (age, performance status, serum LDH, cerebrospinal fluid total protein, involvement of deep brain structures, multiple cerebral lesions, and the IELSG-score) were collected prospectively. Multivariable stepwise Cox regression analyses were used to assess the prognostic value of all factors on progression-free survival (PFS) and overall survival (OS) among patients with available MMSE score at baseline. Age was analyzed as continuous variable, the MMSE-score both as a continuous and as a categorical variable. Results: In univariable analysis, age, MMSE-score and whether the patient received rituximab were statistically significantly prognostic factors for PFS. Age and MMSE-score were statistically significantly associated with OS. In a multivariable analysis of the univariately significant factors only MMSE-score was independently associated with the survival endpoints, as a continuous variable (HR for PFS 1.04, 95% CI 1.01–1.08; OS 1.06 (95% CI 1.02–1.10) and as categorical variable HR (< 27 versus ≥ 27 for PFS 1.55 (1.02–2.35); OS 1.68 (1.05–2.70). In our population, performance status, serum LDH, and CSF protein level were not of prognostic value. Conclusion: Neurocognitive disturbances, measured with the MMSE at baseline, are an unfavorable prognostic factor for both PFS and OS in adult PCNSL patients up to 70 years-old

Neurocognitive functioning and radiologic changes in primary CNS lymphoma patients:results from the HOVON 105/ALLG NHL 24 randomized controlled trial

BACKGROUND: To analyze the effect of treatment on neurocognitive functioning and the association of neurocognition with radiological abnormalities in primary central nervous system lymphoma (PCNSL). METHODS: One hundred and ninety-nine patients from a phase III trial (HOVON 105/ALLG NHL 24), randomized to standard chemotherapy with or without rituximab, followed in patients ≤60 years old by 30-Gy whole-brain radiotherapy (WBRT), were asked to participate in a neuropsychological evaluation before and during treatment, and up to 2 years posttreatment. Scores were transformed into a standardized z-score; clinically relevant changes were defined as a change in z-score of ≥1 SD. The effect of WBRT was analyzed in irradiated patients. All MRIs were centrally assessed for white matter abnormalities and cerebral atrophy, and their relation with neurocognitive scores over time in each domain was calculated. RESULTS: 125/199 patients consented to neurocognitive evaluation. Statistically significant improvements in neurocognition were seen in all domains. A clinically relevant improvement was seen only in the motor speed domain, without differences between the arms. In the follow-up of irradiated patients (n = 43), no change was observed in any domain score, compared to after WBRT. Small but significant inverse correlations were found between neurocognitive scores over time and changes in white matter abnormalities (regression coefficients: −0.048 to −0.347) and cerebral atrophy (−0.212 to −1.774). CONCLUSIONS: Addition of rituximab to standard treatment in PCNSL patients did not impact neurocognitive functioning up to 2 years posttreatment, nor did treatment with 30-Gy WBRT in patients ≤60 years old. Increased white matter abnormalities and brain atrophy showed weak associations with neurocognition

Exposure assessment of radon in the drinking water supplies: a descriptive study in Palestine

<p>Abstract</p> <p>Background</p> <p>Radon gas is considered as a main risk factor for lung cancer and found naturally in rock, soil, and water. The objective of this study was to determine the radon level in the drinking water sources in Nablus city in order to set up a sound policy on water management in Palestine.</p> <p>Methods</p> <p>This was a descriptive study carried out in two phases with a random sampling technique in the second phase. Primarily, samples were taken from 4 wells and 5 springs that supplied Nablus city residents. For each source, 3 samples were taken and each was analyzed in 4 cycles by RAD 7 device manufactured by Durridge Company. Secondly, from the seven regions of the Nablus city, three samples were taken from the residential tap water of each region. Regarding the old city, ten samples were taken. Finally, the mean radon concentration value for each source was calculated.</p> <p>Results</p> <p>The mean (range) concentration of radon in the main sources were 6.9 (1.5-23.4) Becquerel/liter (Bq/L). Separately, springs and wells' means were 4.6 Bq/L and 9.5 Bq/L; respectively. For the residential tap water in the 7 regions, the results of the mean (range) concentration values were found to be 1.0 (0.9-1.3) Bq/L. For the old city, the mean (range) concentration values were 2.3 (0.9-3.9) Bq/L.</p> <p>Conclusions</p> <p>Except for Al-Badan well, radon concentrations in the wells and springs were below the United State Environmental Protection Agency maximum contaminated level (U.S EPA MCL). The level was much lower for tap water. Although the concentration of radon in the tap water of old city were below the MCL, it was higher than other regions in the city. Preventive measures and population awareness on radon's exposure are recommended.</p

Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients

Background: The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL in patients in a large randomised trial. Patients and methods: Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomly assigned to receive standard chemotherapy with or without rituximab and followed by 30 Gy whole brain radiotherapy (WBRT) in patients ≤60 years, completed the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 24 months of follow-up or progression. Differences between treatment arms over time in global health status, role functioning, social functioning, fatigue, and motor dysfunction were assessed. Differences ≥10 points were deemed clinically relevant. The effect of WBRT on HRQoL was analysed in irradiated patients. Results: A total of 160/175 patients eligible for the HRQoL study completed at least one questionnaire and were included. Over time, scores improved statistically significantly and were clinically relevant in both arms. Between arms, there were no differences on any scale (range: −3.8 to +4.0). Scores on all scales were improved to a clinically relevant extent at 12 and 24 months compared with baseline in both arms, except for fatigue and motor dysfunction at 12 months (−7.4 and −8.8, respectively). In irradiated patients (n = 59), scores in all preselected scales, except motor dysfunction, remained stable up to 24 months compared with shortly after WBRT, overall mean difference ranging between 0.02 and 4.570. Conclusion: Compared with baseline, treatment resulted in improved HRQoL scores. The addition of rituximab to standard chemotherapy did not impac

Carbon monoxide and respiratory symptoms in young adult passive smokers: A pilot study comparing waterpipe to cigarette

Objectives: Studies have correlated second hand smoke (SHS) with many diseases, especially respiratory effects. The goal of this study was to measure the impact of SHS on the respiratory symptoms and exhaled carbon monoxide. Material and Methods: The study population consisted of 50 young workers in restaurants serving waterpipes, 48 university students who sit frequently in the university cafeteria where cigarette smoking is allowed and 49 university students spending time in places where smoking is not allowed. Subjects completed questionnaires on socio-demographic characteristics, respiratory symptoms and exposure to SHS. Exhaled carbon monoxide levels were measured. ANOVA and Chi-square tests were used when applicable as well as linear and logistic regression analysis. Results: Exposure to cigarette smoke in university (adjusted odds ratio (ORa) = 6.06) and occupational exposure to waterpipe smoke (ORa = 7.08) were predictors of chronic cough. Being married (ORa = 6.40), living near a heavy traffic road (ORa = 9.49) or near a local power generator (ORa = 7.54) appeared responsible for chronic sputum production. Moreover, predictors of chronic allergies were: being male (ORa = 7.81), living near a local power generator (ORa = 5.52) and having a family history of chronic respiratory diseases (ORa = 17.01). Carbon monoxide levels were augmented by the number of weekly hours of occupational exposure to waterpipe smoke (β = 1.46) and the number of daily hours of exposure to cigarette smoke (β = 1.14). Conclusions: In summary, young non-smoker subjects demonstrated more chronic cough and elevated carbon monoxide levels when exposed to SHS while the effect of waterpipe was even more evident

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Banking and Leverage: Toward a Model of Financial Stability

This paper presents a theoretical model of bank leveraging based on Stein (2011, 2012) and Brunnermeier and Sannikov (2014). The paper offers an analytical review of the literature on bank leveraging and focuses on the adverse effects of excessive leverage and the vulnerabilities and credit contractions that can subsequently occur. Moreover, this paper solves the optimal control problem of the model with a finite time decision horizon to present an analysis of the dynamics of net worth and optimal or sustainable leverage, including a discussion of periods of high and low interest rates. The study shows that overleveraging and optimal debt move in opposite directions. Furthermore, a literature review on bank leverage and monetary policy is presented followed by an analysis of the link between credit growth, GDP growth, and overleveraging in five countries. The findings show that periods of low credit growth are accompanied by periods of low GDP growth because constrained credit limits investments as well as consumption in many cases

Variational methods : Applications to image analysis and to Frenkel-Kontorova model

Cette thèse est décomposée en deux parties. La première est consacrée à l'étude de la restauration d'image et la seconde partie est consacrée à l'étude d'un modèle de Frenkel-Kontorova par des méthodes issues du calcul variationnel et des équations aux dérivées partielles. Au chapitre 1, nous présentons les questions essentielles que nous traiterons dans cette thèse, puis on fait des rappels sur les définitions et quelques propriétés d'espace des fonctions à variations bornées BV , l'espace d'Orlicz et le modèle de Frenkel-Kontorova. Au chapitre 2, nous montrons que les problèmes de minimisation non convexe (restauration d'image) contenant des termes de régularisation sous-linéaires sont mal posés. Au chapitre 3, nous étudions un modèle de restauration avec un terme de régularisation à croissance non standard, proposé par Blomgren et al. : le module du gradient est élevé a une puissance qui dépend elle même du gradient. On montre qu'elle est semi-continue inférieurement pour la topologie faible d'un certain espace d'Orlicz-Sobolev qui lui est associé, ce qui permet un résultat d'existence de la solution. Au chapitre 4, nous étudions un modèle de Frenkel-Kontorova, dont on montre l'existence d'au moins une solution de type travelling wave, u.This thesis is divided into two parts. The first is devoted to the study of image restorationand the second part is devoted to the study of a Frenkel-Kontorova model using methodsfrom the calculus of variations and partial differential equations. In chapter 1, we presentthe key issues we will discuss in this thesis, and recal the denitions and some properties ofspaces of functions of bounded variations BV , Orlicz Sobolev spaces and Frenkel-Kontorovamodel results on image analysis. In chapter 2, we show that the non-convex minimizationproblems (restoration image) involving sublinear regularizing terms are ill-posed. In chapter3, we study a model of restoration with nonstandard increasing regularizing terms,proposedby Blomgren. We show that is lower semi-continuous in the weak topologie of some Sobolev-Orlicz space associated with it, which allows existence result of the solution. In Chaptre 4, we study a Frenkel-Kontorova model, that we show existence of at least a traveling wave type solution, u