Safety of Rituximab biosimilar (Riximyo®) following a single switch from the reference product in patients with Non-Hodgkin's lymphoma: a retrospective study.

Unlike small molecule drugs and generic products, the active component of biologics and biosimilars are not identical chemical entities. Despite bioequivalence, there is limited evidence in clinical practice (i.e. Phase IV post-marketing surveillance) regarding the safety of biosimilar rituximab and even less so for "switching therapy" with respect to safety. Drug substitution by switching aims to realise cost savings by changing therapy involving a reference (biologic) product to a biosimilar. A retrospective analysis of safety outcomes including treatment-emergent adverse effects (TEAEs), rates of death and discontinuation of therapy, for all patients that received switching therapy (from reference to biosimilar rituximab, n = 33) was compared to patients who did not did not switch therapy (received biosimilar rituximab only, n = 18) at an Australian metropolitan cancer centre, over a six-month period. There was no statistical significant differences for any safety outcomes examined. Switching therapy for patients receiving rituximab does not lead to poorer safety outcomes.

Safety evaluation of the food enzyme asparaginase from the genetically modified Aspergillus niger strain ASP.

The food enzyme asparaginase (l-asparagine amidohydrolase; EC 3.5.1.1) is produced with the genetically modified Aspergillus niger strain ASP by DSM Food Specialties B.V. The genetic modifications do not give rise to safety concerns. The food enzyme was considered free from viable cells of the production organism and its DNA. The food enzyme is intended to be used in the prevention of acrylamide formation in foods and in the processing of yeast and yeast products. Dietary exposure to the food enzyme-total organic solids (TOS) was estimated to be up to 0.792 mg TOS/kg body weight (bw) per day in European populations. Genotoxicity tests did not indicate a safety concern. The systemic toxicity was assessed by means of a repeated dose 90-day oral toxicity study in rats. The Panel identified a no observed adverse effect level at the highest dose tested of 1038 mg TOS/kg bw per day, which when compared with the estimated dietary exposure, resulted in a margin of exposure of at least 1311. A search for the similarity of the amino acid sequence of the food enzyme to known allergens was made and no match was found. The Panel considered that the risk of allergic reactions upon dietary exposure cannot be excluded, but the likelihood is low. Based on the data provided, the Panel concluded that this food enzyme does not give rise to safety concerns, under the intended conditions of use.

Numerical assessment of induced electric fields in a worker's hand with commonly used metallic implants under exposure to low frequency magnetic fields.

The European Union's Workers' Directive 2013/35/EU on the minimum health and safety requirements regarding the exposure of workers to electromagnetic fields specifies action levels (ALs) for external electric and magnetic fields, which should protect against induced tissue-internal electric field strengthEiabove the exposure limit values, the latter being defined in order to prevent tissue stimulation at low frequencies. However, although 2013/35/EU explicitly calls for the protection of 'workers at particular risk' (including workers with metallic implants), the AL specified in the Directive have been derived under the assumption that there are no metallic parts present inside the body. Therefore, in the present work, we analysed the situation of a worker's hand and forearm bearing metallic implants (Herbert screw and volar radius plate) used for osteosynthesis after the most common bone fractures of the hand/forearm, exposed to low frequency magnetic fields. The uniform exposure of the whole hand and forearm as well as the exposure to a specific and widely used device, a deactivator for single-use labels of acousto-magnetic electronic article surveillance systems, were considered based on numerical computations using a high-resolution anatomical hand and forearm model. The results obtained indicated that the maximum induced electric field strength averaged in a volume of 2 mm × 2 mm × 2 mm cube was higher in the presence of the metallic implants by a factor of up to 4.2 for bone tissue and 2.3 for soft tissue compared with the case without an implant. Hence, it is obvious that the local induced electric field strengths may be substantially increased by the implants. The extent of this increase, however, is highly dependent on the implant's position inside the body, the implant's geometry, and the field distribution and orientation with respect to the anatomical structure and the implant.

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

Evaluation of System Accuracy, Precision, Hematocrit Influence, and User Performance of Two Blood Glucose Monitoring Systems Based on ISO 15197:2013/EN ISO 15197:2015.

INTRODUCTION: Sufficiently high analytical quality of blood glucose monitoring systems (BGMS) is a prerequisite for efficient diabetes therapy. In this study we assessed system accuracy, measurement repeatability, intermediate measurement precision, user performance, and the influence of hematocrit on two CE-marked blood glucose monitoring systems. For one BGMS, measurement accuracy using venous samples was additionally investigated. METHODS: Study procedures were based on the International Organization of Standardization (ISO) 15197:2013/EN ISO 15197:2015 ("ISO 15197"). User performance included data from 100 subjects who used one test strip lot, whereas for all other analyses three different reagent system lots were used. For system accuracy assessment, 100 capillary samples were measured in duplicate with each of three reagent system lots per system, resulting in 600 results per system. RESULTS: CareSens S Fit and CareSens H Beat both fulfilled the ISO 15197 accuracy criteria with 97.5-100% of each test strip lot's results falling within ± 15 mg/dL or ± 15% of the results of the comparison method and 100% of results in consensus error grid (CEG) zone A for all three lots. User performance evaluation revealed sufficient accuracy in the hands of lay users although some handling errors were documented by study staff. Assessment of measurement repeatability and intermediate measurement precision is given by standard deviation (SD) (glucose levels < 100 mg/dL) and by coefficient of variation (CV) (glucose concentrations ≥ 100 mg/dL). SD was ≤ 4.1 mg/dL and CV ≤ 4.2% for measurement repeatability and SD was ≤ 2.2 mg/dL and CV ≤ 2.6% for intermediate measurement precision. In case of hematocrit influence, both BGMS complied with all three tested lots with the defined criteria. CONCLUSION: Both BGMS analyzed in this study fulfilled the required accuracy criteria of ISO 15197. They showed high precision, good performance in the hands of lay users, and the influence of hematocrit was acceptable in the labeled range.

A culpa é de junho de 2013? Os caminhos da alienação política e a ascensão da extrema direita no Brasil / Is June 2013 to blame? The paths of political alienation and the rise of the far right in Brazil / Juin 2013 est-il coupable ? Les chemins de l'aliénation politique et la montée de l'extrême droite au Brésil / ¿Es junio de 2013 el culpable? Los caminos de la alienación política y el ascenso de la extrema derecha en Brasil

Este artigo apresenta as principais causas e o significado das manifestações maciças de junho de 2013 para discutir como a derrota de seu impulso contribuiu para que uma extrema direita formada posteriormente viesse a se apropriar do sentimento de insatisfação com o sistema político, manipulando-o em um sentido regressivo. Como suporte à sua reflexão, o autor recorre às categorias teóricas de alienação política e angústia social em Franz Neumann

This paper discusses the main causes of and meanings attributed to the mass demonstrations of June 2013 in Brazil, arguing that the defeat of the movement's momentum contributed to the later appropriation and regressive manipulation of the political dissatisfaction by the far right. Franz Neumann's theoretical categories of political alienation and social anxiety help to support the reflection

Cet article porte sur les principales causes et les sens apportées aux manifestations massifs du mois juin de 2013 au Brésil, en affirmant que la défaite de leur dynamisme a contribué pour qu'une extrême droite leur ait confisqué le sentiment d'insatisfaction à l'égard du système politique, en le manipulant dans un sens régressif. Pour soutenir sa réflexion, l'auteur recourt aux concepts d'aliénation politique et d'angoisse sociale chez Franz Neumann

Este artículo presenta las principales causas y el significado de las manifestaciones masivas de junio de 2013 en Brasil para discutir cómo la derrota de su impulso contribuyó para que una extrema derecha, que posteriormente se formará, se apropiara del sentimiento de descontento con el sistema político brasileño, manipulándolo en sentido regresivo. Se utiliza como aporte las categorías teóricas de alienación política y angustia social de Franz Neumann

The Effect of Mice Adaptation Process on the Pathogenicity of Influenza A/South Africa/3626/2013 (H1N1)pdm09 Model Strain.

Influenza virus strain A/South Africa/3626/2013 (H1N1)pdm09 (SA-WT) is a non-mouse-adapted model strain that has naturally high pathogenic properties in mice. It has been suggested that the high pathogenicity of this strain for mice could be due to the three strain-specific substitutions in the polymerase complex (Q687R in PB1, N102T in PB2, and E358E/K heterogeneity in PB2). To evaluate the role of these replacements, SA-WT was passaged five times in mouse lungs, and the genome of the mouse-adapted version of the SA-WT strain (SA-M5) was sequenced. SA-M5 lost E358E/K heterogeneity and retained E358, which is the prevalent amino acid at this position among H1N1pdm09 strains. In addition, in the hemagglutinin of SA-M5, two heterogeneous substitutions (G155G/E and S190S/R) were identified. Both viruses, SA-M5 and SA-WT, were compared for their toxicity, ability to replicate, pathogenicity, and immunogenicity in mice. In mice infected with SA-M5 or SA-WT strains, toxicity, virus titer in pulmonary homogenates, and mouse survival did not differ significantly. In contrast, an increase in the immunogenicity of SA-M5 compared to SA-WT was observed. This increase could be due to the substitutions G155G/E and S190S/R in the HA of SA-M5. The prospects for using SA-M5 in studying the immunogenicity mechanisms were also discussed.

Identification and functional characterization of a novel TRPA1 gene from sea cucumber Apostichopus japonicus and interaction with miR-2013 in response to salt stress.

Salinity is important abiotic factor influencing sea cucumber aquaculture. This study aimed to identify and functional study of a novel transient receptor potential cation channel subfamily A member 1 (TRPA1) involved in salinity stress through interaction with miR-2013 in the sea cucumber. The full-length cDNA sequence was 1369 bp in length and encoded 138 amino acids. The TRPA1 homolog protein was a hydrophilic protein without a signal peptide and was predicted to a spatial structure of seven helices and eight random coils and two major ANK functional domains. Bioinformatic analysis and luciferase reporter assays confirmed TRPA1 as a target gene of miR-2013. Quantitative PCR revealed that miR-2013 was induced upregulation after salinity stress, while TRPA1 showed upregulated expression with maximum expression at 24 h. The expression of miR-2013 and TRPA1 was negatively regulated. Transfection experiments were conducted to validate the role of miR-2013 and TRPA1 in salinity response. The results showed that miR-2013 was upregulated and TRPA1 was downregulated after transfection with miR-2013 mimics, while miR-2013 was downregulated and TRPA1 was upregulated after transfection with miR-2013 inhibitor. Transfection with si-TRPA1 homolog resulted in upregulation of miR-2013 and downregulation of TRPA1 homolog. These findings suggest that miR-2013 can regulate the expression of TRPA1 under salt stress, and highlight the importance of miR-2013 and TRPA1 in salt stress response. miR-2013 mimics improved the survival rate, while miR-2013 inhibitor and si-TRPA1 reduced it. These findings suggest that miR-2013 and TRPA1 play important roles in sea cucumbers adaptation to salinity changes.

The Prevalence of Small for Gestational Age and Extrauterine Growth Restriction among Extremely and Very Preterm Neonates, Using Different Growth Curves, and Its Association with Clinical and Nutritional Factors.

Monitoring the growth of neonates in the Neonatal Intensive Care Unit (NICU) using growth charts constitutes an essential part of preterm infant care. Preterm infants are at increased risk for extrauterine growth restriction (EUGR) due to increased energy needs and clinical complications. This retrospective study compares the prevalence of small for gestational age (SGA) at birth and EUGR at discharge in extremely and very preterm neonates hospitalized in the NICU of a tertiary hospital in Greece, using different growth curves, and it examines the associated nutritional and clinical factors. Fenton2013 and INTERGROWTH-21st growth curves were used to calculate z-scores of birth weight (BW) and weight, length, and head circumference at discharge. The study includes 462 newborns with a mean BW of 1341.5 g and mean GA of 29.6 weeks. At birth, 6.3% of neonates were classified as SGA based on Fenton2013 curves compared to 9.3% with INTERGROWTH-21st growth curves. At discharge, 45.9% of neonates were characterized as having EUGR based on the Fenton2013 weight curves and 29.2% were characterized based οn INTERGROWTH-21st curves. Nutritional factors such as the day of initiation, attainment of full enteral feeding, and the duration of parenteral nutrition were associated with EUGR by both curves. The prevalence of SGA and EUGR neonates differs between the two growth references. This shows that further evaluation of these charts is needed to determine the most appropriate way to monitor infant growth.

Improving Drug-Drug Interaction Extraction with Gaussian Noise.

Drug-Drug Interactions (DDIs) produce essential and valuable insights for healthcare professionals, since they provide data on the impact of concurrent administration of medications to patients during therapy. In that sense, some relevant works, related to the DDIExtraction2013 Challenge, are available in the current technical literature. This study aims to improve previous results, using two models, where a Gaussian noise layer is added to achieve better DDI relationship extraction. (1) A Piecewise Convolutional Neural Network (PW-CNN) model is used to capture relationships among pharmacological entities described in biomedical databases. Additionally, the model incorporates multichannel words to enrich a person's vocabulary and reduce unfamiliar words. (2) The model uses the pre-trained BERT language model to classify relationships, while also integrating data from the target entities. After identifying the target entities, the model transfers the relevant information through the pre-trained architecture and integrates the encoded data for both entities. The results of the experiment show an improved performance, with respect to previous models.

Comparison of Diabetes in Pregnancy Study Group India (DIPSI) and WHO criteria for diagnosis of gestational diabetes by assessment of fetomaternal outcomes.

OBJECTIVE: To evaluate fetomaternal outcomes in women who are normoglycemic by Diabetes in Pregnancy Study Group India (DIPSI) but have gestational diabetes mellitus (GDM) by WHO criteria versus those who are normoglycemic by both DIPSI and WHO criteria. METHODS: This was a prospective, cohort study. A total of 635 women participated. They underwent a 2-h non-fasting oral glucose tolerance test (OGTT) and results were interpreted by DIPSI. Out of 635 women, 52 were lost to follow up and 33 were diagnosed as GDM by DIPSI and excluded from the study. The remaining 550 women, after 72 h from the first test, underwent a 75-g fasting-OGTT and results were interpreted using WHO 2013 criteria. Results of the second test were blinded till delivery. The 550 women were followed for fetomaternal outcomes. Participants with normal DIPSI and normal WHO 2013 OGTT were labeled group 1. Participants with normal DIPSI but abnormal WHO 2013 OGTT were labeled group 2. Fetomaternal outcomes were compared between these groups. RESULTS: Occurrence of GDM by DIPSI was 5.1%, by WHO 2013 criteria it was 10.5%. Composite fetomaternal outcomes occurred more commonly in women with a normal DIPSI but an abnormal WHO 2013 test. Out of 550 women, 492 had normal DIPSI and normal WHO 2013 test. Out of this 492, 116 (23.6%) women had adverse fetomaternal outcomes. Fifty-eight women out of 550 had a normal DIPSI but an abnormal WHO 2013 test. Thirty-seven (63.8%) women out of 58 had adverse fetomaternal outcomes. We found statistically significant association between adverse fetomaternal outcome and GDM by WHO 2013 test (with normal DIPSI test). CONCLUSION: WHO 2013 has superior diagnostic value compared with DIPSI criteria for diagnosis of GDM.

Children as participants in health research in South Africa: A response to Labuschaigne, Mahomed and Dhai.

A complex network of ethico-legal rules makes it difficult for health researchers in South Africa to lawfully recruit adolescents to the kinds of sensitive studies where it may be ethically appropriate to proceed without notifying parents or obtaining parental consent. This article responds to a recent proposal to amend the blanket requirement for mandatory parental consent presently contained in section 71 the South African National Health Act 61 of 2003 [NHA]. The proposed amendment is intended to bring the NHA into alignment with South Africa's 2015 Department of Health Guidelines on Ethics in Health Research by permitting greater flexibility for a health research ethics committee to waive parental consent, and permit adolescents to consent independently. A lacuna in this proposal is highlighted with reference to the requirements of South Africa's Protection of Personal Information Act 4 of 2013 [POPIA]: Even if the NHA is amended as proposed, the goal of aligning South African law with prevailing ethics norms in South Africa would not necessarily be attained, as parental consent may still be required by POPIA. This article investigates whether this goal (of aligning the law with ethics) can be attained in a way that is compliant with POPIA. It is concluded that this is indeed possible in a number of ways, and that the best way to attain this goal is by requesting the South African Information Regulator to issue a guidance note to the effect that all health research projects that are approved by institutional health research ethics committees are to be regarded as being in the public interest, which would qualify such health research projects to be exempted from POPIA's consent requirements.

A Cross-Sectional Study Comparing the Efficacy of Various Growth Charts in Evaluating the Incidences of Small for Gestational Age and Large for Gestational Age at Birth Among Liveborn Neonates Delivered at a Tertiary Teaching Hospital.

Background and objective Growth charts are important in monitoring the growth of neonates. The growth of Indian fetuses is understood to be different from the Western population due to multiple factors. In this study, we aimed to analyze the utility of the application of various growth charts in evaluating the birth weights of liveborn neonates at a tertiary teaching hospital. Methodology A total of 729 liveborn neonates between 24 to 42 weeks of gestation delivered at the study institute during the study period were included. Birth weights were plotted on three growth charts - Fenton 2013, INTERGROWTH-21st (IG-21), and Kandraju et al. chart - and classified as small for gestational age (SGA), or appropriate for gestational age (AGA), or large for gestational age (LGA) according to the respective centiles and sex. The incidences of SGA and LGA were calculated with respect to various charts and compared. Statistical analysis was done using the McNemar Chi-square test for paired categorical variables. Cohen's kappa (K) was used to analyze the concordance between the growth charts. A p-value <0.005 was considered statistically significant. Results Among 668 term neonates, the number of neonates classified as SGA was 313 (46.86%), 236 (35.33%), and 219 (32.78%) according to Fenton 2013, IG-21, and Kandraju et al. chart respectively. The difference in incidences of SGA between Fenton 2013 and IG-21 for term neonates was significant (p=0.0001). The difference between incidences of SGA among term neonates according to Fenton 2013 and Kandraju et al. and IG-21 vs. Kandraju et al. was significant (p=0.0001). Among 61 preterm neonates, the number of neonates classified as SGA was 15, 11, and five according to Fenton 2013, IG-21, and Kandraju et al. respectively. There was no statistically significant difference between the three charts. Among 729 neonates, the number of neonates classified as LGA was 10 (1.37%), 22 (3.02%), and 32 (4.39%) according to Fenton 2013, IG-21, and Kandraju, et al. respectively. The difference in incidences of LGA between Fenton 2013 and IG-21 was significant (p=0.0015). The difference in incidences of LGA between Fenton 2013 and Kandraju et al. was significant (p=0.0001). The difference in incidences of LGA between IG-21 and Kandraju et al. was also significant (p=0.0044). Conclusion Fenton 2013, IG-21, and Kandraju et al. growth charts vary significantly in detecting the incidence of SGA and LGA among term neonates. Among term neonates, IG-21 and Kandraju et al. growth charts are comparable in terms of the estimation of SGA. The Fenton 2013 growth chart showed a higher incidence of SGA among term neonates. The incidence of LGA was highest according to Kandraju et al. growth chart and least according to Fenton 2013. Among preterm neonates, the incidence of SGA as per birth weight was comparable across the three growth charts.

Chemical Survey and Risk Assessment of 56 Pesticides in the Sado River Estuary (Iberian Peninsula, Portugal).

The Sado basin (~8000 km2) is an area where intensive agriculture occurs. However, this region still has few data about the water levels of priority pesticides such as fungicides, herbicides, and insecticides. Therefore, water samples were collected every two months at nine sites along the Sado River Estuary and analyzed by GC-MS/MS to determine the influx of pesticides in that ecosystem. More than 87% of the pesticides were quantified, and 42% and 72% were above the maximum totals established by the European Directives 98/83/EC and 2013/39/EU, respectively. Fungicides (91%), herbicides (87%), and insecticides (85%) attained average annual amounts of ≈3.2 µg/L, ≈1.0 µg/L, and ≈12.8 µg/L, respectively. A mathematical approach was used to evaluate the hazard of the pesticide mixture at the maximum concentrations found in this area. The assessment identified invertebrates as the most at-risk trophic level and identified two chemicals (chlorpyriphos and cyfluthrin) as the primary culprits. This assumption was supported by acute in vivo assays using Daphnia magna. These observations, and the high concentrations of phosphates, indicate that the status of the Sado waters poses environmental and potential human health risks.

Expansion of an Australian food composition database to estimate plant and animal intakes.

Despite evidence for favourable health outcomes associated with plant-based diets, a database containing the plant and animal content of all foods eaten is required to undertake a reliable assessment of plant-based diets within a population. This study aimed to expand an existing Australian food database to include the plant and animal content of all whole foods, beverages, multi-ingredient products and mixed dishes. Twenty-three plant- and animal-based food group classifications were first defined. The food servings per 100 g of each product were then systematically calculated using either a recipe-based approach, a food label-based approach, estimates based on similar products or online recipes. Overall, 4687 (83·5 %) foods and beverages were identified as plant or plant-containing products, and 3701 (65·9 %) were animal or animal-containing products. Results highlighted the versatility of plant and animal ingredients as they were found in various foods across many food categories, including savoury and sweet foods, as well as discretionary and core foods. For example, over 97 % of animal fat-containing foods were found in major food groups outside the AUSNUT 2011-2013 'fats and oils' group. Surprisingly, fruits, nuts and seeds were present in a greater percentage of discretionary products than in core foods and beverages. This article describes a systematic approach that is suitable for the development of other novel food databases. This database allows more accurate quantitative estimates of plant and animal intakes, which is significant for future epidemiological and clinical research aiming to investigate plant-based diets and their related health outcomes.

An investigation of luminescence properties of CaF2: Dy nanophosphor irradiated with gamma rays and low energy proton beams.

This paper reports the luminescence properties of nanocrystalline calcium fluoride doped with dysprosium (CaF2: Dy). The nanophosphor has been synthesized by the chemical co-precipitation technique and the dopant concentration has been optimized at 0.3 mol% using thermoluminescence (TL) intensity emitted post 50Gy gamma dose irradiation of samples doped with different dopant concentrations. X-ray diffraction shows the formation of crystalline particles with an average size of 49.233 nm. Photoluminescence (PL) emission spectrum shows the characteristic peaks at 455 nm, 482 nm, 573 nm corresponding to 4I15/2 to 6H15/2, 4F9/2 to 6H15/2 and 4F9/2 to 6H13/2 Dy3+ transitions respectively. PL excitation spectrum shows a peak at 327 nm which corresponds to the Dy3+ transition of 6H15/2 to 4L19/2. Gamma (of 1.25 MeV) and low energy proton beam (of 30 keV) irradiated nanophosphor shows a variation in TL glow curve structure and peak position with an increase in radiation dose/fluence. However, the nanophosphor shows a wide linear dose response for 60Co gamma radiation in the range 10 Gy - 1.5 kGy and for low energy proton beam in the fluence range of 1012-1014 ions/cm2. Srim 2013 has been used to calculate the ion beam parameters including the range of protons in CaF2: Dy 0.3 mol%. The nanophosphor CaF2: Dy could be further investigated as a potential dosimeter for gamma rays and proton beam by studying its TL properties for different energies of these radiations.

A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B.

BACKGROUND & AIMS: Nucleos(t)ide analogues (NUCs) are the standard and mostly lifelong treatment for chronic HBeAg-negative hepatitis B, as functional cure (loss of HBsAg) is rarely achieved. Discontinuation of NUC treatment may lead to functional cure; however, to date, the evidence for this has been based on small or non-randomized clinical trials. The STOP-NUC trial was designed with the aim of increasing the HBsAg loss rate using a NUC treatment interruption approach. METHODS: In this multicenter, randomized-controlled trial, 166 HBeAg-negative patients with chronic hepatitis B on continuous long-term NUC treatment, with HBV DNA <172 IU/ml (1,000 copies/ml) for ≥4 years, were randomized to either stop (Arm A) or continue NUC treatment (Arm B) for a 96-week observation period. In total, 158 patients were available for final analysis, 79 per arm. The primary endpoint was sustained HBsAg loss up to week 96. RESULTS: Our study met its primary objective by demonstrating HBsAg loss in eight patients (10.1%, 95% CI 4.8%-19.5%) in Arm A and in no patient in Arm B (p = 0.006). Among patients with baseline HBsAg levels <1,000 IU/ml, seven (28%) achieved HBsAg loss. In Arm A, re-therapy was initiated in 11 (13.9%) patients, whereas 32 (40.5%) patients achieved sustained remission. A decrease of HBsAg >1 log IU/ml was observed in 16 patients (20.3%) in Arm A and in one patient (1.3%) in Arm B. No serious adverse events related to treatment cessation occurred. CONCLUSIONS: Cessation of NUC treatment was associated with a significantly higher rate of HBsAg loss than continued NUC treatment, which was largely restricted to patients with end of treatment HBsAg levels <1,000 IU/ml. IMPACT AND IMPLICATIONS: As HBeAg-negative patients with chronic hepatitis B on nucleos(t)ide analogues (NUCs) rarely achieve functional cure, treatment is almost always lifelong. The STOP-NUC trial was conducted to investigate whether discontinuing long-term NUC treatment can increase the cure rate. We found that some patients achieved functional cure after stopping NUCs, which was especially pronounced in patients with HBsAg levels <1,000 at the end of NUC treatment, and that many did not need to resume therapy. The results of the Stop-NUC trial provide evidence for the concept of stopping NUC treatment as a therapeutic option that can induce functional cure.

The Open, Randomized, Positive Control Clinical Trial of Guluronic Acid (G2013) on SARS-CoV-2 Patients.

INTRODUCTION: Recently, the coronavirus disease 2019 (COVID-19) infection, with a vast spectrum of clinical and paraclinical symptoms has been a major health concern worldwide. Therapeutical management of COVID-19 includes antiviral and anti-inflammatory drugs. NSAIDs, as the second-line therapy, are often prescribed to relieve the symptoms of COVID-19. The α-L-guluronic acid (G2013) is a non-steroidal patented (PCT/EP2017/067920) agent with immunomodulatory properties. This study investigated the effect of G2013 on the outcome of COVID-19 in moderate to severe patients. METHODS: The disease's symptoms were followed up during hospitalization and for 4 weeks postdischarge in G2013 and control groups. Paraclinical indices were tested at the time of admission and discharge. Statistical analysis was performed on clinical and paraclinical parameters and ICU admission and death rate. RESULTS: The primary and secondary outcomes indicated the efficiency of G2013 on COVID-19 patients' management. There were significant differences in the duration of improvement of fever, coughing, fatigue/malaise. Also, a comparison of paraclinical indices at the time of admission and discharge showed significant change in prothrombin, D-dimer, and platelet. As the main findings of this study, G2013 significantly decreased the percentage of ICU admission (control:17 patients, G2013:1 patient) and death (control: 7 cases, G2013:0). CONCLUSION: These results conclude that G2013 has sufficient potential to be considered for moderate to severe COVID-19 patients, can significantly reduce the clinical and physical complications of this disease, has a positive effect on modulating the coagulopathy process, and aids in saving lives.

Herpes zoster vaccine effectiveness against herpes zoster and postherpetic neuralgia in New Zealand: a retrospective cohort study.

Background: Herpes zoster (HZ) and associated complications cause significant burden to older people. A HZ vaccination programme was introduced in Aotearoa New Zealand in April 2018 with a single dose vaccine for those aged 65 years and a four-year catch up for 66-80 year-olds. This study aimed to assess the 'real-world' effectiveness of the zoster vaccine live (ZVL) against HZ and postherpetic neuralgia (PHN). Methods: We conducted a nationwide retrospective matched cohort study from 1 April 2018 to 1 April 2021 using a linked de-identified patient level Ministry of Health data platform. A Cox proportional hazards model was used to estimate ZVL vaccine effectiveness (VE) against HZ and PHN adjusting for covariates. Multiple outcomes were assessed in the primary (hospitalised HZ and PHN - primary diagnosis) and secondary (hospitalised HZ and PHN: primary and secondary diagnosis, community HZ) analyses. A sub-group analysis was carried out in, adults ≥ 65 years old, immunocompromised adults, Maori, and Pacific populations. Findings: A total of 824,142 (274,272 vaccinated with ZVL matched with 549,870 unvaccinated) New Zealand residents were included in the study. The matched population was 93.4% immunocompetent, 52.2% female, 80.2% European (level 1 ethnic codes), and 64.5% were 65-74 years old (mean age = 71.1±5.0). Vaccinated versus unvaccinated incidence of hospitalised HZ was 0.16 vs. 0.31/1,000 person-years and 0.03 vs. 0.08/1000 person-years for PHN. In the primary analysis, the adjusted overall VE against hospitalised HZ and hospitalised PHN was 57.8% (95% CI: 41.1-69.8) and 73.7% (95% CI:14.0-92.0) respectively. In adults ≥ 65 years old, the VE against hospitalised HZ was 54.4% (95% CI: 36.0-67.5) and VE against hospitalised PHN was 75·5% (95% CI: 19.9-92.5). In the secondary analysis, the VE against community HZ was 30.0% (95% CI: 25.6-34.5). The ZVL VE against hospitalised HZ for immunocompromised adults was 51.1% (95% CI: 23.1-69.5), and PHN hospitalisation was 67.6% (95% CI: 9.3-88.4). The VE against HZ hospitalisation for Maori was 45.2% (95% CI: -23.2-75.6) and for Pacific Peoples was 52.2% (95% CI: -40.6 -83·7). Interpretation: ZVL was associated with a reduction in risk of hospitalisation from HZ and PHN in the New Zealand population. Funding: Wellington Doctoral Scholarship awarded to JFM.

Spatiotemporal bioavailability of PCDD/Fs and dl-PCBs in wild mussels from the Portuguese Atlantic coast.

This study aimed to assess the spatiotemporal bioavailability of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in wild adult mussels, Mytilus galloprovincialis, collected along the Portuguese Atlantic coast between 2009 and 2020. The work is part of a national environmental monitoring program. The purpose was to evaluate the dioxins' temporal trends, the human and ecological risks, and the correlation between mussels' location and the main pollutant sources in Portugal. The levels and congener patterns of the most toxicity-relevant 17 PCDD/Fs and 12 dl-PCBs were determined, with the dl-PCBs dominant. The sum of Σ17PCDD/Fs and Σ12dl-PCBs values ranged from 2.0 to 4.0 ng WHO-TEQ kg-1, (wet weight basis), below the limits established by the European Commission for contamination in fish and fishery products (6.5 ng per kg-1). The study included five years - 2009, 2010, 2016, 2018 and 2020 -, allowing to verify the impact of European Directive 2013/39/UE against the pollution of water in Portugal; it was observed that dioxin levels in mussels diminished over the time. Statistical analysis allowed verification of different spatial trends of dl-PCB profiles along the Portuguese Atlantic coast. The mono-ortho dl-PCB pentachlorinated congener IUPAC #118 prevailed in 2009 and 2018 in all sampling sites, and it was predominant in 2010, 2016 and 2020, followed by the congeners IUPAC #105, #156 and #167. The IUPAC #167, #169 and #123 were the most abundant hexachlorinated congeners, and the IUPAC #77 the most abundant tetrachlorinated congener. This work emphasises the importance of monitoring dioxins and mapping the congeners in Atlantic coastal ecosystems, to contribute to their elimination.