Mental health services in Gauteng, South Africa: A proxy evaluation using pharmaceutical data

Background: South African legislation advocates for equitable access to mental healthcare services integrated into general healthcare settings. Mental, neurological, and substance use (MNS) disorders are often comorbid. Pharmacoepidemiology provides indirect evidence of service provision for conditions amenable to medicine treatment. Aim: The study aims to evaluate medicine procurement for MNS disorders at different service levels in the health system. Setting: The Public health sector, Gauteng province formed the setting for the study. Method: A secondary analysis of the Gauteng pharmaceutical database was conducted using Anatomic Therapeutic Chemical (ATC) and defined daily dose (DDD) methodology. Anatomic Therapeutic Chemical classes of medicines for MNS disorders were included. Defined daily doses and costs were calculated per 1000 population served by each facility and service level. Statistical comparisons were made using chi-square testing. Results: General healthcare settings accounted for 90% (R118 638 248) and specialised hospitals for 10% (R13 685 032) of expenditure on medicines for MNS disorders, procuring 94% (n = 49 442 474) and 6% (n = 3 311 528) of DDDs, respectively. Although district clinics procured 60% of DDDs, they procured the least per 1000 population served, whereas district hospitals procured the most. For almost all ATC classes, procurement differed significantly between municipalities at every service level and between specialised hospitals. Conclusion: In Gauteng province, most medicines for MNS disorders are procured by general healthcare services, but access to care may not be equitable. While population coverage at district clinics appears low, district hospitals may experience the greatest care burden. Research regarding quality of care at each service level is recommended. Contribution: This study provides insight into service provision for MNS disorders.

A network pharmacology and molecular docking approach in the exploratory investigation of the biological mechanisms of lagundi (Vitex negundo L.) compounds against COVID-19

Coronavirus disease 2019 (COVID-19) is an inflammatory and infectious disease caused by severe acute respiratory syndrome coronavirus 2 virus with a complex pathophysiology. While COVID-19 vaccines and boosters are available, treatment of the disease is primarily supportive and symptomatic. Several research have suggested the potential of herbal medicines as an adjunctive treatment for the disease. A popular herbal medicine approved in the Philippines for the treatment of acute respiratory disease is Vitex negundo L. In fact, the Department of Science and Technology of the Philippines has funded a clinical trial to establish its potential as an adjunctive treatment for COVID-19. Here, we utilized network pharmacology and molecular docking in determining pivotal targets of Vitex negundo compounds against COVID-19. The results showed that significant targets of Vitex negundo compounds in COVID-19 are CSB, SERPINE1, and PLG which code for cathepsin B, plasminogen activator inhibitor-1, and plasminogen, respectively. Molecular docking revealed that α-terpinyl acetate and geranyl acetate have good binding affinity in cathepsin B; 6,7,4-trimethoxyflavanone, 5,6,7,8,3',4',5'-heptamethoxyflavone, artemetin, demethylnobiletin, gardenin A, geranyl acetate in plasminogen; and 7,8,4-trimethoxyflavanone in plasminogen activator inhibitor-1. While the results are promising, these are bound to the limitations of computational methods and further experimentation are needed to completely establish the molecular mechanisms of Vitex negundo against COVID-19.

Available evidence on HIFU for focal treatment of prostate cancer: a systematic review

ABSTRACT Purpose: Prostate cancer (PCa) is the second most common oncologic disease among men. Radical treatment with curative intent provides good oncological results for PCa survivors, although definitive therapy is associated with significant number of serious side-effects. In modern-era of medicine tissue-sparing techniques, such as focal HIFU, have been proposed for PCa patients in order to provide cancer control equivalent to the standard-of-care procedures while reducing morbidities and complications. The aim of this systematic review was to summarise the available evidence about focal HIFU therapy as a primary treatment for localized PCa. Material and methods: We conducted a comprehensive literature review of focal HIFU therapy in the MEDLINE database (PROSPERO: CRD42021235581). Articles published in the English language between 2010 and 2020 with more than 50 patients were included. Results: Clinically significant in-field recurrence and out-of-field progression were detected to 22% and 29% PCa patients, respectively. Higher ISUP grade group, more positive cores at biopsy and bilateral disease were identified as the main risk factors for disease recurrence. The most common strategy for recurrence management was definitive therapy. Six months after focal HIFU therapy 98% of patients were totally continent and 80% of patients retained sufficient erections for sexual intercourse. The majority of complications presented in the early postoperative period and were classified as low-grade. Conclusions: This review highlights that focal HIFU therapy appears to be a safe procedure, while short-term cancer control rate is encouraging. Though, second-line treatment or active surveillance seems to be necessary in a significant number of patients.

Assessment of the Potential Risks Associated with the Proposed Use of Composted Waste from the Production of Bacitracin as a Soil Additive

Bacitracin is a hexapeptide antibiotic, with a substituted thiazolidine nucleus, produced by some strains of B. licheniformis. It is mainly active against Grampositive bacteria, although many differences in susceptibility exist among the bacterial species. Alpharma A.S. Norway has produced bacitracin for use in human medicine since 1954. Until 1998, the fermentation waste from the production of bacitracin was added to animal feed in some European countries, including Norway, to promote growth of pigs and domestic fowl. In 1998, fermentation waste containing bacitracin as a food additive was banned by the EU to reduce the risk of developing bacitracin-resistant bacteria in animals, and the subsequent possible transfer of such bacteria to humans via the food chain. Use of fermentation waste containing bacitracin as a feed additive has not been officially banned in Norway, but it is no longer used for this purpose. Alpharma is therefore actively seeking alternative uses for their production waste. As the waste material is rich in nutrients, the company proposes that it could be developed as a soil additive by fermenting it with chipped bark and lime. The Norwegian Food Safety Authority (Mattilsynet) commissioned the Panel on Biological Hazards of the Norwegian Scientific Committee for Food Safety (Vitenskapskomitéen for mattrygghet) to develop a risk assessment regarding the use of composted waste material from Alpharma’s production of bacitracin, as a soil additive. In response, an ad hoc Working Group of experts was appointed with the mandate to draft a risk assessment which should include the following elements: assessment of risk to human health and/or the environment in relation to residual content of bacitracin in the finished soil additive product and assessment of the risk in relation to dissemination of the production strain and antimicrobial resistance genes. The Panel on Biological Hazards concludes that the risks to human health and the environment posed by residual bacitracin present in the finished product are minimal. Furthermore, as Bacillus licheniformis is considered essentially non-pathogenic, occurring rarely as an opportunistic pathogen, the risk posed by this bacterium to human health or the environment is very low. It is reasonable to assume that during the early composting process horizontal transfer of bacitracin and erythromycin resistance genes, from the B. licheniformis producer strain to environmental bacteria, will exceed background levels. However, this is considered to represent a low risk to human health and the environment.

In silico assessment of the binding of reported bioactive compounds from Phaseolus vulgaris L. (Fabaceae) towards the wild-type and mutant estrogen receptor-alpha

Background@#Breast cancer is one of the leading causes of deaths in women worldwide, affecting nearly 7.8 million people. In 2020 in the Philippines, there were around 150,000 Filipinos who were newly diagnosed with the disease. The complex pathogenesis of breast cancer in addition to the emergence of resistance to therapy makes the treatment very challenging. Compounds that can antagonize the effects of estradiol towards ER-α, especially the mutant Y537S type are sought for. @*Objectives@#The focus of this study was the in-silico assessment of the reported secondary metabolites from Phaseolus vulgaris L. (fam. Fabaceae) towards the wild-type and mutant ER-α. Bioisosteric replacement was conducted to generate analogs that can possibly have a comparable binding affinity as estradiol towards estrogen receptors alpha. @*Results@#Majority of the secondary metabolites present in Phaseolus vulgaris L. belong to the group of phytoestrogens, phytosterols, and plant hormones. These groups of compounds exhibited favorable binding energies toward the wild-type and mutant (Y537S) estrogen receptors alpha. Moreover, they bind to the same ligand binding pocket as estradiol, involving similar interactions and amino acid residues. @*Conclusion@#Compounds from Phaseolus vulgaris L. can potentially target ER-α. Four gibberellin A19 analogs were generated that exhibited favorable binding towards the wild- and mutant- ER-α and may be further optimized to obtain a promisin gcompound against breast cancer.

Microarray and bioinformatic analysis of conventional ameloblastoma: an observational analysis

Abstract Ameloblastoma is a highly aggressive odontogenic tumor, and its pathogenesis is associated with many participating genes. Objective We aimed to identify and validate new critical genes of conventional ameloblastoma using microarray and bioinformatics analysis. Methodology Gene expression microarray and bioinformatic analysis were performed using CHIP H10KA and DAVID software for enrichment. Protein-protein interactions (PPI) were visualized using STRING-Cytoscape with MCODE plugin, followed by Kaplan-Meier and GEPIA analyses that were used for the candidate's postulation. RT-qPCR and IHC assays were performed to validate the bioinformatic approach. Results 376 upregulated genes were identified. PPI analysis revealed 14 genes that were validated by Kaplan-Meier and GEPIA resulting in PDGFA and IL2RA as candidate genes. The RT-qPCR analysis confirmed their intense expression. Immunohistochemistry analysis showed that PDGFA expression is parenchyma located. Conclusion With bioinformatics methods, we can identify upregulated genes in conventional ameloblastoma, and with RT-qPCR and immunoexpression analysis validate that PDGFA could be a more specific and localized therapeutic target.

Inmunoexpresión de p53 y su relación con el grado de severidad en displasia epitelial oral / Immunoexpression of p53 and its relationship with the degree of severity in oral epithelial dysplasia

Introducción: La displasia epitelial oral (DEO) es la presencia de alteraciones celulares y tisulares, lo que puede significar una etapa anterior al desarrollo del cáncer. Múltiples marcadores han sido considerados para estimar su potencial neoplásico y evolución a carcinoma, incluyendo a la molécula p53, se considera como participe de diversos fenómenos de la homeostasis celular. Objetivo: Determinar la relación entre la inmunoexpresión de p53 DO-7 y PAb 240 con el grado de severidad de la displasia epitelial oral. Material y métodos: Se analizaron nueve muestras de DEO (tres para cada grado de severidad). La inmunoexpresión de p53 tipo silvestre (DO-7) y forma mutada (PAb 240), fue determinada a través de ensayo de inmunohistoquímica por peroxidasa. Se obtuvieron la media y desviación estándar y se realizó la prueba χ2 (p < 0.05). Resultados: La edad media fue de 65.7 ± 11.4 años, la zona anatómica con mayor presencia de DEO es el borde lateral de la lengua. Ocho de nueve muestras fueron positivas para DO-7 y solo dos para PAb 240. Conclusiones: Nuestros resultados indican que, aunque la expresión de p53 DO-7 podría estar relacionada parcialmente con la patogénesis de la displasia epitelial, no todas las displasias presentaron la forma mutada de p53 (PAb 240). Lo cual coincide con el comportamiento biológico incierto de las displasias al poder permanecer sin cambios, involucionar o transformarse

Introduction: Oral epithelial dysplasia (OED) is the presence of cellular and tissue alterations, which may mean a stage prior to the development of cancer. Multiple markers have been considered to estimate its pathogenic potential and evolution to neoplasms, including the p53 molecule, considered as participating in various phenomena of cellular homeostasis. Objective: To determine the relationship between the immunoexpression of p53 DO-7 and PAb 240 with the degree of severity of oral epithelial dysplasia. Material and methods: Nine OED samples were analyzed (three for each degree of severity). The immunoexpression of wild-type p53 (DO-7) and mutated form (PAb 240) was determined through a peroxidase immunohistochemical assay. The mean and standard deviation were obtained, and χ2 test (p < 0.05) were performed. Results: The mean age was 65.7 ± 11.4 years, with a greater presence of OED in the anatomical area of the lateral side of the tongue. Eight out of nine samples were positive for DO-7 and only two for PAb 240. Conclusions: Our results indicate that, although the expression of p53 DO-7 could be partially related to the pathogenesis of epithelial dysplasia, not all dysplasias presented the mutated form of p53 (PAb 240), which coincides that not all dysplasias have a potential for malignant transformation and that could be related to other oncogenic mechanisms (AU)

Análisis de microdensidad vascular y factores de crecimiento en carcinoma oral de células escamosas / Analysis of vascular microdensity and growth factors in oral squamous cell carcinoma

Introducción: El carcinoma oral de células escamosas (COCE) es una neoplasia epitelial maligna que se presenta frecuentemente entre la quinta y sexta década de la vida. Su compleja patogénesis incluye el proceso de angiogénesis y la regulación del microambiente tumoral como mecanismos de progresión tumoral. Objetivo: Determinar la relación entre las variables clínicas e histológicas del COCE con la inmunoexpresión de VEGF, FGF-1, FGFR-1, TGFB-1, TGFBR-II y CD105. Material y métodos: Nueve casos de COCE; tres bien (BD), tres moderado (MD) y tres pobremente diferenciados (PD) obtenidos del Departamento de Patología y Medicina Bucal, División de Estudios de Postgrado e Investigación. Se aplicó la técnica de inmunohistoquímica por peroxidasa para identificar la expresión de VEGF, FGF-1, FGFR- 1, TGFB-1, TGFBR-II y CD105. El análisis de inmunoexpresión se realizó con el programa ImageJ. Se aplicó la prueba de Kruskal-Wallis y correlación de Spearman (p < 0.05). Resultados: La inmunoexpresión de VEGF fue mayor en los COCE PD, FGFR-1 fue positivo en los BD, mientras que FGF, TGFB-1 y TGFBR-II fueron negativos. El análisis de microdensidad vascular (MVD) indicó mayor número de vasos CD105 positivos en los carcinomas BD, seguidos de los PD y MD. Conclusión: Considerando los resultados obtenidos podemos concluir que la angiogénesis es un fenómeno constante independiente del grado de diferenciación que durante el proceso de transformación de una neoplasia requerirá la formación de vasos sanguíneos y que este proceso puede ser modulado por factores de crecimiento tales como los analizados en este trabajo (AU)

Introduction: Oral squamous cell carcinoma (OSCC) is a malignant epithelial neoplasm that frequently occurs between the fifth and sixth decade of life. Its complex pathogenesis includes the angiogenesis process and the regulation of the tumor microenvironment as mechanisms of tumor progression. Objective: To determine the relationship between the clinical and histological variables of OSCC with the immunoexpression of VEGF, FGF-1, FGFR-1, TGFB- 1, TGFBR-II and CD105. Material and methods: Nine cases of OSCC; three well (WD), three moderate (MD) and three poorly differentiated (PD) obtained from the Oral Medicine and Pathology Department, Division of Graduate Studies and Research. The peroxidase immunohistochemistry technique was performed to identify the expression of VEGF, FGF-1, FGFR-1, TGFB-1, TGFBR-II and CD105. The immunoexpression analysis was performed with the ImageJ software. The Kruskal-Wallis and Spearman correlation test were performed (p < 0.05). Results: VEGF immunoexpression was higher in PD OSCC, while FGFR-1 was predominantly positive in WD; FGF, TGFB-1 and TGFBR-II were negative. Vascular microdensity analysis (MVD) indicated a greater number of CD105 positive vessels in WD carcinomas, followed by PD and MD. Conclusion: Considering the results obtained, we can conclude that angiogenesis is a constant phenomenon independent of the degree of differentiation; that during the transformation process of a neoplasm it will require the formation of blood vessels and that this process can be modulated by growth factors such as those analyzed in this work (AU)

Mental health of healthcare workers during the COVID-19 outbreak: A rapid scoping review to inform provincial guidelines in South Africa

COVID-19 is prevalent in sub-Saharan Africa. The healthcare response to the pandemic depends upon a mentally and physically healthy workforce. Infectious disease outbreaks cause high psychosocial stress among healthcare workers, which may impact negatively on workplace functioning. To understand which mental health conditions may occur and which interventions could be considered, we conducted a rapid scoping review. Using a 2018 systematic review as the starting point, PubMed, Cochrane, Web of Science and MEDLINE databases were searched for any type of evidence published in English between 2014 and 2020 on mental health of healthcare workers exposed to infectious disease outbreaks; 19 primary studies and 13 opinion pieces were included. Depression, anxiety, post-traumatic stress, and other mental health conditions were noted among healthcare workers exposed to COVID-19 and other outbreaks. Although no effectiveness studies were identified, certain proposed interventions may be implemented by healthcare leaders. Further research is recommended

The Link between Antimicrobial Resistance and the Content of Potentially Toxic Metals in Soil and Fertilising Products

Potentially toxic metals (PTM), along with PTM-resistant bacteria and PTM-resistance genes may be introduced to soil and water through sewage systems, direct excretion, land application of biosolids (organic matter recycled from sewage, especially for use in agriculture) or animal manures as fertilisers, and irrigation with wastewater or treated effluents. The Norwegian Food Safety Authority (NFSA) asked the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) for an assessment of the link between antimicrobial resistance (AMR) and potentially toxic metals (PTM) in soil and fertilising products. The NFSA would like VKM to give an opinion on the following question related to the influence of potentially toxic metals on antimicrobial resistance: Can the content of arsenic (As), cadmium (Cd), chromium (CrIII + CrVI), copper (Cu), lead (Pb), mercury (Hg), nickel (Ni), and zinc (Zn) in soil and fertilising products that are relevant for Norway play a role in the development, spreading, and persistence of bacterial resistance to these elements, as well as cross or co-resistance to antimicrobial agents? VKM appointed a working group, consisting of two members of the Panel on Biological Hazards, to prepare a draft Opinion document and answer the questions. The Panel on Biological Hazards has reviewed and revised the draft prepared by the working group and approved the Opinion document “The link between antimicrobial resistance and the content of potentially toxic metals in soil and fertilising products”. In this report we assess the following PTM: arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni), mercury (Hg), lead (Pb), and zinc (Zn), because of their possible presence in fertilisers and their potential to induce AMR in bacteria. This assessment is based on internationally published data. There is no systematic monitoring for toxic metals in soils in Norway, and the levels are expected to be highly variable depending on the input sources, previous and current agricultural practices, and the characteristics of the soil. Data on PTM in fertilising products added to soil are also fragmented and limited. Fertilising materials, in the form of sewage sludge or livestock manure, will add toxic metals to the existing levels in soil, and in areas of intensive agriculture, the levels will be expected to be highest. The additive effect of toxic metals in fertilising materials must be assessed from a long-term perspective, as these metals accumulate in the environment. Development of AMR can be partly regarded as a dose- and time-dependant response to exposure to different drivers for resistance. There is an indication that the presence of potentially toxic metals is a driver for development of AMR in exposed bacteria, but the dose and time exposure most likely to cause this effect is not known. Investigation of PTM-driven co-selection of AMR in environments impacted by agriculture and aquaculture should focus especially on Cu and Zn, which are added to animal feed, and on Cd because of its high concentration, in comparison with other PTM, in inorganic fertilising products. The naturally occurring background resistance in environmental bacteria complicates the estimation of the effect of PTM exposure on development of resistance. In addition, it is difficult to distinguish between the natural resistome and an elevated abundance of AMR in environmental samples. Spreading of resistance towards the PTM evaluated in this assessment involves cross- and co-resistance to antimicrobial agents used in prophylaxis and therapy in animals and people. Most important are those cases where toxic metal resistance is coupled to resistance towards highly important and critically important antibiotics. This has been described in some of the published articles included in this assessment. We do not fully understand the mechanisms behind persistence of AMR, and removing drivers for development and spread of resistance may result in a decrease in the levels of resistance, but not necessarily full disappearance. There is lack of knowledge regarding links between the level and concentration of PTM in fertilising products and soil and development of resistance in bacteria. Data regarding the routes and frequencies of transmission of AMR from bacteria of environmental origin to bacteria of animal and human origin were lacking in the published articles reviewed here. Due to the lack of such data, it is difficult to estimate the probability of development, transmission, and persistence of PTM resistance in the Norwegian environment. More research is needed to explain the relationship between development of resistance against potential toxic metals and resistance toward antimicrobial agents in bacteria.

Risk Assessment of Specific Strains of Lactobacillus rhamnosus Used as "Other Substances"

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. These risk assessments will provide NFSA with the scientific basis for regulation of the addition of “other substances” to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of Lactobacillus rhamnosus Rosell-11 ND, Lactobacillus rhamnosus W71, Lactobacillus rhamnosus GG and Lactobacillus rhamnosus Lr-329 based on previous risk assessments and also publications retrieved from literature search. The risk of the Lactobacillus strains listed above was assessed for the general population. However, in previous assessments of probiotics published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups with mature gastro-intestinal tract. VKM has also assessed the risk of L. rhamnosus Rosell-11 ND, L. rhamnosus W71, L. rhamnosus GG and L. rhamnosus Lr-329 in food supplements and other foods independent of the dose and have assessed exposure in general terms. VKM concludes that it is unlikely that L. rhamnosus Rosell-11 ND, L. rhamnosus W71, L. rhamnosus GG and L. rhamnosus Lr-329 would cause adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.

Microorganisms in Biostimulants

In March 2016, the EU Commission presented a proposal for new regulations on fertilising material. The regulation includes product rules for a wide range of organic and inorganic products. Microbial biostimulants is one of the categories of products that are included. Biostimulants, in the draft EU regulation, are defined as fertilising materials that affect nutrient processes independently of the product's own nutrient content and with the purpose of improving nutrient utilisation, tolerance for abiotic stress or quality of the crop. Positive list in which species of these bacterial genera are listed: Azotobacter spp, Rhizobium spp., Azospirillum spp and Mycorrhizal fungi are a part of the regulation. Since the import and use of these organisms are the responsibility of both the Norwegian Food Safety Authority and the Norwegian Environment Agency, they asked VKM to submit a joint report on effects on health (humans, plants and animals), biodiversity and dispersal, quality of agricultural land and on soil environment. Conclusions: Health risks: Based upon our literature review, we have found no indication of any specific diseases in plants, animals or humans induced by the discussed microorganisms. A few reported cases of human disease are caused through wound infections or injections in immunocompromised patients. These represent a situation where any microorganism may induce infections and is not specific for the agents discussed in this report. In summary, the risk of any disease caused by the discussed microorganisms is considered negligible. Environmental risks: In soil the biodiversity, competition, adaptation and functional redundancy of microorganisms are extremely high. This means that introduced microorganisms have a very small chance for establishing, and even less so for affecting biodiversity and soil functioning. Introduction of nitrogen fixing species or fungi that can transport P to plants (mycorrhiza) will lead to an increase in the primary production. However, even a large increased activity for these processes will not outcompete naturally occurring symbiotic N-fixation or growth of inherently non-mycorrhizal plant species. Thus, the risks associated with introduced non-pathogenic microorganisms are very low.

Health Risk Assessment of a Food Supplement Containing Lactobacillus reuteri Protectis®

The Norwegian Scientific Commitee for Food Safety (VKM) appointed a working group of experts to answer a request from the Norwegian Food Safety Authority regarding health risk assessment of Lactobacillus reuteri Protectis® in a food supplement intended for use by infants and young children. The mandate of this health risk assessment was not to evaluate the health claims related to the products as such health claims are assessed by EFSA. The specific strain DSM 17938 is a “daughter strain” of the strain ATCC 55730 which was originally isolated from normal human milk. ATCC 55730 harbours two plasmids carrying transferable resistance genes against tetracycline and lincosamides respectively. The “daughter strain” DSM 17938 was established in 2008 by curing the ATCC 55730 for these plasmids, but is in all other respects claimed to be identical to ATCC 55730 and bioequivalence of the two strains has been suggested. The strain DSM 17938 was still resistant to tetracycline (although at a considerably lower level than ATCC 55730) and a number of other antibiotics, but these resistances were all considered being intrinsic by FBO. The absence of possible transferable/mobile genes has, to our knowledge, not been confirmed in later studies. We are not aware of any data indicating that L. reuteri has been the cause of serious human diseases – and none of the studies examined has reported any adverse or undesirable short time effects. It has also been used in preterm infants with dosage corresponding to the actual recommended doses - without reporting any adverse, short term reaction. There is therefore no evidence leading to consider the strain DSM 17938 at the dosage recommended as unsafe. However, more long-term data are still lacking and the long-term safety for the age groups considered in this assessment cannot be established. As evidence is accruing that the early microbial composition of the infant gut is important for the development of the gut flora and the immune system of the growing child, it is not possible to exclude that a daily supply of a particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, albeit still unknown, adverse effects on it’s development. As the long-term data are lacking it is not possible to answer whether the amount of the food supplement or the age of the infant or young child is of importance. However, if later long-term data should reveal any adverse reaction, it is reasonable to assume that the actual age group will be the most vulnerable. As the safety was not entirely established, the question of whether there are any vulnerable groups (i.e. premature, infants or children with diseases) where there are health risks associated with the intake of Lactobacillus reuteri Protectis®, as a food supplement was not considered.

CWD in Norway

The Norwegian Food Safety Authority (NFSA) and Norwegian Environmental Authority (NEA) asked the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) for an opinion on factors associated with the introduction of Chronic Wasting Disease (CWD) to Norway. VKM appointed a working group consisting of two members of the Panel on Biological Hazards, one member of Panel on Animal Health and Welfare, and two external experts to prepare the answer to the questions. The Panel on Biological Hazards has reviewed and revised the draft prepared by the working group and approved the opinion. CWD was diagnosed in March 2016 in a wild reindeer (Rangifer tarandus) from the Nordfjella mountain area in Norway and in May and June in two mooses (Alces alces) in Selbu in South Trøndelag County, approximately 300 km north from the first case. There is currently no information to determine the origin(s) of CWD agents in Norway. However, the sporadic or genetic (somatic mutation) occurrence of prion disease in cervids cannot be excluded, nor can introduction from North America or other countries. Furthermore, there is no evidence that it has not been circulating at low levels in the Norwegian cervid populations for years, but has not previously been identified. In this scientific opinion, information on prion diseases in general, and CWD in particular, is presented in the light of experiences with this disease in North America. Prions are among the most resilient pathogens known and dissemination of prions into ecosystems is likely to result in long-term problems. Prions bind strongly to soil and remain infectious. In CWD, prions are present in most peripheral organs and also shed into the environment via saliva, faeces, and urine, as well as with the placenta. CWD transmits easily among cervids, either through direct contact, or indirectly via the environment. Migration of animals is relevant for the spread between areas. Strain diversification might occur in CWD and may influence transmission properties of the agents. Clinical signs of CWD are non-specific and do not alone enable confirmation of the diagnosis. Analysis of tissue from the brainstem at the level of the obex by approved methods is necessary for diagnosis of CWD. Prion infectivity is assessed by bioassays, often involving transgenic mice. In vitro conversion assays, like protein misfolding cyclic amplification (PMCA), provide sensitive quantification of converting activity, which is a good approximation of infectivity. Genetic variation (polymorphisms) in the gene that encodes PrP (PRNP) can modulate sensitivity towards CWD. The level of such genetic variation in Norwegian wild and semi-domesticated cervids is currently unknown. Cattle and sheep are at very low risk of developing CWD and it is highly unlikely that prion diseases in sheep or cattle are the origin of CWD. Although transmission of CWD to humans has never been known to occur, and animals other than cervids have not been found to be infected, indicating a species barrier, this possibility cannot be excluded. Thus, measures for reduction of human exposure are recommended. Taking into account uncertainties regarding the plasticity of the CWD agents and the lack of transmission data from the Norwegian isolates, this scientific opinion considers the zoonotic risk of CWD to be very low.

CWD in Norway – A State of Emergency for the Future of Cervids (Phase II)

The Norwegian Food Safety Authority (Mattilsynet, NFSA) and the Norwegian Environment Agency (Miljødirektoratet, NEA) requested the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) for a scientific opinion on Chronic wasting disease (CWD) in cervids. The project was divided into two phases, and VKM published the scientific opinion from phase I “CWD in Norway” in June 2016. The current report is the result of phase II. VKM was asked to provide updated information on food safety, aspects important for transmission of CWD within and between populations and species, and the potential origin of the disease in Norway. Moreover, VKM was asked to highlight important risk factors with regard to disease transmission, and how these risk factors might affect choice of management strategy. Finally, VKM was asked to highlight relevant management strategies from North America or elsewhere. VKM appointed a working group consisting of one member of the Panel on Microbial Ecology, one member of the Panel on Biological Hazards, and five external experts, as well as VKM`s secretariat to answer the questions from NEA and NFSA. One member of the Panel on Alien Organisms and Trade in Endangered Species (CITES), one member of the Panel on Animal Health and Welfare, as well as one member of the Panel on Biological Hazards commented on the draft report. The Panel on Biological Hazards assessed and approved the final report. Background: Chronic wasting disease (CWD) is a prion disease that affects deer, moose, reindeer, and related species (cervids). Prion diseases are chronic neurodegenerative diseases that occur naturally in humans and ruminants, and are invariably fatal. Some prion diseases, such as classical scrapie in sheep and goats and chronic wasting disease (CWD) in cervids, are contagious, spreading directly between animals or via environmental contamination. In contrast, prion diseases known to affect humans are not known to be contagious. Prions are extraordinary agents consisting of misfolded protein aggregates that are remarkably stable and can remain infectious for years in the environment. Prion proteins are present in most animals, but the misfolding makes them very hard to break down. Consequently, misfolded prion proteins accumulate in the brain and eventually in other tissues, causing damage to those tissues. Until recently, CWD was only known from North America and South Korea. During a routine marking event in April 2016, a female reindeer (Rangifer tarandus) of the Nordfjella wild reindeer herd in Norway exhibited unusual behaviour, and died shortly afterwards. This unusual death was routinely investigated, and the animal was diagnosed with CWD. This was the first time CWD had been diagnosed outside North America and South Korea and the first case of natural CWD in reindeer. In addition, two moose (Alces alces) in Selbu, Norway were diagnosed with CWD in May 2016. Selbu is located approximately 300 km northeast of the Nordfjella mountain range. Currently there is considerable uncertainty regarding the nature of the CWD diagnosed in the two moose. Some of the characteristics of these cases indicate consistency with atypical prion disease, as described in domestic animals, but a final conclusion depends on the results from ongoing investigations. Following the diagnosis in reindeer, Norwegian authorities initiated a screening programme in which hunters were requested to collect tissue and the heads of dead cervids during the 2016 hunting season. Animals that had died from causes other than hunting were also tested for CWD. Since March 2016, 4629 samples of moose, 2550 samples of red deer, 627 samples of roe deer, 860 samples of reindeer, 2494 semi-domesticated reindeer, 163 farmed deer and 104 samples of unidentified species were tested for CWD. Two additional cases of CWD were diagnosed in wild reindeer in the Nordfjella population. Together with a clinical, pathological and epidemiological picture consistent with contagious CWD, as described from North America, this indicated that there is an ongoing outbreak of CWD in the wild reindeer population of the northern part of Nordfjella wild reindeer range. Results: An increase in the distribution and prevalence of CWD will increase exposure of other species, including domestic animals and humans, to this infectious agent. There is currently no evidence indicating transmission of CWD to domestic animals or humans, either by direct contact with cervids, cervid meat, or other products from cervids, or through the environment. VKM continues to support the conclusion from phase I concerning food safety of meat from cervids, that the zoonotic risk of CWD (transmission to humans) is very low. Preliminary results from characterisation of the moose cases and the agent involved indicate that important features deviate significantly from those found in the reindeer and in North American cervids, raising uncertainty with regards to the zoonotic potential. Therefore, based on the data currently available, VKM is not able to reach an evidence-based conclusion regarding the food safety of meat from moose and other cervids infected with this potentially new variant of CWD. Whereas direct transmission (animal-to-animal) seems most important in the early phases of a CWD epizootic, the role of indirect transmission (from the environment) increases as the prevalence increases. Once contagious CWD is established, it is very likely that the disease will increase in prevalence within the affected population and spread to contact populations. The rate of increase in prevalence, the resulting impact in a given population, and the efficacy of spread will depend on a range of environmental factors, and the characteristics of the species and population in question. For example, in affected populations of a gregarious species like reindeer, CWD is likely to lead to population decline in the long-term. Experiences from North America indicate that prions aggregate in the environment, making eradication of the disease extremely difficult once it has been allowed to develop and become endemic. It is therefore important that efficient measures are implemented at the VKM Report 2017:9 9 earliest opportunity in order to have a realistic chance of eradicating local occurrence of CWD and preventing further spread. Contagious CWD found in a confinable population, such as many wild reindeer herds, should be managed by eradication of the host population, fallowing of the area (> 5 years), and restocking from a healthy population. The report explains that culling of the Nordfjella reindeer herd is a necessary, immediate response to the current situation. However, as part of an adaptive management strategy, this measure should be under active review and may be revised in the event that new cases of CWD are discovered. In contrast, in continuous populations, such as most red deer, moose, and roe deer populations, spatially targeted culling within a defined containment zone should be used to control a CWD outbreak. Confinement of CWD-infected populations should be increased where possible and contact with other populations of cervids restricted, for example by fencing, herding, enhancing natural or man-made obstacles, or decreasing the densities of the relevant cervid populations. Potential “hotspots” for disease transmission (supplementary salt-licks, supplementary feeding sites etc.) should be eliminated in areas with CWD as well as the surrounding areas, and should further be considered for other parts of the country. Precautionary measures should be implemented to prevent anthropogenic spread of the disease. Finally, increasing the national surveillance of CWD in cervids is essential to ensure that there is a comprehensive basis for future evidence-based management. This is required to ensure that cases and spread of disease are identified as soon as possible, as late discovery will limit the chances for successful eradication of CWD in Norway.

Evaluación de la citotoxicidad de Biodentine, IRM y MTA en cultivos de fibroblastos del ligamento periodontal humano / An evaluation of the cytotoxicity of Biodentine, IRM and MTA in cultures of human periodontal ligament fibroblasts

Introducción: Los materiales para la obturación retrógrada son diversos. Actualmente, IRM y MTA son las alternativas clínicas más utilizadas, no obstante, es relativamente reciente la introducción de materiales a base de silicatos tricálcicos tal como Biodentine. Objetivo: Determinar la citotoxicidad de fibroblastos del ligamento periodontal humano expuestos a medios de cultivo condicionados con Biodentine, IRM y MTA. Material y métodos: 1 × 103 fibroblastos del ligamento periodontal humano fueron expuestos a medios DMEM/F12 condicionados con MTA, IRM y Biodentine en tres protocolos diferentes. Se realizó un ensayo de MTT para determinar la viabilidad celular a las cero, 24, 48, 72 horas, siete y 14 días. Se realizó una prueba ANOVA (p < 0.05). Resultados: En los tres protocolos con los diferentes medios de cultivo condicionados, la viabilidad de las células fue predominantemente proliferativa; sin embargo, las células expuestas a Biodentine mostraron una tendencia mayor que la MTA o la IRM. Conclusión: Las células expuestas a la Biodentine mostraron un comportamiento proliferativo a los 14 días de análisis. Se debe realizar más investigación a nivel in vivo y clínico para obtener más información sobre la conducta de estos materiales empleados para la obturación retrógrada (AU)

Introduction: The materials for retrograde filling are diverse. Currently, IRM and MTA are the most commonly used clinical alternatives, however, the introduction of materials based on tricalcium silicates such as Biodentine is relatively recent. Objective: To determine the cytotoxicity of human periodontal ligament fibroblasts exposed to culture media conditioned with Biodentine, IRM and MTA. Material and methods: 1 × 103 fibroblasts of the human periodontal ligament were exposed to DMEM/F12 media conditioned with MTA, IRM and Biodentine in 3 different protocols. An MTT assay was performed to determine cell viability at 0, 24, 48, 72 hours, seven and 14 days. An ANOVA test was performed (p < 0.05). Results: In the three protocols with the different conditioned culture media, the viability of the cells was predominantly proliferative, however, the cells exposed to Biodentine showed a higher tendency than the MTA or the IRM. Conclusion: The cells exposed to the Biodentine showed a proliferative behavior at 14 days of analysis. More research should be done at in vivo and clinical level to obtain more information about the behavior of these materials used for retrograde filling (AU)

Terapia láser de baja frecuencia en el manejo del dolor en pacientes con osteonecrosis mandibular / Low level laser therapy in the management of pain in patients with osteonecrosis of the jaw

La terapia láser de baja frecuencia (TLBF) o fotobioestimulación es aquella que cuya luz provoca la regeneración y remodelación ósea, la restauración de la función neural, la disminución del dolor y la modulación del sistema inmune; esta terapia es un coadyuvante junto a la terapia conservadora y/o quirúrgica. Se considera un estándar de oro para el manejo del dolor en la osteonecrosis en aquellos pacientes que consumen o han consumido bifosfonatos como terapia para inhibir la resorción ósea. La Sociedad Americana de Investigación de Hueso y Minerales (SAIHM) definió la osteonecrosis mandibular como «un área de hueso expuesto en la región maxilofacial que no cicatriza dentro de las ocho semanas posteriores a la identificación, en un paciente que está recibiendo o ha estado expuesto a bifosfonatos y que no ha recibido radioterapia en la región craneofacial¼. En este reporte presentamos dos casos de pacientes con osteonecrosis mandibular relacionada a bifosfonatos tratados con TLBF. Se evaluó el dolor antes y después de la terapia con la escala visual análoga (EVA). Ambos casos tuvieron disminución del dolor al 100%. Se presentan los métodos de diagnóstico clínico y radiográfico, el tratamiento elegido y los resultados obtenidos (AU)

Low level laser therapy (LLLT) or photobiostimulation is one whose light causes bone regeneration and remodeling, restoration of neural function, reduction of pain, and modulation of the immune system; this therapy is an adjuvant together with conservative and / or surgical therapy. It is considered a gold standard for pain management in osteonecrosis in those patients who consume or have used bisphosphonates as antiresorptive therapy. The American Society for Bone and Mineral Research (ASBMR) defined osteonecrosis of the jaw as «an area of exposed bone in the maxillofacial region that does not heal within eight weeks after identification by a health care provider, in a patient who was receiving or had been exposed to a BP and who has not received radiation therapy to the craniofacial region¼. In this report we present two cases of patients with mandibular osteonecrosis related to bisphosphonates treated with LLLT. Pain before and after visual analogue scale (VAS) was evaluated. Both cases had pain reduction at 100%. The methods of clinical and radiographic diagnosis, the treatment chosen and the results obtained are presented (AU)

Validación de un instrumento para medir la calidad de vida en niños con mucositis orofaríngea en tratamiento por cáncer / Validation of an instrument to measure the quality of life in children with oropharyngeal mucositis undergoing cancer treatment

Resumen Introducción: La mucositis orofaríngea (MO) es una de las principales complicaciones del tratamiento oncológico que reduce significativamente la calidad de vida (CV) del paciente. El objetivo fue traducir, adaptar de manera cultural y validar una nueva versión en español del instrumento Oropharyngeal Mucositis-Specific Quality-of-Life (OMQoL) en pacientes pediátricos. Métodos: Estudio transversal de validación, multicéntrico, realizado para la traducción y adaptación del OMQoL del inglés al español en pacientes de entre 8 y 16 años con MO. Se midió la confiabilidad mediante el Alfa de Cronbach; la validez del contenido y el constructo, con un análisis factorial exploratorio; y la validez convergente, con las correlaciones de las escalas para MO de la Organización Mundial de la Salud (OMS), la Oropharingeal Mucositis Assessment Scale (OMAS) y con el Pediatric Quality of Life-3 (PedsQL-3) módulo cáncer en español. Resultados: Participaron en el estudio 193 niños con una media de edad de 10.91 ± 2.38 años, de los cuales 101 (52.3%) fueron de sexo femenino. En esta muestra, 80 niños (41.5%) presentaron leucemia aguda linfoblástica y 111 (57.5%) presentaron MO grado 2 y 3. El análisis factorial resultó con cuatro dimensiones con cargas > 0.40. De los 31 ítems del OMQoL, seis fueron eliminados. El Alfa de Cronbach del OMQoL español fue de 0.954. Las correlaciones de Spearman (r) con las escalas de la OMS y OMAS fueron significativas (r = −0.720 y r = −0.689; p<0.01, respectivamente); con el PedsQL-3 módulo cáncer existió una moderada correlación (r = 0.426; p < 0.01). Conclusiones: La nueva versión del OMQoL en español demostró propiedades psicométricas adecuadas, y resulta un instrumento confiable y válido para medir la CV en niños con MO.

Abstract Background: Oropharyngeal mucositis (OM) is one of the primary complications arising during oncological treatment, which significantly reduces the patient's quality of life (QoL). The aim of this study was to translate, culturally adapt, and validate the use of a new Spanish version of the Oropharyngeal Mucositis-Specific Quality-of-Life instrument (OMQoL) for pediatric patients. Methods: A multicentric, cross-sectional validation study was conducted to translate and adapt OMQoL from English to Spanish for its use by children with OM aged 8-16 years. Reliability was measured using Cronbach's alpha; content and construct validity, in conjunction with exploratory factor analysis. The convergent validity, with the correlations of the scales for OM defined by the WHO, OMAS (Oropharingeal Mucositis Assessment Scale) and the PedsQL-3 cancer module in Spanish. Results: One hundred and ninety-three children with mean age of 10.91 ± 2.38 years participated in the study, out of which 101 (52.3%) were females. In this sample, 80 children (41.5%) suffered from acute lymphoblastic leukemia and 111 (57.5%) had grade 2 and 3 OM. The factorial analysis resulted in four dimensions with loads >0.40. Among the 31 items of the OMQoL, six were eliminated. Cronbach alpha of OMQoL-Spanish was 0.954. Spearman´s correlations (r) with the OMS and OMAS scales were significant (with r = −0.720 and r = −0.689; p < 0.01, respectively). Moderate correlation was observed with the PedsQL-3 cancer module (r = 0.426; p < 0.01). Conclusions: OMQoL-Spanish demonstrated adequate psychometric properties, resulting in a reliable and valid instrument for measuring QoL in children with MO.

Risk Assessment of Specific Strains of Lactobacillus acidophilus Used as "Other Substances"

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. These risk assessments will provide NFSA with the scientific basis for regulation of the addition of “other substances” to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of Lactobacillus acidophilus W37, Lactobacillus acidophilus DDS-1, Lactobacillus acidophilus La-5 and Lactobacillus acidophilus La-14 based on previous risk assessments and also publications retrieved from literature search. The risk of the Lactobacillus strains listed above was assessed for the general population. However, in previous assessments of probiotics published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups with mature gastro-intestinal tract. VKM has also assessed the risk of L. acidophilus W37, L. acidophilus DDS-1, L. acidophilus La-5 and L. acidophilus La-14 in food supplements and other foods independent of the dose and have assessed exposure in general terms. VKM concludes that it is unlikely that L. acidophilus W37, L. acidophilus DDS-1, L. acidophilus La-5 and L. acidophilus La-14 would cause adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.

Risk Assessment of Specific Strains of Bifidobacterium spp. Used as "Other Substances"

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements sold in Norway. These risk assessments will provide NFSA with the scientific basis for regulation of the addition of “other substances” to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/or physiological effect. It is added mainly to food supplements, but also to other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects. The present report is a risk assessment of Bifidobacterium lactis Bi-07, Bifidobacterium bifidum W23, Bifidobacterium longum Rosell-175, Bifidobacterium breve Rosell-70, and Bifidobacterium animalis sub. lactis Bb12 based on previous risk assessments and also publications retrieved from literature search. The risk of the Bifidobacterium strains listed above was assessed for the general population. However, in previous assessments of probiotics published by VKM, concerns have been identified for specific groups. Therefore, the risk was assessed for the age group with immature gastro-intestinal microbiota (age group 0-36 months), population with mature gastro-intestinal microbiota (>3 years) and vulnerable groups with mature gastro-intestinal tract. VKM has also assessed the risk of Bifidobacterium spp. in food supplements and other foods independent of the dose and have assessed exposure in general terms. VKM concludes that it is unlikely that B. lactis Bi-07, B. bifidum W23, B. longum Rosell-175, B. breve Rosell-70, and B. animalis sub. lactis Bb12 would cause adverse health effects in the general healthy population with mature gastro-intestinal tract. However, no data on long-term adverse effects on infants and young children were identified. As evidence is accruing that the early microbial composition of the neonatal gut is important for the development of the gut microbiota and the immune system of the growing child, it is not possible to exclude that a daily supply of a single particular bacterial strain over a prolonged period of time to an immature gastro-intestinal tract may have long-term, although still unknown, adverse effects on that development.