Evaluation of candidate International Standards for meningococcal capsular polysaccharide groups W and Y.

Two candidate International Standards for meningococcal capsular group W and Y (MenW and MenY, respectively) polysaccharides were assessed for their suitability as quantitative standards in various physicochemical assays. The study was designed to evaluate the intended purpose of these standards, namely, to standardize the quantification of the respective polysaccharide content in meningococcal polysaccharide and conjugate vaccines and their intermediate components. Twelve laboratories from eleven different countries participated in the collaborative study of candidate preparations for International Standards for MenW and MenY polysaccharide (coded 16/152 and 16/206, respectively). Unitage was assigned using the Resorcinol assay. Our proposals, on the basis of data from the Resorcinol assay were: 1) candidate standard for MenW polysaccharide (16/152) to be assigned a content of 1.015 ± 0.071 mg MenW polysaccharide per ampoule (expanded uncertainty with coverage factor k = 2.13, corresponding to a 95 % level of confidence) and 2) candidate standard for MenY polysaccharide (16/206) be assigned a content of 0.958 ± 0.076 mg MenY polysaccharide per ampoule (expanded uncertainty with coverage factor k = 2.26, corresponding to a 95 % level of confidence). The amount of polysaccharide per ampoule remained consistent under all stability conditions over a 36-month period.

Opportunities and limitations to environmental management system (EMS) implementation in UK small and medium enterprises (SMEs) - A systematic review.

Human activity has been the primary driver of wicked problems that have resulted in the twinned climate and biodiversity crises, that must now urgently be addressed by all sectors of society. Such impacts are primarily driven by economic activity and how business is conducted. Small and medium-sized enterprises (SME) make up the majority of global and UK business with relatively unquantified environmental impact. The present study investigates how UK-based SMEs experience environmental management systems (EMS) - tools used to systematically identify the environmental impact of products and processes - to identify key opportunities and limitations to their implementation. Between 2000 and 2021 the topic has received a consistent, but low level of attention, with a marginal increase that coincides with the introduction of environment, social, and governance (ESG) requirements. The study synthesized the findings of 30 publications identified in a systematic review of literature that were comprised of case studies and review articles. Internal drivers for embarking on an EMS were resource use efficiency and cost-savings, and market advantage was a frequent external driver. Limitations were often more internal than external, and included inadequacies in human resource, knowledge and skill to undertake an EMS in house. Legal compliance featured as both a key internal and external driver, but a lack of mandate for EMS implementation and external (e.g., governmental) support were critical external limitations. Consequently, key focal areas to upscale the ambition of EMS for SMEs were the provision of guidance and training, as well as top-down pressure. Overall, there are increasing pressures upon the SME sector to improve their sustainability performance due to the trickle-down effect of stronger, international ESG related policy and legislation into the value chain and EMSs may offer an established framework to enable SMEs to move with larger corporates into a more sustainable future.

Collaborative study for the calibration of a replacement International Standard for Diphtheria Antitoxin Equine.

The International Standard for Diphtheria Antitoxin Equine is essential for the standardisation of assays used to determine the potency of therapeutic diphtheria antitoxin products produced from equine serum. This paper describes the production and characterization of the 2nd International Standard for Diphtheria Antitoxin Equine and its calibration in International Units. Calibration was performed by toxin neutralization test in vivo and in vitro (Vero cell assay), and potency was expressed relative to the 1st International Standard to ensure continuity of the International Unit. The candidate standard (NIBSC product code 18/180) was assigned a unitage of 57 IU/ampoule based on results from 14 laboratories in 9 different countries and was established by the World Health Organisation Expert Committee on Biological Standardization in 2021.

Collaborative study for the calibration of a replacement International Standard for tetanus toxoid for use in flocculation test.

Here we report the results of a study to establish a replacement WHO International Standard (IS) for tetanus toxoid for use in flocculation test. The standard was calibrated in flocculation units (Lf) against the 2nd IS using the Ramon flocculation method. At its 70th meeting in October 2019, WHO ECBS established the material (coded 16/302) as the 3rd WHO IS, with an assigned value of 970 Lf/ampoule from the results of seventeen laboratories across ten different countries. The study also provided an opportunity to assess the use of alternative methods for measuring Lf. Participants were asked to use an in-house Enzyme Linked Immunosorbent Assay (ELISA) developed at NIBSC, or other suitable in-house methods, to determine ELISA-specific Lf values (Lf-eq units are specific only for pre-calibration of antitoxin in the flocculation test) of 16/302 to compare to those of the flocculation test. Nine laboratories participated by performing the NIBSC ELISA, one laboratory performed flocculation by laser light-scattering following an in-house protocol, and three laboratories performed ELISA following in-house protocols. The results intimate that these alternative methods could be useful for monitoring consistency of production at different stages of vaccine manufacturing.

The development and establishment of a heat inactivated preparation of Mycobacterium tuberculosis (H37Rv) as the first international standard for nucleic acid amplification techniques.

A need to develop an inactivated Mycobacterium tuberculosis (Mtb) preparation, to be used as a DNA standard, as an important and urgent requirement for Tuberculosis (TB) diagnostics standardization was identified in 2018. A candidate material was generated using a heat inactivated culture of Mtb strain H37Rv. A lyophilised preparation was evaluated for its suitability as an International Standard for molecular detection of Mtb DNA in an international collaborative study. Together with the use of quantitative PCR assays and rapid diagnostic tests, this candidate standard was demonstrated to be fit-for-purpose. Based on the results from this collaborative study, it is proposed this lyophilised heat inactivated Mtb preparation (NIBSC code: 20/152) to be established by the World Health Organization Expert Committee on Biological Standardization, as the First WHO International Standard for Mycobacterium tuberculosis (H37Rv) for nucleic acid amplification techniques with an assigned unitage of 6.3 log10 or 2 × 106 International Units per vial. The intended uses of this IS are for calibration of secondary or in-house reference preparations used in the assays for the molecular detection of Mtb DNA. It may also be used for assay validation and monitoring the performance in terms of limit of detection of rapid diagnostic tests.

Monoclonal Antibodies as SARS-CoV-2 Serology Standards: Experimental Validation and Broader Implications for Correlates of Protection.

COVID-19 has highlighted challenges in the measurement quality and comparability of serological binding and neutralization assays. Due to many different assay formats and reagents, these measurements are known to be highly variable with large uncertainties. The development of the WHO international standard (WHO IS) and other pool standards have facilitated assay comparability through normalization to a common material but does not provide assay harmonization nor uncertainty quantification. In this paper, we present the results from an interlaboratory study that led to the development of (1) a novel hierarchy of data analyses based on the thermodynamics of antibody binding and (2) a modeling framework that quantifies the probability of neutralization potential for a given binding measurement. Importantly, we introduced a precise, mathematical definition of harmonization that separates the sources of quantitative uncertainties, some of which can be corrected to enable, for the first time, assay comparability. Both the theory and experimental data confirmed that mAbs and WHO IS performed identically as a primary standard for establishing traceability and bridging across different assay platforms. The metrological anchoring of complex serological binding and neuralization assays and fast turn-around production of an mAb reference control can enable the unprecedented comparability and traceability of serological binding assay results for new variants of SARS-CoV-2 and immune responses to other viruses.

Development of a high-speed bioaerosol elimination system for treatment of indoor air.

We developed a high-speed filterless airflow multistage photocatalytic elbow aerosol removal system for the treatment of bioaerosols such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human-generated bioaerosols that diffuse into indoor spaces are 1-10 µm in size, and their selective and rapid treatment can reduce the risk of SARS-CoV-2 infection. A high-speed airflow is necessary to treat large volumes of indoor air over a short period. The proposed system can be used to eliminate viruses in aerosols by forcibly depositing aerosols in a high-speed airflow onto a photocatalyst placed inside the system through inertial force and turbulent diffusion. Because the main component of the deposited bioaerosol is water, it evaporates after colliding with the photocatalyst, and the nonvolatile virus remains on the photocatalytic channel wall. The residual virus on the photocatalytic channel wall is mineralized via photocatalytic oxidation with UVA-LED irradiation in the channel. When this system was operated in a 4.5 m3 aerosol chamber, over 99.8% aerosols in the size range of 1-10 µm were removed within 15 min. The system continued delivering such performance with the continuous introduction of aerosols. Because this system exhibits excellent aerosol removal ability at a flow velocity of 5 m/s or higher, it is more suitable than other reactive air purification systems for treating large-volume spaces.

International collaborative study to evaluate and calibrate two recombinant L chain Ferritin preparations for use as a WHO International Standard.

OBJECTIVES: To evaluate and calibrate two candidate preparations for the 4th International Standard for Ferritin (Human, Recombinant) (codes: 19/118 and 19/162) against the 3rd International Standard for Ferritin (Human, Recombinant) (code: 94/572), and three serum commutability samples in an international collaborative study involving 12 laboratories in nine countries. METHODS: Eleven of the 12 participating laboratories performed Ferritin quantitation using automated assay platforms and one laboratory used a manual ELISA kit. RESULTS: There was better overall agreement between all laboratories and between assay methods for the potency of preparation 19/118 than for preparation 19/162. The overall geometric mean potency (from all methods) of the candidate 4th International Standard, 19/118, was 10.5 µg/ampoule, with inter-laboratory variability, expressed as % geometric coefficient of variation (GCV), of 4.7%. Accelerated stability studies have predicted both 19/118 and 19/162 to be very stable for long term storage at -20 °C. CONCLUSIONS: The candidate 4th International Standard for Ferritin (Human, Recombinant) (19/118) has been shown to be immunologically similar to the 3rd International Standard for Ferritin (Human, Recombinant) (94/572). It was recommended to and accepted by the WHO Expert Committee on Biological Standardization that 19/118 be established as the 4th International Standard for Ferritin (Human, Recombinant) with an assigned potency of 10.5 µg/ampoule and expanded uncertainty limits 10.2-10.8 µg/ampoule (95% confidence; k=2.23).

A collaborative study to establish the national standard for SARS-CoV-2 RNA nucleic acid amplification techniques (NAAT) in Taiwan.

The conventional PCR remains a valuable method to detect the newly emergent coronavirus rapidly and accurately. Our investigation aimed to establish the standard materials of SARS-CoV-2 for NAAT detection. We provided formalin-inactivated SARS-CoV-2 and confirmed RNA copy numbers. In addition, the virus genome was confirmed with whole-genome sequencing and identified as Wuhan/WI04/2019. Seven laboratories were invited for this collaborative study, according to the reporting data, we determined the SARS-CoV-2 with the unit of 6.35 Log10 copies/mL as the national standard. The availability of the national standard (NS) of SARS-CoV-2 will facilitate the standardization and harmonization of SARS-CoV-2 NAAT assays.

The World Organisation for Animal Health - current and potential roles in safe international trade of bees and other insects.

The World Organisation for Animal Health (WOAH, founded as OIE) is the recognised intergovernmental standard-setting organisation for animal health and welfare. The WOAH mandate is to support its members in the prevention of the spread of animal diseases of concern, as listed in the Terrestrial Animal Health Code (Terrestrial Code). Once a disease, infection or infestation is listed, national Veterinary Authorities have the obligation regularly to notify WOAH of the presence or absence of the listed disease. In regard to insects, the scope of the Terrestrial Code limits its recommendations to preserving the health of bees (species of the genus Apis, extended to the genus Bombus and to the stingless bees for one disease). However, it does not include standards to mitigate the potential animal health risks associated with the international trade of other insects. A description of the standard-setting process and a review of the history of the standards for bee health highlight the resources and requirements to expand the scope of the Terrestrial Code to include recommendations for animal health risk mitigation measures for the safety of international trade in insects. Any initiative to develop guidance on insect trade should include WOAH in its role as the sole global standard-setting organisation on animal health and welfare matters. This aligns with the WOAH commitment to a One Health approach.

L'Organisation mondiale de la santé animale (OMSA, fondée en tant qu'OIE) est l'organisation inter-gouvernementale reconnue pour l'élaboration de normes relatives à la santé et au bien-être des animaux. L'OMSA a pour mandat d'apporter un soutien à ses Membres afin de prévenir la propagation des maladies animales d'importance majeure listées dans le Code sanitaire pour les animaux terrestres (Code terrestre). Dès lors qu'une maladie, une infection ou une infestation figure sur cette liste, les Autorités vétérinaires ont l'obligation de notifier régulièrement à l'OMSA la présence ou l'absence de cette maladie sur leur territoire. S'agissant des insectes, le champ d'application du Code terrestre limite ses recommandations à la préservation de la santé des abeilles (espèces du genre Apis, avec l'inclusion du genre Bombus et des abeilles sans dard pour une maladie). Néanmoins, le Code terrestre ne contient pas de normes visant à atténuer les risques pour la santé animale associés aux échanges internationaux d'autres insectes. La description faite par les auteurs du processus d'élaboration des normes et leur aperçu rétrospectif de la mise au point des normes relatives à la santé des abeilles font ressortir les ressources et les conditions nécessaires pour élargir le champ d'application du Code terrestre afin d'y inclure des recommandations portant sur les mesures d'atténuation des risques pour la santé animale applicables à la sécurité sanitaire des échanges internationaux d'insectes. Toute initiative visant à fournir des orientations sur les échanges d'insectes devrait inclure l'OMSA dans son rôle d'unique organisation chargée de l'élaboration des normes internationales relatives à la santé animale et au bien-être des animaux. Cette exigence est en cohérence avec l'engagement de l'OMSA en faveur de l'approche Une seule santé.

La Organización Mundial de Sanidad Animal (OMSA, fundada como OIE) es la organización intergubernamental facultada para ejercer funciones normativas en materia de sanidad y bienestar de los animales. La OMSA tiene por mandato ayudar a sus miembros a prevenir la propagación de una serie de enfermedades animales de importancia, recogidas en el Código Sanitario para los Animales Terrestres (Código Terrestre) de la OMSA. La inclusión de una enfermedad, infección o infestación en la lista de la OMSA obliga a las autoridades veterinarias nacionales a dar cuenta periódicamente a la OMSA de la presencia o ausencia de esa patología en su territorio. Por lo que respecta a los insectos, en el Código Terrestre solo se formulan una serie de recomendaciones para proteger la salud de las abejas (categoría que corresponde a las especies del género Apis, extensible también al género Bombus y, en el caso de una enfermedad, a las abejas sin aguijón). El Código Terrestre, sin embargo, no contiene norma alguna destinada a mitigar los posibles riesgos zoosanitarios ligados al comercio internacional de otros insectos. Los autores describen el proceso normativo y repasan la historia de las normas relativas a la sanidad de las abejas, con lo que ponen de relieve los recursos y demás elementos necesarios para conferir mayor alcance al Código Terrestre incluyendo en él recomendaciones sobre medidas de mitigación del riesgo zoosanitario para un comercio seguro de insectos a escala internacional. Toda iniciativa encaminada a marcar pautas sobre el comercio de insectos debería incluir a la OMSA, única organización con potestad normativa mundial sobre temas de sanidad y bienestar de los animales, lo que además se encuadra en el compromiso de la OMSA con los planteamientos de «Una sola salud¼.

[ISO 1999:2013 part 1 : Revised probability model for calculating noise-induced hearing loss]. / ISO 1999:2013 Teil 1 : Überarbeitetes Wahrscheinlichkeitsmodell zur Berechnung des lärmbedingten Hörverlusts.

The ISO 1999:2013 norm describes a method of calculating the statistically expected permanent threshold shift (PTS) due to noise. Input parameters are noise level LEX,8h related to an 8­hour working day, duration of noise exposure in years, gender, and age. The background is a formula based on four datasets of measured values from larger surveys. Within its defined scope, ISO 1999 provides audiometric hearing curves for the frequencies 0.5, 1, 2, 3, 4, and 6 kHz for probability percentiles 5 to 95. This international standard is a useful additional tool for estimating the most probable cause of hearing disability when compared to the hearing curve in a noise worker's threshold audiogram and thus for deciding whether an occupational noise-induced hearing loss is likely to be present or not. According to the formula given in ISO 1999, sets of curves were recalculated separately for women and men to make them easily accessible in a new, expanded, and modernized graphical representation in this publication. Thus, according to ISO 1999, the following applies for the assessment: The higher the age, the more likely a noise-induced hearing threshold shift is to recede behind an age-related hearing threshold shift.

Establishment of a WHO Reference Reagent for anti-Mullerian hormone.

BACKGROUND: There is a need for a reference material to support the development and ensure the quality of immunoassays for human AMH. A batch of ampoules, coded 16/190, containing lyophilised recombinant AMH was evaluated in a WHO Collaborative Study. The aims of the study were to determine the AMH content in terms of the calibration of each immunoassay method, to predict long-term stability and to assess the suitability of the preparation to calibrate AMH immunoassays. METHODS: Study participants were asked to report the AMH content of specific dilutions of coded ampoules of 16/190 and a comparator preparation containing approximately half the AMH content. In each assay, participants also reported the AMH content of 22 patient samples to assess commutability. A robust all-laboratory geometric mean of the content estimates was determined using the laboratory geometric mean estimates. Commutability was assessed using a difference in bias approach. Stability was predicted by the measurement of thermally accelerated degradation samples. RESULTS: Seven laboratories performed twenty-one immunoassay method-platform combinations, sixteen of which provided data which met the validity criteria, giving a consensus geometric mean estimate of AMH content of 511 ng/ampoule (95% CI, 426-612, n = 16, GCV 42%) and a robust geometric mean of 489 ng/ampoule. By contrast, the GCV% for the all-laboratory geometric mean of the relative content estimates for the comparator sample to 16/190 was 12%. Commutability was assessed using 20 of the 22 representative patient samples. Of the valid assays, 16/190 was within the limits of acceptable commutability for 6 methods, partially commutable for a further 3 methods and non-commutable when measured by 7 methods. The preparation was predicted to be highly stable when stored at - 20 °C. CONCLUSION: The majority of methods met the validity criteria. Content estimates showed a high between-method variability, yet assays exhibited a similar proportionality of response as demonstrated using the comparator sample. 16/190 was commutable in some but not all methods. On the basis of these results, it was agreed by the WHO Expert Committee on Biological Standardization to establish 16/190 as a WHO Reference Reagent for AMH with a content defined by consensus immunoassay of 489 ng/ampoule.

ISO/TC 249 platform promotes the development of international standardization and trade for the Chinese medicines industry.

The trade of Chinese medicines (CMs) has developed rapidly worldwide. There is an urgent need for international standards of CMs in international trade. A newly established technical committee TC249 in the International Organization for Standardization (ISO) provides a platform for developing the international standards of traditional Chinese medicine. This article introduces the overview and development strategy of the international standardization of CMs. A quality assurance system for the entire industrial chain was well designed in the fields of seedlings, medicinal materials, and manufactured products. The general standards, testing method standards, and standards for single herbal medicines meet the urgent needs of the market and should be developed with high priority to promote the international trade of CMs and guarantee the quality and safety of clinical use. This article also introduces the significance, classification, and procedures for developing international standards of CMs and helps us better understand the international standardization work of CMs.

Optimization and evaluation of the method for the determination of the manganese content in manganese ores and concentrates as described in ISO 4298:1984.

It has been 36 years since ISO 4298:1984 was published, yet the role of sodium pyrophosphate in the oxidation of manganese(II) by potassium permanganate in this standard has not been fully recognized. The sample and reagent dosages exceed the actual detection needs, which creates challenges in the test operation and waste liquid treatment. In this study, a more scientific expression for the principle and reaction and the dosage of pyrophosphate in ISO 4298:1984 are discussed. The pyrophosphate ligand is involved in the oxidation of manganese(II) by potassium permanganate, and plays a role in preventing Mn(II) precipitation or Mn(III) dismutation during the whole reaction. The most appropriate amount of saturated sodium pyrophosphate is 150 mL for the test of manganese ores and concentrates with manganese content from 15% to 60%. The method developed by reducing sample size and reagent consumption was evaluated with ten certified reference materials, showing high accuracy and meeting the analytical performance requirements. These results can provide technical support for the revision of ISO 4298:1984. Graphical abstract.

Removal of the innocuity test from The International Pharmacopoeia and WHO recommendations for vaccines and biological products.

The innocuity test was indicated as a quality control test to release pharmaceutical and biological products to the market. The test was intended to detect possible extraneous toxic contaminants derived from the manufacturing processes of the product. The test was included in WHO Recommendations and Guidelines for vaccines, biotherapeutics and blood products and in some monographs on antibiotics in The International Pharmacopoeia. Over the past years, the requirements in WHO Recommendations/Guidelines for conducting the test evolved such that it could be waived for routine release of product once consistency of production was established to the satisfaction of the NRA, or that the need for this test should be discussed and agreed with the NRA. However, some users of WHO written standards for biologicals (i.e., Recommendations, Guidelines) and WHO specifications for pharmaceuticals (i.e., The International Pharmacopoeia) requested that the innocuity test be deleted from WHO written standards based on its lack of specificity and scientific relevance. In response to that request, we studied the history of this test and its use by the member states of WHO, and the recommendations in WHO written standards. The outcomes of the study were reviewed by the relevant WHO Expert Committee on Biological Standardization and Expert Committee on Specifications for Pharmaceutical Products who then decided to discontinue this test in WHO Recommendations for vaccines and biologicals and to omit the test from The International Pharmacopoeia.

Transforming Research and Clinical Knowledge in Spinal Cord Injury (TRACK-SCI): an overview of initial enrollment and demographics.

OBJECTIVE: Traumatic spinal cord injury (SCI) is a dreaded condition that can lead to paralysis and severe disability. With few treatment options available for patients who have suffered from SCI, it is important to develop prospective databases to standardize data collection in order to develop new therapeutic approaches and guidelines. Here, the authors present an overview of their multicenter, prospective, observational patient registry, Transforming Research and Clinical Knowledge in SCI (TRACK-SCI). METHODS: Data were collected using the National Institute of Neurological Disorders and Stroke (NINDS) common data elements (CDEs). Highly granular clinical information, in addition to standardized imaging, biospecimen, and follow-up data, were included in the registry. Surgical approaches were determined by the surgeon treating each patient; however, they were carefully documented and compared within and across study sites. Follow-up visits were scheduled for 6 and 12 months after injury. RESULTS: One hundred sixty patients were enrolled in the TRACK-SCI study. In this overview, basic clinical, imaging, neurological severity, and follow-up data on these patients are presented. Overall, 78.8% of the patients were determined to be surgical candidates and underwent spinal decompression and/or stabilization. Follow-up rates to date at 6 and 12 months are 45% and 36.3%, respectively. Overall resources required for clinical research coordination are also discussed. CONCLUSIONS: The authors established the feasibility of SCI CDE implementation in a multicenter, prospective observational study. Through the application of standardized SCI CDEs and expansion of future multicenter collaborations, they hope to advance SCI research and improve treatment.

World Trade Organization disputes related to animal diseases.

Four trade disputes concerning animal diseases have undergone the formal dispute resolution procedure of the World Trade Organization (WTO). These cases clarify a number of provisions of the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS Agreement). A national measure that contradicts a standard set by the World Organisation for Animal Health (OIE), for example by prohibiting a product that is permitted under the OIE standard, is not 'based on' that standard. Such a measure must be based on an appropriate risk assessment. For animal diseases, this means not only assessing the likelihood of entry, establishment or spread of the disease, and the associated biological and economic consequences, but also assessing each feasible mitigation measure. Any mitigation measure imposed must be rationally supported by the risk assessment. A highly trade-restrictive measure, such as a ban, is more easily justified if the identified risk is high. A measure imposed to protect health cannot impose stricter requirements on one product than on another with a similar level of risk. A WTO Member acts inconsistently with the SPS Agreement if an alternative measure, which is technically and economically feasible and restricts trade less, would achieve the desired level of protection. Countries must adapt their SPS requirements to reflect the disease risk of the area or zone from which a product comes and for which it is destined. Procedures to assess risk and determine the disease status of a region must be completed without unjustified delays, and only the information necessary for this can be requested of the exporter.

Quatre différends commerciaux en lien avec des maladies animales ont été soumis à l'Organisation mondiale du commerce (OMC) en vue de déclencher la procédure formelle de règlement des différends. Ces cas ont permis de clarifier un certain nombre de dispositions de l'Accord sur l'application des mesures sanitaires et phytosanitaires (Accord SPS). Ainsi, une mesure nationale contredisant une norme établie par l'Organisation mondiale de la santé animale (OIE), par exemple en interdisant un produit que ladite norme de l'OIE autorise, ne peut en aucun cas se prévaloir d'être « basée sur ¼ cette norme. Les mesures de ce type doivent se fonder sur une évaluation appropriée du risque. S'agissant des maladies animales, cela signifie qu'il faut non seulement évaluer les probabilités d'entrée, d'établissement ou de dissémination de l'agent causal de la maladie en question, ainsi que les conséquences biologiques et économiques qui en résultent, mais aussi évaluer une par une les différentes mesures d'atténuation réalisables. Toute mesure d'atténuation imposée doit être fondée de manière rationnelle sur cette évaluation du risque. Les mesures fortement restrictives, par exemple les interdictions, sont d'autant plus faciles à justifier que le risque identifié est élevé. Une mesure appliquée pour un produit déterminé dans le but de protéger la santé ne peut pas imposer de conditions plus strictes que celles portant sur d'autres produits présentant un niveau de risque similaire. Un membre de l'OMC agirait de manière incompatible avec l'Accord SPS s'il existe une mesure alternative, techniquement et économiquement réalisable mais moins contraignante pour le commerce, qui permettrait d'atteindre le niveau de protection requis. Les pays doivent adapter leurs exigences sanitaires et phytosanitaires en fonction du risque de maladie dans les régions ou zones de provenance et de destination du produit. Les procédures visant à évaluer le risque et à déterminer le statut d'une région au regard d'une maladie déterminée doivent être menées à terme sans délai injustifié et elles constituent le seul objet des informations exigibles auprès du pays exportateur.

El procedimiento oficial de solución de controversias de la Organización Mundial del Comercio (OMC) ha sido aplicado a cuatro litigios comerciales relacionados con enfermedades animales. Estos casos han resultado esclarecedores por lo que respecta a algunas de las disposiciones del Acuerdo sobre la Aplicación de Medidas Sanitarias y Fitosanitarias (Acuerdo MSF). Si una medida nacional contraviene una norma dictada por la Organización Mundial de Sanidad Animal (OIE), por ejemplo porque prohíbe un producto que según esa norma debe estar permitido, no se considera que tal medida está «basada en¼ la norma en cuestión. Semejante medida debe reposar en una adecuada determinación del riesgo. En el caso de las enfermedades animales, ello supone no solo determinar la probabilidad de penetración, establecimiento o propagación de la patología, así como sus posibles repercusiones biológicas y económicas, sino también evaluar cada una de las medidas factibles de mitigación. Toda medida de mitigación que se imponga debe ser una consecuencia racional del proceso de determinación del riesgo. Una medida que sea muy restrictiva del comercio, como pueda ser una prohibición, se justificará más fácilmente cuando se haya determinado previamente que existe un gran riesgo. Una medida destinada a proteger la salud no puede imponer a un producto requisitos más estrictos que a otro que entrañe un nivel parecido de riesgo. Un Miembro de la OMC no estará respetando el Acuerdo MSF cuando exista una medida alternativa, que sea técnica y económicamente factible y restrinja en menor medida el comercio, con la que se pueda lograr el nivel deseado de protección. Los países deben adaptar sus requisitos sanitarios y fitosanitarios al riesgo de enfermedad reinante en la zona de origen y la zona de destino del producto en cuestión. Los procedimientos para evaluar el nivel de riesgo de una región y determinar la situación de una enfermedad en ella deben ser aplicados sin demoras injustificadas y solo cabe pedir al exportador la información que sea necesaria para llevar a cabo este proceso.

[Design and application of quality standard of Dao-di herbs].

Dao-di herbs, which are widely recognized as medicinal materials with a high quality and good efficacy in clinic, are now facing the dilemma of absence of standard. This study focused on a pivotal scientific problem of design and application of quality standard of Dao-di herbs, and systematically illustrated the general rules for the quality standard of Dao-di herbs involving "four rules, six core contents, and three key methods". The quality standard of Dao-di herbs shall be fully based on literatures as well as habitat, planting/breeding, processing, characters, chemical-pharmacological/toxic data. The common requirements for the quality standard of Dao-di herbs contain "clear source, explicit origin, rational indicator, gradable quality, and multiple detection methods". Notably, traditional experiences and modern techniques, quality tracing management system, "quality determination by distinguishing characters" method, rapid detection technology, effective/toxic substances control method, were comprehensively applied in this standard to purse the objectification, automation, and intellectualization of detection technology. Appearance characters, chemical components, and bioactive parameters, unified effective/toxic indicators, quality markers, and pharmacopeial control indicators and reasonable ranges were included in rigorous quality standards for Dao-di herbs. Besides, simple grading method shall be developed to guide the implementation of "high quality-high price" policy. Eventually, the new quality standards for Dao-di herbs will lead international standards and promote the high-quality development of Dao-di herbs.

Standardization of Nucleic Acid Tests: the Approach of the World Health Organization.

The first World Health Organization (WHO) international standards (ISs) for nucleic acid amplification techniques were established two decades ago, with the initial focus on blood screening for three major viral targets, i.e., hepatitis C virus, hepatitis B virus, and human immunodeficiency virus 1. These reference materials have subsequently found utility in the diagnosis and monitoring of a wide range of infectious diseases in clinical microbiology laboratories worldwide. WHO collaborating centers develop ISs and coordinate international studies for their evaluation. The WHO Expert Committee on Biological Standardization is responsible for the endorsement of new standardization projects and the establishment of new and replacement ISs. Potencies of ISs are defined in international units (IU); the reporting in IU for assays calibrated with an IS (or secondary standards traceable to the IS) facilitates comparability of results for different assays and determination of assay parameters such as analytical sensitivities.

Copy Number Heterogeneity, Large Origin Tandem Repeats, and Interspecies Recombination in Human Herpesvirus 6A (HHV-6A) and HHV-6B Reference Strains.

Quantitative PCR is a diagnostic pillar for clinical virology testing, and reference materials are necessary for accurate, comparable quantitation between clinical laboratories. Accurate quantitation of human herpesvirus 6A/B (HHV-6A/B) is important for detection of viral reactivation and inherited chromosomally integrated HHV-6A/B in immunocompromised patients. Reference materials in clinical virology commonly consist of laboratory-adapted viral strains that may be affected by the culture process. We performed next-generation sequencing to make relative copy number measurements at single nucleotide resolution of eight candidate HHV-6A and seven HHV-6B reference strains and DNA materials from the HHV-6 Foundation and Advanced Biotechnologies Inc. Eleven of 17 (65%) HHV-6A/B candidate reference materials showed multiple copies of the origin of replication upstream of the U41 gene by next-generation sequencing. These large tandem repeats arose independently in culture-adapted HHV-6A and HHV-6B strains, measuring 1,254 bp and 983 bp, respectively. The average copy number measured was between 5 and 10 times the number of copies of the rest of the genome. We also report the first interspecies recombinant HHV-6A/B strain with a HHV-6A backbone and a >5.5-kb region from HHV-6B, from U41 to U43, that covered the origin tandem repeat. Specific HHV-6A reference strains demonstrated duplication of regions at U1/U2, U87, and U89, as well as deletion in the U12-to-U24 region and the U94/U95 genes. HHV-6A/B strains derived from cord blood mononuclear cells from different laboratories on different continents with fewer passages revealed no copy number differences throughout the viral genome. These data indicate that large origin tandem duplications are an adaptation of both HHV-6A and HHV-6B in culture and show interspecies recombination is possible within the Betaherpesvirinae.IMPORTANCE Anything in science that needs to be quantitated requires a standard unit of measurement. This includes viruses, for which quantitation increasingly determines definitions of pathology and guidelines for treatment. However, the act of making standard or reference material in virology can alter its very accuracy through genomic duplications, insertions, and rearrangements. We used deep sequencing to examine candidate reference strains for HHV-6, a ubiquitous human virus that can reactivate in the immunocompromised population and is integrated into the human genome in every cell of the body for 1% of people worldwide. We found large tandem repeats in the origin of replication for both HHV-6A and HHV-6B that are selected for in culture. We also found the first interspecies recombinant between HHV-6A and HHV-6B, a phenomenon that is well known in alphaherpesviruses but to date has not been seen in betaherpesviruses. These data critically inform HHV-6A/B biology and the standard selection process.