Autosomal recessive polycystic kidney disease (ARPKD) and other hepatorenal fibrocystic diseases (HRFD) are relatively rare recessive disorders that constitute an important set of childhood nephropathies. Little is known about fundamental pathogenesis, and advances toward clinical trials will require well-characterized patient cohorts and the development of predictive and prognostic biomarkers. Such studies in rare diseases require greater collaboration than the efforts in common diseases where large patient repositories can be built at a single site. For the HRFD, clinical and translational research studies would be well served by centralized case accrual that coordinates collection of clinical data, biospecimens (DNA and tissues), and genetic information. As a part of the NIH-funded Hepatorenal Fibrocystic Disease Core Center, we have established a web-accessible portal to enroll patients with ARPKD and other HRFD and compile baseline and longitudinal clinical information in a REDCap-based clinical database. This central database is structured to collect clinical data from patients throughout the Americas . By using informatic analyses, we have defined the first data-driven estimates of ARPKD-related neonatal mortality, as well as the incidence and prevalence of this disease. These data indicate that while ARPKD is a rare disorder, there are hundreds of patients potentially available for deep clinical phenotyping in the United States alone. The centralization and sharing of clinical information and biomaterials from ARPKD and other HRFD patients hold the potential to accelerate progress in understanding disease pathways. Once the database is mature, the well-characterized patient cohorts will provide an important resource for developing clinical trials to evaluate new targeted therapeutic interventions in this spectrum of disorders. Multiple single gene disorders that are characterized by renal cystic disease and extrarenal manifestations involve proteins that are critical in the structure/function of the primary apical cilium . As a rein utero with enlarged, echogenic kidneys, as well as oligohydramnios secondary to poor urine output. Significant perinatal mortality results from severe pulmonary hypoplasia and secondary respiratory insufficiency. Among survivors, the clinical phenotype can be quite variable with systemic hypertension, renal insufficiency, and portal hypertension due to portal tract fibrosis  constitutes an important set of childhood nephropathies due to the associated high disease burden and early mortality. For example, in ARPKD, affected children typically present fibrosis . The rarfibrosis .PKHD1 and other genes involved in the HRFD disorders, pathogenic mechanisms remain poorly understood. Factors that modulate disease expression are not well defined, and there remains wide-spread pessimism about prognosis for many of these patients. To optimize clinical decision-making and develop more effective targeted therapies, the natural history of ARPKD and other HRFD needs to be better characterized; the impact of recent advances in neonatal care and pediatric renal replacement therapy on patient survival must be systematically evaluated; and predictive/prognostic markers must be developed and validated to inform the design of new clinical trials.Despite the identification of Research in such rare diseases requires greater collaboration than the efforts in common diseases where patient resources are routinely available and large repositories can be built locally. For the HRFD, experimental studies would be well served by coordinated case accrual with integration of clinical data, biospecimens (DNA and tissues), and genetic information from individual patients through a unique identifier. The centralization and sharing of clinical and genetic information, as well as biomaterials, would provide a critical resource for accelerating research progress.Our group has previously described the ARPKD clinical experience in North America . We deveTherefore, with funding from the National Institutes of Health, we established the Hepatorenal Fibrocystic Disease Core Center (HRFDCC),® (HF) Database, which captures and stores deidentified, longitudinal electronic health record (EHR) patient data from more than 500 facilities in the United States and then aggregates and organizes it into consumable data sets. For these analyses, we focused on estimating the US-based incidence and prevalence of ARPKD, the most common of the HRFD, using data for the 5 years (2010–2014) before the ICD-10 coding system was implemented (October 2015).As a group, the HRFD are relatively rare. The estimated incidence of each disorder is largely derived from limited clinical and genetic studies. There are no prevalence estimates available in the literature. To ascertain the size of the potential cohort available for recruitment to the HRFDCC Clinical Database, we performed a systematic review using the national Cerner Health FactsIn brief, we developed an Oracle-based local instance of the HF Database and ascertained the number of unique patients age 0–29 years) with the ARPKD ICD-9 diagnosis code 753.14) between January 2010 and December 2014. We determined the annual number of unique ARPKD newborns (<1 month of age) and the annual number of all newborns (<1 month of age) in the HF Database. We also determined the annual number of US births from the National Vital Statistics Report.4 between9 years wWe believe that our analyses provide reasonable estimates of incidence, annual neonatal mortality rate, and the prevalence for ARPKD. Moreover, these data indicate that for this rare disease, there are hundreds of patients available for deep clinical phenotyping in the United States alone.The HRFDCC Clinical Database focuses on patients aged 0–35 years who have renal imaging consistent with ARPKD or another HRFD  and one PKHD1 gene or other HRFD genes;Mutations detected in the Clinical/imaging evidence of biliary fibrosis and/or portal hypertension;Hepatic histopathology consistent with ductal plate malformation;Family history consistent with autosomal recessive inheritance.Of note, the classic renal sonographic findings in ARPKD involve enlarged, diffusely echogenic kidneys with poor corticomedullary differentiation. With the development of high-resolution ultrasound, the sonographic pattern of ARPKD, particularly in older infants and children, can include scattered medullary and cortical macrocysts (due to dilated collecting ducts becoming enclosed cysts that enlarge) that are superimposed on the background of diffuse hyperechogenicity .Participants are excluded if they have autosomal dominant polycystic kidney disease (ADPKD) or renal dysplasia, with or without urinary tract malformations.Electronic case report forms (CRFs) were developed to collect initial patient data and follow-up information at yearly intervals. These CRFs have built-in edit checks tagged to each data field to minimize the risk of missing or duplicated data. The Initial Visit CRF records demographic characteristics , date of birth, date of diagnosis, specific clinical diagnosis, last contact, and death (if applicable). Additional information includes family history and parental consanguinity. Perinatal data are also collected, e.g., whether the diagnosis was made prenatally, and if so, the diagnostic modality used, e.g., sonography or genetic analysis.The Follow-up Visit CRF records interval changes and the date of last contact. When applicable, the date and cause of death are specified. The follow-up data entries are planned to occur annually.Each CRF  includes the following.Patient data: age, body measurements;Pulmonary status: ventilation, supplemental oxygen;Patient laboratory data;Renal data: clinical issues , radiological findings, biopsy results;Renal replacement therapy: dates , dialysis modality, donor source (living-related donor versus cadaveric), and the status of the graft at last contact;Hepatic data: symptoms, radiological findings, biopsy results. If appropriate, the date of liver transplantation and donor source;Medication data: start and end date, dose;Other therapeutic interventions: supplemental feeding , endoscopy, surgical procedures ;Related data: whether genetic testing has been performed; availability of biosamples.We leveraged the previously reported North American ARPKD Database to establish the HRFDCC Clinical Database as a secure, HIPAA-compliant, web-based portal for clinical data entry.The HRFDCC Clinical Database implements an IRB-approved algorithm for clinical data entry that obviates the need for the contributing physician to obtain local IRB approval. In brief, the patient/family contacts the website, indicates interest in participating in the research study, and downloads the study informed consent and a Release of Medical Information Authorization form. The HRFDCC Clinical Database research nurse is automatically alerted by a system-generated e-mail, which provides the participant contact information. Prompted by this alert, the research nurse contacts the participant to review the informed consent and address questions about the study. The signed consent and the medical records can be returned to the study team by mail or FAX.Upon receipt of the signed consent, a unique identifier is autogenerated for the participant. The HRFDCC Research Nurse Data extracts data from each corresponding medical record and enters these data into the password-restricted database using the participant’s unique identifier. The database is housed on a dedicated server at the Children’s National Health System and secured by communication channels that use https and Secure Socket Layer encryption. Therefore, the data in the servers are restricted to authorized personnel.Built into the database design are the following features.Real-time mechanism for rules-based edit checking and data validation.Real-time alert mechanism to flag data of particular interest and notify appropriate individuals.Capability to generate summary reports about the cohort’s demographics and aggregate clinical and genetic data or other reports as requested.A search function, so that as the Database matures, researchers can mine the data using specific clinical and genetic queries.The study has been approved by the CNHS IRB, and the consent is available in English, Spanish, Portuguese, and French, allowing recruitment of patients from North, Central, and South America.As a single-site demonstration project, we developed a computer algorithm to identify ARPKD patients who meet eligibility criteria for HRFDCC Clinical Database. The algorithm was built to run queries based upon the ARPKD ICD-9 code (753.14), using the i2b2 Clinical and Translational Research Informatics Data Warehouse, a resource developed by the Clinical and Translational Science Institute at Children’s National (CTSI-CN) as a repository of patient data from the Cerner EHR. The i2b2 query returned a cohort of 41 patients. With IRB approval, the medical record number was obtained for each patient. Manual EHR review revealed that 20 of 41 (49%) patients met the eligibility criteria for ARPKD. The remaining 21 (51%) patients had diagnoses ranging from ADPKD, renal dysplasia, multicystic dysplastic kidney, to mothers of affected fetuses.2 and 22.9% requiring either dialysis or preemptive transplantation. Comorbidities related to periportal fibrosis included splenomegaly, varices with or without associated bleeding, and cholangitis. The frequency of these ARPKD-related morbidities largely reflect that in previous reports  limited computer literacy, (2) language barriers, (3) delays in completing the informed consent process, (4) burden on the local physician—the initial database design required local physicians to complete the online data entry forms using the patient unique identifier, and (5) parental expectation that genetic analysis would be part of the protocol, with return of results to the family for clinical use. Our inability to provide free genetic testing has been a particularly significant limiting factor. This issue was further compounded by a concurrent NHGRI-sponsored study We have taken a multipronged approach to address these issues, including (1) enhanced partnership with patient advocacy groups such as the Polycystic Kidney Disease Foundation to advertise the HRFDCC Clinical Database; (2) translation of the study protocol and informed consent into Spanish, French, and Portuguese; (3) enhanced central support to field family questions and assist with initial enrollment; and (4) centralized data entry using medical records obtained through a Release of Medical Information, thus obviating the burden on local physicians. In addition, we are working to improve the positive predictive value and the sensitivity of the computable algorithm for EHR-based patient discovery through a process of iterative i2b2 queries validated by manual record review. This approach has been used by others to rapidly and accurately identify a sickle-cell disease cohort within the EHR . We willA key issue that remains to be addressed is how best to incorporate genetic analysis into our protocol, both to improve enrollment and to allow analysis of potential genotype–phenotype correlations in this diverse cohort. Following the collaborative model developed between ARegPKD, the European ARPKD registry study (reviewed in this issue), and the German NEOCYST (Network for Early Onset Cystic Kidney Disease) Consortium, we are exploring mutually beneficial, cost-effective partnerships with the NIH-funded programs that are using next-generation sequencing technologies to accelerate the use of genetic analysis in clinical care (e.g., the Duke Task Force for Neonatal GenomicsIn summary, we have established a REDCap-based clinical database to compile baseline and longitudinal clinical information on patients with ARPKD and other HRFD. Our informatic analyses indicate that while ARPKD is a rare disorder, there are hundreds of patients potentially available for deep clinical phenotyping in the United States alone. Once the database is mature, well-characterized HRFD cohorts will provide an important resource for designing clinical trials to evaluate new, targeted therapeutic interventions in this spectrum of disorders.The study has been approved by the CNHS Institutional Review Board, and the consent is available in English, Spanish, Portuguese, and French, allowing recruitment of patients from North, Central, and South America.BA interpreted the data/drafted and revised the article. DK, HM, and JB developed and performed the informatics analyses. LG-W conceptualized the article, provided guidance with the content of the article, and critically reviewed and revised the article. All authors approved the final article as submitted.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


PLOS Genetics, Justice et al. link genetic alterations and neural circuitry development, revealing a novel role for the PRRG4 as a regulator of Roundabout (Robo) receptor subcellular localization in the nervous system [Achieving a correct set of neuronal connections during development is key for a healthy functioning nervous system. Autism, which is characterised by impairments in social interaction, language, and range of interests, has been hypothesised to originate from defective synaptic function and abnormal brain connectivity ,2. Moreos system .Drosophila, the decrease in Robo in the growth cone membrane of precrossing commissural neurons is regulated by Commissureless (Comm), which sorts Robo to the late endosome for degradation [Both in vertebrates and invertebrates, the Slit/Robo repulsive pathway plays a major role in regulating how commissural neurons cross the midline while they navigate towards their targets on the contralateral side of the nervous system (reviewed by ). As theradation ,7 , the di


Indoor malaria transmission reduction across sub-Saharan Africa has been attained through implementation of long-lasting insecticidal nets and indoor residual spray interventions with small-scale larval source management. Improvement of house structures in sub-Saharan Africa can lead to zero indoor malaria transmission with evidence from West Africa, East Africa and Middle East countries. Residual malaria transmission cannot be targeted well with LLINs and IRS alone, but with incorporation of house structures modifications it may be possible. Anopheles gambiae s.s. all but disappearing, leaving Anopheles arabiensis, which is known to be capable of feeding extensively on humans early in the evenings, before human go indoors, as the only remaining vector species of the An gambiae s.l. complex [In recent past, malaria control has been successful for reduction of mortality and morbidity related cases upto 438,000 malaria deaths  worldwide per annum , which i complex ; shifts  complex  and shif complex . More efAn. gambiae s. l. in doors but not for Culicine species [The main routes for mosquito house entry are eaves, open window and doors –16. The  species . ReductiThe major role to be played by the construction industry (private–public sector collaboration) and public health entomology include capacity building to human resource available in the firms already practicing construction on mosquitoes house entry control by house structure modifications which includes, house walls height increase, eaves sealing, and house window and door screening. Capacity building by introduction of modules for public health entomologists and structural engineering in colleges for adapting training curriculum to changing epidemiological and entomological determinants, more implementation or operational research.Public health entomologists, who are part of National Malaria Control Programmes (NMCP’s) across sub-Saharan Africa, have to play the role of educating the community on vector behaviour and house entry points. The shortage of public health entomologists in sub-Saharan African might be a problem to reach the rural community , but theIn Africa, the major challenges expected towards house modification for malaria control are traditions (for some tribes on house style) socio-economic status  and settMalaria control in sub-Saharan Africa should be taken as a multi-sectorial effort to maintain and exceed attained control efforts . There sThis commentary demonstrates that collaboration between public and private sectors under the national malaria control programmes to assess options for addressing residual transmission can have measurable outputs. This can be achieved under programmatic conditions through pilot studies with strong monitoring, evaluation and operational research components, similar to what has been done by the Onchocerciasis Control Programme in West Africa.


Multidimensional gradients of inorganic compounds influence microbial activity in diverse pristine and anthropogenically perturbed environments. Here, we suggest that high-throughput cultivation and genetics can be systematically applied to generate quantitative models linking gene function, microbial community activity, and geochemical parameters. Metal resistance determinants represent a uniquely universal set of parameters around which to study and evaluate microbial fitness because they represent a record of the environment in which all microbial life evolved. By cultivating microbial isolates and enrichments in laboratory gradients of inorganic ions, we can generate quantitative predictions of limits on microbial range in the environment, obtain more accurate gene annotations, and identify useful strategies for predicting and engineering the trajectory of natural ecosystems. The Hitchhiker’s Guide to the Galaxy, the Earth is described as “a computer of such infinite and subtle complexity that organic life itself shall form part of its operational matrix”1. Understanding the workings of the Earth as a deterministic computational entity remains a tantalizing object, and characterizing the relationship between organic life and the rest of the “operational matrix”  is a central theme in the environmental sciences. Although careful studies have yielded insights into how physical and chemical laws influence microbial fitness and function in response to some environmental parameters, a major challenge lies in scaling laboratory experiments to landscape-wide predictions of gene and microbial fitness  on microbial growth kinetics and metabolism7. Additionally, recent advances in high-throughput genetics can be leveraged  to rapidly identify genetic determinants important for fitness in a given growth condition11  are not environmentally relevant. To address this shortfall, we have begun to array metals and other inorganic compounds such as in an “80 metals plate” (50). By varying the inoculum, respiratory substrates, and other parameters, experimentalists can gain insights into how other dimensions of the environment influence the inhibitory potency of these inorganic ions on gene-microbe-metabolism fitness.Microbes rely on both organic and inorganic cofactors and nutrients and live in complex multidimensional gradients of beneficial, neutral, and toxic compounds plate”  to creat16. High concentrations of metals are toxic to cells, and many metals also serve no catalytic role. Therefore, resistance mechanisms to metals have evolved. Metals are toxic to microorganisms because of their redox activity and because antimetabolic metals can compete with cofactor metals for binding to biological ligands and proteins17. Not surprisingly, microorganisms have evolved mechanisms for coping with metal stress, and these mechanisms vary by microorganism, metabolic state, or metal and are different depending on the metal concentration18. As an example, iron and its interactions with other transition metals and microbial cells are fairly well studied. Iron is an essential metal for a variety of metalloproteins. Under limiting concentrations of iron, other transition metals can interfere with high-affinity iron uptake systems and metalloregulatory proteins19, but at higher concentrations, some transition metals are toxic because of their ability to catalyze the production of reactive oxygen species20. Thus, the mechanism of toxicity and the mechanisms of resistance will be different depending on the concentrations of the metals. Very few studies systematically evaluate metal toxicity under both excess and limiting concentrations of essential metals, but by quantifying the toxicity of larger panels of metals under these conditions, we can obtain “structure-activity” information for inorganic compounds and their toxicity against, for example, uptake and efflux systems (Organic life exists and evolves in a matrix of both organic and inorganic compounds. One indelible mark of this evolutionary history consists of the diverse metallocofactors incorporated into enzymes that enable chemistry impossible for catalysts composed solely of C, H, N, O, P, and Ssystems . A micro21. Against respiratory sulfate reduction, monofluorophosphate, molybdate, and perchlorate are all selective inhibitors with varying selectivities, potencies, and modes of inhibition against the central enzymes in the sulfate reduction pathway22. Some redox-active metals are more inhibitory of aerobically growing cells than anaerobic cells because they can reduce oxygen to superoxide and catalyze Fenton chemistry. By quantifying the inhibitory or stimulatory potencies of large panels of inorganic compounds against microbial isolates and enrichments carrying out various metabolic activities selective compounds can be identified and the degree of their selectivity quantified. Quantification of these tipping points will improve biogeochemical reactive transport models that incorporate predictions of microbial metabolic activities.Metal requirements and toxicity are influenced by the metabolic state of a microorganism. Microorganisms can grow with a range of electron donors, carbon sources, and electron acceptors. All of these metabolisms have unique metal requirements and sensitivities to inorganic antimetabolites and toxins. As such, metals can be selective inhibitors or promoters of different metabolisms. For example, zinc can be more inhibitory of bacteria growing under glucose catabolic conditions versus other carbon sources because zinc inhibits key enzymes in glycolysis23, nor is the elemental composition of biosphere. From this perspective, the “infinite and subtle complexity”1 of the natural world has more to do with the fractal complexity of natural gradients, heterogeneous mixtures in soil, complex water currents, and the corresponding conglomerate of microbial activity in this geochemical milieu. Thus, although we may not reach a comprehensive and flawless model of biogeochemical processes on Earth from bottom-up measurements of microbial fitness and physiology, we are likely to greatly increase the resolution of our models through careful, high-throughput experimentation.Multidimensional microbiology is poised to become the norm in the 21st century. Alongside rapidly improving computational and analytical tools, high-throughput microbial physiology will enable massively parallel measurements of microbial fitness in complex gradients of environmentally relevant conditions. Rarefaction curves from genome sequencing datasets imply that the genetic diversity of life is not infinite


This study addressed school-contextual features of social disorder in relation to sixth-grade students’ experiences of bullying victimization and mental health complaints. It investigated, firstly, whether the school’s concentrations of behavioural problems were associated with individual students’ likelihood of being bullied, and secondly, whether the school’s concentrations of behavioural problems and bullying victimization predicted students’ emotional and psychosomatic health complaints. The data were derived from the Swedish National Survey of Mental Health among Children and Young People, carried out among sixth-grade students (approximately 12–13 years old) in Sweden in 2009. The analyses were based on information from 59,510 students distributed across 1999 schools. The statistical method used was multilevel modelling. While students’ own behavioural problems were associated with an elevated risk of being bullied, attending a school with a higher concentration of students with behavioural problems also increased the likelihood of being bullied. Attending a school with higher levels of bullying victimization and behavioural problems predicted more emotional and psychosomatic complaints, even when adjusting for their individual level analogues. The findings indicate that school-level features of social disorder influence bullying victimization and mental health complaints among students. Mental health problems often begin to surface during adolescence and the school environment can play an important role in supporting young people’s well-being. Peer relations and the behaviour of others are stressors that many young people may face difficulties with at some stage. However, some youth experience additional stressors related to the broader social environment at school that can also negatively influence their mental health. The current study investigates the role of behavioural problems in terms of conduct disorder and hyperactivity and bullying victimization as school contextual stressors and how these relate to adolescents’ emotional and psychosomatic health complaints.Stemming from criminological literature, social disorganization theory  proposesWhen applied to the school context, expressions of social disorganization may signal to students that the school social environment is volatile and unsupportive ,5,6. InvComparatively little research has examined the effects of behavioural measures of school disorganization on student health. School climate research shows that perceiving a supportive social environment is associated with less bullying victimization ,10 and bHowever, it is important to consider both individual and school-level effects in these associations because they reflect different types of social processes. Through social disorganization processes, the presence of bullying and other behavioural problems in a school  may create a stressful social environment and elevate students’ anxiety, thus “spilling over” to other students’ well-being. Therefore, greater bullying and behavioural problems in a school may be associated with poorer mental health among students irrespective of their own behavioural problems and experiences of bullying victimization.(1)Is a larger concentration of students with behavioural problems within a school associated with an increased risk of bullying victimization among its students?(2)Is a larger concentration of students with behavioural problems within a school associated with more emotional and psychosomatic health complaints among its students?(3)Is a larger concentration of students who are bullied within a school associated with more emotional and psychosomatic health complaints among its students?Accordingly, focussing on school-aggregated measures of behavioural problems and bullying victimization whilst simultaneously adjusting for their student-level analogues as well as the sociodemographic composition of schools, the following research questions will be addressed:The study draws on data from the Swedish National Survey of Mental Health among Children and Young People carried out in 2009 ,29. The The current study focused on behavioural problems and bullying victimization, as well as two types of mental health complaints: emotional and psychosomatic complaints.Behavioural problems were examined using the conduct and hyperactivity subscales of the Strengths and Difficulties Questionnaire (SDQ) . The folBullying victimization was based on a three items subscale  from the KIDSCREEN-52 quality of life questionnaire ,32: If yEmotional complaints were assessed using 13 items also from the KIDSCREEN-52 instrument ,33. The Psychosomatic complaints were captured by the PsychoSomatic Problems scale (PSP) , which iWithin each school, the mean response on bullying victimization and behavioural problems were calculated to form aggregated school-level measures.As proxy controls for school sociodemographic factors are often associated with student mental health, school-specific information about the proportion of students who were born abroad and the proportion of parents with a post-secondary education was included in the analyses. This information was retrieved from The Swedish National Agency for Education’s official database .In the analyses where bullying victimization serves as the dependent variable, two-level binary logistic regression models were performed using the ‘xtmelogit’ command in Stata 14. First, the between-school variation in bullying victimization was calculated through an empty model. Two additional models were fitted. In Model 1, we examined if behavioural problems at the individual level increased the risk of being bullied. In Model 2, the aggregated school-level measure of behavioural problems was added in order to assess whether there were any additional school contextual effects of behavioural problems on bullying victimization. In Model 2, also the school-level control variables measuring school sociodemographic characteristics were included. In all models, the intra class correlation coefficient (ICC) was calculated. ICC for binary outcomes provides approximate information on the share of the total variation in the outcome variable that can be attributed to the school-level.Emotional and psychosomatic complaints were analysed by means of two-level linear regression models, using the ‘xtmixed’ command in Stata 14. Scores for emotional and psychosomatic complaints were transformed into z-scores  so that results could be expressed in standard deviations and more easily comparable across the two outcomes. Also for these outcomes, an empty model was first fitted in order to evaluate the between-school variation in emotional and in psychosomatic complaints. Four additional models were estimated for each outcome. Model(s) 1 included gender and bullying victimization at the individual level. Model(s) 2 added behavioural problems at the individual level. Model(s) 3 added the aggregated school-level measures of bullying victimization and of behavioural problems, and Model(s) 4 finally controlled for school-level sociodemographic characteristics. ICC was calculated for all models, presenting the proportion of variation in the dependent variable that can be attributed to school-level differences.Descriptive statistics of the sample are presented in This study examined features of school-contextual social disorder in relation to sixth-grade students’ experiences of bullying victimization and mental health complaints, both of which are important precursors of later expressions of severe mental ill health ,36 and tWith regards to bullying victimization, we found that at the individual level, behavioural problems increased the risk of being bullied, reflecting findings from earlier studies ,25,26,27The analyses also showed that sociodemographic characteristics of the school were linked with both bullying victimization and mental health complaints. In accordance with previous research on Swedish data ,43, the The study also demonstrated clear links between social disorganization at the school-level and students’ mental health complaints. Larger concentrations of behavioural problems and of bullying victimization were associated with more emotional and psychosomatic complaints, even when adjusting for students’ own behavioural problems and experiences of bullying victimization. These results reflect and extend those from earlier studies which showed that the occurrence of bullying victimization among classmates is associated with poorer mental well-being, even among students who are not directly exposed themselves ,18,19,20This study was based on a total sample of Swedish sixth-graders, and thus the findings present a picture of the broader student population that is rarely captured. Nevertheless, there are also limitations. The data were cross-sectional and investigations of longitudinal associations are needed to better understand causal links and long-term impacts of social stressors on student well-being. Although KIDSCREEN-52’s social acceptance and bullying subscale is a well-established and commonly applied measure of bullying victimization ,42,45, tFinally, in an international perspective, Sweden has very low rates of self-reported bullying victimization compared to other countries ,48 and tThis study applied social disorganization theory to the school context by focusing on behaviour problems in relation to sixth-grade students’ experiences of bullying victimization and mental health complaints. It demonstrated that a school context characterized by social disorder is associated with an increased risk of bullying victimization and with more mental health complaints, irrespective of the students’ own behavioural problems and experiences of bullying victimization as well as school sociodemographic factors.The findings are consistent with the assumptions of social disorganization theory  in that


The evolution of methods to assess genotoxicity of test compounds is thought to be one of the important subjects in The Japanese Environmental and Mutagen Society (JEMS). In 1970, the Ministry of Education of Japan (at that time) organized a research group , and started a systematic research on the genotoxic effects induced by chemical substances. Considering the importance of this issue through the outcomes of the research group, JEMS was established in 1972, and President Tazima organized the 1st annual meeting in the August in Tokyo with the participation of experts in this field working in national institutes, universities and others in Japan. The discovery that food additives possessed genotoxic potential triggered various scientific activities in the field of genotoxicity. Another important point was the correlation between genotoxicity and carcinogenicity, in which the establishment of the reverse mutation assay played an important role. Other critical factors, such as side effects of drugs, occupational cancer, and environmental pollution due to genotoxic chemicals, emphasized the importance of genotoxicity tests for human safety. The tests performed to assess genotoxicity from 1960s to 1980s will be described to understand that many different genotoxic methodologies were discussed in these periods. Food additives and genotoxicity tests are interrelated, in which the most important food additive is 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (AF-2). Initially, I would like to introduce the words written by M. Ishidate, Jr. who was the first Director of the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan: “The safety of AF-2 used in tofu (bean curd) as a germicide was questioned in Japan a few years ago. Initially, geneticists pointed out that the AF-2 was mutagenic in microorganisms, such as bacteria, and was clastogenic in cultured human lymphocytes. Subsequently, its carcinogenicity in mice was demonstrated, after which administrative measures were taken to regulate the use of AF-2 .” In 197Salmonella typhimurium, the so-called “Ames test.” His research group examined approximately 300 substances using Ames test and found a high correlation between carcinogenicity and genotoxicity, indicating that this test could be used for the screening of carcinogenic chemicals as it consumed less time. However, AF-2 initially showed negative results in Ames test with bacterial strains such as TA1535 and TA1538. Therefore, new and more sensitive test strains were constructed, such as TA100 and TA98, by introducing the plasmid pKM101 into TA1535 and TA1538 strains, respectively. Both TA100 and TA98 strains showed positive results with AF-2, particularly in TA100 [mucAB genes on pKM101 although they were not well studied at that time. About thirty years later, it was revealed that mucAB genes encode a DNA polymerase R1 related to translesion DNA synthesis, which causes mutation due to mis-incorporation of bases opposite DNA lesions generated by chemicals, such as AF-2. Consequently, five to six tester strains, including TA100 and TA98, were used as standards in routine testing for the reverse mutation assay. The relationship between genotoxicity tests and food additives is close, as mentioned above. I would like to describe an outline of the evolution of genotoxicity tests at the initial stage (1960’s to 1980’s).At the beginning of 1970s, Prof. B. N. Ames developed, as a new test system for genotoxicity, the reverse mutation assay using Around 1945, certain chemicals were recognized to possess genotoxic potential, but the situation at such a preliminary stage is omitted here. In 1965, Food Sanitation Council in Japan published Standards for Designation of Food Additives and for Revision of Use Regulation of Food Additives, in which only two tests, namely, acute toxicity test and chronic toxicity test were adopted for toxicity evaluation .One of the notable food additives prior to the emergence of AF-2 was sodium cyclohexylsulfamate (“cyclo”). This substance, which was approved in 1956 as a food additive in Japan, was used worldwide. In 1968, however, the Food and Drug Administration (FDA) of United State announced that some metabolites derived from “cyclo” were responsible for chromosomal damage in experimental animals. In 1969, US government announced that “cyclo” was carcinogenic in experimental animals and prohibited its use . Back agFirst screening testMore than two test systems using microorganisms with different characteristicsExamination of chromosomal aberrations using cultured mammalian cellsDrosophila or recessive mutations based on specific-locus method using silkwormsExamination of sex-linked recessive lethal mutations using Second screening testMetabolism, and host-mediated assayIn vivo chromosomal aberration testDominant lethal testSpecific-locus test using miceBiotransformationIn vivo test using mammalsIn 1973, the issue of AF-2 occurred by findings that AF-2 induced mutagenicity and DNA damage in microorganisms and clastogenicity in cultured human lymphocytes and rat bone marrow cells. The use of AF-2 was prohibited officially in 1974 following the demonstration of its carcinogenicity in mice. In response to this, several administrative correspondences were published, including the Interim Standard of Genetic Safety Evaluation of Food Additives issued by the Joint Committee of Toxicity and Food Additives in the Food Sanitation Council. The genotoxicity tests adopted in this standard are as follows :First scAccording to the standard, the second screening test should be performed on those substances that show positive results in the first screening test or on those substances that are judged very important , even though negative results were obtained. In the second screening test, chromosomal aberration test using cultured mammalian cells and/or gene mutation tests using insects should be conducted. When substances show positive results in the second screening test or are judged very important, even though negative results were obtained in the second screening test, in vivo tests using mammals should be performed .S. typhimurium TA1535, TA1536, TA1537 and TA1538 or Escherichia coli WP2 should be conducted in the first screening test, and test organisms such as E. coli Sd-4, Saccharomyces cereviciae 1765-5A and Neurospora crassa ad-3 could be included. In addition, the DNA repair (damage) test using Bacillus subtilis rec+/rec− (Rec-assay), E. coli pol+/pol−, S. typhimurium hrc+/hrc− are indicated, and the metabolic activation system using liver homogenates from 2 or 3 mammals such as rats and mice should be adopted in the above tests. For the second screening tests and in vivo tests, some practical recommendations are made in the guidelines, for example, as the use tester strains for the mouse specific-locus test, the PW strain developed by Kiyoshi Tutikawa of the National Institute of Genetics of Japan is described, in addition to the PT strain developed by W. L. Russell and the HT strain developed by M. F. Lyon [According to the implementation guidance of this standard, the reverse mutation assay using B. subtilis (rec+/rec−) (including metabolic activation) and E. coli  (liquid and solid method)DNA repair test using S. typhimurium  (including metabolic activation)Reverse mutation assay using Tests using microorganismsChromosomal aberration test using Chinese hamster cells  (including metabolic activation) and human diploid cells (HE2144)Sister chromatid exchange test using Chinese hamster cells (Don) (including metabolic activation) and human diploid cells (HE2144)Micronucleus test using cultured mammalian cellsChromosomal aberration test using rat bone marrow cellsTests using mammalian cellsSpecific-locus test using silkwormsDrosophilaTest (M-5 method) using Tests using insectsIn 1973, the MHW founded Carcinogenicity Research Group for technical development of short-term screening tests of chemical carcinogens. In 1975, the research group of Technical Development of Short-Term Screening Tests of Chemical Carcinogens by Utilization of Genotoxicity Tests”  and the research group of Animal Experiments of Carcinogenicity on Genotoxic Chemicals”  was organized. About 30 substances were evaluated by the Short-Term Screening Tests group for a period of one year, and genotoxicity tests primary used by this group are as follows :Tests usAccording to the guidelines, when test substances showed positive or inconclusive results in the screening group, they were examined by the carcinogenicity test using experimental animals, according to their social demand or production volume. In this way, the usefulness of diverse genotoxicity tests was investigated.Reverse mutation assay using bacteriaDNA repair test using bacteriaChromosomal aberration test using cultured mammalian cellsMicronucleus test using mouse bone marrow cellsDominant lethal test using mice or rats.Feasible testsGene mutation test using bacteriaGene mutation test using insectsGene mutation test using cultured mammalian cellsSister chromatid exchange test using mammalian cellsUnscheduled DNA synthesis test using mammalian cellsSpecific-locus test using miceReciprocal translocation test using mice or ratsSpot test using miceTests with requirement for further considerationsChromosomal aberration test using insectsMitotic recombination or gene conversion tests using yeastsCell transformation test using cultured mammalian cellsTests with technical difficultiesIn 1979, the Carcinogenicity Research Group of the MHW tried making a tentative selection from many genotoxicity tests based on the data obtained previously and the trends in overseas as follows [The drug for human use is one of the representatives among various chemical substances. The Thalidomide case in 1961 led to reviewing and strengthening the pharmaceutical regulatory system as well as the guidelines for testing the reproductive toxicity of drugs, which were established in 1965. In 1967, the Basic Policies for Approval to Manufacture Drugs was issued in the form of a notification by the Director General of the Pharmaceutical Affairs Bureau, the MHW . In 1980In 1982, the MHW organized a research group of experts to establish the guidelines for toxicity tests of drugs and undertook a review of the guidelines in Japan, referring to those of other countries [A correlation between chemicals and occupational cancer attracted attention since 1965 and became a public health concern in 1975. Therefore, the Industrial Safety and Health Law was established and enforced by Ministry of Labor (at that time), and safety measures for protection of people from occupational diseases were implemented. According to this law, prior to new chemicals being introduced into the workplace, these compounds should first be examined for adverse effects, and commensurate preventive measures should be performed. However, sufficient effective outcomes were not achieved because a definite regulatory obligation was not offered to companies. Therefore, the Industrial Safety and Health Law was revised and enforced in 1977 and implemented in 1979 [The law requires that the genotoxicity test or an equivalent or superior test should be performed to evaluate the chemical’s carcinogenicity, instead of the carcinogenicity test using experimental animals. Almost all companies performed the genotoxicity tests, and their outcomes were reported to the Ministry of Labor. The Ministry of Labor obtained opinion from experts regarding the reverse mutation assay as the most appropriate test, because the assay was found to be quick, simple and reproducible. Therefore, in 1979, the Ministry of Labor issued the Standards for Genotoxicity Tests using Microorganisms .During 1970s, environmental pollution caused by PCB became a serious problem. This issue led to the reconsideration of awareness of chemical safety, and the Act on the Evaluation of Chemical Substances and Regulation of Their Manufacture, was enforced in 1973 as the world’s first and implemented in 1974. Chemicals such as PCB with high bioaccumulation, non-biodegradation, and chronic toxicity should be designated as the Specified Chemical Substance for the implementation of required regulations.The list of tests indicated at first did not include the genotoxicity test that was added in 1984 without any explanation of test protocols . MoreoveConsideration of regulations for the substances such as agricultural chemicals, of which categories had been already regulated by other laws, was omitted.Outlines of the evolution of genotoxicity test methods are described above and essential items are shown in Fig.


Purpose This article shares learning from an innovative demonstration program integrating maternal, infant, and young child nutrition (MIYCN) and family planning (FP) services in western Kenya, providing recommendations for future work to expand MIYCN and FP integration. Description Six health facilities reorganized to integrate MIYCN and FP services and community health volunteers (CHVs) promoted MIYCN and FP in adjacent communities in Bondo Sub-County over a 1-year period. At the facility level, each provider was directed to provide both sets of services in a single room during FP, antenatal care, postnatal care, or child consultation visits (a “one stop shop” approach). At community level, CHVs were to conduct household visits equipped with new integrated materials and incorporate MIYCN and FP within community activities. Assessment Although the “one stop shop” approach, where one provider offers all integrated services in one room, was initially proposed for all facilities, this worked most effectively in the dispensary and health centers. The sub-county hospital adapted the approach such that integrated services were offered by more than one provider during a visit, with clients linked from one provider to another through same-day intra-facility referrals. CHVs were generally able to incorporate MIYCN and FP content within household visits and community activities; however some knowledge gaps were noted after initial training, necessitating additional refresher training. Conclusion This demonstration experience revealed that future replication efforts should enable sub-county team leadership, assess facility readiness, streamline data collection, build local buy-in, and prioritize dispensaries and health centers with high client loads. This paper describes the learning from a demonstration initiative implemented in Bondo Sub-County, Kenya which integrated family planning and maternal, infant, and young child nutrition information and services. The findings of this paper can be used to inform future integration efforts in Kenya and similar settings.Family planning (FP) and maternal, infant, and young child nutrition (MIYCN) are critical components of care for women during pregnancy, childbirth, and their child’s first 2 years of life. Optimal FP and MIYCN practices have mutually beneficial effects on maternal and child health and nutrition. Meta-analyses demonstrate that close birth intervals increase the risk of neonatal, child, and maternal mortality; stunting in children; and poor pregnancy outcomes  has mandated integrated services since 2009, with the National Reproductive Health and HIV&AIDS Integration Strategy  provide health education, services, and facility referrals as needed to households in their catchment areas. At the time of the intervention, CHVs provided contraceptive pills and condoms, and referred clients to health facilities for other FP methods. CHVs are supervised by a community health extension worker (CHEW) who serves as the link between CHVs and the health facility. Each CHEW supervises approximately 25 CHVs. While CHVs are expected to deliver an integrated package of information and services, gaps in counseling on FP and nutrition exist and synergies between nutrition and FP are not adequately emphasized.As part of an effort to address unmet need for FP and improve MIYCN practices, the USAID-funded Maternal and Child Health Integrated Program (MCHIP), in collaboration with the Kenya Ministry of Health, introduced an innovative demonstration program to integrate MIYCN and FP counseling and services in selected sites in Bondo Sub-County in 2011. The primary objective of the intervention was to take advantage of the synchronic timing of PPFP and MIYCN messages and interventions to enhance and strengthen linkages between these services.The purpose of this paper is to establish the feasibility of integrating FP and MIYCN into existing antenatal, maternity, postnatal, and child health services. Recommendations are offered for future work to expand MIYCN and FP integration in Kenya and similar settings.The demonstration took place in six health facilities and adjacent community units in Bondo Sub-County, Siaya County, Nyanza Region over the course of 1 year , and FP consultations. The intended approach involved: (1) realigning services so that clients could receive MIYCN and FP services in the same room, offered by the same provider ; (2) training service providers and providing ongoing supportive supervision on MIYCN and FP in the six health facilities; and (3) introducing evidence-based MIYCN-FP communication materials  to support provision of integrated services. Due to limited funding, birth attendants were not trained in nor could offer immediate postpartum IUDs and tubal ligation. However, in order to respond to observed gaps in provision of long-acting FP methods, providers were offered coaching and continuing medical education on these skills during the program period.At community level, the program sought to strengthen existing community FP and nutrition activities. The approach involved: (1) training CHVs and their supervisors, CHEWs, on the links between MIYCN and FP and how to integrate the two services; (2) engaging CHEWs and Sub-County Health Management Teams (SCHMTs) to provide supportive supervision to CHVs; (3) orienting CHVs and CHEWs on use of existing nutrition and FP materials and newly developed MIYCN-FP communication materials ; and (4) incorporating MIYCN-FP within existing community activities, such as CHV home visits, community dialogues, mother support groups, and health action days.Training for facility providers and CHVs used participatory approaches with training modules that included content on the rationale for integration , key MIYCN and PPFP concepts, common barriers and facilitators for use of nutrition and FP services, an overview of strategies for integrating services, orientation to the communication materials and supplemental registers, practical review, and action planning.Findings and lessons learned are drawn from multiple sources Table . After i“one stop shop” approach  thought it improved quality of services. No respondents perceived that it decreased the quality of services. When asked how knowing that FP services were available affected their willingness to come to the clinic that day, 74% of clients said that it increased their willingness; no clients indicated that it decreased their willingness to come for services that day.During supportive supervision visits, most service providers demonstrated knowledge of MIYCN-FP integration. However, supervision visits after the initial training revealed gaps in CHV knowledge about PPFP, especially in regard to return to fecundity, LAM criteria, and the transition to other modern methods. Supervisors noted that health workers gave more emphasis to breastfeeding as compared to complementary feeding and maternal nutrition information. As a result, refresher trainings were held across sites to discuss challenges and address knowledge gaps. After refresher trainings, supervision teams noted enhanced CHV counseling skills and ability to convey MIYCN-FP information.Supervision visits revealed that except for IUDs and female condoms, FP commodities were generally available at the six health facilities. Temporary stock-outs of implants occurred at some facilities in light of widespread demand for this method. One facility in-charge noted, “There is still need to train providers in the maternal department on how to administer long-term FP methods, which all of them lack [training on].”Health facility staff generally recognized benefits of integrating services. For example, one health center in-charge noted “… for the women who come this side, it is an advantage to them because it is time saving… because rather than telling them to go to the FP room after coming here, she gets everything in one room, one stop shop.” Another provider mentioned, “The client is able to get this method without necessarily moving from one point to another point…it has also reduced the waiting time of this client.” However, several staff and facility in-charges reported concerns with workload associated with the integrated approach. Infrastructure limitations, including lack of availability of dedicated private space for provision of integrated services, were also cited as a barrier to the “one stop shop” approach.Facility providers and CHVs experienced challenges with completing the supplemental registers. During an early round of supportive supervision, these registers were observed to be only partially completed, not complete, or could not be traced. Health workers indicated that the supplemental ledger added to their workload and they prioritized completing either the government registers or the supplemental register. Over time and with coaching during the supervision visits, improvements in data collection were noted, but not to a level where data from those registers could be used to monitor program performance.During supportive supervision, providers reported marked increases in the number of FP clients at demonstration sites since the rollout of integrated services. The Bondo Contraceptive Prevalence Rate (CPR) Survey, a representative survey of the whole sub-county conducted in 2014, revealed that Bondo had an impressively high CPR, considerably higher than the Nyanza Province (now Nyanza Region) rates from the KDHS 2008–2009. LAM represented 4% of the contraceptive method mix, whereas the KDHS 2008–2009 revealed less than 1% use of LAM within the method mix in Nyanza  is extremely low (Moore et al. At the community level, program implementers should consider engaging champions to promote optimal practices alongside CHVs, and incorporate specific activities to reach men, grandmothers, and other family and community members, who play an important role in influencing MIYCN and FP practices in Kenya (Nyanga et al. how to operationalize integration of services to reduce missed opportunities for care. It highlights that there are complexities that are not always fully comprehended at the start of the endeavor. The integration initiative demonstrates feasibility of integrating MIYCN and FP services at health centers and dispensaries, complemented by community-level integration activities. Additional small-scale replications with robust evaluation components are needed to assess impact on FP unmet need, exclusive breastfeeding, and other infant and young child nutrition outcomes and should be conducted in other parts of Kenya or other countries in the region with different cultural or social contexts before going to full scale. Changes in practices and use of services should be closely documented. Attention will be needed to monitor the adaptation that will inevitably be needed to fit with those new contexts.This process learning makes an important contribution to the global dialogue on


Lack of adherence to procurement policiesLack of an effective coordinating bodyMisalignment of laboratory policies, treatment guidelines, and minimum service packagesCountries have had mixed results in adhering to laboratory instrument procurement lists, with some limiting instrument brand expansion and others experiencing substantial growth in instrument counts and brand diversity. Important challenges to advancing laboratory harmonization strategies include: Lack of adherence to procurement policiesLack of an effective coordinating bodyMisalignment of laboratory policies, treatment guidelines, and minimum service packagesCountries have had mixed results in adhering to laboratory instrument procurement lists, with some limiting instrument brand expansion and others experiencing substantial growth in instrument counts and brand diversity. Important challenges to advancing laboratory harmonization strategies include: In 2014, the Joint United Nations Programme on HIV/AIDS released its 90-90-90 targets, which make laboratory diagnostics a cornerstone for measuring efforts toward the epidemic control of HIV. A data-driven laboratory harmonization and standardization approach is one way to create efficiencies and ensure optimal laboratory procurements. Following the 2008 “Maputo Declaration on Strengthening of Laboratory Systems”—a call for government leadership in harmonizing tiered laboratory networks and standardizing testing services—several national ministries of health requested that the United States Government and in-country partners help implement the recommendations by facilitating laboratory harmonization and standardization workshops, with a primary focus on improving HIV laboratory service delivery. Between 2007 and 2015, harmonization and standardization workshops were held in 8 African countries. This article reviews progress in the harmonization of laboratory systems in these 8 countries. We examined agreed-upon instrument lists established at the workshops and compared them against instrument data from laboratory quantification exercises over time. We used this measure as an indicator of adherence to national procurement policies. We found high levels of diversity across laboratories’ diagnostic instruments, equipment, and services. This diversity contributes to different levels of compliance with expected service delivery standards. We believe the following challenges to be the most important to address: (1) lack of adherence to procurement policies, (2) absence or limited influence of a coordinating body to fully implement harmonization proposals, and (3) misalignment of laboratory policies with minimum packages of care and with national HIV care and treatment guidelines. Overall, the effort to implement the recommendations from the Maputo Declaration has had mixed success and is a work in progress. Program managers should continue efforts to advance the principles outlined in the Maputo Declaration. Quantification exercises are an important method of identifying instrument diversity, and provide an opportunity to measure efforts toward standardization. In 2014, the Joint United Nations Programme on HIV/AIDS (UNAIDS) released targets of testing 90% of people living with HIV/AIDS, placing 90% of those with HIV/AIDS on antiretroviral therapy, and ensuring that 90% of those on antiretroviral therapy are virally suppressed.In 2008, a consensus meeting on clinical laboratory testing, harmonization, and standardization was held in Maputo, Mozambique. Representatives of governments, multilateral agencies, development partners, professional associations, and academic institutions sought to address overarching laboratory challenges that had limited the scale-up of services for tuberculosis, malaria, and HIV diagnosis and care.Those attending the meeting—120 experts and policy makers from 33 countries, including representatives from 28 sub-Saharan African countries—were invited to reach a consensus on technical and operational guidance for strategic planning for responsive laboratory development. Participants recognized a need to address the challenges limiting the uptake of diagnostic services in resource-limited settings. These challenges included lack of or insufficient leadership and advocacy, human resources, national laboratory policies, strategic and financial planning, physical infrastructure, supply chain management, and quality management systems.,To address these issues, participants recommended that countries adopt a tiered laboratory system strategy within a harmonized network. A tiered laboratory system features stratified levels of laboratories  based upon agreed testing services, with each level offering increased technical testing complexity and capacity . This tiA tiered laboratory system, within a harmonized network, is critical to strengthening public health laboratory services.In addition to the call for government leadership in the Maputo Declaration, the meeting resulted in technical and operational recommendations to guide the harmonization and standardization of clinical laboratory testing in developing countries. Key recommendations from group breakout sessions included the following:Prioritize laboratory system coordination by developing national laboratory policies, establishing departments of laboratory systems within ministries of health, and calling upon donors and partners to support national governments in this effort.Define and establish the minimum test offerings required at each level of an integrated, tiered laboratory network, as well as the associated diagnostic instruments, equipment, and human resources required to provide such services.Prioritize supply chain systems and maintenance and service contracts for laboratory-based equipment at all levels of the laboratory network.The 2008 Maputo Declaration recommended prioritizing coordination of national laboratory systems.Following the 2014 Ebola outbreak in Western Africa, a follow-on harmonization meeting was held in Freetown, Sierra Leone, in October 2015. This meeting extended the call for international and local laboratory partners to increase capacity and further emphasized the need to develop tiered laboratory networks. The Freetown meeting brought together the African Society for Laboratory Medicine, WHO-AFRO, and ministry of health officials from more than 20 countries in Africa. The meeting resulted in the “Freetown Declaration on Developing Resilient Laboratory Networks for the Global Health Security Agenda in Africa,” which announced the need to effectively integrate tiered laboratory networks into disease surveillance and public health institutes.From 2008 to 2015, expenditures for laboratory instruments and commodities have increased substantially among all countries, with the aim of addressing access to critical HIV-related laboratory services. PEPFAR, The Global Fund, CHAI, and others have led efforts to expand coverage of diagnostic instrumentation as part of the global response to the HIV epidemic. Between 2007 and 2016, the United States Agency for International Development’s (USAID’s) primary PEPFAR procurement mechanism was PFSCM’s Supply Chain Managment System. USAID’s financial contribution through this mechanism toward instrument procurements and laboratory commodity requirements increased from US$33,759,096 (2008) to $82,152,562 (2015) following the Maputo Declaration, for a total contribution of $511,475,320 across 43 countries.Now 8 years after Maputo, we review in this article how this financial and technical support has enhanced efforts to implement harmonization strategies as part of scale-up efforts. The terms “harmonization” and “standardization” are often used interchangeably among laboratory practitioners and policy makers. Here we define “laboratory harmonization” as a process of coordinating host country governments and stakeholders in the procurement and placement of laboratory products within a defined tiered laboratory network. This process is informed through consultation with key stakeholders, such as physicians, program leads, laboratory professionals, and procurement officers to develop technical policies. We define “standardization” as the process of implementing and adhering to the established technical policies.Standardization is the process of implementing and adhering to established technical policies.Laboratory harmonization is the process of coordinating governments and stakeholders in a defined tiered laboratory network.Harmonization and standardization efforts offer considerable benefits. In South Africa, an integrated and standardized tiered service delivery model for CD4 (cluster of differentiation 4) testing could improve turnaround times by ensuring appropriate placement and integration of POC technologies within the conventional tiered laboratory structure. These efforts demonstrated a reduction of R125 million (US$8.8 million) in HIV/AIDS program costs annually.Establishing minimum diagnostic test offerings and standardized testing methods within the tiered health network.Reducing variation in laboratory products across different facilities, thereby improving commodity logistic systems, standardized quality control practices, and quality assurances.Simplifying the identification and quantification of laboratory-based products.Training laboratory staff more efficiently.Improving coordination in laboratory instrument procurement, maintenance, and placement practices.Laboratory harmonization and standardization offer many benefits, including reduced costs and improved turnaround times.Over the past 9 years, PFSCM’s Supply Chain Management System, a project funded by PEPFAR and administered by USAID, facilitated laboratory harmonization and standardization workshops in 7 African countries at the request of the respective ministries of health. The USAID | DELIVER PROJECT and U.S. Centers for Disease Control and Prevention (CDC) with PEPFAR provided direct assistance for an eighth workshop. These workshops were held in a mix of PEPFAR-supported sub-Saharan African countries . In general, requests for workshops were initiated to address HIV supply chain challenges  as well as suboptimal instrument placement and high levels of instrument diversity related to increasing numbers of donated instruments for rapid scale-up of HIV programs.Facilitated laboratory harmonization and standardization workshops were held in 8 sub-Saharan African countries.Each harmonization and standardization workshop had these overall objectives:Arrive at consensus on the methodology for harmonization and standardization.Establish national minimum test offerings and methodologies to be employed at each laboratory tier for each test.Derive an evidence-based list of harmonized diagnostic instruments to support the required laboratory services.Establish the minimum ancillary equipment requirements at each tier.Define the staffing complement required at each tier to support the recommended laboratory services.Determine a strategic implementation plan, with defined roles and responsibilities.A technical consultation document released following the 2008 Maputo meeting was used as a reference standard to initiate workshops. This document details a notional list of tiered test offerings, diagnostic instruments, and ancillary equipment, as well as human resource templates, that countries can use as a starting point to guide their laboratory harmonization efforts.We view facilitation of harmonization and standardization workshops as a 2-step process. Phase 1, at the start, is for policy stakeholders, implementers, clinicians, and key program, procurement, and laboratory staff to define what testing services are required within the health system and at what tier of the laboratory system they should be offered .In Phase 2, laboratory experts establish the appropriate diagnostic methods to be used for testing services at each tier. The experts then develop a proposed harmonized list of diagnostic instruments by tier, the necessary ancillary equipment, and the staffing required for the defined testing menu. These lists are then translated into a national harmonization and standardization policy for implementation. The instrument harmonization approach is informed by existing coverage of diagnostic instruments and the degree of instrument diversity. Standardized instrument lists should not be limited to one particular brand, but should include several brands to disperse risk across diagnostic specialties and eliminate the potential for monopolization.Past evaluations associated with implementation of the Maputo Declaration have been limited. A review of previous work on laboratory harmonization implementation focused on selection of the most appropriate tests and equipment types within the clinical cascade, as well as on how tiered networks are defined.http://www.forlabtool.com), which is a multimethod laboratory forecasting tool, developed in partnership with USAID and CHAI. Laboratory instrument data were extracted by country for multiple forecasting periods. These data would help measure adherence to instrument procurement practices against established harmonization and standardization instrument policies in the countries where we held workshops.Recognizing these limitations, we sought to measure implementation progress over time in the 8 countries in which harmonization and standardization workshops were held. We did this by analyzing available annual HIV laboratory quantification data. These data include instrument types and brands as a component of commodity forecasting over time. We organized standardized data import templates from ForLab , before we initiated the national forecasting exercises within ForLab. We performed additional validation at the conclusion of each national laboratory quantification exercise for commodity budgeting and procurement purposes. Additionally, we assessed initial harmonization and standardization proposals for potential instrument reductions by comparing existing diagnostic instrument variety against proposals that were developed at the time of each harmonization and standardization workshop (where data were available). When our harmonization workshops were held, attendees identified recurring challenges to implementing harmonization proposals. These challenges were reviewed to identify obstacles to address as part of implementing harmonization and standardization efforts.In workshops, attendees identified challenges to address when implementing harmonization and standardization efforts.The intent of this analysis is (1) to illustrate the efforts made to conduct harmonization and standardization workshops to influence laboratory development; (2) to determine how well these countries have done; and (3) to describe what potential underlying challenges must be overcome to advance laboratory harmonization and standardization efforts.,The highest levels of instrument diversity, in manufacturer brand or unique diagnostic instrumentation types, were found in chemistry and hematology . ChemistAs with CD4 testing instrumentation, glucometers and hemoglobinometers (POC devices) contribute to high instrument counts, but unlike CD4 instrumentation, these devices also contribute to high levels of instrument diversity, with ministries, donors, implementing partners, and other stakeholders procuring many brands. High brand diversity further adds to higher levels of unique commodity types. For example, a CD4 test run on a FACSCount requires a minimum of 6 different items: CD4 reagents, a control kit, clean solution, rinse solution, FACSFlow sheath fluid, and thermal paper. Thus, if a country has 5 different types of CD4 instruments, more than 30 different commodities may be required for CD4 testing alone.A CD4 test run on a FACSCount requires a minimum of 6 different items; thus, if a country has 5 types of CD4 instruments, more than 30 different commodities may be required for CD4 testing alone.Many countries are using multiple open systems  for chemistry instrumentation, which helps reduce commodity variation by allowing for sharing of reagents and general consumables, but it introduces challenges in training and variation with instrument maintenance. Hematology is a closed system market , and these systems require many commodity types to keep instruments operational.Following HIV harmonization and standardization workshops, participants proposed substantial reductions in instrument diversity, ranging from a 17% reduction in Country D’s existing CD4 instruments to a high of 88% for Country H’s chemistry testing instruments . As mentWe compared the earlier adopters of the Maputo Declaration—Country B (2012), Country C (2007), Country F (2009), and Country G (2007)—and found notable differences between countries in implementation and adherence to harmonization strategies .Different countries had different levels of implementation and adherence to harmonization strategies.,Country B and Country G have been successful at limiting instrument brand expansion. Country B’s success is partly due to PEPFAR, which has historically provided funding for and coordinated closely with partners and the ministry of health around procuring laboratory instrumentation with the goal of complying with standardized instrument lists. Country G has succeeded by limiting commodity availability and supporting procurement and distribution of commodities only for approved instrumentation. Both of these countries have improved national laboratory forecasting efforts, which are now led by national quantification committees and have directly influenced commodity availability and improved laboratory logistic system proficiency due to reduced commodity counts. For example, as part of its harmonization efforts, Country G designed an initial laboratory logistics system in 2007 that reduced commodity types from more than 400 down to 185 HIV-specific products. Once the national logistics system was established and institutionalized, the commodity profile was later expanded to include a full array of diagnostic products (more than 380), further expanding the breadth of services offered and improving the overall planning and procurement practices associated with laboratory service delivery overall, not just HIV-related services.National laboratory quantification committees can directly influence commodity availability and improve laboratory logistic systems.,Conversely, Country C and Country F appear to have had less success in implementing an approach that would reduce instrument diversity, and instead have experienced substantial growth in brand diversity. Country F has seen marked increases in chemistry and hematology instrument diversity, much of which was driven by POC technology, with molecular instrumentation being the only diagnostic area that has remained constant. As stated earlier, in many countries the coordination efforts associated with implementing national laboratory plans and adherence to harmonization and standardization policies have been inconsistent and frequently problematic.Another 4 of the evaluated countries—Country A, Country D, Country E, and Country H—have developed harmonization and standardization proposals only within the last 3 years, so it is difficult at this point to determine how well these countries will succeed at advancing their procurement practices to better align to their proposed strategies.Throughout the harmonization and standardization efforts facilitated by PFSCM’s Supply Chain Management System, in-country program leads, stakeholders, and workshop participants expressed recurring challenges in advancing harmonization strategies. Overall, 10 recurring challenges were identified across countries: the structure of and lack of adherence to existing procurement policies, misalignment of service delivery policies and guidelines, lack of defined laboratory tiers, lack of an effective coordinating body responsible for laboratory harmonization, and issues with equipment maintenance, data availability, managing frequent shifts in technology, human resources, competing priorities, and political agendas. To advance the harmonization and standardization agenda at a national level, we believe that 3 of the challenges identified by participants are the most important to address: (1) lack of adherence to procurement policies , (2) lack of an effective coordinating body, and (3) misalignment of laboratory policies, treatment guidelines, and minimum services.Across countries, 10 recurring challenges to laboratory harmonization have been identified.There are high levels of instrument diversity in laboratory diagnostic instruments, equipment, and services across health facilities. The lack of coordination in the procurement and deployment of laboratory equipment contributes to different levels of compliance with service delivery standards across facilities that provide similar levels of care.Compounding this challenge, procurement agents and national governments may see reducing instrument diversity as reducing competitiveness. They may assume that limiting the number of types of diagnostic instruments will lead to sole and single sourcing of instruments and reagents, creating monopolies and restricting competition, which contradicts most country-level procurement regulations.If harmonization and standardization policies were static, this argument could hold true, but policies must be dynamic and based on instrument and vendor performance. In addition, over time, systems and clinical demands shift, technology advances, and existing instruments age and become obsolete. Countries thus must update standardized instrument lists to align service delivery expectations and ensure that laboratories can provide the necessary services with instruments that perform well, with reliable vendor support. Monitoring instrument and vendor performance should be continuous. These performance measures have traditionally been linked to commodity logistics systems, which are based on procurement lead times and instrument repair response times that inform replenishment of reagents. Historically, these systems have had challenges, but with meaningful technical support and investment from PEPFAR, commodity logistics systems are improving. Harmonization and standardization policy reviews should occur at a minimum of every 2 years, and should use annual laboratory quantification and logistics data to measure progress and general instrument and vendor performance, but also to assess the potential for introducing new technology.Harmonization and standardization policies must be dynamic and based on instrument and vendor performance.Many countries do have a national laboratory directorate or coordinating body responsible for guiding laboratory development, but they are unable to prioritize laboratory harmonization and move the harmonization agenda from proposal to actual policy. This may be due to national priorities or political agendas, with laboratory technical working groups operating without a formal mandate or authority. Formalizing laboratory technical working groups with specific terms of reference, authority, and accountability would support advocacy efforts and help finalize harmonization and standardization proposals, as well as guide implementation.Additionally, technical working groups should be charged with monitoring instrument procurement and placement, as well as laboratory technology development. This will ensure that ministries of health define processes for evaluating new technologies before they are deployed. The working groups should also guide ministries in developing policy for laboratory network development and other national laboratory interests. Once policy is finalized by the technical working groups, it is critical to ensure stakeholder adherence to standardization of procurement practice, as well as instrument placement.Technical working groups should be charged with monitoring instrument procurement and placement, as well as laboratory technology development.In many countries, laboratory policies, minimum packages of care, and national HIV/AIDS care and treatment guidelines are not aligned at the time of harmonization and standardization workshops. Laboratory and treatment policies and guidelines may have been updated with differing frequencies and without coordination between laboratory staff and clinicians. Many laboratories may have been providing tests that were outdated or not aligned with the minimum care needs by tier, or tests that were not clearly defined within existing laboratory policy and/or strategy documents.Laboratories may provide tests that are outdated or not aligned with the appropriate tier’s minimum care needs.For example, the harmonization and standardization effort in Country A began with a review of the country’s laboratory strategic plan, the essential health service package, the integrated health service plan, and the HIV/AIDS care and treatment guidelines. In Country E, a policy review was initiated with the country’s norms and standards for medical laboratories, the laboratory strategic plan, and the HIV/AIDS prevention and treatment guidelines. When long-standing strategic plans cover many years and HIV treatment guidelines are more dynamic, these documents can quickly diverge in regard to priorities, implementation planning, and overall expectations associated with laboratory service delivery.Additionally, budget growth and scale-up efforts for laboratory, program, and clinical needs increasingly diverge, further widening the gap between clinical needs and laboratory service capacity.In most cases, the harmonization and standardization workshops were the first time clinicians and program staff had met in a large forum to discuss laboratory service delivery challenges, to define minimum test offerings by tier, and to advance a coordinated and aligned way forward.To address these challenges, it is important to ensure that when treatment guidelines or minimum packages of care are updated, laboratory personnel have the opportunity to inform decision makers of existing laboratory capacity and scalability. Laboratory, clinician, and program staff should be engaged frequently to ensure that the laboratory network evolves to meet clinical and program needs. Laboratory investigations should be fully integrated into clinical and preventive protocols and programs, with the rational use of essential tests relevant to the level and type of facility.As consumers of laboratory tests, clinicians should help laboratory programs determine test offerings for each laboratory tier based on the established national health care package, clinical importance, cost, suitability to the environment, and level of expertise of the service provider and end users.Tests offered at each laboratory tier should be based on the established national health care package, clinical importance, cost, suitability, and level of provider expertise.We recognize several limitations to the analysis described here. Our current analysis targets HIV-related diagnostics only. This choice was due to the high quality of HIV laboratory data that was available. It should be noted that all harmonization and standardization workshops included all diagnostic services and were not limited to just HIV diagnostics.Our analysis targets HIV-related diagnostics only, due to the high quality of available data.,The primary measure of harmonization and standardization in this article was limited to instrument brand diversity, as a way to measure compliance to procurement from a national standardized instrument list. Other evaluations have sought to focus on appropriateness of tests and equipment types within the clinical cascade, as well as on how tiered networks are defined and implemented.Implementing a harmonization and standardization policy and demonstrating alignment to a standardized instrument list can take many years. Half of the countries included in this analysis had completed harmonization workshops before 2013, the other half completed their workshops more recently. A follow-up evaluation in a few years could identify additional challenges not considered here, or could demonstrate further compliance and success.The Maputo Declaration and, more recently, the Freetown Declaration, called on national governments to prioritize laboratory system development and emphasized the need to foster national ownership; more importantly, participants at these two meetings urged donors and partners to commit to working in close coordination to support efforts to strengthen sustainable public health laboratory systems.Although the list of tiered test offerings and diagnostic instruments included in the Maputo DeclarationOverall, harmonization and standardization efforts have been implemented with mixed success, with some countries only recently implementing measures to introduce harmonization policies. Effectively implementing a harmonization and standardization policy and demonstrating alignment to a standardized instrument list can take many years. For example, the rate of replacing existing equipment with approved instruments depends on instrument life span. Using harmonization and standardization principles as programs scale up, with new instruments purchased for replacements and network expansion at new sites, will limit growth in instrument and brand diversity. Leveraging scorecards, as recommended by the Freetown Declaration, may be another way to advance these efforts.Since the inception of the global response to the HIV epidemic, procurements of HIV-related diagnostic instruments have increased markedly. A data-driven laboratory harmonization and standardization approach is one way to ensure optimal use of laboratory-based instrument diagnostics and to create efficiencies in product procurement, placement, training, and use. This will be increasingly important to efforts to achieve UNAIDS’ 90-90-90 targets.However, less has been done to regulate procurement and reduce instrument diversity within chemistry and hematology, where critical safety monitoring tests for antiretroviral therapy are performed, or to provide highly needed general health and screening diagnostics. As a result, chemistry and hematology now represent the highest levels of instrument diversity within laboratory networks.A high level of instrument diversity has a great impact on laboratory commodity forecasting, supply chain systems, equipment maintenance, and quality laboratory service delivery. Although many years have passed since the Maputo meeting in 2008, the 2015 Freetown Declaration illustrates the continued need to improve adherence to harmonization and standardization practices. Improved coordination is required, as well as the development, implementation, and—more importantly—monitoring and updating of laboratory harmonization and standardization policies over time. Developing a tiered laboratory network, procuring from standardized instrument lists, as well as ensuring the alignment of laboratory policies, minimum packages of care, and national care and treatment guidelines, are all critical to achieving the benefits of harmonization and standardization.As donor contributions and priorities shift in response to viral load scale-up as part of the 90-90-90 effort among HIV practitioners, there is potential for less support and focus on chemistry and hematology instrumentation, as well as on other diagnostic specialties. Support for HIV programs has historically included procurement of chemistry- and hematology-related commodities and instruments, with the assumption that local governments will assume responsibility for these lower-cost tests moving forward. It is therefore critical to improve efforts to ensure that national ministries of health can expand and sustain not only their existing HIV-related laboratory services but also the general public health laboratory services, to serve broader health and surveillance needs. It is important for program managers, supply chain activity managers, and others to work with their colleagues to understand the capacity, use, and placement of instrument-based diagnostics. There is still a need to reduce excess numbers of products, improve use, decrease costs, and increase efficiency.Important gains have already been achieved within national laboratory networks, but there is still a need to ensure that countries are able to provide continued quality laboratory services in an efficient and sustainable manner. The Maputo and Freetown Declarations provide a detailed strategic approach that is critical to ensure a coordinated and sustainable laboratory development agenda to address the broader health security agenda in Africa.


In this paper we present a description of the Horizon2020, Marie Skłodowska-Curie Action funded, research and training programme CONTEXT: COllaborative Network for Training and EXcellence in psychoTraumatology. The three objectives of the programme are put forward, each of which refers to a key component of the CONTEXT programme. First, we summarize the 12 individual research projects that will take place across three priority populations: (i) refugees and asylum seekers, (ii) first responders, and (iii) perpetrators and survivors of childhood and gender-based violence. Second, we detail the mentoring and training programme central to CONTEXT. Finally, we describe how the research, together with the training, will contribute towards better policy, guidelines, and practice within the field of psychotraumatology. The goal of CONTEXT is to build capacity and expertise, and foster innovative practice and social enterprise, in the area of psychotraumatology. To achieve this goal, CONTEXT puts forward the following three interdependent objectives: (1) advance scientific knowledge regarding psychological responses to trauma across varying populations and contexts; (2) address the shortage of human resources for mental health by training highly qualified professionals with the skills to navigate the complex, contextually-specific aspects of trauma-related psychological distress across different countries, sectors, and disciplines; and (3) develop and translate evidence into innovation, improved social policy, and practice by promoting social innovation and entrepreneurial skills among the next generation of psychotraumatologists.It is increasingly recognized that an international, interdisciplinary, and intersectoral approach is required if we are to adequately and equitably address the complexities of mental health to better serve the growing needs of our global population  refugees and asylum seekers; (ii) first responders, including police officers, humanitarian workers, and individuals who work with children who have experienced direct trauma; and (iii) survivors and perpetrators of childhood and gender-based violence. These individual research projects, completed by 12 international doctoral researchers, combined with a state-of-the art mentoring and training programme, will contribute towards the achievement of objective 2. Finally, the current paper considers how achieving objectives 1 and 2 will contribute towards improved policy, guidelines, and practice within the field of psychotraumatology.1.1.In 2016, 65.6 million individuals were forcibly displaced worldwide with over one million refugees entering Europe . Evidence suggests that non-specialized personnel can provide psychological care, and that their work contributes towards reducing the treatment gap between demand and availability of mental health services for refugees, asylum seekers, and internally displaced persons . Post-migration stressors can have a greater or equivalent impact on mental health, when compared with pre-migration trauma  among asylum-seeking and refugee populations who have experienced sexual violence (Project 3). Knowledge regarding CPTSD, as per the proposed International Classification of Diseases 11th version (ICD-11) guidelines . The global mental health literature demonstrates that trauma experienced by a parental figure can adversely affect offspring and subsequent generations . Managerial and organizational factors can significantly impact humanitarian aid workers’ wellbeing  trauma risk management strategy evaluation study (Project 6). Police officers, on average, experience over three traumatic incidents for every six months of service, making them highly vulnerable to PTSD . Professionals working with survivors of child abuse are at high risk for adverse mental health outcomes . Over the last three years the number of sick days taken by PSNI officers due to poor mental health or stress has increased by more than 60%, reaching nearly 40,000 sick days last year alone  to compound one’s likelihood of experiencing violence, to perpetrate it, to recover from it, or to be rehabilitated. Projects are designed to produce recommendations for one of three partner organizations: the Probation Board of Northern Ireland (PBNI), the Danish Children’s Centres, and the Dublin Rape Crisis Centre (DRCC). However, it is hoped that the findings will also contribute to trauma-informed approaches to combatting GBV and VAC with generalizability across contexts.Investigating Childhood Trauma and Mental Health in an Offender Population (Project 9). While not all people who are maltreated as children become violent perpetrators in later life, experiencing abuse has been identified as a risk factor for criminality  from the PBNI, project 9 will examine associations between early trauma, mental health problems, and violent offending. Findings will inform recommendations for preventive intervention. Ardino, . Using aInvestigating Polyvictimization in Child Abuse Cases (Project 10). This examines multiple victimizations . The experience of sexual violence can have profound psychological effects on an individual. Despite this, few survivors seek professional help . Understanding the process whereby offenders desist from violent offending is imperative to reduce the burden of recidivism and to prevent the cycle of trauma from progressing. Psychological factors have been particularly under-investigated. This project, conducted with the PBNI, will identify both risk and protective factors that will inform strategies aimed at reducing the risk of reoffending.2.Policies and Practices for Mental Health in Europe and the EU’s Joint Action on Mental Health and Wellbeing  international networking and intersectoral collaboration by means of fellows spending at least 50% of their time in the non-academic settings; (2) interdisciplinary training by means of formal taught programmes delivered by both academic and non-academic experts from diverse backgrounds; and (3) experiencing and learning how to conduct research across academic and non-academic settings, so as to ensure that empirical findings can be efficiently translated into clinical and operational practice, ultimately improving the lives of traumatized persons and those that work with victims of trauma. The result is a unique research training designed to increase human resources for mental health in Europe. Upon completion, graduates will be in a unique position to convert their research findings into interventions and practices for social benefit, thereby contributing towards closing the existing gap between research and practice sectors.3.Mental health disorders make up a significant proportion of Europe’s overall burden of disease (Wittchen et al.,