This article provides an overview of public health efforts by the U.S. Environmental Protection Agency (EPA) during the past two decades to protect children’s health from environmental hazards. It highlights examples of concrete steps and accomplishments toward improving environmental protection and health outcomes achieved through public policy, rules and regulations, increased scientific understanding, and public health messaging. Additionally, examples of future challenges for better understanding and improving children’s environmental health are discussed. Children do not react like adults when exposed to environmental chemicals because their organ systems and metabolic capabilities are not fully developed. Children eat, breathe, and drink more, relative to their body mass, than adults. Their exposures to environmental chemicals differ from that of adults due to child-specific behaviors, such as hand-to-mouth and object-to-mouth activities, crawling on the ground, and breastfeeding. Meanwhile, research shows that exposures to environmental chemicals in homes, schools, food, and common household products may be associated with chronic conditions such as asthma, diabetes, obesity, attention-deficit disorders, learning disabilities, and autism .The efforts of the U.S. Environmental Protection Agency (EPA) to enhance consideration of the potential for early-life susceptibility stem from the 1993 National Research Council’s “Pesticides in the Diets of Infants and Children”  and the de minimis cancer risk to humans, the Natural Resources Defense Council brought suit and prevailed. The court stated that only Congress could change the provision designed to protect the public from carcinogens in processed foods and animal feeds in the Food Additives Amendment of 1958, known as the Delaney Clause  to help implement the order across the federal government. To date, the task force, co-chaired by the U.S. EPA and the Department of Health and Human Services (DHHS), has focused on issues including lead, racial and ethnic asthma disparities, healthy homes, chemical exposures, and climate change.The Executive Order required the creation of the “President’s Task Force on Environmental Health Risks and Safety Risks to Children”  in 1997. Although the agency’s mission has always been to protect human health and the environment, C.M. Browner and subsequent agency leaders have recognized that protecting children from environmental hazards required explicit and dedicated resources. The office promotes the protection of children by leading and/or partnering with other parts of the agency to ensure that actions by the U.S. EPA take into account any heightened risks faced by children, to help identify research gaps, and to encourage and expand health outreach efforts.Reaching parents. The U.S. EPA’s outreach and education efforts are designed to gather together the most important suite of key issues and public health messages on a given topic and share it widely. Outreach materials on topics such as asthma prevention, secondhand smoke, and impacts of climate change on children are available at the agency’s “Protecting Children’s Environmental Health” web site (https://www.epa.gov/children).Reaching health care providers. In the field of pediatrics, concerns about environmental influences on disease were infrequently considered in the 1990s. A 1995 Institute of Medicine report identified the lack of curricula on topics in environmental medicine in the training of physicians .ysicians . In orde edition . In 1999 in 2012 . Additiohttp://www.pehsu.net/)—a network of experts in reproductive and children’s environmental health—has been jointly funded by the U.S. EPA and the Agency for Toxic Substances and Disease Registry to provide medical advice, outreach, and training about prevention, diagnosis, treatment, and management of environmental health illnesses for children. From 1999 to 2014, PEHSU conducted approximately 8,000 consultations and educational activities, reaching more than 700,000 individuals .Exposure assessment. In the early 2000s, the U.S. EPA began a process to consider how behavioral and physiological changes associated with childhood life stages could impact exposures to environmental hazards. Although environmental laws have referred to children as a subpopulation, two important risk assessment guidance documents published by the U.S. EPA in the mid-2000s emphasized the importance of distinguishing between population groups that form a relatively fixed portion of the population  and life stages or age groups that are inclusive of the entire population. The term “life stage” refers to a distinguishable time frame in an individual’s life characterized by unique and relatively stable behavioral and/or physiological characteristics that are associated with development and growth. Thus, the U.S. EPA is evolving to view childhood as a sequence of life stages, including infancy and adolescence through adulthood, rather than considering children as a fixed subpopulation.In 2005, the U.S. EPA’s “Guidance on Selecting Age Groups for Monitoring and Assessing Childhood Exposures to Environmental Contaminants”  was publTo support implementation of the guidance, the U.S. EPA published the “Child-Specific Exposure Factors Handbook” . The infAn example of the application of these exposure tools is the use of both the age-grouping guidance and exposure factors handbook data in “Perchlorate Supplemental Request for Comments” (see Table 2 in Risk assessment. An adage in the field of toxicology attributed to the Swiss scientist Paracelsus (1493–1541) is that “the dose makes the poison.” This simplification does not take into account two potentially important factors. The first involves the issue of timing of exposure or dose, as some chemicals exhibit unique and enhanced toxicity during critical windows of development that can impact the nature and severity of disease  for those cases where chemical specific data are lacking when assessing cancer risk, but only for carcinogens that act via a mutagenic mode of action:For exposures before 2 years of age, a 10-fold adjustment.For exposures between 2 and < 16 years of age, a 3-fold adjustment.For exposures after turning 16 years of age, no adjustment.in utero exposure and chemicals that do not meet the threshold of evidence that the agency is considering for judging whether a chemical has a mutagenic mode of action. Special attention should be given to hormonally active compounds and genotoxic chemicals that do not meet the threshold of evidence requirements”  should be regarded as a group within the general population that is particularly sensitive to lead. Based on new scientific information regarding adverse neurodevelopmental outcomes  for lead (Pb) has been to protect children from the neurodevelopmental effects of airborne lead exposure . Under aoutcomes , 2013c,  in 2008 . The prehttps://www.epa.gov/ace) indicators report shows that the median concentration of lead in the blood of children between the ages of 1 and 5 years dropped from 15 μg/dL in 1976–1980 to 1.0 μg/dL in 2011–2012, a decrease of 93% (https://www.epa.gov/ace/biomonitoring-lead).The public health impact of the U.S. EPA’s regulatory actions, including the banning of lead in paint and automotive gasoline in the 1970s and 1980s, has resulted in a significant reduction of children’s exposure to lead. The U.S. EPA’s “America’s Children and the Environment”  pesticides are thought to act through a common mode of action by inhibiting nerve function through inhibition of acetylcholinesterase . Prior thttps://www.epa.gov/ace/environments-and-contaminants-chemicals-food).In addition, many agricultural uses of OPs were also restricted  or discontinued or cancelled . The risk assessment supporting these actions retained the 10-fold safety factor defined by the FQPA for the protection of children . The U.SScientific information on risks associated with chlorpyrifos exposure continues to develop, further illustrating risks to children’s health. Based on a revised risk assessment identifying drinking water and occupational risks , the U.SIn recent years, the U.S. EPA has established new regulations to address climate change under the authority granted by the Clean Air Act. The final rules controlling emissions of greenhouse gasses from light-duty (cars and light trucks) and medium- and heavy-duty vehicles are examples of such standards , 2012. Ihttps://www.epa.gov/research-grants/niehsepa-childrens-environmental-health-and-disease-prevention-research-centers) and NIEHS (https://www.niehs.nih.gov/research/supported/centers/prevention/)].Building on the imperative of the Executive Order 13045, the U.S. EPA and the National Institute of Environmental Health Sciences (NIEHS) have jointly funded the Children’s Environmental Health and Disease Prevention Research Centers since 1998. These multidisciplinary research centers examine how environmental factors affect children’s health and promote translation of basic research findings into intervention and prevention methods to prevent adverse health outcomes [see U.S. EPA .Better characterization of child-relevant exposure pathways such as soil and dust ingestion.Models that more accurately reflect the dynamic and variable nature of growth that can appropriately represent early-life stages, especially given the expanded use of physiologically based pharmacokinetic models in risk assessment.Data to illuminate possible links between early-life exposure to environmental chemicals and chronic disease in adulthood  .Improved reporting and application of epidemiology findings in risk assessment, so that the observations in children may be better used in decision-making.https://www.epa.gov/chemical-research/federal-research-recycled-tire-crumb-used-playing-fields). The continued engagement of the research community in children’s environmental health is needed to help address these challenges and protect our nation’s children for generations to come.There will remain emerging children’s environmental health concerns that have not yet been discovered or addressed. For example, questions about the safety of recycled tire crumb used in athletic fields and playgrounds has recently led to a new federal-wide (including U.S. EPA) effort—Federal Research on Recycled Tire Crumb Used on Playing Fields (Building on two decades of experience, the U.S. EPA continues to focus its efforts in three principal areas—science to better understand early-life susceptibility, consideration of children in environmental regulations, and outreach to inform health care providers and the public.Much of the U.S. EPA’s work during the past 20 years to protect children from environmental hazards can be considered primary prevention. These are actions and measures at the population level that minimize hazards to health and that inhibit the emergence and establishment of factors known to increase the risk of disease. For example, the U.S. EPA’s regulations for Pb and OP pesticides have reduced children’s exposures and thus, the potential for neurodevelopmental disease.The evolution and expansion of children’s environmental health protection over the past two decades has been remarkable. At the U.S. EPA, significant efforts have been made to address the special susceptibility of children, and our work continues to address emerging environmental concerns to ensure that children’s environments are free of hazards and support healthy development.


Mycoplasma genitalium as a cause of urethritis, cervicitis, pelvic inflammatory disease (PID), infertility and ectopic pregnancy. Commercial nucleic acid amplification tests (NAATs) are becoming available, and their use in screening for M. genitalium has been advocated, but M. genitalium’s natural history is poorly-understood, making screening’s effectiveness unclear. We used a transmission-dynamic compartmental model to synthesise evidence from surveillance data and epidemiological and behavioural studies to better understand M. genitalium’s natural history, and then examined the effects of implementing NAAT testing. Introducing NAAT testing initially increases diagnoses, by finding a larger proportion of infections; subsequently the diagnosis rate falls, due to reduced incidence. Testing only symptomatic patients finds relatively little infection in women, as a large proportion is asymptomatic. Testing both symptomatic and asymptomatic patients has a much larger impact and reduces cumulative PID incidence in women due to M. genitalium by 31.1% (95% range:13.0%-52.0%) over 20 years. However, there is important uncertainty in M. genitalium’s natural history parameters, leading to uncertainty in the absolute reduction in PID and sequelae. Empirical work is required to improve understanding of key aspects of M. genitalium’s natural history before it will be possible to determine the effectiveness of screening.There is increasing concern about  Mycoplasma genitalium, as a cause of a range of morbidities2 including mucopurulent cervicitis6, pelvic inflammatory disease (PID)11, tubal factor infertility13, and ectopic pregnancy in women18; urethritis, balanitis, posthitis and balanoposthitis in men21; and increased HIV acquisition and transmission22. An increasing array of commercial nucleic acid amplification tests (NAATs) are available, for example, the Bio-Rad Dx CT/NG/MG® assay23, many of which are non-invasive (urine-based), and using them to screen for M. genitalium has been advocated24, and this may reduce the incidence of serious, costly sequelae in women25.There is increasing concern about the sexually-transmitted bacterium, 27. Uncertainty in the natural history of M. genitalium needs to be accounted for in analyses of the likely impact of screening26. Extensive screening for Chlamydia trachomatis has been implemented by several countries – for more than a decade in England, and yet the impact of this screening is still poorly-understood28. In large part this is because natural history of C. trachomatis is still not well-understood, reflected by wide variation in the values of key parameters used in mathematical models29; only in recent years has evidence synthesis been used to improve estimates31.However, there is uncertainty in its importance as a cause of disease, whether public health intervention is justified and, if so, how best to interveneet al. “transmission dynamics and duration of infection [are] both important factors in understanding the management of [M. genitalium] in the population”14. We used a transmission-dynamic model to synthesise evidence32 from studies of the natural history and epidemiology of M. genitalium, and surveillance data, to identify the parameters that are most important in contributing to uncertainty in its transmission dynamics. We then examined the potential impact of using NAATs for (i) diagnostic testing of symptomatic patients, and (ii) diagnostic testing of symptomatic patients plus screening of asymptomatic patients, of both sexes, on incidence of infection and diagnoses in each sex and incidence of serious sequelae in women.As highlighted by Walker M. genitalium’s epidemiology is represented by compartments for asymptomatic infected individuals, symptomatic infected individuals not seeking treatment, symptomatic infected individuals seeking treatment, and women with asymptomatic, symptomatic and treated PID33. The model is stratified by sex, and into ‘activity classes’ with low, medium, and high rates of sexual partner change. Interaction between activity classes is determined by a mixing matrix, with an assortativeness coefficient specifying the amount of like-with-like interaction34. The model is summarised by the flow diagram in Fig. 30.We developed a transmission-dynamic compartmental mathematical model in which 35 and diagnosed cases were recorded. In general practice, microscopy is not used at all and people are managed according to symptoms. Women with symptoms of mucopurulent cervicitis would be treated (and the diagnosis recorded in surveillance), whilst asymptomatic women with infection would only be treated (and recorded in surveillance) through partner notification.We used surveillance data from England, where all symptomatic men and 5% of asymptomatic men attending sexual health clinics received screening for non-chlamydial non-gonococcal urethritis (NCNGU) with urethral gram stain microscopyM. genitalium, and a proportion of those will have been cured by it. M. genitalium can be treated with azithromycin, doxycycline and cefoxitin, with treatment failure rates ranging from 5–60%39. Moxifloxacin is more effective but is often reserved as a second-line treatment38.Symptomatic cases of NCNGU were given first-line treatment with azithromycin; a proportion of these cases (estimates are described below) will have been due to 44. Some parameter estimates were well-defined, including sexual partner change rates45; time-delays associated with seeking and receiving care47; the proportion of symptomatic patients abstaining from sexual activity whilst seeking care48; and the effectiveness of treatment49. Natural history parameters of M. genitalium were more uncertain, due to variation between studies of estimates or due to a lack of studies. These include the transmission probability; the proportion of infections that are symptomatic; the latent period and duration of infection; and the rate of progression to PID. In the univariate analysis, the model was run using intermediate values of all the ranges of the parameters while allowing one parameter at a time to vary between the minimum and maximum of the range. The most influential parameters were then varied in the model calibration step.To identify which parameters have the greatest impact on the model output , prior ranges for parameters values were defined, based on literature and expert opinion Table 8,9,36,40M. genitalium is not routine, we use surveillance data on diagnoses of NCNGU in men from sexual health clinics in the UK in 2000–200950, complemented by estimates of the proportion of NCNGU that is due to M. genitalium (i.e. 10–46%52). In men in the UK, there were ~65,000 annual diagnoses of urethritis due to NCNGU, ~10% of which were asymptomatic epidemiologically-treated cases50. The model was calibrated to estimated numbers of annual M. genitalium diagnoses in men , and the prevalence in women (i.e. 3.3% (95% CI: 2.6–4.1%))11. Candidate parameter sets were generated by Latin Hypercube Sampling from the prior ranges of parameters that were uncertain and influential. Parameter sets were accepted if both the annual diagnoses and prevalence fell within the specified ranges defined by the data: the female prevalence generated by the model had to fall in the range 2.6–4.1%, and the annual number of male diagnoses had to fall between 6,500–29,900 . The parameter-selection process was run until 200 accepted parameter sets were obtained , which comprise the posterior distribution. Sensitivity analysis was then performed to determine the most influential parameters, by calculating partial rank correlation coefficients (PRCCs)53.The model represents the UK population aged 18–40 years, with 10 million individuals of each sex. Since testing for M. genitalium infections in women progressing to PID of 2.1%, 4.5%, and 8.5%11.After selection of parameter sets to represent uncertainty in transmission dynamics, the model was used to examine the impact of NAAT testing of (i) symptomatic individuals of both sexes in both genitourinary medicine (GUM) and general practice (GP) clinics (plus the 5% of asymptomatic patients in GUM who were being tested by microscopy because those clinics would be unlikely to stop testing that patient group), and (ii) all symptomatic patients of both sexes in both GUM and GP clinics plus asymptomatic patients attending GUM. In addition to higher diagnosis rates, it was assumed that NAAT testing would allow for more effective treatment, so that treatment failure rates would be lower. In scenario analysis, we varied the progression rate parameter, Model code (available on request) was implemented using Matlab version 2016b.The model was able to reproduce the observed epidemiological data . In the univariate sensitivity analysis that was performed to determine which parameters would be varied in the model calibration step, the most influential parameters associated with uncertainty in the model output were proportion of infections that are symptomatic; proportion of symptomatics abstaining from sex; the proportion of those patients who seek care; time from onset to care-seeking; per-capita rate of care-seeking; proportion of patients who go to GUM, directly or via GP; sexual mixing pattern (assortativeness coefficient); transmission probabilities; proportion of partners traced; treatment failure rate; and natural recovery rates. ), natural history of infection (ϕ(f), ϕ(m), z(f), z(m), γ(f), γ(m)), use of and performance of the health service (ρ(f), dseek, fGUM, fGP), and the treatment failure proportion (ζ), prior and posterior mean values were different, indicating that the surveillance data were informative, although in most cases the prior and posterior ranges were similar.For parameters that were varied in probabilistic sampling, the prior ranges are reported in Table M. genitalium, with estimates of 155,700 , 306,000 , and 605,000  over 20 years, corresponding to proportions of untreated infections in women progressing to PID of 2.1%, 4.5%, and 8.5%, respectively . We calculated PRCCs for each parameter with respect to symptomatic male cases, epidemiologically treated male cases, and female prevalence, as well as for reductions in female and male incidence and PID prevalence . This will reduce incidence of other serious sequelae arising from PID such as ectopic pregnancy and tubal factor infertility. Using NAAT testing for M. genitalium in general practice/community and specialist settings, instead of urethral smear microscopy testing of symptomatic men in GUM and syndromic management of both sexes, greatly reduces the incidence of infection and PID, particularly when symptomatic and asymptomatic patients are tested. This is for several reasons. Firstly, coverage of testing can be greater, as it can be offered to more patients (in community settings as well as GUM), and will likely be more acceptable to men than urethral smear microscopy. Secondly, women can be tested by NAAT, meaning that treatment of infection in women is not dependent upon either having symptomatic infection or being a notified partner of a man diagnosed with infection. Thirdly, detecting infection in women then enables contact tracing to find their male partners, further-reducing infection in the population. Moreover, with antibiotic resistance in M. genitalium causing increasing concern54, an important benefit of NAAT diagnosis of M. genitalium infection rather than syndromic management of NCNGU is that it allows use of a more-appropriate treatment regimen; NAATs can detect genetic determinants of drug resistance.We find that screening for 55: specifically, incidence falls immediately and remains lower than prior to intervention, whilst the diagnosis rate initially increases and then falls, and in the long-term the diagnosis rate may be lower or higher than prior to the intervention. A diagnosis rate that remains elevated may be interpreted wrongly as indicating a failure of the intervention or even a higher incidence of infection than prior to intervention.Importantly, our modelling shows that patterns observed in rates of diagnosis differ from patterns in underlying incidence, which needs to be taken into account when assessing surveillance data, as has previously been highlighted for gonorrhoeaM. genitalium, and the impact of screening and treatment. We have identified key natural history parameters whose values are uncertain, which leads to considerable uncertainty in the magnitude of the effect of screening. Further research is required to obtain better estimates of these parameters before it can be determined how effective NAAT-based screening for M. genitalium is likely to be. Natural history studies of sexually-transmitted infections typically concentrate on women, due to concern about serious sequelae, but since most infected women become infected from men it is important to know parameter values for both sexes, to inform effective control policies. We note that results are not always as expected: in the case of C. trachomatis, established infections clear more slowly in men than women, which is the opposite of what is typically assumed31.To our knowledge, we are the first to use a transmission-dynamic model to synthesise evidence on the natural history and epidemiology of M. genitalium transmission are the proportion of infections that are symptomatic (and proportion of those that are treated), duration of untreated infection, and infectivity, in both sexes. Measurement of these parameters will involve a variety of studies56, including analysis of surveillance data; it is possible to calculate population prevalence of infection based on rates of screening and diagnosis57. To maximise the value of surveillance data it is important to have a good understanding of the processes that lead to patients being tested and diagnosed to be able to make more-precise inferences57, e.g. what proportion of diagnosed infections are in symptomatic vs asymptomatic individuals, and what is each patient’s reason for testing, e.g. due to symptoms, being a notified partner of a diagnosed case, having been at perceived risk of infection and sought a test, or having been offered screening by a healthcare provider.Our analysis shows that particularly important for M. genitalium58. Estimates of the duration of untreated infection are best obtained from cohort studies in which individuals are followed over months or years without infections being treated, which have been performed for M. genitalium in women59 (see Smieszek & White 201660 for a synthesis of those studies) but not men. Such studies are only possible where testing for and treating M. genitalium is not the standard of care. It is therefore vital to conduct studies urgently before screening and treating M. genitalium becomes common due to adoption of multiplex NAAT testing.Combining data from contact tracing with whole-genome sequencing of isolates allows estimation of the timing of transmission from person to person, which provides lower-bound information on the duration of infection; this has been done for gonorrhoea and could be applied to C. trachomatis and M. genitalium provide an opportunity for large-scale surveillance, of M. genitalium, at minimal cost, through unlinked anonymous testing for M. genitalium of samples from patients who are screened for C. trachomatis, in order to identify risk groups in whom screening for M. genitalium would be justified. Additionally, diagnosis of NCNGU requires ruling-out of C. trachomatis and N. gonorrhoeae, so using a multiplex test that detects those organisms plus M. genitalium would be a simple way to monitor the proportion of NCNGU that is associated with M. genitalium and examine associations with age, sex, and location. Such studies are important since the positive predictive value (PPV) of the test depends upon the prevalence of infection in those screened, as well as test sensitivity and specificity, and only in groups where prevalence is sufficiently high is the PPV high enough to justify screening for treatment. It might be appropriate to target M. genitalium testing by age, or according to patient characteristics 63. Geographic targeting may be appropriate, since it is likely that prevalence will vary geographically, as it does for C. trachomatis57.Multiplex NAATs that test for both M. genitalium should be recommended, due to uncertainty in key natural history parameters identified in our analysis. The ongoing uncertainty in the impact of chlamydia screening highlights the need for caution. We hope that this work will enable empirical research activity to be focused where it will be most effective in informing public-health decision-making.In conclusion, it is unclear at present whether screening for Supplementary Information


To translate, adapt and validate the Smartphone Addiction Inventory (SPAI) in a Brazilian population of young adults.We employed the translation and back-translation method for the adaptation of the Brazilian version SPAI (SPAI-BR). The sample consisted of 415 university students. Data was collected through an electronic questionnaire, which consisted of the SPAI-BR and the Goodman Criteria (gold standard). The retests were carried out 10–15 days after the initial tests with 130 individuals.2 = 767.861, CFI = 0.913, TLI = 0.905, RMSE = 0.061, WRMR = 1.465). The Kuder-Richardson Coefficient showed good internal consistency. The analysis of the ROC curve established an area under the curve of 86.38%. The Intraclass-Correlation Coefficient of 0.926 between the test and the retest demonstrated an excellent temporal stability. The high correlation between SPAI-BR and the Goodman Criteria (rs = 0.750) established the convergent validity.The SPAI-BR maintained semantic, idiomatic and conceptual equivalences from the original scale. The Confirmatory Factor Analysis confirmed the One-factor model of the SPAI with good fit indexes (xThe SPAI-BR is a valid and reliable tool for the detection of Smartphone Addiction in Brazilian university students. Smartphones are essential tools in our everyday life. They provide applications for communication, information, education, and entertainment. They have also been used for data collection, to prevent and treat psychiatric disorders, chronic diseases and to improve elders’ quality of life –9. AlthoSmartphone addiction is a technological addiction, defined by Griffiths as a behavioral addiction that involves human-machine interaction . SeveralStudies in several countries reported a high prevalence of smartphone addiction, especially among university students. The prevalence of smartphone addiction in young students is estimated at 6% in Italy ; 38% in In terms of negative consequences, the diagnosis of smartphone addiction is associated with sleep disorders –33; deprAlthough no specific diagnostic criteria for smartphone addiction exist, the study of this disorder seems to be an important issue. Screening instruments are important as they are a first step to the phenotyping process of research. No validated instrument for the screening of smartphone addiction is available in Brazil. Around the globe, the “Smartphone Addiction Scale” (SAS) and, theThe main aim of this study was to validate the SPAI for use in the Brazilian population. We hypothesize that a Brazilian version of the SPAI (SPAI-BR) is a valid tool for the screening of smartphone addiction in Brazilian young adults.This was a cross-sectional and prospective study for the assessment of psychometric features of the Brazilian version of the Smartphone Addiction Inventory. The Committee of Ethics in Research of the Federal University of Minas Gerais (UFMG) approved this study (CAAE 54066516.0.0000.5149). Participants provided their written informed consent about the voluntary nature of the study, its risks, and its benefits. This study did not include minors and it was carried out in accordance with the latest version of the Declaration of Helsinki.This study was developed at the Universidade Federal de Minas Gerais (UFMG) from March to June of 2016. We recruited a convenience sample of students from different graduate courses at UFMG.All undergraduate students that have a smartphone with all day internet access , excluding subjects with visual or hearing impairment, were eligible to participate. We based the sample profile on previously recognized risk factors for smartphone addiction , 40, 41.We calculated the sample size based on the recommendations of Hair et al. , to use Lin and Chang developed and validated the SPAI for the screening of Smartphone Addiction in a Taiwanese sample of graduate students in 2014 . AuthorsPavia et al. (2016) translated, adapted and validated an Italian version of the SPAI in a sample of 485 college students from the University of Palermo in Sicily . Non-valDue to the lack of a specific diagnostic criteria for smartphone addiction, we used Goodman’s Criteria for addictions as the gold standard for this study . GoodmanThe SPAI was translated into Brazilian Portuguese language and edited for syntax and content by five experts on addictions. After adjustments, it was back translated by a native English speaker linguist. Original and back-translated versions were reviewed, compared and adjusted for equivalence by consensus among the study team and the linguist. Additional editing of the Brazilian version of the SPAI (SPAI-BR) was made to improve the understanding of the questions after a pilot study performed on a group of 10 students. Moreover, we opted to use a dichotomic version of the SPAI-BR in order to decrease time of completion and increase efficiency for its use in health surveys. Finally, we performed a second pilot test with 40 graduate students using the final version of the SPAI-BR to assess mean time of questionnaire completion.The final questionnaire was composed of three sections: 1. demographic data: gender, race, birth date, marital status, and family income; 2. SPAI-BR; and 3. Goodman’s Criteria. For data collection, we used an electronic data collection system based on tablet computers. In sum, we transferred the whole questionnaire to the web-based platform iSurvey®  and installed the software on tablet computers. Respondents completed the demographic questionnaire and the SPAI-BR (self-applied) and handed the tablet to a psychiatrist who performed a structured interview assessing Goodman’s Criteria. Data was uploaded through Wi-Fi, transmitted to a database and exported to SPSS format . Data bank in SPSS format can be seen in In the descriptive analysis, we calculated mean, standard deviation, median, quartiles and minimum /maximum for continuous variables. For categorical variables, we calculated frequency and proportion. Data normality was assessed using Kolmogorov-Smirnov test.2), Comparative Fit Index (CFI), Tucker-Lewis Index (TLI), Root Mean Square Error (RMSE) and Weighted Root Mean Square Residual (WRMR). The overall model fit was judged using the following cutoff values: for the CFI and TLI, values larger than 0.90 are considered indicators of acceptable fit , and it does not change the clinical applicability of the instrument.Besides all the reasons above, we attribute the low internal consistency of the “tolerance” factor to the fact that we have converted the original Likert instrument into a dichotomous format and because the ‘Tolerance’ factor is formed by only three items. Internal consistency is normally influenced by both factors, as demonstrated in previous studies , 73. KliThe temporal stability of the SPAI-BR was excellent (ICC = 0.926), which shows the reliability of the instrument. In addition, the positive correlation between the SPAI-BR and the Goodman Criteria (Spearman's rho = 0.751) indicated that both instruments allow the detection of the same construct, establishing the convergent validity of the SPAI-BR.Regarding the determination of possible cutoff points for SPAI-BR, some considerations must be made. The choice of a cutoff point will depend on the purpose of the instrument (diagnosis or screening) and the prevalence of smartphone addiction in the population in which the test will be applied. In addition, no cutoff point has full accuracy, so diagnostic errors will always occur.The decision theory approach considers costs and benefits of correct and incorrect classifications through the screening instrument , 67. SomWe must consider that both correct and incorrect classifications by a screening instrument will incur in medical costs. Lower cutoff points cause more false positives, increasing direct treatment costs. Higher cutoff points generate more false negatives, harming many ill individuals who will not be treated. In this sense, we used the same proportions of costs of screening and treatment in a mental health setting as established by Smits and colleagues , 67. In One possible limitation of this study was the fact that it was carried out with a convenience sample composed of UFMG students, and therefore it could be expected that the application of this same instrument in a community sample would present different results. Therefore, data from this study cannot be generalized to other populations. However, the instrument validation process is continuous and, generally, its initial phase is carried out with the population at greater risk for the construct under analysis. Future studies with heterogeneous populations are required so that SPAI-BR will be considered valid for application across the general population.Another limitation concerns the gold standard used to diagnose smartphone addiction in this study. The lack of a validated gold standard for the screening of smartphone addiction may compromise the accuracy of criterion validity of the SPAI-BR. However, Goodman’s Criteria is the best approximation of a gold standard, as is very similar to the diagnostic criteria for addictions in DSM 5 and ICD 10.In conclusion, present data confirms that SPAI-BR is accurate and reliable for the quick and easy detection of patients with smartphone addiction in a Brazilian population of university students. Further studies should validate the SPAI-BR in other populations, such as children, elderly and clinical populations.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 TableNote: T1 = test of the factor “compulsive behavior”, T2 = test of the factor “functional impairment”, T3 = test of the factor “withdrawal”, T4 = test of the factor “tolerance”, TT = test of the total SPAI-BR, R1 = retest of the factor “compulsive behavior”, R2 = retest of the factor “functional impairment”, R3 = retest of the factor “withdrawal”, R4 = retest of the factor “tolerance”, RT = retest of the total SPAI-BR.(DOCX)Click here for additional data file.S3 TableNote: CI = confidence interval; +PV = Positive Predictive Value; -PV = Negative Predictive Value.(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S1 File(SAV)Click here for additional data file.


The aim of this study was to examine whether low-grade inflammation (LGI) is associated with a subsequently increased risk of infection.We included 15,754 healthy participants from the Danish Blood Donor Study, who completed a questionnaire on health-related items. LGI was defined as a C-reactive protein level between 3 and 10 mg/L. Infections were identified by ICD-10 codes in the Danish National Patient Register and ATC-codes in the Danish Prescription Register. Multivariable Cox proportional hazard analysis was used as the statistical model.During 53,302 person-years of observation, 571 participants were hospitalized for infection. Similarly, during 26,125 person-years of observation, 7,276 participants filled a prescription of antimicrobials. LGI was associated with increased risk of hospital-based treatment for infection only among men : 1.10–2.34) and specifically infections were abscesses and infections of the skin and subcutaneous tissue. Similarly, LGI was associated with the overall use of antimicrobials among men, and particularly with phenoxymethylpenicillin and broad-spectrum antimicrobials for treatment of urinary tract infections. The difference between men and women was not statistically significant.In a large cohort of healthy individuals, LGI was associated with an increased risk of infection among healthy male blood donors. C-reactive protein (CRP) is a well-known acute phase protein and a part of the innate immune response. CRP levels increase rapidly during acute inflammation, and is elevated in several pathological processes, including chronic inflammatory diseases, cancer, and tissue damage . CRP is Accordingly, CRP above 10 mg/L in plasma is routinely used as a marker of infection in the clinical ward. An increased CRP level is associated with several diseases , and a CSlightly elevated CRP levels, also known as low-grade inflammation (LGI), is reported to occur in approximately 10% of healthy individuals ,8; a resLGI may either reflect subclinical infection or it may be a result of immune activation and exhaustion of immune cell subsets with consequently increased infection risk. An association between LGI and risk of subsequent infection has been established in a few studies previously –17. The To examine whether LGI is associated with an increased risk of infection, it is necessary to minimize the effect of potential confounders. In this respect, blood donors—who represent a particularly healthy subset of the population—are especially suitable as a study cohort.The Danish Blood Donor Study has been described in detail previously ,14,18–21www.dbds.dk). Currently, more than 100,000 blood donors aged 18–67 years participate in the study. Participants filled out a four-page questionnaire on health-related items, regarding current smoking status, alcohol consumption, physical activity, diet, anthropometric measurements, and (among women) use of contraception, childbirth, and menopausal status. Plasma samples were stored and donors granted permission to link their data to public registers.Briefly, DBDS was initiated in March 2010 as a multicenter public-health study and bio bank .Participants were excluded if they had missing responses to any of the following questionnaire items: current smoking status , height , and weight . Furthermore, participants with CRP above 10 mg/L were excluded (141) to prevent possible cases of prevalent infection. In total, 1,159 women and 1,234 men were thus excluded leaving a total of 15,754 participants with corresponding measurements of CRP for the analyses.For more detailed information on the participants and the measurement of CRP, see Sørensen et al. .To identify the first infection-related hospital visit , participants were followed from inclusion via the Danish National Patient Register. The register was established in 1977 ,23 and hDischarge information was based on the International Classification of Diseases, 8th Revision (ICD-8), until the end of 1993, and on the 10th revision thereafter .Date and ICD-10 codes for a discharges with a diagnosis of infection were identified and included apart from chronic infections (other than chronic tonsillitis), condyloma, fungal infections, and parasitic infections.Diagnosis codes are divided into different types, and we used A (primary diagnosis), B (secondary diagnosis), and G .Infections were grouped into subgroups (previously defined in ): abscesFor specific ICD-10 codes—see Information on antimicrobial prescriptions was collected from The Danish National Prescription Register (DNPR). DNPR was established in 1994 and maintains information on all prescribed drugs dispensed from Danish pharmacies. This information includes the unique personal identification number of the patient, the type of drug according to the Anatomical Therapeutic Chemical classification system, and the date of prescription .Dispensed prescriptions for all antimicrobial agents prescribed for oral treatment of bacterial (J01x) or viral infections (J05x) were identified. Furthermore, national Danish guidelines for primary care were followed for specific calculations on prescriptions resulting from infections of specific anatomical locations ,27 and pFurthermore, an analysis was performed with commonly prescribed broad-spectrum penicillins: amoxicillin (J01CA04) and amoxicillin with enzyme inhibitor (J01CR02). These antimicrobials do not reflect a specific anatomical site.Some major chronic diseases could be potential confounders associated with infection. To assess the burden of disease, Charlson’s Comorbidity Score (CCS)  was inclWe followed common practice by defining LGI as a CRP level above 3 mg/L and below or equal to 10 mg/L ,32,33.Multivariable Cox proportional hazards analysis with age as the underlying timescale was used to examine the association between LGI and treatment for infection at a hospital. Study participants were followed from the date of inclusion in DBDS until either the first infection-related contact to the hospital, emigration, death, or end of follow-up (31 December 2013), whichever came first. The same method was used to determine the association between LGI and receiving prescriptions of antimicrobials, however, with follow-up until 31 December 2012.The results were presented in two models. Model 1 represents a crude Cox proportional hazard analysis without any adjustments. Model 2 includes adjustments for BMI ≥ 30 (yes/no), comorbidity (using CCS defined as above), and current smoking status at inclusion (yes/no). We decided to stratify for sex a priori because of the focus on sex-specific differences discovered in earlier publications by others and us ,29,34.Interaction tests between LGI and the predictors were included in all models and removed when confirmed insignificant. Furthermore, proportionality was checked by plotting the observed and the fitted survival curves and log–log plots.Data are presented as numbers, medians with ranges, or frequency statistics. Risk estimates are presented as hazard ratios (HRs) with 95% confidence intervals (CIs).Incidence rates are shown as events per year at risk.Stata/MP 13.1 for windows  was used for statistical analysis.Oral and written informed consent was obtained from all participants. The Ethical Committee of Central Denmark (M-20090237) approved the study. Additionally, the bio-bank and research database were approved by the Danish Data Protection Agency (2007-58-0015).The characteristics of the participants at the time of inclusion have been reported previously ,18–21,35There were no differences between the excluded participants and the participants in the study with regard to sex distribution (P = 0.18). For age, however, there was a difference (P = 0.009). Yet, comparing the mean value for age between the two groups; age was 39.7 for the participants in the study and 40.5 for the excluded.For participants with missing values for smoking, there was no difference with regard to BMI (p = 0.30) or sex (p = 0.06), when compared to participants with available values. However, the participants with missing values were slightly older . For participants with missing values for BMI, there were no differences in distribution of smoking (p = 0.12) or sex (p = 0.18). Again, for age the participants with missing values were slightly older (40.5 vs 39.7 years). We consider the difference in age too small to affect results.The results of the Cox regression analysis are presented in After stratifying for sex, baseline LGI was associated with an increased risk of subsequent infection among men  but only a slight tendency was observed among women . There was however, not a significant difference between men and women. The difference between men and women was not statistically significant (interaction between sex and LGI: P = 0.116).Among men, LGI was most strongly associated with abscesses  and infections of the skin and subcutaneous tissue . When additional adjustment for current smoking status and obesity was applied, the associations were slightly attenuated for infections overall  and similarly for abscesses  and infections of the skin and subcutaneous tissue .Additional adjustment for OC use among women did not alter results (data not shown).The results are presented in After stratifying for sex, LGI was associated with increased risk of prescriptions for oral antimicrobial agents overall among men  but again, only a slightly tendency was observed among women . Similar to the analysis above, the difference between men and women was not significant although a tendency was found (interaction between sex and LGI: P = 0.213).The strongest effects among men were seen with phenoxymethylpenicillin , dicloxacillin/flucloxacillin , and with pivampicillin/ciprofloxacin/nitrofurantoin/trimethoprim . After additional adjustments for current smoking, obesity, and comorbidity, the associations were only slightly reduced: antimicrobials overall , for phenoxymethylpenicillin , and for pivampicillin/ciprofloxacin/nitrofurantoin/trimethoprim the association increased , while the association for dicloxacillin/flucloxacillin were now only a tendency. Among women an association was observed for phenoxymethylpenicillin, macrolides, and for pivampicillin/ciprofloxacin/nitrofurantoin/trimethoprim. However, with additional adjustments for current smoking, obesity, and comorbidity, only the association between LGI and macrolides and LGI and pivampicillin/ciprofloxacin/nitrofurantoin/trimethoprim persisted see .Additional adjustment for OC use among women did not alter results (data not shown).To ensure that the positive association between LGI and infection was not caused by an ongoing infection at inclusion, specific analyses were done with exclusion of hospital admissions/dispensed prescriptions within 30 days after inclusion. The omission did not change results. Thus, for hospital-related treatment for infection overall the HR associated with LGI for model 2 was 1.61 (CI: 1.11–2.35) among men and 1.07 (CI: 0.76–1.52) among women. Similarly, for dispensed prescriptions of antimicrobials overall the HR for model 2 was 1.16 (CI: 1.01–1.34) among men and 1.04 (CI: 0.95–1.14) among women. Similar findings were found for all subgroups and were consistent to the findings in Tables LGI was associated with increased risk of subsequent infection among men in this large cohort of healthy individuals. The association was evident both when defining an infectious event as a hospital contact due to infection and as a dispensed prescription of an antimicrobial. With respect to specific associations, the strongest were found for hospital contacts due to abscesses and to infections of the skin and subcutaneous tissue. Similarly, for dispensed prescriptions of phenoxymethylpenicillin; the most frequently used drug against upper respiratory tract infections and pivampicillin/ciprofloxacin/nitrofurantoin/trimethoprim; commonly used to treat urinary tract infections. An association among women was only found for macrolides and pivampicillin/ciprofloxacin/nitrofurantoin/trimethoprim.To our knowledge, an association between LGI and later susceptibility to infection has not been described in healthy individuals previously.The association was not driven by admissions/prescriptions in the month succeeding inclusion. Infections which were subclinical at donation and evolved to clinical infections within short time after donation, were thus not likely the explanation.Obesity is a major determinant of LGI ,37 and iSmoking and alcohol consumption are also determinants of LGI ,13. SmokAdditional adjustment for alcohol consumption was included in a separate analysis due to the high percentage of missing answers. The adjustment did not alter conclusions (data not shown).Similarly, the analyses were adjusted for various forms of comorbidities (using CCS); yet only a small percentage had comorbidities and CCS had no significant impact on our results .Among women, the use of OC was a main cause of LGI  and therThe association does not seem to be explained by relevant confounders even though residual confounding cannot be ruled out. It can therefore be concluded that LGI was independently associated with risk of infection among men. Only a few other studies have assessed this association and none of these included individuals who were selected to be healthy at inclusion. Because blood donors are thoroughly screened for symptoms at every visit to the blood bank and deferred if not asymptomatic, this study supports that LGI and increased risk of infection are not simply caused by an underlying disease. In stead we share the hypothesis, suggested by another study , namely The validity of the study was strengthened by a well characterized and uniformly asymptomatic study population at baseline. The data collection was structured and participation rate was high. Blood donors must comply with strict criteria to be allowed to donate and are permanently excluded from blood donation if diagnosed with chronic diseases such as diabetes, cancer, hypertension, or even statin-treated hypercholesterolemia. In this study, only 3.2% of the participants had a CCS ≥ 1 and adjustment for CCS or excluding participants with a score ≥ 1 did not affect the results. The participants were followed for a maximum of 2.75 years. Consequently, the time at risk of comorbidity was short. The short follow-up increases the likelihood that the exposure variable was constant during the follow-up, and CRP is relatively constant over time . CRP wasEnd points was defined by two different approaches to define end points; namely, ICD-10 codes, and dispensed prescriptions of antimicrobialsThere are limited data on the validity of infection-related ICD-10 codes; however, a large review showed, that the Danish national patient register is a valuable tool for epidemiological research .ATC-codes reflect the medicine that the participants received. As such, the codes serve as a proxy for the occurrence of an infection; yet it is well known that antimicrobials are often prescribed outside of their proper indication. The manner in which general practitioners treat infections can vary. For mild, uncomplicated infections, some general practitioners are probably more inclined to treat with antibiotics than others, some use broad-spectrum antibiotics where narrow-spectrum antibiotics could have been used, and others are inclined towards waiting for the immune system to clear the infection.It should be noted that although we observed a direct correlation between LGI and infection susceptibility, this could also be explained by a causal model in which the individuals with LGI have an underlying disorder that leads to more frequent hospital-related treatment for infection and use of antimicrobials. Our inclusion of comorbidity as an adjustment does not indicate that an underlying disorder is the reason for the association.Blood donors are only allowed to donate if they report that they feel perfectly healthy and they are to report use of medication. At every donation, the blood donors are asked again and whether they have consulted a doctor since last donation. Persons with known diabetes are not allowed to donate blood—but because blood sugar levels are not measured in the blood banks, undiagnosed diabetes and impaired fasting glucose among the participants cannot be ruled out. Similarly, for other diseases associated with LGI, e.g. cancer, cardiovascular disease and autoimmune diseases, no screening apart from the questionnaire is performed. Because these diseases may also alter the susceptibility to infection, we can only conclude that our findings apply to self-reported healthy individuals.We chose a priori to stratify for sex, however, in combined analysis of men and women only a tendency to a difference in the effect of LGI was found between sexes. Moreover, the high number of tests performed could lead to false positive findings and confirmation in other cohorts would be valuable.This first ever study on LGI and subsequent infection among self-reported healthy individuals showed that LGI was associated with subsequent susceptibility to infection among men, mainly involving abscesses and other infections of the skin and subcutaneous tissue, the use of phenoxymethylpenicillin, and antimicrobials for treatment of urinary tract infections.S1 File(DOCX)Click here for additional data file.


The present study aimed at investigating how healthy older adults (HOA) and cognitively impaired patients (CIP) differ in a discrete Fitts’ aiming task. Four levels of task difficulty were used, resulting from the simultaneous manipulation of the size of the target and its distance from home position. We found that movement times (MTs) followed Fitts’ law in both HOA and CIP, with the latter being significantly slower and more affected by increased task difficulty. Moreover, correlation analyses suggest that lower information processing speed (IPS) and deficits in executive functions (EFs) are associated with decline of sensorimotor performance in Fitts’ task. Analyses of strategic variations showed that HOA and CIP differed in strategy repertoire (which strategies they used), strategy distribution , and strategy execution . These findings further our understanding of how strategic variations used in a sensorimotor task are affected by cognitive impairment in older adults. Declines of cognitive  main effect of strategies on collected measures ; (b) interaction effects between the strategy factor and one or several factors on strategy use and strategy performance; and (c) age-related differences in strategy use and performance . In the cognitive domain, several studies used the strategy perspective to compare performance’ declines during healthy and cognitively impaired older adults  as a function of the difficulty of the task) in HOA and in CIP. We expected to observe longer MTs and steeper slopes in CIP than in HOA. Moreover, we wanted to examine the role of EFs and information processing speed (IPS) on participants’ performance by correlating participants’ slopes with scores on specific neuropsychological tests. Second, we analyzed group differences in strategic variations. Concerning strategy repertoire, we predicted that CIP would use fewer strategies than HOA, starting from lower IDs. Additionally, we expected that HOA and CIP would exhibit different strategy preferences and strategy distributions. As a result of declines in EFs and IPS, we predicted that CIP would be more dependent on the visually guided deceleration phase, which would lead them to use most frequently strategies with sub-movement corrections . Also, for both groups, strategy selection should be influenced by task difficulty. Finally, we analyzed strategy performance as a function of task difficulty in each group. We predicted that group differences in MTs would depend on the strategy used and would be larger for strategies with sub-movement corrections.mean age = 73.6 years; age range: 66–89 and 10 CIP; mean age = 81.7 years; age range: 65–90), voluntarily participated to the study. HOA lived independently and were recruited from the community of Marseille, whereas CIP were on long-term stay nursing home residents at the Centre Gérontologique Départemental of Marseille. All participants had no history of neurological  or psychiatric disorders  or alcohol and substance abuse. Moreover, they had no uncorrected visual impairment and did not suffer from any upper-limb dysfunctions or pain that could affect the achievement of the task. They were unfamiliar with the task and the apparatus.Twenty-one right-handed participants . Then, to ensure the construct group consistency all participants completed a battery of questionnaires assessing their functional status. The battery consisted of the Katz’s Index of Independence in Activities of Daily Living Scale-6 items , the functional status , and the neuropsychological status . After a presentation of the experiment, each participant signed an informed written consent, approved by the local ethic committee of Aix-Marseille University, in accordance with the ethical standards laid down in the Declaration of Helsinki.We ensured that none of the HOA obtained a score lower than 26 on Montreal Cognitive Assessment, lower than six on Index of Independence in Activities of Daily Living Scale, lower than four on Instrumental Activities of Daily Living Scale, and higher than six on Short Form of the Geriatric Depression Scale, in order to be included in the current study. Sociodemographic characteristics, self-reported functional status, and neuropsychological scores are shown in Table Participants were comfortably seated on a chair at a height-adjusted table, with their dominant hand resting on their lap and their non-dominant forearm resting on a USB digitizer  positioned on the tabletop right in front of them, in portrait orientation. The digitizer was connected to a portable PC . Using a hand-held non-marking stylus , participants were asked to perform discrete rapid-aiming movements, from an initial home position towards a target. The home position, represented as a red circle of 0.5 cm diameter, was always aligned with the center of the target, which was represented by a red horizontal rectangle . Home and target positions were printed on a white paper sheet and inserted under the transparent plastic film cover of the digitizer. Aiming movements involved shoulder flexion and elbow extension with full stops on home position (movement initiation) and on target position (movement termination). To avoid trunk compensations, participants were required to keep their belly pressed against the table.In this experiment, the task’s ID was scaled via the manipulation of both the size of the target and its distance from home position. Four ID levels, ranging from 3 to 6 bits by increments of 1 bit were used. The different ID conditions are detailed in Table Before each trial, participants were asked to hold still the stylus on the home position until they heard a beep. They were free to initiate their movements at any time following the onset of the beep and were informed that it was not necessary to minimize reaction times. However, they were firmly instructed to keep optimal speed-accuracy trade-off that is “to move as fast as possible from the home position to the target position and to stop on it”. Before each ID condition, participants were allowed to complete three (unrecorded) familiarization trials. Then, they were requested to perform four blocks of 16 trials each, for a total of 64 trials. To prevent fatigue, a short rest was allowed between each trial and each block. For each ID condition, the allowed error rate was 12.5% . If more than two trials were missed, the missed trials were repeated at the end of the condition.optimal algorithm of Teasdale et al. (The pen-tip raw displacement data were recorded using a customized software (ICE) developed at the laboratory  at a sampling frequency of 250 Hz. The recorded data were filtered using a second-order dual pass (no phase-lag) Butterworth filter with a cutoff frequency of 10 Hz. First, second and third derivatives of displacement  were then computed in MATLAB . Movement onset and offset were determined on the basis of velocity profiles using the e et al. . The criefficiency functions. Namely, we analyzed the ID-MT relationships using simple linear regression models carried out on mean group values. Second, to check whether the prescribed IDs were respected or not , and 1.96 is the boundary of a normal distribution at 95%. Then, we compared the distributions of movement end points  and the prescribed ones (centered on target distance and bounded by target edges). These comparisons yielded no significant statistical differences (ts < 1). As a consequence, the prescribed ID levels were used for all participants.First, this procedure allowed us to calculate for each trial, in each condition MTs that correspond to the times to reach the target. MTs were then used to calculate primary sub-movement was defined as the moment of time when one of the following three events occurred after the velocity reaches its peak: (a) the velocity crossed zero, changing from positive to negative; (b) the acceleration crossed zero, changing from negative to positive; or (c) the jerk crossed zero, changing from positive to negative. This procedure enabled us to calculate kinematic variables that were related to the type of secondary sub-movement identified  = 14.11, MSe = 68.34, p < 0.05.All trials containing errors (9.6%) were removed  = 16.55, MSe = 21, 308, F = 116.90, MSe = 1215, F = 4.83, MSe = 1215, MTs were significantly larger in CIP than in HOA . This result showed a multiplicative slowing in CIP, with a slowing rate of 41%.Efficiency functions resulting from linear fittings of the ID-MT relation in each group, along with corresponding equations, are displayed in Figure z scores of Trail Making Test and Victoria Stroop Test performance on the one hand, and of Digit Symbol Coding Test and Symbol Search Test performance on the other hand, for EFs and IPS, respectively. Higher index of EFs and lower index of IPS corresponded to a decreased performance whereas lower index of EFs and higher index of IPS corresponded to an increased performance. Participants’ slopes were positively correlated with index of EFs, as increased scores in EF tests were linked to a poorer performance. Moreover, they were negatively correlated with index of IPS, as decreased scores in IPS tests were linked to a poorer performance.We conducted Pearson partial correlation, controlling for age group and years of formal education, to examine the role of EFs and IPS on participants’ performance. Table In sum, the present results showed that MTs followed Fitts’ law in both HOA and CIP. Moreover, correlation analyses suggest that slower IPS and altered EFs are associated with poorer sensorimotor performance in the Fitts’ task.R2 corresponding to squared semi-partial correlations) before and after the variance associated with a composite measure of EFs and IPS were controlled. For example, the influence of variations in EFs on effects of group on slopes can be determined by comparing the proportion of variance associated with group before and after index of EFs was controlled.To assess mediational effects of executive control and IPS between groups and slopes, we compared the proportion of variance accounted for by group . Group effect was no longer significant after controlling for index of EFs, t(17) = 1.46, p = 0.16. Additional analyses showed that R2 associated with group was reduced to 0.18 after controlling index of IPS. Thus, the group-related variance was reduced by 49% , but group effect was still significant after controlling for index of IPS, t(17) = 2.19, p = 0.04.Examination of the values . The overshoot strategy, which is generally rarely used  = 10.04, MSe = 0.24, F = 7.16; see Figure F < 1). This resulted from the fact that HOA increased the number of strategies used as a function of difficulty  = 12.48), but not CIP .To examine group differences in strategy repertoireTo analyze group differences in strategy distribution, a three-way ANOVA (Group × Difficulty × Strategy), with repeated measures on Difficulty  and Strategy , was carried out on mean percentages of use of the two most often used strategies. The undershoot strategy, which was used on only 10% of trials, was excluded from this analysis to break the dependence between cells. On average, participants used the one-shot strategy (58%) more often than the progressive-deceleration strategy (32%).F = 26.95, MSe = 159.8, F = 23.86,) on easier trials, and these two strategies equally often on harder trials .As shown in Figure F = 20.46, MSe = 16, 225, F = 62.06, MSe = 2160, F = 58.73), or than with the undershoot strategy  = 84.77). Also, participants were faster with the progressive-deceleration strategy than with the undershoot strategy  = 36.74). The Group × Strategy interaction was also significant  = 15.70, MSe = 2160, Fs > 9.82), differences between the two groups were the largest with the undershoot strategy (246 ms) and with the progressive-deceleration strategy (130 ms); they were the smallest with the one-shot strategy (82 ms).To analyze group differences in strategy execution, a two-way ANOVA (Group × Strategy), with repeated measures on the last two factors was carried out on MTs. As can be seen in Figure The present study aimed at determining whether group differences in strategic variations might explain, at least partly, differences in sensorimotor performance between individuals with cognitive impairments and HOA. In the following, we discuss our findings with regards to observed group differences and their possible underlying processes.As a prerequisite, we first assessed quantitative changes associated with normal and pathological aging effects on MTs and efficiency functions in Fitts’ aiming task. Preliminary analyses showed group differences in all neuropsychological tests that were administered (except for the test assessing depression). Given that IPS and EFs are both involved in this Fitts’ task, and that HOA and CIP differed on tests assessing these functions, it can be hypothesized that they could have contributed to the emergence of group differences.The CIP showed longer MTs than the HOA. These results are consistent with those reported by Goldman et al.  and Yan Our results showed that the number of strategies differed between groups of participants and depended upon trial difficulty. Specifically, HOA used fewer strategies on lower IDs relative to higher IDs. In contrast, CIP used an equal number of strategies for both lower and higher IDs. That is, HOA adults were able to focus on a smaller strategy repertoire  on lower IDs and increase the number of strategies on higher IDs. In contrast, CIP used all types of strategies on both lower and higher IDs. This suggests that they may have been unable to focus on using the strategies with no-corrective sub-movements  and to inhibit most demanding available strategies including corrective sub-movements . Consistent with this, CIP used the progressive-deceleration strategy more often than HOA on lower IDs. One possibility is that given their decreased EFs, CIP were unable to inhibit strategies with corrective sub-movements like the progressive-deceleration on lower IDs in order to focus on strategies like one-shot that are easy to execute on lower IDs (and efficient). This interpretation is suggested by participants’ performance on neuro-psychological tests that showed deficits in EFs of CIP .As in our previous studies .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.


Micro- and nanosize lignin has recently gained interest due to improved properties compared to standard lignin available today. As the second most abundant biopolymer after cellulose, lignin is readily available but used for rather low-value applications. This review focuses on the application of micro- and nanostructured lignin in final products or processes that all show potential for high added value. The fields of application are ranging from improvement of mechanical properties of polymer nanocomposites, bactericidal and antioxidant properties and impregnations to hollow lignin drug carriers for hydrophobic and hydrophilic substances. Also, a carbonization of lignin nanostructures can lead to high-value applications such as use in supercapacitors for energy storage. The properties of the final product depend on the surface properties of the nanomaterial and, therefore, on factors like the lignin source, extraction method, and production/precipitation methods, as discussed in this review. HenceLignin in nanoscale can be one of the keys to maximize valorization of the input feedstock in a biorefinery, and “you can make anything you want out of lignin… except money”  is changLignin is a highly irregularly branched polyphenolic polyether, consisting of the primary monolignols, p-coumaryl alcohol, coniferyl alcohol and sinapyl alcohol, which are connected via aromatic and aliphatic ether bonds  as well A possibility for overcoming the issue of high complexity and inhomogeneity is the use of the lignin at submicron scale, since nanostructured materials can have considerably different properties from larger-dimensional material of the same composition . ProductA wide range of applications for lignin nanomaterials is reported in the literature. This review gives an overview of the present applications and their performance in the final product or process. Lignin shows many unique properties such as resistance to decay and biological attacks, ultraviolet (UV) absorption, high stiffness, and the ability to retard and inhibit oxidation reactions. Therefore, it offers the potential to produce high-value products from a large-volume feedstock ,15. IncoNanofillers can improve mechanical properties like stiffness, strength and toughness as well as thermal stability and barrier properties . Those nDel Saz-Orozco et al.  used sofNevárez et al.  incorporE), and elongation at break (εb), are very important indicators for the selection of diverse applications for polymeric formulations [Tensile properties, like the tensile strength (σ), modulus  values from 15 to 91.61 and improved its photo stability. In their most recent work, different spherical sizes of the incorporated lignin were investigated, including lignin in nanoscale [Qian et al. ,48 used anoscale . It was Yang et al. ,19,31,32Lignin contains different phenolic monomer fragments and is an important source of natural antibacterial compounds. Phenolic fragments containing a double bond in α, β positions of the side chain and a methyl group in the γ position show, in general, the most inhibitory effect . Lignin Silver nanoparticles, on the other hand, also show effective antimicrobial, antifungal and antiviral properties ,56. HowePopa et al.  and GîlcZimniewska et al.  impregnaPseudomonas syringae pv. tomato (Pst). This bacterium affects tomatoes production worldwide causing serious damage to all organs, including fruits that result unmarketable [Xanthomonas arboricola pv. pruni (CFBP 3894) and Pectobacterium carotovorum subsp. odoriferum (CFBP 1115) bacterial plant pathogens [Xanthomonas arboricola pv. Pruni and Pseudomonas syringae pv. tomato concentrations in the tests with incorporated LNPs were significantly lower compared to the neat polymers. However, increasing CFU concentrations were observed in each sample between 3 h and 24 h but remained at lower CFU concentrations compared to the neat polymers [The antibacterial activity of LNPs incorporated in polymer films for food packaging was evaluated by Yang et al. ,32. A lirketable . In the athogens . The respolymers ,32.+ ions in an aqueous solution of AgNO3 and coated with polydiallyldimethylammonium chloride (PDAC) to shift the zeta potential of the particles to positive values. Those silver infused particles are capable of neutralizing common Gram-negative and Gram-positive human pathogens as well as quaternary amine-resistant bacteria. The amount of silver used was 10 times less in comparison to conventional silver nanoparticles and aqueous AgNO3 solution. + ions which cause the bacteria to die. The silver-infused lignin particle is supposed to not contain Ag+ ions after utilization and remain as a biodegradable lignin particle, whereas the silver nanoparticle still releases Ag+ ions after utilization.Richter et al.  combinedLignin is an effective free-radical scavenger, which can reduce oxygen radicals, and retard and inhibit oxidation reactions ,69. MostLu et al.  comparedThe improvement of RSA depending on the particle size of hardwood dioxane lignin and softwood alkali lignin was investigated by Yearla et al. . The sph50 (dosage of lignin at free RSA = 50%) of each lignin was calculated, where a higher antioxidant activity is indicated by a lower IC50 value. The IC50 values are 0.18 ± 0.01 mg/mL, 0.30 ± 0.02 mg/mL and 0.60 ± 0.05 mg/mL for LNPs precipitated by the second method, non-nanoscale lignin and LNPs precipitated by the first method, respectively. This indicates a dependency of the free RSA on the precipitation method of the LNPs.Ge et al.  investigYang et al.  investigSurfactants consist of polar head groups and nonpolar tails and are categorized by the chemistry of their headgroup, including anionic species based on fatty acids and sulfonate derivatives , cationiNypelö et al.  stabilizWei et al.  used alkNanoparticles grafted with surface active polymer chains can decrease surface and interfacial tensions and create stable Pickering emulsions ,85,86. G2 bubbling and precipitation by N2 bubbling. The dispersion and precipitation ability is determined by the grafting density and chain length of the 2-(diethyl-amino)ethyl methacrylate (DEAEMA) units where shorter chain length resulted in faster flocculation of the grafted lignin when switching to N2 bubbling. The diameters of the produced particles showed a range of 237–404 nm, and concentration of 1 g/L grafted lignin based on the water content was sufficient to gain Pickering emulsions with a water-to-decane volumetric ratio of 4:1.Qian et al.  developeCarbon nanostructures such as fibers and particles offer numerous possibilities for applications like batteries, supercapacitors, fuel cells, structural composites, filtration devices. Fluorescence carbon nanoparticles can be applied for biological labeling, bioimaging, and other optoelectronic device applications. Therefore, this topic is rapidly gaining interest in research ,94,95,962 atmosphere. These carbon fibers with diameters from 100 to 500 nm were fabricated into supercapacitors for capacitive energy storage and demonstrated outstanding electrochemical performance [Hu and Hsieh  producedformance . The capWang et al.  utilizedGonugunta et al.  successfYiamsawas et al.  methacryCarbon dots are, due to their optical stability, low toxicity, biocompatibility and ease of functionalization, an interesting class of carbon nanoparticles ,105,106.Currently, based on the number of published research papers, the use of lignin nanostructures in the medical field as drug carriers seems to be the most investigated field of application. Generally, the nanocarriers can be distinguished in two categories: (1) hollow particles where the carried substance is encapsulated; (2) solid and porous particles infused with the carried substance.In recent years, microencapsulation processes have gained significant interest in academic and industrial research ,114,115.2O2 reduced the size of the capsules in comparison with the use of just sonication, where PEG achieved the smallest sizes. The biocompatibility study of theses capsules with Chinese hamster ovary cells shows promising results for a potential use in the biomedical field. The release study was conducted in water using the same surfactant and surfactant concentration as used by Chen et al. [Lignin nano- and microcapsules for the transport of hydrophobic and hydrophilic substances with different releasing properties via miniemulsion polymerization are reported in literature ,125,126.Xylaria sp. IBWF A55-2009, which has an important role in the recycling of lignin [Yiamsawas et al.  used intf lignin . Figure In a further work, Yiamsawas et al  was prodTen et al.  synthesiZhong et al.  encapsulA layer-by-layer method was used by Wand and Zhao  in orderIn the case of solid particles, the active agent is incorporated in the LNPs already during the precipitation step as shown by Figueiredo et al.  and Dai 3O4 nanodispersion as antisolvent. Resveratrol (RSV), a bioactive molecule, was used as active ingredient. In order to incorporate RSV in the LNP, it was mixed with the solvent and incorporated during the precipitation process and resulted in an average hydrodynamic LNP diameter of 180 nm. Cytological and animal tests were conducted and showed good anticancer effects, enhanced by in vitro RSV release, stability and accumulation and better tumor reduction  and benzazulene (BZL), and a water-soluble drug, capecitabine (CAP), were also incorporated in the LNPs during the precipitation process. All LNPs exhibited low cytotoxicity at concentrations up to 100 mg/mL in different cell lines. Overall, these LNPs showed important features for drug delivery and biomedical applications, including biocompatibility, very good stability, an ability to load hydrophobic drugs and sustain their release, and good cellular interaction. Furthermore, the particles including Fe3O4 showed superparamagnetic behavior, which makes them promising for magnetic targeting and magnetic-resonance imaging.Figueiredo et al.  used simDifferent application fields of lignin from micro- to nanosize were identified from the literature ranging from simple polymer blends with improved mechanical properties to promising drug carriers for cancer treatment. Consequently, the possibility of applying lignin in high-value pharma fields was also shown. The parameters influencing the properties of the final product include the lignin source, the method of extracting lignin from the lignocellulose raw material, the production/precipitation method of the nanoparticles which influences the surface properties of the particles and, in the case of polymer blends, the processing/blending method.This is clearly an opportunity to tailor the properties of the final product by optimizing the whole process chain. On the other hand, considering a whole biorefinery in which switching raw materials and lignin-extraction methods is not easily possible, it is crucial to determine suitable final products for existing processes. Moreover, changing raw lignocellulose quality might influence the LNP and final product quality. Nevertheless, a large number of potential high-value applications are within the range of vision for micro- and nanosize lignin particles.


The appropriate sanitation conditions and pre-pregnancy body mass index (BMI) were shown to have a protective effect against VAD. Conversely, serum retinol levels were reduced with trimester progression, favoring VAD occurrence.Globally, vitamin A deficiency (VAD) affects about 19.1 million pregnant women. Its occurrence is classically associated with inadequate food intake and may also be associated with socioeconomic factors and the presence of infection. The aim of this study was to determine the factors related to serum retinol levels among pregnant teenagers. The sample consisted of 89 pregnant adolescents, from whom socioeconomic, obstetric, anthropometric, and food consumption data were collected. Serum concentrations of retinol and the supposed presence of infection were determined by high-performance liquid chromatography and C-reactive protein quantification, respectively. The serum retinol concentrations were classified according to the criteria of the World Health Organization. We adopted a 5% significance level for all statistical tests. Serum retinol levels were significantly and positively associated with sanitation ( Vitamin A is an essential micronutrient for all life cycles, especially in times of intense cell proliferation and differentiation, such as in pregnancy. During pregnancy, vitamin A is important for cell division, growth, and maturation of fetal organ and skeletal systems. It is also important for the development and maintenance of the immune and visual systems ,2,3. TakVitamin A deficiency (VAD) is considered a public health problem and is among the main micronutrient deficiencies, present in more than 100 countries, including Brazil ,6,7. GloIts occurrence is classically associated with low intake of vitamin A from food sources ,12, but In Brazil, VAD has been documented in the northeast and in some parts of the southeast ; howeverThis was a cross-sectional study evaluating a sample of 89 pregnant adolescents, aged 10–19 years old, who attended a maternity school in Teresina, Piauí, northeastern Brazil. Inclusion criteria were that participants were pregnant adolescents who initiated prenatal care at 20 weeks or less of gestation; that they did not receive vitamin supplements containing vitamin A up to 5 months before conception and during pregnancy; that they were not carriers of disease clinically proven to start pre-pregnancy , that they were nonsmokers, and that they were experiencing single-fetus pregnancies.g for 10 min in a refrigerated centrifuge, the serum was separated and 200 μL of serum were used for the assay. For the determination of retinol levels, first we performed saponification of the samples, to break ester bonds and obtain retinoids, and then performed an extraction with hexane (Merck), adding 1 mL of saline (0.9% NaCl) and 3 mL of hexane in each tube. The total volume of hexane was then evaporated to dryness in a vacuum samples concentrator, determining the concentration of retinol to the classification of pregnant women as per the cutoffs recommended by Word Health Organization [Serum concentrations of retinol (dependent variable) were evaluated in a chromatographic AGILENT 1100 coupled to detector diode array  ,19. Bloon = 89) and applied at baseline, and 40% were replicated at the second moment (n = 36), considering the range of up to 2 months [The usual dietary intake was evaluated considering the data collected through 24-h recalls (24HR) applied in duplicate. Data from 24HR were used , parity, and gestational age.Schooling was determined in complete years of formal study with approval, by making the following classifications: (1) <8 years of study; and (2) ≥8 years of study. The total family income was divided into minimum wage and defined as the sum of the income of persons with remuneration that occupied the same household; included in this amount were incentives from government programs. The level of per capita income was divided into: (1) up to ¼ minimum wage; (2) more than ¼ to ½ minimum wage; and (3) over ½ to two minimum wages .The sanitation conditions were considered: (1) adequate when there were water services connected to the public network with internal plumbing, regular garbage collection, sewage connected to the public network or existence of a septic tank; and (2) inadequate when one of the sanitation services was absent .Regarding obstetric data, parity was defined as the number of pregnancies that resulted in live or stillbirth, excluding cases of abortion. Gestational age was calculated in weeks from reliable date of the last menstrual period, confirmed by ultrasound, with subsequent confirmation by the method recommended by Capurro et al. . The gesWeight and height measurements were obtained with an electronic scale (Welmy model W200/5), with a capacity of 200 kg and 0.050 kg sensitivity, coupled to a metric scale for height measurements with 2.0 limit meters and sensitivity of 1.0 cm. In the evaluation of gestational nutritional status, patients were grouped into three classifications: low weight, adequate, or pre-obesity/obesity. The inclusion of pregnant women in one of these categories was carried out according to the Ministry of Health of Brazil , which rz-score <−2 (low weight); z-score ≥−2 to <+1 (adequate); z-score ≥+1 <+2 and z-score ≥+2 (pre-obesity/obesity).For the classification of pre-gestational nutritional status, BMI/age (BMI/A) was used as proposed by the World Health Organization (WHO) . The cutThe inferred presence of infection was defined by the cutoff value equal or higher than (≥)5 mg/L for the acute-phase reactant C-reactive protein (CRP) ,34. CRP ®, v.12 , where they were analyzed. A descriptive univariate analysis was performed .Statistical analysis: Data were organized directly in the software database StataThe assumption of normality of the quantitative variables was verified by the Shapiro–Wilk test when necessary, there was log-natural transformation for the normality of the data. The assumption of homogeneity of variances was checked using the Levene test.p < 0.20 in correlation analyses were included in the multiple linear regression (MLR) model with backward selection. In the final model of MLR, variables with a p-value < 0.05 were considered significant. The assumptions for MLR were confirmed in residue analysis.To compare serum retinol levels between or among groups in each categorical variable, we used respectively the Mann–Whitney or the Kruskal–Wallis test. To check the correlation between serum retinol levels and quantitative variables of the study, we used the Pearson correlation coefficient. The level of significance in the tests was 5%. The variables with Ethical aspects: The present study is approved in the Brazil Platform (Opinion Number: 1687138). It is noteworthy that all survey data were preceded by participant confirmation of understanding of the content by informed consent. For participants under the age of 18, this term was also signed by the legal guardians.10). The mean (±SD) retinol level found in the study was 0.92 mmol/L (±0.42), and VAD (retinol < 0.70 mmol/L) was diagnosed in 34.8% of pregnant women, indicating the existence of a serious public health problem in this population.p = 0.033), with the highest average retinol levels in the group having an adequate sanitation service . Also, there was a difference in retinol levels, comparing both moments of blood collection (p = 0.002) with the highest mean retinol levels in the group that was in the first trimester of pregnancy .Analyzing the data shown in Analyzing to food intake, significant difference is only observed between the average intake of vitamin A and iron; for vitamin A, there is a higher average consumption in relation to the recommended value for the group and for iron, the average consumption is lower than that recommended .p = 0.008), BMI at the time of blood collection (p = 0.019) and basic sanitation (p = 0.033), and negatively correlated with the trimester at the time of blood collection (p = 0.002).The results of the correlations between serum retinol levels and the different study variables are described in p-values less than 0.20 in correlation analyses were selected to participate in the MLR model: sewage connected to the public network or existence of septic tank, basic sanitation, trimester at the time of blood collection, pre-gestational nutritional status and nutritional status at the time of blood collection. The model results, obtained by backward stepwise procedure, are presented in The following variables with p = 0.008) in serum retinol; increasing a trimester reduced serum retinol in 0.239 μg/dL (p = 0.001); and each kg/m2 more than pre-pregnancy BMI increased serum retinol levels of pregnant adolescents by 0.853 mg/dL (p = 0.002). Taken together, these three variables explained 21.3% of the variation in serum retinol levels of the studied population , it was confirmed that only basic sanitation, the trimester at the time of blood collection and pre-gestational nutritional status remained significantly related to serum levels of retinol. The existence of a proper sanitation service determined an increase of 0.235 μg/dL (pulation . The anapulation  showed tAccording to the WHO criteria , the freTurning our eyes to Brazilian studies, we realize the impossibility of establishing appropriate comparisons due to the lack of data regarding pregnant adolescents. Thus, despite analyzing adult pregnant women, a study conducted by Fernandes et al. , which eThe low serum retinol levels may be associated with biological, socioeconomic, environmental and anthropometric factors. Accordingly, Miglioli et al.  emphasizRegarding socioeconomic conditions, in this study it was observed that most of the women had access to water supply, sewage collection, and proper waste disposal, resulting in suitable sanitation. This showed a positive linear correlation with retinol levels. According to Aktar et al. , this reCRP levels ≥5 mg/L were present in 82% of the population studied, but this result was not correlated with retinol levels. At this point it is important to remember that CRP is not a specific marker of infection; more than that, as an acute phase protein, it is primarily part of the innate immune response and its increase can occur in many different conditions. In fact, CRP levels above normal ranges are recognized as a common state in pregnancy, reflecting the adaptations that occur in maternal immunity and which are necessary for the support of the unborn child. Thus, CRP increase is natural in a healthy pregnancy, rising with advancing gestational age ,40.Regarding obstetric variables, there was a negative linear correlation between gestational age and serum retinol levels, which is a similar result to those found in other studies ,36,37. IThere is a clear scarcity of studies correlating levels of serum retinol and nutritional status of pregnant adolescents. In our study, serum retinol levels showed positive correlation with both pre-pregnancy BMI and BMI at the time of blood collection, but only pre-pregnancy BMI remained significantly associated after MLR analysis. Conversely, Andert et al. , in a stWith regard to food consumption, there was no significant correlation between any of the investigated nutrients and retinol serum levels, which can possibly be explained by the small sample size as well as the absence of large variability among the group.Divergent results of this study were found by Williams, Eka, and Essien , who assHowever, it is important to highlight that in this study the application of the assessment tool of food consumption was carried out by trained nutritionists and the possible limitations of the method were strictly controlled. Moreover, the replication of the method and the correction of intrapersonal variance of each nutrient provide appropriate information of the usual intake of populations , which eOur results showed that VAD is a serious public health problem evaluated in this population, leading to significant and preventable risks in the course of pregnancy, the pregnant adolescent and fetal development. Adequate sanitation conditions have been shown to have a protective effect against VAD, as well as the highest pre-pregnancy BMI. Conversely, increase in the trimester resulted in a reduction in serum retinol, favoring the occurrence of VAD. More research is needed to examine the factors related to the occurrence of VAD in pregnant adolescents, which could serve as a basis for the development of nutritional intervention strategies directed to this population. Moreover, considering the high prevalence of VAD observed in this study, as well as its impact on the pregnancy process, there is a need for regular assessment of the nutritional status of prenatal vitamin A in teens in order to achieve early diagnosis and proper management of this nutritional deficiency.


In 2006, Klein and colleagues conducted the first randomized control trial (RCT) to analyze the benefit of adding metformin to treat weight gain induced by second-generation antipsychotics (SGAs) in children and adolescents . In thisYouth obesity has reached epidemic proportions around the world. Obesity impacts both youth physical and mental health. Overweight habitus creates multiple physical limitations, increases the incidence of multiple medical comorbidities including diabetes and hypertension, and raises the rates of morbidity and mortality at adulthood , 3. In aSecond-generation antipsychotics are used for the treatment of mania, psychosis, depression, impulsivity, and aggression in children and adolescents . While wThe positive effects of lifestyle interventions on reducing SGA-induced weight gain and on overall mental health make them an attractive treatment option. A brief description of some of the evidence for the efficacy of lifestyle interventions will be provided. A recent meta-analysis of adults has indirectly demonstrated that the amount of weight loss due to lifestyle interventions may be similar to that provided by use of pharmaceutical agents . Though Metformin is a biguanide antidiabetic agent. Multiple mechanisms have been proposed for its effect on weight loss. These include its ability to decrease insulin resistance (reversing the insulin resistance caused by antipsychotics) and reduce hepatic glucose production , 12. Whiz-score was 1.72 (SD = 0.99) for the placebo group’s weight change and 0.09 (SD = 0.25) for BMI, versus z-score of −0.14 (SD = 0.29) and −0.14 (SD = 0.20), respectively, in the metformin-treated group. These results were statistically significant. Also the rate of children with an indication for a glucose tolerance test was greater in the placebo group (p < 0.01), and consequently, more children taking placebo had impaired glucose tolerance. There was no significant difference in rates of adverse events.Klein et al.  was the Anagnostou et al.  subsequeThus, data from existing RCT-based studies for evaluating the benefits of using metformin to reduce antipsychotic-induced weight gain in youth have been contradictory. Existing data have limitations, including small sample size, inconsistent cross-study methodologies, and limited time frames. Larger and more longitudinal RCTs are needed and are currently underway [see IMPACT trial by Reeves et al. ] and wilJG—substantial contribution to designing the work, acquisition of information, drafted and revised the work, approved final version, and agreed to be accountable for all aspects of the work. TR—substantial contribution to designing and outlining the work, revised it for important intellectual content, approved final version, and agreed to be accountable for all aspects of the work.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. The reviewer, GR, and handling editor declared their shared affiliation, and the handling editor states that the process nevertheless met the standards of a fair and objective review.