Necrotic tissue infection can worsen the prognosis of severe acute pancreatitis (SAP), and probiotics have been shown to be beneficial in reducing the infection rate in animal experiments and primary clinical trials. However, the results of multicenter randomized clinical trials have been contradictory. Our aim in this study was to systematically review and quantitatively analyze all randomized controlled trials with regard to important outcomes in patients with predicted SAP who received probiotics.A systematic literature search of the PubMed, Embase and Cochrane Library databases was conducted using specific search terms. Eligible studies were randomized controlled trials that compared the effects of probiotic with placebo treatment in patients with predicted SAP. Mean difference (MD), risk ratio (RR) and 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel fixed- and random-effects models. A meta-analysis on the use of probiotics in the treatment of critically ill patients was also performed to serve as a reference.P = 0.47), total infections , operation rate , length of hospital stay  or mortality .In this study, 6 trials comprising an aggregate total of 536 patients were analyzed. Significant heterogeneities were observed in the type, dose, treatment duration and clinical effects of probiotics in these trials. Systematic analysis showed that probiotics did not significantly affect the pancreatic infection rate (RR = 1.19, 95% CI = 0.74 to 1.93; Probiotics showed neither beneficial nor adverse effects on the clinical outcomes of patients with predicted SAP. However, significant heterogeneity was noted between the trials reviewed with regard to the type, dose and treatment duration of probiotics, which may have contributed to the heterogeneity of the clinical outcomes. The current data are not sufficient to draw a conclusion regarding the effects of probiotics on patients with predicted SAP. Carefully designed clinical trials are needed to validate the effects of particular probiotics given at specific dosages and for specific treatment durations. Acute pancreatitis (AP) is a common disease that affects about 270,000 people annually in the United States, and its incidence has been increasing by 5% every year in the United States and Europe ,2. SeverThe results of the PROPATRIA trial (probiotic prophylaxis in patients with predicted severe acute pancreatitis), published in 2008  dominated by the Dutch Acute Pancreatitis Study Group), showed that probiotics had harmful effects , which dsevere acute pancreatitis was approved at the Atlanta symposium. The MeSH headings pancreatitis, Lactobacillus, prebiotics, synbiotics and probiotics were used, but the language was not restricted to English only. Articles were compiled into a database, and duplicates were removed. The abstracts were then screened for relevance. In the case of multiple articles published by the same study group for the same study period, only the most recent paper was selected. Subsequently, full-text papers of the selected studies published in English were screened for eligibility. If the study was published in another language, we contacted the corresponding author to check whether it had been translated into English. The translated studies were included, and nontranslated studies were eliminated. A systematic literature search for probiotic use in critical illness was also performed. An additional Microsoft Word file describing this search in more detail is available in Additional file A systematic literature search was performed in the PubMed, Embase and Cochrane Library databases. The search was restricted to human evidence published since 1992, which was the year in which the term We included all human RCTs in which the effects of probiotics in SAP patients were investigated. We excluded (1) trials that included patient cohorts with mild AP and in which the SAP results were not reported separately and (2) studies that included cohorts for which the essential outcomes were not reported. The search and inclusion or exclusion of articles were carried out by two authors (SG and TL). In cases of uncertainty or disagreement, a third author was consulted (CW).From among the included studies, the following variables were extracted (if available): definition of predicted SAP, sample size, types of probiotics used and duration of use, intervention in the control group and clinical outcomes. The internal validity was determined using the Jadad score  and six 2 test was used to assess heterogeneity between trials, and I2 values were used to assess the extent of inconsistency. The Mantel-Haenszel random-effects model and fixed-effects model were used to analyze data with and without significant heterogeneity, respectively. Two-sided P-values <0.05 were considered to indicate statistical significance.All pooled data were analyzed using Review Manager (RevMan) version 5.2.6 software (Cochrane Informatics and Knowledge Management Department). Risk ratio (RR) with 95% confidence interval (CI) was used for dichotomous outcomes, and mean difference (MD) was used for continuous outcomes. The χThe results of the literature search are depicted in Figure Pediococcus pentosaceus, Leuconostoc mesenteroides, L. paracasei and L. plantarum . In total, L. plantarum was used in three trials: Bifidobacterium longum, L. bulgaricus, L. paracasei, L. mesenteroides and P. pentosaceus were used in different combinations in two trials, and B. bifidum, B. lactis, Enterococcus faecalis, L. acidophilus, L. casei, L. lactis, L. salivarius and Streptococcus. thermophilus were used in just one trial. The lowest daily dose of probiotics was 3 × 107 bacteria, and the highest dose was 8 × 108 bacteria. The length of treatment was reported clearly in five studies, ranging from 7 to 28 days and not reported clearly in one study [In the six RCTs included in the meta-analysis, a total of 14 strains of probiotic bacteria were used Table . One trine study -27, and ne study  and 28 dne study .In the aggregate, the six included studies comprised 536 participants, and the number of participants per study ranged from 25 to 298. Among the 536 participants, 275 received EN with probiotics and 261 received probiotic-free EN. The prediction variables for SAP varied between the trials: an Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥8 was considered as an indicator in three studies -25, Glaset al. [P = 0.24) [The relevant baseline characteristics were reported in detail in three studies ,26,27, bet al.  reported = 0.24) . Researc = 0.24) ,26,27. I = 0.24) ,26,27. T = 0.24) ,26,27, a = 0.24) ,28. The  = 0.24) ,24,26,27 = 0.24) ,26-28.P = 0.33). Moreover, there was no significant heterogeneity between the studies .The clinical outcomes are shown in Figure et al. [P = 0.57). Moreover, there was no significant heterogeneity between the studies .Researchers in three studies reported total infection rates in an aggregate of 416 patients. A significantly lower total infection rate was observed in the probiotics group compared to the control group in one study , and thet al. [P = 0.71). The heterogeneity between studies was significant .In four studies comprising a total of 460 patients, researchers reported the number of patients who underwent surgery. In one study, a significantly higher number of patients in the probiotics group than in the control group underwent surgery . The diet al. [et al. [P = 0.35). The heterogeneity between studies was significant .In three studies comprising 369 patients, the investigators reported the duration of hospital stay. Significantly shorter hospital stays were reported in the probiotics group in two studies , and noet al. [P = 0.25). There was no significant heterogeneity across studies .In five studies comprising 509 patients, researchers reported the mortality rates. Significantly higher mortality was observed in the probiotics group in one study , and noP < 0.01). We also performed a meta-analysis of the use of probiotics in patients with critical illness with subgroup analyses conducted according to the antibiotic types and treatment durations. Additional files P < 0.01 vs. RR = 1.19, 95% CI = 0.98 to 1.45, P = 0.09) and pneumonia  , and boThe second aspect to be considered is the dose of probiotics, as the same probiotics can have opposite effects at different doses . The dosThe final factor to be considered is the duration of treatment, although it is still not clear whether the effects of probiotics are influenced by this variable . An inteThe PROPATRIA trial, which was the best in terms of methodological quality (Jadad score of 5), also had the highest number of participants, and the investigators used Ecologic 641 for the treatment of patients with predicted SAP, but with no beneficial effects. Some ongoing studies were abandoned after the dismal results of the PROPATRIA trial , and eveThe history of probiotic treatment of SAP is similar to that of immune formula treatment of critical illnesses. Both treatments were documented to be beneficial in animal experiments and primary clinical trials, but subsequent multicenter, prospective, randomized clinical trials showed adverse effects, which made the efficacy of the treatments questionable . HoweverIn the interpretation of the results of this meta-analysis, the limited number of available trials, the methodological quality of the included trials and the heterogeneity of the included trials should be noted. Only six RCTs with relatively low methodological quality were included , and considerable heterogeneity was observed among these trials with regard to the effect of probiotics. The limited number of RCTs hampered the subgroup analysis conducted to understand the cause of the heterogeneity. Upon reviewing 11 major clinical practice guidelines for AP ,29-38, wAlthough the results indicate that probiotics had neither beneficial nor adverse effects, the current data are not sufficient to draw conclusions about the effects of probiotics in patients with SAP, so further studies are needed. However, the types of probiotics and treatment strategies used vary considerably across studies, so probiotic/probiotic mixtures, their appropriate dosages and treatment duration must be considered carefully before clinical trials are conducted. Moreover, considering the risks reported for certain probiotics, further clinical trials should be carefully designed to avoid any potentially harmful effects. In addition, RCTs on patients with critical illness can serve as a reference for future studies on SAP treatment.● The current data are not sufficient to draw conclusions about the effects of probiotics in patients with SAP because of the limited number of trials and their heterogeneity. Nonetheless, the possibility cannot be ruled out that patients with predicted SAP can benefit from particular probiotics when administered at the appropriate dose and for the correct duration.● The types of probiotics used and the treatment strategies employed play an important role in the heterogeneity of clinical outcomes reported in different RCTs.● Further investigations on the effects of probiotics in patients with SAP are needed, but further clinical trials should be carefully designed to avoid any potentially harmful effects. RCTs in patients with critical illness can serve as a reference.AP: Acute pancreatitis; CI: Confidence interval; CRP: C-reactive protein; EN: Enteral nutrition; MD: Mean difference; MOF: Multiple organ failure; RCT: Randomized controlled trial; RR: Risk ratio; SAP: Severe acute pancreatitis.The authors declare that they have no competing interests.SG, ZY, TL, HW and CW were involved with study conception and design. SG, ZY and TL were involved in data acquisition. SG, ZY, HW and CW interpreted the data and results of the analyses. SG and ZY drafted the manuscript, which was critically revised for intellectual content by TL, HW and CW. All authors read and approved the final manuscript.SG and TL are pancreatic disease specialists. SG is also an intensivist at the Pancreatic Disease Institute (PDI), Union Hospital of Huazhong University of Science and Technology (HUST). ZY is a pancreatic disease specialist and the resident of the Clinician Investigator Program who is currently performing a study about fluid resuscitation in severe acute pancreatitis. HW is the deputy head of the PDI, Union Hospital of HUST. CW is the head of the PDI, the head of the Department of Surgery and the Director of the Surgical Teaching and Research Section of Union Hospital of HUST. CW is also the Vice Chairman of the Pancreatic Disease Group of the Chinese Medical Association, the Vice Chairman of the Pancreatic Cancer Committee of the Chinese Anti-Cancer Association and the Chairman of the Hubei Pancreatic Disease Association.Systematic literature search for studies on the use of probiotics in critical illness.Click here for fileRisk of bias.Click here for fileAnalysis of subgroups by treatment duration in predicted SAP.Click here for fileAnalysis of subgroups by types of probiotics used in critical illness.Click here for fileAnalysis of subgroups by treatment duration in critical illness.Click here for file


Juvenile myoclonic epilepsy (JME) is the most common idiopathic generalized epileptic syndrome, mostly initiated before adolescence. It is usually preceded by myoclonic jerks (sudden brief involuntary muscle spasm) in the second decade of life. JME may be presented with different types of seizure activity. Simple bilateral myoclonic seizure is the most seen clinical presentation of JME . Family Levetiracetam: Pharmacology Levetiracetam (LEV) [(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide] is an anti-epileptic drug that has become one of the most prescribed drugs for the management of epileptic syndromes -20. LessPurpose We have reviewed some of the most outstanding studies available for analysis in the PubMed and Medline databases about the effect of LEV concerning seizure control. These studies have been dedicated to find the efficacy and tolerability of LEV in different therapeutic regimens, different epileptic syndromes, as well as in different age groups. The side effects of LEV are a great matter of concern and they were investigated in some studies are indicated. Levetiracetam in different epileptic syndromes: Tonekaboni SH et al. administered LEV as an add-on therapy for 45 children aged 0.6–15 years (mean age 5.9 years). These children were known to have JME that is not responding to most conventional drugs. The starting dose was 20mg/kg/day and was increased at one-week intervals by 10mg/kg/day to a maximum dose of 60mg/ kg/day, if it was necessary. In the 12 week period of follow up, four children (8.7%) became seizure free, four more children (8.7%) indicated an increase in seizure frequency, and in 8 (17.4%) and 13 28.3%) patients, seizure frequency decreased by 75–99% and 50–74%, respectively. They concluded that LEV was effective in 54.3% of patients and decreased seizure frequency to at least 50% of the baseline seizure frequency. They also found that sex, age, duration of disease, type, and cause of seizure, EEG, and imaging data, and type of epileptic syndrome had no significant correlations with improvement in the epileptic course. Finally, they claimed that LEV is an effective add-on therapy in patients with refractory epilepsy . Magaudd.3% patieEfficacy and possible side effects of LEV in pediatrics In childhood epilepsy, the negative effects of antiepileptic drugs on cognitive functions duringdevelopment of the brain are as important as seizure control. Lagae et al. indicated that 77 children (.5–16 years) with different etiologies of childhood epilepsy with both partial and generalized seizure attacks were divided into a trial of “mono therapy” or “add-on therapy” with LEV, as if they met the inclusion criteria for each group. The effect of LEV on behavior and alertness was one of the primary goals of this study. In each group, LEV was started at 10mg/kg/day in two equal dosages and was increased by 10mg/kg weekly to a maximum of 60 mg/kg/day according to efficacy and tolerability. Previous anti-epileptic medications were administered simultaneously with the first 12 weeks of medications. Crucial data were collected using patients diaries and history to calculate the frequency of seizures.Overall quality of life representing both efficacy and tolerability was scored by parents on a scale of 0–10, with 10 being the best overall quality of life. There was a median reduction of 50% and 81% in the add- on group and the mono-therapy group, respectively. In both groups, there were patients who became seizure free. LEV has not proved to be a superior or an inferior choice of anti-epileptic drug in generalized or partial seizures in different epilepsy syndromes or in combination therapy with other anti-epileptic drugs. The main adverse effect of LEV was tiredness and it was seen only in the add-on group. This adverse effect was dose-dependent and 4/6 of patients with tiredness had taken >45mg/kg/ day. In the mono-therapy group, anorexia was seen in only one child. In about 1/4 of the patients, there was a positive effect on alertness and behavior. This means that children were more capable of communicating with caregivers and were better handled and structured. This effect was not because of seizure reduction as there was a reduction of less than 50% in 7/18 and 7/16 of patients who showed increased alertness and better behavior, respectively. Quality of life was reported to be better in the mono-therapy group as parents rated median score of 8 versus 6 in the add-on group. They believed that LEV could be beneficial for both partial and generalized seizures -33.Maw J investigated the efficacy and tolerability of LEV in children aged 10 years and younger as an add-on therapy. They gathered initial data from 26 patients who suffered from different epilepsy syndromes, with a median age of 7 years (ranged from 14 months to 10 years). All patients previously received antiepileptics with a median number of 4 . LEV was started at once daily dosage of 10–15mg/kg/day and was increased every two weeks if tolerated (early reported side effects were labeled as tolerable). The mean maintenance daily dose was 36.9 mg/kg/day . The most common adjunctive anti-epileptics were sodium valproate, lamotrigine, carbamazepine, and one of the benzodiazepines. Best response to LEV was seen in patients with partial-onset seizures and the worst was seen in myoclonic seizures patients. Two children with PEHO  andAlpers’ disease showed no response to LEV, and it was suspended after 6 and 9 weeks, respectively. In three patients, pre-existing myoclonic seizures worsened after administration of LEV. Two of these three other seizure types, nevertheless showed minor improvements. One patient claimed adverse effects of excessive sleepiness as the reason for the suspension of the trial. According to these findings, investigators view LEV to be a well-tolerated anti-epileptic with a negligible amount of adverse effects. However, there is evidence reporting a higher rate of behavioral disturbances in children withneurological disorders after initiation of LEV in the treatment . It mighPrimary generalized epilepsy (PGE) is routinely treated with valproic acid. More recently, lamotrigine, topiramate, gabapentin, carbamazepine, phenytoin, tiagabine, and vigabatrin are no longer prescribed as they may aggravate absence seizures or myoclonic jerks . JeffreyAlthough this study had a small group of patients to investigate, because of precise, complete documentedclinical, and paraclinical information; it can be relied on and is considered a reliable source. This study suggested that LEV can be safe and effective choice for patients with PGE and especially for those who are refractory to other AEDs .As we have previously discussed, the main side effect of LEV is somnolence but Eric H. Kossoff indicated that four patients had extreme behavioral changes and psychosis were reported. The first case was a five-year-old girl with a history of multifocal epilepsy and with mild mental retardation. She had a ketoge nic diet as her only treatment before starting LEV. She was given 250 mg of LEV twice a day. She began having visual hallucination of spiders two weeks after starting LEV and was seizure free over the prior two-week period. After abrupt discontinuation of LEV, her symptoms were resolved and did not recur. The second case was a 13-year-old boy with history of refractory complex partial seizures and left lobe sharp waves on his EEG. He also had a learning disability and oppositional behavior toward authority figures. About 3 months after beginning LEV mono-therapy at 500 mg twice a day, he had an acute onset of auditory and visual hallucinations of a female person in his room. His psychosis was resolved as LEV was dismissed.The third case involved a 16-year-old girl with a right temporoparietal lobe dysembryoplastic neuroepithelial tumor. She was on carbamazepine mono-therapy for further evaluation of surgical treatment. She had history of complex partial epilepsy and Weschler full-scale IQ of 76 (borderline intelligence). She was given 500 mg twice a day as she was preparing for surgery. On day 2 of LEV administration, she became acutely agitated and attempted to run away from home. An EEG showed the right temporal lobe slowing but no epileptiform discharges. Psychiatry approved drug-induced psychosisand 3 days later, she was almost back to her status. The fourth case 4 was a 17-year-old girl with a history of mild cognitive impairment, depression, and left temporal lobe epilepsy related to head trauma from 10 years ago. She was on carbamazepine at a dose of 800 mg three times a day and LEV was added at 1,000mg twice a day in two week period titration. After 30 days of administration, she started to have headaches, lethargy, and auditory hallucination of a sound outside her bedroom telling her to sing and dance. LEV was discontinued and the sound was gone. One-month later medication started at a lower dosage of 500 mg twice a day without any psychotic symptoms recurrence. Possible causes for these adverse effects may be a rapid initiation of the dose, high total dose, young age, and underlying cognitive or behavioral abnormalities. Finally, the writers suggested slow initiation of 10mg/kg/day and increased to 20mg/kg/day over a four week-period, especially in patients with comorbid neurobehavioral abnormalities .Albert Verrotti et al. conducted research on the efficacy and tolerability of LEV as mono-therapy in patients with JME. In this multicenter, prospective, long-term, and open label treatment, 32 patients  with JME were included and median age was 13 years and three months . Newly diagnosed patients and EEG-specificw abnormalities (3–6 spike/poly-spike slow wave discharge) were enrolled in the study. LEV was started at 250 mg once each evening and escalated gradually to a maximum dose that ranged from 1,000–2,500 mg/ daily. All patients were followed up at 6 and 12 months after and patient diaries and history were taken for the number and type of seizures, adverse effect, response to LEV treatment, as well as its outcome. Physical and neurological examinations, laboratory assessment of CBC, UA, blood Cr and BUN, amylase, AST and ALT and electrocardiography was performed. At the 6-month follow up, 15 patients were seizure free (100% seizure control) and 14 were responders (>50% reduction of seizures) and 3 were in marginal effects group (<50% reduction of seizures). At the 12 month follow up, all patients were seizure free except those in the marginal group at the 6 month follow up. There were no abnormal findings in follow up examination tests and there were no side effects reported. This study revealed that LEV could be effective in JME as a first line mono-therapy .In conclusion, LEV is a novel anti-epileptic drug that is chemically related to a previous known drug,piracetam, but with different mechanism of action. It appeared to be effective in decreasing myoclonicseizures with different etiologies, which varied from epileptiform EEG abnormalities to refractory generalized epilepsy in children or adults and idiopathic generalized epilepsy, juvenile myoclonic seizures, and even epileptic syndromes like Unverricht-Lundborg Disease. This new medication can be used even as mono- or add-on therapy to previous anti-epileptic drugs but greater positive effects were observed in patients who took LEV as mono-therapy. One of the amazing advantages of LEV is that it can be started at a high therapeutic dosage and is well tolerated. The median starting dosage varied according to patients underlying disease, age, and disease severity but it can range from 250 mg–1,000 mg daily in a single or a double dose. Median maintenance dosage can vary from 2,000–3,000 mg daily. Myoclonic seizure responds dramatically and different studies have reported a seizure absence of > 50% in more than 90% of patients in both mono- or add-on therapy, but a greater number are seizure free in the mono-therapy group and JME. However, physicians cannot ignore the evidence of behavioral side effects in pediatric patients. Most patients who showed worsening of the condition or had unchanged clinical course also had refractory generalized epilepsy. It is well-known in the literature that sodium valproic acid is the drug of choice for newly diagnosed myoclonic seizures but according to previous studies it was demonstrated that the side effects of LEV, mainly tiredness and somnolence, are by far less and much safer compared to valproic acid. This is the case especially in female patients mainly because of the teratogenicity effects of valproic acid in pregnancy and because of polycystic ovarian syndrome in females of reproductive age. Further investigations should be conducted on large sample groups to evaluate its efficacy and tolerabilityin specific age groups and clinical conditions such as pregnancy.Hashemiaghdam: Main Author, Contribution to Conception and design, Analysis and interpretation, Data collection, Writing the article,Critical revision of the article, Final approval of the article ,Statistical analysis, Overall responsibility Sharifi: Main Author, Contribution to Conception and design, Analysis and interpretation, Data collection, writing the article, Critical revision of the article Dr. Miri: Co-Author contribution to Conception and design, Critical revision of the article, Final approval of the article Dr. Tafakhori: Corresponding author, contribution to Conception and design, Analysis and interpretation, Critical revision of the article, Final approval of the article, Statistical analysis, Overall responsibility.


Homo, along with facial flattening and reorientation to form a high nasal cavity. The nasal passage conditions the inhaled air in terms of temperature and humidity to match the conditions required in the lung, and its anatomical variation is believed to be evolutionarily sensitive to the ambient atmospheric conditions of a given habitat. In this study, we used computational fluid dynamics (CFD) with three-dimensional topology models of the nasal passage under the same simulation conditions, to investigate air-conditioning performance in humans, chimpanzees, and macaques. The CFD simulation showed a horizontal straight flow of inhaled air in chimpanzees and macaques, contrasting with the upward and curved flow in humans. The inhaled air is conditioned poorly in humans compared with nonhuman primates. Virtual modifications to the human external nose topology, in which the nasal vestibule and valve are modified to resemble those of chimpanzees, change the airflow to be horizontal, but have little influence on the air-conditioning performance in humans. These findings suggest that morphological variation of the nasal passage topology was only weakly sensitive to the ambient atmosphere conditions; rather, the high nasal cavity in humans was formed simply by evolutionary facial reorganization in the divergence of Homo from the other hominin lineages, impairing the air-conditioning performance. Even though the inhaled air is not adjusted well within the nasal cavity in humans, it can be fully conditioned subsequently in the pharyngeal cavity, which is lengthened in the flat-faced Homo. Thus, the air-conditioning faculty in the nasal passages was probably impaired in early Homo members, although they have survived successfully under the fluctuating climate of the Plio-Pleistocene, and then they moved “Out of Africa” to explore the more severe climates of Eurasia.We are flat-faced hominins with an external nose that protrudes from the face. This feature was derived in the genus  Homo was weakly sensitive to the ambient atmosphere conditions in evolution, but was formed passively by facial reorganization in this genus. Even though the inhaled air is not adjusted well within the nasal cavity in humans, it can be fully conditioned subsequently in the pharyngeal cavity, which is lengthened in flat-faced Homo. Thus, despite an impaired air-conditioning conformation in the nasal passages, Homo members must have survived successfully under the fluctuating climate of the Plio-Pleistocene, and then they moved “Out of Africa” in the Early Pleistocene to explore the more severe climates and ecological environments of Eurasia.This is the first investigation of nasal air conditioning in nonhuman hominoids based on computational fluid dynamics with digital topological models of the nasal passage made using medical imaging. Our comparative results of humans, chimpanzees, and macaques show that the inhaled air is conditioned poorly in humans compared with nonhuman primates. We also show that our protruding external nose has little effect on improving air conditioning. The nasal anatomy in  Homo [Homo from the other hominin lineages, adequate air conditioning must have been maintained, particularly to ensure their successful survival in the severely fluctuating climate of the Pleistocene and their subsequent spread from Africa to Eurasia [A flat, short face is one of the legacies of the genus Homo , 2. The Homo –3. ConseHomo , the nasHomo . This paHomo . HoweverHomo –10. The Homo , 12. TheHomo . InsuffiHomo , 12. Thu Eurasia , 14.In this study, we compared the principles and performance of air conditioning in humans, chimpanzees, and macaques by using a computational fluid dynamics (CFD) model  to simulHomo from the other hominin lineages lineage, using nonhuman primates as a model for the latter hominins.We evaluated the performance among the three species in varied ambient atmospheric conditions, and discuss the evolutionary modifications in air-conditioning performance in the divergence of This study for animals was performed in strict accordance with the recommendations in the third edition of the Guidelines for the Care and Use of Laboratory Primates at the Primate Research Institute of the Kyoto University (KUPRI), Inuyama, Japan. The protocol was approved by the Animal Welfare and Animal Care Committee at KUPRI . The chimpanzees were anesthetized intramuscularly with 3.5 mg ketamine hydrochloride  and 0.035 mg medetomidine hydrochloride  per kilogram of body weight. The anesthesia was maintained with sevoflurane  delivered in oxygen through a precision vaporizer and a rebreathing circuit. The macaques were anesthetized intramuscularly with 2.5 mg ketamine hydrochloride and 0.1 mg medetomidine hydrochloride per kilogram of body weight. Every effort was made to minimize suffering. The daily care and housing facilities strictly conformed to the recommendations in the third edition of the Guidelines for the Care and Use of Laboratory Primates at the KUPRI. To ensure the animals' health and welfare, their general appearance was daily monitored and recorded, along with their daily food and fluid intake.This study for humans was performed in strict accordance with the recommendations in the Declaration of Helsinki, Ethical Principle of Medical Research Involving Human Subjects prepared by the World Medical Association. All subjects gave an informed consent. The protocol was approved by the Human Research Ethics Committee of KUPRI (Permit Number: H2011-06).Pan troglodytes [Macaca fuscata, and two Rhesus macaques, M. mulatta—which were reared at KUPRI, Inuyama, Japan, were scanned using a computed tomography scanner  at the KUPRI  at the Brain Activity Imaging Center, ATR-Promotions, Seika, Japan . Among tThe CFD simulations with heat and water exchange were performed as described , 18. The−4 mm, depending on the size of the subjects, was generated from the modified STL data using Gambit 2.4  in each subject; i.e., up to 1.6% of the flow velocity for the same frontal contour.The voxel data of the nasal passage anatomy were reconstructed from computed tomography scans for nonhuman primates and magnetic resonance imaging scans for human volunteers. The black area representing the air filling the nasal passage was extracted first by using a threshold of brightness with Avizo 7 (FEI), and then the voxel data were reconstructed. After converting the voxel data to STereo Lithography (STL) data, these were modified into data representing the smooth surface using Magics 9.5 . Finally, a tetrahedron mesh with the mesh size of Δx = 2.10 to 3.65×10The no-valve and horizontal nasal vestibular topology models were generated from the original smoothed STL data using Rhinoceros . We defined the basal plane for making the modifications as almost parallel to the narrow channel between the nasal vestibule and the nasal cavity, which approximately corresponded to the nasal valve . Using tBoundary conditions for calculation). These values are lower than the critical Re value of 2300 denoting the transition between laminar to turbulent flow, and much lower than the Re of 5000 which is considered to be completely turbulent [We performed steady-state analyses to examine the airflow, where the turbulence model was not employed. A steady simulation is reasonable under a normal breathing frequency and flow rate in the resting stage in humans , 18–24. urbulent , 21, 24.urbulent . We usedurbulent  to modelThe simulation was governed by the Navier–Stokes equation—the conservation of momentum t, u, p, ρ, v, K, T, Cp, F, and D denote time, velocity, pressure, density, kinematic viscosity, thermal conductivity, temperature, specific heat, mass fraction of water, and mass diffusion coefficient, respectively. We regarded a solution as being of steady-state, after T (time) advanced substantially: we repeated the steps of calculation sufficiently until the values of system parameters reach the criterions of convergence, i.e, continuity, X,Y,Z-velocity, energy, and H2O reach 1×10−4, 1×10−5, 1×10−7, and 1×10−4, respectively, by the FLUENT 6.3.Here The wall of the nasal passage was modeled by the tissue and epithelial layers  to simulQep from the tissue side is determined by Qlatent is calculated from L and Wbl denote the specific latent heat and water flux from the surface of the epithelial layer, respectively. L is defined by Qtotal, is defined by TS, TTis, Kep and δep denote the temperature of the surface, the tissue layer temperature, the thermal conductivity of the epithelial layer and the epithelial layer thickness, respectively. TTis is constant, set here at 34°C, the temperature commonly measured in the human nasal region. The predicted air-conditioning performance is slightly inferior compared with that in reality for chimpanzees and macaques having higher body temperature. Nevertheless, this value is commonly used here for simulation both in humans and non-human primates, to examine the differences of air-conditioning performance which are caused by the morphological differences in nasal passage anatomy between them. The thermal conductivity of the mucous membrane Kep is 0.6 W/mK that is thermal conductivity of water [TS is determined by Qtotal, which comprises Qep and Qlatent.of water , becauseof water , 18. TS Wbl is the water flux from the boundary layer, which is determined from Wep is the water flux from the tissue layer, which is determined from F, FS, FTis, δbl, δep, Dbl, and Dep denote the water fraction in the boundary layer, the water fraction on the epithelial surface, the water fraction on the tissue layer, the boundary layer thickness, the epithelial layer thickness, mass diffusion coefficient of the boundary layer, and mass diffusion coefficient of the epithelial layer, respectively. Dbl and Dep are 3.0 × 10−5 m2/s and 2.6 × 10−5 m2/s, respectively [FTis is 3.34% of the water mass fraction in 100% of the relative humidity at 34°C. It is noted that diffusion in the boundary layer is greater than that of the membrane layers [FS gives FS was fixed as the boundary condition for water exchange. This boundary condition was implemented as a user-defined function in FLUENT software.Here ectively . FTis ise layers . The watNote that the nasal vestibule is covered with epidermis, where water is not exchanged .The external nostril was modeled as a free inlet, and no-slip boundary conditions were applied at the walls, while the outward velocity was assigned at the pharynx .The time-averaged velocity of the inhaled air at the pharynx was calculated based on estimates of the resting tidal volume and the respiratory rate, as well as the measurement of the cross-sectional area of the pharyngeal region at a given position for each subject . The croThe resting tidal volume was estimated by TV and BW denote the estimate of the resting tidal volume (ml) and measured body weight (kg), respectively.Here, The resting respiratory rate was estimated by f denotes the estimate of the respiratory rate .Here, Finally, the time-averaged velocity was calculated by FV and CA denote the time-averaged flow velocity (m/s) and the measured cross-sectional area at a given location of the pharynx (mm2), respectively.Here, The CFD simulations were performed in three ambient atmospheric air conditions: cold–dry, 10% RH at 5°C (0.05% MF); hot–dry, 5% RH at 40°C (0.23% MF); and warm–wet, 60% RH at 30°C (1.58% MF).The resulting spatial pattern of the vector quantity representing the velocity and direction of the airflow is illustrated using streamlines in different colors that was computed from the points on the plane of external nostrils , 18. TheOur simulations of CFD showed that the airflow direction in the nasal cavities of chimpanzees and macaques differs in some key regions from that in humans. In humans, the inhaled air flows upward along the ascending vestibular region into the nasal cavity and downward to the oropharynx , whereasIn our simulations, the inhaled air was conditioned well in chimpanzees and macaques, even in severe ambient conditions Figs ; Table 1The no-valve model resulted in a few changes in the airflow direction and air-conditioning performance for each human subject ; Table 2In this CFD study, we used the same simulation conditions to compare the air-conditioning performance in humans and non-human primates. It should be noted that MRI scans were used for reconstructing the nasal passage models in humans, while CT scans were used in nonhuman primates. A same type of tissue is resolved differently between the two modalities. In a precise sense, mixing CT and MRI scans potentially alters the thickness of the airway and flow velocities for a same subject. Nevertheless, the present results using MRI scans also show an airflow pattern, velocities, and air-conditioning performance that are similar to those by a same CFD model using a CT-based model in humans . Such miHomo have a nasal passage in a manner analogous to chimpanzees rather than humans, suggesting that they probably show the effective air-conditioning performance as seen in non-human primates. However, the characteristic facial reorganization in Homo has precluded the developmental elongation of the oral and nasal cavities [Homo from the other hominin lineages. Rather, the nasal region is regarded just as a buffering module for facial reorganization, in contrast with other modules, including the jaw, eye, and braincase, which have been modified yet have maintained their independent functions. Thus, human nasal topology was probably modified passively by evolutionary facial reorganization in early Homo, and such an evolutionary modification was not prevented by impaired the air-conditioning performance.The nasal topology is often regarded as being evolutionarily sensitive to the ambient atmospheric conditions of a habitat such as temperature and humidity for a given clade –48. In fcavities –10 and hcavities , 48, butHomo is believed to confer some functional advantages during air conditioning, such as retaining the water vapor from expired air [Homo lineage since it was diversified from the other hominins, including australopithecines, in the beginning of the Early Pleistocene.The unique external nose in ired air  or generired air , 44. Theired air , but theired air , 44. Furired air . IrrespeHomo from the other hominin lineages, facial flattening and reorganization has reduced the dimensions of the horizontal oral cavity along with the nasal cavity and pushed the tongue down toward the pharynx, thereby lengthening the vertical pharyngeal cavity [Homo [Homo members, must have survived such fluctuations in climate, before they moved “Out of Africa” in the Early Pleistocene to explore the more severe climates and ecological environments of Eurasia.Inhaled air can be adjusted through the pharyngeal cavity to be fully conditioned in humans, even though it is not fully adjusted in the nasal cavity. In the phyletic divergence of l cavity , 9. Althty [Homo , 50, thety [Homo , 51. Thity [Homo –54. Howety [Homo , 55. TheS1 Table†estimate.abbreviations: MRI, magnetic resonance imaging; CT, Computed Tomography; CA, cross-sectional area at the oropharyngeal level; TV, estimated tidal volume; f, estimated frequency of breath; FV, flow velocity at the pharyngeal level. *CT scans of chimpanzees and macaques used here are deposited and released at the Digital Morphology Museum, KUPRI (dmm.pri.kyoto-u.ac.jp/archive/), under PRICT #.(DOCX)Click here for additional data file.S1 Fig(A) Human volunteer 1; (B) human volunteer 3; (C) human volunteer 5; (D) human volunteer 6. The streamlines (upper) and contours (bottom) indicate the airflow direction and velocity distributions through the nasal passage, respectively. The streamline number reflects the relative airflow volume for a given subject.(TIF)Click here for additional data file.S2 Fig(A) chimpanzee Mari; (B) chimpanzee Pendesa; (C) chimpanzee Reiko; (D) macaque Mff963; (D) macaque Mff1859; (F) macaque Mff2115; (G) macaque Mm1701; and (H) macaque Mm1715. The streamlines (upper) and contours (bottom) indicate the airflow direction and velocity distributions through the nasal passage, respectively. The streamline number reflects the relative airflow volume for a given subject.(TIF)Click here for additional data file.S3 Fig Human volunteer 1,  human volunteer 3,  human volunteer 5,  human volunteer 6.  No-valve model and  horizontal models. The streamlines (upper) and contours (bottom) indicate the airflow direction and velocity distributions through the nasal passage, respectively. The streamline number reflects the relative airflow volume for a given subject.(TIF)Click here for additional data file.


The mortality risk associated with congenital airway anomalies (CAA) in children with congenital heart disease (CHD) is unclear. This study aimed to investigate the factors associated with CAA, and the associated mortality risk, among children with CHD.This nationwide, population-based study evaluated 39,652 children with CHD aged 0–5 years between 2000 and 2011, using the Taiwan National Health Insurance Research Database (NHIRD). We performed descriptive, logistic regression, Kaplan–Meier, and Cox regression analyses of the data.Among the children with CHD, 1,591 (4.0%) had concomitant CAA. Children with CHD had an increased likelihood of CAA if they were boys , infants , or had a congenital musculoskeletal anomaly , and were typically identified 0–3 years after CHD diagnosis . The mortality risk was increased in children with CHD and CAA , even after adjusting for confounders . Mortality risk also changed by age and sex (adjusted HR and 95%CI are quoted): neonates, infants, and toddlers and preschool children, 1.67 (1.40–2.00), 1.93 (1.47–2.55), and 4.77 (1.39–16.44), respectively; and boys and girls, 1.62 (1.32–1.98) and 2.01 (1.61–2.50), respectively.The mortality risk is significantly increased among children with CHD and comorbid CAA. Clinicians should actively seek CAA during the follow-up of children with CHD. Congenital heart disease (CHD) is a gross structural anomaly of the heart or intrathoracic great vessels that is present at birth and manifests with actual or potential functional significance . It is oAside from cardiac complications, non-cardiac comorbidities may also influence the health of patients with CHD , 7. It iMost studies to date have focused on the association of all ECA categories with CHD –13. ConcThe National Health Insurance Research Database (NHIRD) in Taiwan offers a nationwide population-based, multi-institutional database for research purposes. The aim of this study was to use the NHIRD to examine the associations between CAA and CHD, and to evaluate the mortality risk associated with CAA among children with CHD.The Institutional Review Board of Taipei Veterans General Hospital, Taiwan, approved this study. Because all personal identifying information had been encrypted before the database was released, the review board requirement for written informed consent was waived.This study was based on data from the NHIRD released by the National Health Research Institute (NHRI). Taiwan began the National Health Insurance (NHI) program in 1995 to provide comprehensive health care for its population. Enrollment in the NHI program is mandatory and data presently exists for more than 23 million people, representing approximately 99% of Taiwan’s population . The NHIAll information that may potentially identify an individual patient was encrypted before the release of the database. The confidentiality of the NHIRD was maintained in accordance with the data regulations of the NHI Administration, Ministry of Health and Welfare and the NHRI, Taiwan. The NHRI guard the privacy of all beneficiaries and provide the NHIRD to researchers who have obtained ethical approval.A retrospective population-based cohort study was conducted from January 1, 2000 to December 31, 2011. All inpatient data from NHIRD were collected for analysis over this 12-year period. Using the CHD diagnostic codes in the NHIRD , 43,770 children with CHD, aged 0–5 years, were identified. Patients born before January 1, 2000 were excluded . The final CHD study cohort comprised 39,652 children. The first date for each patient’s CHD diagnosis recorded in the NHIRD was defined as the index date. Information regarding the sex, age at CHD diagnosis, follow-up period, comorbidities, and in-hospital mortality was collected for analysis. The age at CHD diagnosis was grouped as follows: neonates (newborn up to 28 days), infants (aged more than 4 weeks but less than 12 months), and toddlers and preschool children (aged between 1 and 5 years). Mortality was defined according to the discharge status recorded in the NHIRD. All of the enrolled patients were followed-up until death or December 31, 2011, whichever was earlier.Patients with the diagnostic code for CAA, defined as 748 in the ICD-9-CM format , were idp-values < 0.05 were considered statistically significant.All data were linked by SQL server 2008  and analyzed by the IBM SPSS statistics for Windows, Version 19.0 . The data were expressed as median  or percentage where appropriate. Chi-square or Fisher’s exact tests were used to assess the differences between the categorical variables. Multivariate logistic regression was applied to assess the associations between CAA and CHD. Odds ratios (OR) and 95%confidence intervals (CIs) are quoted as appropriate. The Kaplan–Meier analysis and log-rank test were used to estimate the cumulative incidence of mortality among children with CHD with and without CAA. Finally, Cox regression analyses with hazard ratios (HRs) were used to evaluate the mortality risk associated with CAA among children with CHD. For all tests, 2-tailed During the 12-year study period, 39,652 children with CHD were enrolled, including 19,713 (49.7%) boys and 19,939 (50.3%) girls. Most of those with CHD were diagnosed as neonates . The median follow-up period was 7 (3–9) years. The most common ECA among children with CHD was CAA , followed by musculoskeletal , and chromosomal  anomalies. In total, 2,533 patients (6.4%) died during the follow-up, of which 199 (7.9%) had CAA.p < 0.001). The CHD diagnostic age as infants (5.8%) and those in the first 0–3 years of follow-up had the highest rates of CAA in each sex and age stratum (p < 0.001). Children with all other ECA, except those with integumentary anomalies, had significantly higher rates of associated CAA (p < 0.001) (CAA occurred in children with CHD at rate of 4.8% in boys and 3.2% in girls (< 0.001) .Children with CHD had a significantly higher probability of having CAA if they were boys , neonates , or infants  at CHD diagnosis. There was an elevated risk of diagnosis of CAA during the 0–3 years  and 4–7 years  after CHD diagnosis. Furthermore, there was a significantly greater probability of children with CHD having a CAA if they had any of the following ECA: musculoskeletal , eyes/ears/face/neck , nervous system , chromosomal , cleft lip/palate , genital , and gastrointestinal  .p < 0.001)  .The diffp < 0.001). The increased mortality in children with CHD and CAA remained after stratifying the data by sex  and age . A significant difference in mortality was found in patients with follow-up at 0–3 years  and 4–7 years . Mortality rates were also higher in children with concomitant CHD and CAA associated with additional nervous system , musculoskeletal , and genital  anomalies. Overall, the mortality rate was significantly higher in children with CHD associated with CAA  than in those without CAA   than those with CHD without CAA, and this difference remained after adjusting for sex, age at CHD diagnosis, and other comorbidities . With respect to the stratified analysis of mortality risk in children with CHD and CAA, mortality risk was significantly higher than for CHD without CAA by sex  and age  strata. The overall and stratified results of the Cox regression analyses for mortality risk in patients with CHD and CAA are shown in To date, this is the first large-scale nationwide population-based analysis to investigate the factors associated with CAA, and the associated change in mortality risk, in a population of children with CHD. This study of 39,652 children aged 0–5 years with CHD demonstrates that boys, infants, and those with other congenital musculoskeletal anomalies are most likely to have an associated CAA, and that the condition is most likely identified 0–3 years after the diagnosis of CHD. In addition, there is evidence that children with CHD associated with CAA have a significantly elevated mortality risk, with an aHR of 1.76 after a median 7-year follow-up period.The heart starts to differentiate around the third week of embryonic stage , and theMost studies to date have reported that the prevalence of ECA among children with CHD is 20% to 30%, which is much higher than that in the general population , 33, 34.CAA is an often unrecognized problem in children with CHD, and early identification of this congenital respiratory pathology is essential for appropriate management , 35. BecThough CAA has been noted to occur more frequently in patients with underlying genetic or syndromic disease, such as Trisomy 21, VACTERL, and Klippel-Feil , 37–39, The mortality data presented in other studies of children with CHD are conflicting. Jenkins et al. reported that the mortality rate for CHD surgery was 7.3% , while WPrevious studies have often failed to explore the differences in mortality according to the presence or absence of ECA; in this study, we specifically clarify the CHD mortality associated with the presence of CAA. We have demonstrated that the mortality rate was significantly greater for CHD with CAA (12.5%) than that without CAA (6.1%), and that statistical significance remained when stratifying by sex, age, time after CHD diagnosis , and the presence of congenital nervous, musculoskeletal, and genital anomalies. After adjusting for sex, age, and comorbidities, the added mortality risk of CAA in CHD patients is 1.76 times higher than in those without CAA. Together, these results imply that CAA is an unfavorable prognostic factor in children with CHD. The significantly elevated mortality risk may be due to the long-term interaction of the cardiovascular and respiratory pathologies that lead to increased morbidity . The priAlthough boys with CHD  were more likely to be diagnosed with CAA, the mortality risk for girls with CHD and CAA  was higher than that of boys . There is no adequate explanation for these sex-based differences among children with both CHD and CAA. Further investigation is needed to understand these differences.The results of stratified analyses demonstrate that, compared to children with CHD without CAA, children with CHD diagnosed as toddlers and at preschool have the highest mortality risk . The different mortality risk in different age strata may reflect the prolonged and complex pathophysiological interaction between CAA and CHD. The later CHD is diagnosed, the more profound the interaction between the respiratory and cardiovascular systems will be. Additional research is needed to draw meaningful conclusions.The results of the Kaplan–Meier analysis showed that the cumulative incidence of mortality among children with CHD increased with a steeper slope in the first 0–3 years after CHD diagnosis, and then stabilizes thereafter. This pattern was true of patients with and without CAA, although the magnitude differed between each. In addition, the difference in the cumulative incidence of mortality only became prominent during the first 0–3 years after the CHD diagnosis, implying that this may be a critical period for these children. CAA may be responsible for the differences in cumulative incidence of mortality.To our knowledge, this is the first large-scale nationwide population-based cohort study to assess the association between CAA and CHD and focusing on the added mortality risk of CAA. The major strengths of the current study are the population-based design, the complete coverage of CAA and CHD in the population (precluding the possibility of loss to follow-up), and the longitudinal follow-up. Nevertheless, this study has some limitations that are worth considering. First, because it is epidemiologic in nature, it cannot establish causative links, only associations. Second, personal information is not documented in the database, including the clinical phenotypes and severities of CAA and CHD, environmental factors, and lifestyle factors. Therefore, an analysis of the possible relationships between these personal characteristics and the mortality risk is not possible. Third, because the study was conducted in Taiwan, the extent to which the findings can be generalized to other population warrants further discussion. Additional large studies, with a longer follow-up period, involving different age strata, and in different countries, are required to make definitive conclusions.Children with CHD are most likely to be diagnosed with CAA if they are boys, infants at the time of CHD diagnosis, or have another congenital musculoskeletal anomaly. Further, most children are diagnosed with CAA 0–3 years after the CHD diagnosis. In addition, the overall and the sex- and age-stratified mortality risks are significantly increased in children with CHD and comorbid CAA. We recommend that clinicians be vigilant for CAA during the follow-up of children with CHD. Further studies are warranted to elucidate the potential mechanisms underlying the differences in mortality that we identified in association with CAA.


Background. Lifestyle interventions focusing on healthy diet and physical activity (PA) are effective in reducing health risks in controlled research settings. The aim of this study was to investigate the one-year results of the BeweegKuur lifestyle intervention implemented nationwide in Netherlands for people with a weight-related health risk. Materials and Methods. Data were requested from all 160 locations participating in the BeweegKuur. In a one group pretest/posttest study, one-year changes in health outcome variables and time spent on physical activity were tested with dependent t-tests. Associations between one-year changes in weight and waist circumference and sociodemographic factors and uptake of the program were analysed with ANOVA. Results. Data for 517 participants from 47 locations were available for analysis. One year after the intervention, weight reduced by 2.9 kg , waist circumference by 4.3 cm , and blood glucose by 0.5 mmol/L . Physical activity increased significantly. Higher uptake of the program was associated with a larger decrease in waist circumference. Conclusion. The results of the study suggest that lifestyle interventions implemented in real-life primary healthcare settings with tailor-made supervision can contribute meaningfully to primary prevention. Worldwide, age-standardized prevalence of obesity in adults almost doubled between 1980 and 2008 . As inac BeweegKuur was implemented in local, real-life primary healthcare settings spread over Netherlands [Within a nationwide implementation project commissioned by the Dutch Ministry of Health, Welfare, and Sport, theherlands . The obj BeweegKuur project was started in 2007 because the former Dutch Minister of Health wanted to implement a lifestyle intervention nationwide, accessible, and reimbursed by health insurance for the whole target group. Together with national stakeholders, an intervention was designed based on existing interventions and known effective elements. The intervention took place in the primary healthcare setting. The aim of the project was to optimize nationwide implementation [ BeweegKuur to a certain extent to the local situation. Also, these locations were allowed to use their own quality-assured procedures for testing and measuring health parameters. Locations applied voluntarily to join, resulting in 160 participating locations spread over Netherlands in 2011. Every location was allowed to include a maximum of 40 participants per year. Local healthcare professionals were supported by one of 20 regional primary care support structures, which in turn were instructed by the Netherlands Institute for Sport and Physical Activity (NISB). All professionals supporting participants received training on the BeweegKuur; lifestyle advisors (LSAs) and physiotherapists received a three-day course and the dieticians a one-day course. BeweegKuur protocols and other guidelines were available for all healthcare professionals.The pilotentation . This waentation , 19. On  BeweegKuur intervention in itself was to achieve health benefits through increased PA and improved dietary behaviour. The BeweegKuur's starting point was the general practitioner's (GP) practice. The GP referred patients with a weight-related health risk ;had a BMI between 25 and 30 in combination with a waist circumference ≥88 cm for women and ≥102 cm for men and/or comorbidity;had a BMI between 30 and 35, regardless of waist circumference and comorbidity;had a BMI between 35 and 40, regardless of waist circumference but without comorbidity.Comorbidity included hypertension, dyslipidaemia, diabetes mellitus, cardiovascular disease, osteoarthritis, and sleep apnoea.The GP was responsible for screening for contraindications, based on current medical guidelines and standards in the Netherlands, and decided whether a person could participate in theMeasurements were taken during sessions with the LSA and included weight, BMI, waist circumference, blood glucose, and blood pressure. Data from the first and last sessions were used for the analyses. Anthropometric and blood pressure measurements were conducted according to standardized procedures in the GP practice. For blood glucose, LSAs registered whether blood glucose was measured in a fasting state or not, according to local procedures. Only fasting-state measurements were used for analysis. Physical activity was self-reported using the standardized short version of the validated SQUASH questionnaire . Activitt-test. A p value of <0.05 was considered to be statistically significant. All tests were two-sided. ANOVA was conducted to test whether sociodemographic factors, uptake of the program, and change in physical activity were related to changes in weight and waist circumference, followed by the Games-Howell post hoc test (p < 0.05) [Data analyses were conducted using SPSS for Windows (version 18). One-year changes in weight, BMI, waist circumference, blood glucose, blood pressure, and physical activity were normally distributed for the overall population and the different subgroups. One-year changes were tested with a paired samples'  < 0.05) .The LSAs from 81 of the 160 locations sent back the registration files. Complete data for 517 participants from 47 locations (mean = 11 persons/location) were available for analysis; participants in the other locations had not yet finished the intervention at the time of data retrieval.http://dx.doi.org/10.1155/2015/484823).The background characteristics of participants are described in One year after the start of the intervention, weight and waist circumference had significantly reduced by 2.9 kg (3.0% of baseline) and 4.3 cm (3.8%) . Other hYounger participants lost on average more weight than older participants . Larger  BeweegKuur was positively related to participants reducing weight, waist circumference, blood pressure, and blood glucose and increasing their physical activity. The largest changes in waist circumference were observed in participants with higher uptake of the program.This study has shown that participation in the real-life lifestyle intervention BeweegKuur carried out in a few locations [ BeweegKuur appeared to be more effective. In these interventions, weight loss was on average between 0.5 and 2.5 kg and waist circumference decreased from 0.4 to 4.2 cm after 1 to 1.5 years.In this study, weight and waist circumference reduced by 2.9 kg and 4.3 cm, respectively, after one year. These effects were stronger than that found in a previous effect evaluation of an earlier and less developed version of theocations . The larocations , the Dutocations , the Finocations , and theocations , the Bew BeweegKuur, participants were referred to the most appropriate exercise program, depending on the level of weight-related health risk. Participants followed sessions with the physiotherapist, and the LSA designed a tailor-made program and provided coaching and supervision, according to the person's needs. Additionally, participants were referred to local sport facilities with personalized programs adjusted to their physical and mental capabilities. In none of the other intervention studies participants received similar tailor-made supervision to increase their PA [ BeweegKuur compared with other intervention studies. In the BeweegKuur, light to moderate and vigorous PA were increased by 2.1 and 1.7 hours a week, respectively. The Hoorn Prevention Study found a decrease in PA after one year [ BeweegKuur on PA may be due, at least partly, to the strong focus on optimal implementation, based on the results of extensive formative evaluation in relation to the nationwide implementation project [In thetheir PA , 15, 25.one year  and the one year . The con project , 19. BeweegKuur, participants had individual sessions with the LSA, but most sessions with the dietician and the physiotherapist were in groups. Alongside the benefits of individual coaching, group counselling can promote group cohesion, generally having a beneficial effect on behaviour change [ BeweegKuur was an extensive program, and uptake of the program was high in comparison with other interventions. Fifty-five percent of BeweegKuur participants visited the LSA six times or more. In the FIN-D2D program, only 29% of the participants had three or more sessions in usual primary healthcare [In ther change , 27–29. r change , 25. Moralthcare , and 43%althcare , 12. We  BeweegKuur was designed as an implementation project aimed at optimizing local and nationwide implementation of lifestyle interventions and not primarily as a research project [ BeweegKuur was well embedded in local-practice working standards, but the structure of the project led to several drawbacks for this study. No control group could be included and the response rate was relatively low, thereby limiting adjustment for potential confounders.Initially, the project . ConsequThe design of the whole project did not include very strict quality control procedures for data collection. Individual LSAs were responsible for data entering. This might have led to potential information bias, with structural overestimation of the results of the intervention. Differences in measurement methods could also have led to bias but are unlikely to contribute to overestimation of associations. All measurements were carried out with instruments and tests available in professional general practices. These instruments meet professional quality standards, and therefore we believe that the effect on measured differences is within the range of total variation of these parameters. BeweegKuur were not collected. In Vermunt et al.'s study [The study locations included in the analysis were spread across the country, representing the Dutch target group. The study population might be a selective group, as data for persons who did not complete the's study  on the eNotwithstanding these methodological limitations, this study can contribute to a growing understanding of an effective implementation methodology regarding lifestyle interventions in real-life primary care settings, as knowledge on this essential step is limited. This study gives an indication that the essential elements of the intervention seem to be a number of sessions with the healthcare professionals, a combination of individual and group sessions, tailor-made supervision and counselling, and referral to local sport facilities with personalized programs. The latter element is described in detail by Elsman et al. . BeweegKuur lifestyle intervention demonstrated positive results on physical activity and anthropometric outcomes. Due to limitations of the study design, it cannot be ruled out that reported outcomes overestimate the results that can be achieved in the entire population. However, the effect evaluation indicates that a well-implemented intervention, combining individual and group sessions and tailor-made supervision by local healthcare professionals, can result in substantial lifestyle and health changes in persons who fully participate.One-year results of theSupplemental Table 1: shows the socio-demographic characteristics of the Dutch population and BeweegKuur intervention participants. Supplemental Table 2: shows baseline measurements and changes in anthropometric outcomes and physical activity after one year split by gender.


Few studies have assessed the association between the rs1414334 C/G polymorphism in the HTR2C gene and the development of the metabolic syndrome in patients treated with atypical antipsychotics. To provide further evidence, a cross-sectional study was conducted in Spain between 2012 and 2013 in 166 patients with these characteristics. In these patients, the association between the polymorphism and the presence of the metabolic syndrome was determined by implementing binary logistic regression models adjusted for variables associated with the metabolic syndrome. We did not confirm previous claims that the C allele of the polymorphism was linked to the metabolic syndrome: the association was in the opposite direction and non-significant. This conclusion held after taking gender and lifestyle variables into account. Cardiovascular disease is the leading cause of mortality in the world , 2014. IIn this type of patient, taking atypical antipsychotics can cause an increase in the probability of having the metabolic syndrome , 2005. TAmong the genes involved, previous studies have reported an association between specific polymorphisms in the HTR2C gene and development of the metabolic syndrome in these patients , 2014. 5For this reason, multiple genetic variants of the HTR2C gene have been studied. Various polymorphisms such as –759C, –697C/G, –997G/A, –1,165A/G have been evaluated, finding associations with the development of the metabolic syndrome. At times these associations have shown conflicting results , 2011. OThis behavior has also been noted in the 759C/T and 997G/A polymorphisms in the HTR2C gene, where some authors have found these polymorphisms to have a protective nature against the metabolic syndrome, whilst others have found them to be of risk and the remainder found no difference , 2014. AThe proposed study was conducted in the Elche, Crevillente and Santa Pola Department of Health of the Valencian Community, which is a Mediterranean region located in southeastern Spain. In its mental health services, coverage is provided to approximately 325,000 inhabitants . Health care is universal and free for all patients, except those with an irregular immigration status.In this cross-sectional, observational study, a sample of inpatients and outpatients treated for at least three months with atypical antipsychotics  was analyzed. For the sample, consecutive patients attending Mental Health Services of the Valencian Community at the Elche, Crevillente and Santa Pola Department of Health between December 2012 and June 2013 were selected. All patients had to be of legal age (>18 years) and have a diagnosis of a psychotic disorder. This was defined as having a psychiatrist’s diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder or other psychotic disorders, or bipolar disorder, and continuous treatment with antipsychotic medication , 2000. TThe study was approved by the Clinical Research Ethics Committee of the General University Hospital of Elche on November 20, 2012.The primary variable was the diagnosis of the metabolic syndrome using the ATPIII criteria , 2004, iSecondary clinical variables were: age (years), gender, diagnosis (schizophrenia or other) , 2000, yThe following variables related to lifestyle were obtained by conducting the National Survey of Health and the European Health Survey , 2011: uGenomic DNA was extracted from EDTA blood samples using the semi-automated QIAcube system . The rs1414334 C/G polymorphism was analyzed by real-time PCR using a pre-developed assay  for allelic discrimination in a 7300 Real-Time PCR System (Applied Biosystems). The reaction was carried out with a TaqMan genotyping PCR master mix (Applied Biosystems), according to the protocol provided by Applied Biosystems.http://www.ncbi.nlm.nih.gov/snp).The rs1414334 polymorphism allele C/G is described in the SNP database  is different from 1. For this calculation we assumed C allele in 30% of cases and 13% of controls, a control/case ratio of 2:1 and a type I error of 5% , 2012. Wt-test, and then selected those variables with the smaller p-value. Thus the adjusted OR were obtained. The goodness-of-fit of the final model was assessed using the likelihood ratio test.All variables were described using frequencies (absolute and relative), means and standard deviations. A stepwise logistic regression model was constructed to determine the relationship between the polymorphism and the metabolic syndrome. Since we had 68 events (metabolic syndrome), the model could only hold a maximum of six explanatory variables (one for every 10 events) , 2015. ASince the HTR2C gene is X-linked, all the analyses were carried out for men and women separately. This is important because women encounter a very different situation than men. Women can be heterozygote, whereas men cannot, which creates a completely different biological scenario. This is also important with respect to previous articles published on this topic , 2012.All analyses were performed with a significance of 5% and for each relevant parameter its associated confidence interval (CI) was calculated. The statistical package used was IBM SPSS Statistics 19 .p-value < 0.430)  –3.p < 0.05): older age (p = 0.038) and antidepressants (p = 0.044). The rs1414334 C allele did not show any difference (p = 0.164). When we analyzed the factors associated with the metabolic syndrome (p = 0.062) (direction contrary to prediction).The descriptive and analytical characteristics of the total sample are shown in syndrome , no varip = 0.011). On the other hand, the logistic regression model only showed one significant factor associated with the metabolic syndrome (older age), and the C allele of the polymorphism had the same association as was found in the total sample . Finally (t-test), no significant factors associated with our outcome, and the studied polymorphism had the same result as in the total sample and in the men .In the men , we note Finally , in the This study found no statistically significant association between the presence of the C allele of the rs1414334 polymorphism in the HTR2C gene and the metabolic syndrome.The main strength of this study is that it provides greater knowledge of the association between the polymorphism analyzed and the metabolic syndrome. Moreover, all the variables that the Dutch group did not analyze in their studies were taken into account, such as physical activity, diet and smoking , 2012. TRegarding limitations, we must bear in mind that our design is cross-sectional, thus we could not establish causal relationships between the factors analyzed and the presence of the metabolic syndrome. In other words, our study, as in the Dutch group’s study , 2014, oAlthough several studies address the possible associations between different HTR2C gene polymorphisms and the presence of the metabolic syndrome, only the Dutch studies focus on the rs1414334 polymorphism , 2014. TIn agreement with The set of studies by the Dutch group indicates that the presence of the C allele of the HTR2C rs1414334 gene polymorphism appears to be associated with the metabolic syndrome. Our findings, however, do not support this association. As mentioned above, this could be due to differences between our patients and those of the Dutch group or could indicate type 1 error in the original findings. To distinguish these possibilities, we would need multicentre studies evaluating the association in different antipsychotic treatments, preferably using a prospective design. However, before investing in such research, it would be helpful to establish whether this SNP has a functional influence.10.7717/peerj.2163/supp-1Data S1Regular physical activity was assessed on a scale as follows: 0, sitting; 1, standing; 2, walking or moving around; 3, great effort. Physical activity during leisure time was measured using the following scale: 0, never; 1, less than once per month; 2, once or several times per month; 3, one or more times per week. The scale of all the food was rated as: 0, daily; 1, three or more times a week; 2, once or twice a week; 3, less than once a week; 4, never or almost never. The binary variables were categorized as 0 (No) and 1 (Yes), except for gender .Click here for additional data file.


Despite the well-established association between baseline depressive symptoms and risk of all cause-mortality, limited information exists on racial differences in the residual effects of baseline depressive symptoms above and beyond socioeconomic status (SES) and physical health on this link. The current study compared Blacks and Whites for the residual effects of depressive symptoms over SES and health on risk of long-term all-cause mortality in the U.S.Data were obtained from the Americans’ Changing Lives Study, a nationally representative longitudinal cohort of U.S. adults with up to 25 years of follow-up. The study followed 3,361 Blacks and Whites for all-cause mortality between 1986 and 2011. The main predictor of interest was baseline depressive symptoms measured at 1986 using an 11-item Center for Epidemiological Studies-Depression scale. Covariates included baseline demographics (age and gender), SES (education and income), and health  measured at 1986. Race (Black versus White) was the focal moderator. We ran a series of Cox proportional hazard models in the pooled sample and also stratified by race.In the pooled sample, higher depressive symptoms at baseline were associated with higher risk of all-cause mortality except when the CMC, SRH, and BMI were added to the model. In this later model, race interacted with baseline depressive symptoms, suggesting a larger effect of depressive symptoms on mortality among Whites compared to Blacks. Among Whites, depressive symptoms were associated with increased risk of mortality, after controlling for SES but not after controlling for health . Among Blacks, depressive symptoms were not associated with mortality before health was introduced to the model. After controlling for health, baseline depressive symptoms showed an inverse association with all-cause mortality among Blacks. Although the effect of baseline depressive symptoms on mortality disappeared after controlling for health among Whites, SRH did not interfere (confound) with the effect of depressive symptoms on mortality among Blacks.The effect of depressive symptoms on increased risk of all-cause mortality, which existed among Whites, could not be found for Blacks. In addition, race may modify the roles that SES and health play regarding the link between depressive symptoms and mortality over a long period of time. A considerable body of literature has shown that baseline depression and depressive symptoms predict increased risk of subsequent mortality due to all- or specific-causes –6. GrowiThere is a need to study the residual effect of depression or depressive symptoms above and beyond demographics, socioeconomic status (SES), and overall and health indicators such as self-rated health (SRH), chronic medical conditions (CMCs), and body mass index (BMI) , 2. As CRace and ethnicity alter the complex associations between SES, depression, and health , 32–36. We conducted this study to compare Blacks and Whites for effects of depressive symptoms over SES and health  in predicting long-term risk of all-cause mortality in a nationally representative cohort of American adults.Data were obtained from Americans’ Changing Lives (ACL) study . The ACLN = 3,361, Whites = 2,205, and Blacks = 1,156).Stratified multistage probability sampling was applied in the ACL study. At baseline, the study population consisted of 3,617 adults older than 24 years old. Non-institutionalized continental U.S. residents were included in the study. Wave 1 represented 70% of sampled households and 68% of sampled individuals. Blacks and older adults (age >60 years) were oversampled in ACL. We focused on Whites and Blacks in our analysis  was used to extract the all-cause mortality data, including the date of death and the cause of death. Death certificates are filled out by physicians after a person’s death in the U.S., and it is used as the source of the NDI. , 17We used the 11-item Center for Epidemiological Studies-Depression scale (CES-D) , 42. In Participants were asked whether they had been informed by a health care provider about having any of the seven focal conditions of interest, including hypertension, diabetes, chronic lung disease, heart disease, stroke, cancer, and arthritis. Answers to each condition were scored as 0 or 1, resulting in a scale of 0–7 for total CMC , 41.Self-rated health was a single-item scale on subjective overall health, with five categories: poor, fair, good, very good, and excellent. SRH was treated as a dichotomous measure, where the original five categories were collapsed to the poor/fair versus good/very good/excellent categories. SRH has shown acceptable test–retest reliability and validity , 45–49.Data were collected at baseline on gender  and age (in years).Data were collected at baseline on education (years of schooling) and household income .Participant’s race was based on self-reported race and ethnicity, collected at baseline in 1986 with several survey items. Participants responded open-endedly to the question, “In addition to being American, what do you think of as your ethnic background or origins?” Respondents were then asked a multiple-choice question, “Are you white, black, American Indian, Asian, or another race?” and allowed to answer with multiple categories. This analysis only included non-Hispanic White and non-Hispanic Black respondents. All Hispanic individuals were dropped from the analysis.Informed consent was obtained from all participants of the ACL study. Our study was approved by the University of Michigan institutional review board in accordance with The Code of Ethics of the World Medical Association .P-value <0.05 was considered significant.Stata 13.0  was used to account for the complex sample design of the ACL study by applying sampling and non-response weights. Taylor series linearization was applied for the estimation of standard errors in a subsample analysis framework. Hazard ratios  were reported. A The only main predictor of interest was baseline depressive symptoms measured at 1986. Covariates included baseline SES (education and income), SRH, CMC, and BMI all measured at 1986. Outcome was time to all-cause mortality from 1986 to 2011. Time to all-cause mortality was calculated in months as the timeframe between baseline and death. Time to censoring was calculated in months as the timeframe between baseline and loss to follow-up or baseline and 2011.A series of Cox proportional hazards models were used to assess the residual effect of baseline depressive symptoms on all-cause mortality over demographics, SES, and health. First, we ran four models in the pooled sample. Model 1 only included high depressive symptoms at baseline (CES-D > mean) and demographic variables. Model 3 was the full model as it controlled for CMC, SRH, and BMI as well as other variables. Model 4 included the interaction term between race and high depressive symptoms (CES-D > mean) at baseline. In the next step, we ran four models for Whites and four models for Blacks in a step-by-step fashion. Model 1 only included depressive symptoms and demographics. Model 2 included socioeconomic variables as well. Model 4 accounted for all the variables.estat concordance command in Stata to calculate the C statistics for our Cox regression models in the pooled sample based on race. Harrell’s C [(E + T/2)/P] was 0.82, 0.84, and 0.79 in the pooled sample, Whites, and Blacks, respectively. Somers’ D statistics were 0.64, 0.67, and 0.59 for the pooled sample, Whites, and Blacks, respectively. Thus, performance of the model was only slightly lower among Blacks compared to Whites. Despite reporting C statistics, we did not aim to measure overall adequacy of our models, as we did not aim to find risk prediction models. Instead, our aim was to test one association of interest among Blacks and Whites . Third, health has different roles on the link between baseline depressive symptoms and long-term risk of all-cause mortality among Whites and Blacks. Although CMC suppresses the effects of depressive symptoms on mortality among Blacks, SRH explains (confounds) the same link among Whites.Our first findings on the stronger predictive role of baseline depressive symptoms on all-cause mortality for Whites compared to Blacks are in line with a growing body of evidence, suggesting that depressive symptoms, SRH, and hostility may have a weaker predictive role for long-term mortality of Blacks compared to Whites , 18–21. A recent study found that baseline depressive symptoms predict subsequent risk of major depressive disorder (MDD) 15 years later among Whites but not Blacks, suggesting a weaker effect of depressive symptoms on subsequent all-cause mortality among Blacks . This fiThe unexpected protective residual effect of depressive symptoms on all-cause mortality over SES and health for Blacks is not easy to explain. Nesse has discussed an evolutionary explanatory model of depression. In this model, depression and lack of motivation may be a healthy reaction and may increase an organism’s ability to cope with the adaptive challenges characteristic of unpropitious situations . Some beOur study showed suppressor effects of health status on the association between depressive symptoms and mortality among Blacks, which means controlling for CMC, BMI, and SRH is required if we want to study variability of mortality in Blacks due to depressive symptoms. Results suggest that researchers should decompose variance of mortality of Blacks attributable to health-related variables  from what might be explained by depressive symptoms . Other eRace and ethnicity alter the additive effects of depression/depressive symptoms and CMC on mortality , 13, 14.We found that in the pooled sample and also among Whites but not Blacks, CMC and SRH explained the association between baseline depressive symptoms and all-cause mortality. Houle showed that CMC may mediate the effect of depressive symptoms to all-cause mortality . Among BWe also found that baseline SRH explained (confounding) the effect of depressive symptoms on mortality for Whites but not Blacks. Although SRH may reflect different aspects of health across populations, the SRH-depression link may also vary based on race and ethnicity. It is also shown that race modifies the relationship between SRH and mortality , 62, 63.There have been some studies investigating the predictive role of depressive symptoms on subsequent mortality. Houle, Atlantis et al., and White et al. showed a mediating effect of CMC on CES-D to all-cause mortality , 22, 65.Our findings have implications for racial health disparities in the U.S., which have existed for several decades, particularly a lower life expectancy for Blacks –68. The As our study is subject to a number of limitations, the results should be interpreted with caution. First, we used the baseline depressive symptoms, CMC, SRH, and BMI; however, all these conditions are dynamic and subject to change over time. Second, we did not control for the effect of baseline MDD diagnosed by a clinician. Third, we could not control for the use of antidepressants by the participants. Fourth, we did not control for other potential covariates, including daily activity or access to medical care. We also did not check for a potential interaction of depressive symptoms with gender and age, considering that older adults were oversampled in ACL study and depressive symptoms are more prevalent in women than men. Fifth, we used a self-reported measure of CMC. Although high validity of self-rated medical conditions is known , 70, futOverall, our findings are suggestive of a moderating effect of race on residual effects of baseline depressive symptoms over SES and health on subsequent risk of all-cause mortality over a 25-year follow-up period in the U.S. Further research is needed to better understand the exact mechanisms behind Black–White differences in the complex links between SES, physical health, and mental health on all-cause mortality in the U.S.Informed consent was obtained from all participants included in the study.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation  with the Helsinki Declaration of 1975, as revised in 2000. University of Michigan Institutional review board (IRB) approved the study protocol.SA designed and analyzed this work, and contributed to draft and revision. EM-Z made an extensive literature review, drafted and revised the manuscript. ML and VM-F provided contribution to the first draft and also revisions. All authors confirmed the last version.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.


P < 0.001, P = 0.001, and P = 0.015, resp.). Large for gestational age children showed higher high sensitivity C-reactive protein levels (P < 0.001) than small for gestational age. High birth weight is associated with higher levels of high sensitivity C-reactive protein, body mass index, waist circumference, and skinfolds. Large for gestational age altered high sensitivity C-reactive protein and promoted additional risk factor for atherosclerosis in these school children, independent of current nutritional status.Studies have shown associations of birth weight with increased concentrations of high sensitivity C-reactive protein. This study assessed the relationship between birth weight, anthropometric and metabolic parameters during childhood, and high sensitivity C-reactive protein. A total of 612 Brazilian school children aged 5–13 years were included in the study. High sensitivity C-reactive protein was measured by particle-enhanced immunonephelometry. Nutritional status was assessed by body mass index, waist circumference, and skinfolds. Total cholesterol and fractions, triglycerides, and glucose were measured by enzymatic methods. Insulin sensitivity was determined by the homeostasis model assessment method. Statistical analysis included chi-square test, General Linear Model, and General Linear Model for Gamma Distribution. Body mass index, waist circumference, and skinfolds were directly associated with birth weight ( Environmental factors acting early in life influence the risk of developing adult cardiovascular disease (CVD). Birth weight and/or infant weight and accelerated weight gain during childhood are associated with an increased risk of these disorders . Recent Thus, both high sensitivity C-reactive protein (hs-CRP) and low birth weight have emerged as predictors of CVDs, but the relationship between these two variables is still unclear. Thinness at birth or during infancy and accelerated body mass index (BMI) gain during childhood/adolescence are associated with a proinflammatory/prothrombotic state in adult life. An altered inflammatory state could be one link between small newborn/infant size and adult cardiovascular disease .Study has shown that low birth weight is associated with higher concentrations of hs-CRP in adults , but stuTherefore, the objective of this study was to further investigate the relationship between hs-CRP and birth weight and other risk factors  for cardiovascular disease in school children in southern Brazil.We conducted a population-based cross-sectional study in the city of Garibaldi, south Brazil. The city has currently 30,165 inhabitants and 21 elementary public schools with a total of 1,464 students 5–10 years old. Data was collected between 2011 and 2012, after approval of the Research Ethics Committee of the Institute of Cardiology of RS. All parents signed an informed consent and all children agreed to participate.Sample size was determined according to the study by Rondó et al. (2013) , which iAnthropometric measurements were repeated three times, nonconsecutively, and mean values were used in the analyses. Participants should be barefoot and wearing light clothes (shorts for boys and shorts and t-shirts for girls). Weight was measured using a digital scale (Techline) with a variation of 100 g. For height measurements, children stood in vertical position, with feet parallel and with the heels, shoulders, and buttocks touching the wall, and a stadiometer with accuracy of 0.1 cm was used.BMI, determined as weight in kilograms divided by height in meters squared, was used to assess the nutritional status, based on the BMI-for-age standards determined by the World Health Organization (WHO)  and valuFor measurement of the waist circumference (WC), children were placed in standing position, with the abdomen relaxed and arms along the body. The measuring tape was positioned around the natural waist line, in the narrower region between the thorax and the pelvis, at the midpoint between the last rib and the iliac crest, with a firm but not compressive force. The measurement was made at the time of expiration . Body coAll measures were performed by a registered dietitian (CB) and two previously trained undergraduate nutrition students.Parents or caretakers were asked to bring birth registrations on the day of the scheduled interview, for collection of information on birth weight and gestational age at birth. Birth weight was categorized as proposed by the WHO , with thBirth weight according to gestational age was classified according to the curve developed by Lubchenco et al. (1963) : small fμUI/mL), both measured in fasting, and dividing by 22.5 [Blood was collected according to the protocol provided by the Brazilian Society of Cardiology  and was  by 22.5 .The statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS), version 21.0. The chi-square test was used for categorical variables. All data sets were tested for normality with Kolmogorov Smirnov Test. Variables with normal distribution were analyzed with one-way ANOVA, and asymmetric variables were analyzed with Mann-Whitney test. For regression analyses with control of confounding factors, linear models were used for data with normal distribution, and linear models with gamma distribution were used for asymmetric variables. The best adjusted model between all anthropometric variables was verified by the Akaike information criteria. Statistical significance was set at alpha <0.05.A total of 612 school children were evaluated. Of those, 572 presented complete data and were included in this study. Mean age of the participants was 8.6 (±1.46) years, and 51.5% were male. Analysis of maternal age at birth showed that 16.7% of the school children were born to teenage mothers, and 86.1% were Caucasian.The prevalence of school children with very low and low birth weight was 7.7% and 5.6%, respectively, and 86.8% had adequate birth weight. The frequency of school children born SGA was 2,1%, AGA 79.6% and LGA was 18.2%.P < 0.001). The maternal age and ethnicity did not differ significantly with the hs-CRP (P < 0.001). The same was observed for the waist circumference and skinfolds  (A higher proportion of boys than girls (23.7% versus 12.5%) had LGA  .P < 0.001, P = 0.03, and P = 0.02, resp.). Other biochemical parameters analyzed showed no statistically significant differences . The association between hs-CRP levels and LGA was also present after adjusting for gender, body mass index, waist circumference, and skinfolds (P < 0.001)  .The results observed in the evaluation of school children in southern Brazil showed that high birth weight is associated with higher levels of high sensitivity C-reactive protein, body mass index, waist circumference, and skinfolds.The prevalence of school children born with LGA was 18.2%, and the prevalence of school children born SGA was 2.1%. Scientific evidences around the world have shown concern with the increasing prevalence of low birth weight, which has been associated with several health complications. However, the present study highlights that high birth weight may also be related to several complications shown by anthropometric, metabolic, inflammatory, and biochemical results, thus contributing to the early development of the cardiovascular risk factors in school children. This represents a new association between birth weight and early outcomes associated with overweight, dyslipidemia, and metabolic and inflammatory changes. Singhal et al.  showed tHowever, the association between birth weight and BMI contradicts considerable evidence that a high birth weight programs less susceptibility rather than greater susceptibility to cardiovascular disease (CVD) risk factors , 17. PreThe analysis of birth weight and metabolic indicators showed higher values of glycaemia, insulin, and HOMA-IR in the children with LGA, but this association was not significant when BMI was considered a controlling factor. Factors related to obesity, such as the accumulation of abdominal fat and hyperinsulinemia, are also associated with the thrombogenic and inflammatory profile. Atherogenic, thrombogenic, and inflammatory metabolic changes contribute to a higher risk of coronary heart disease in obese children and adolescents, with accumulation of fat in the abdominal area . It is kHigh levels of inflammatory markers such as IL-6, tumor necrosis factor, and CRP are related to general and abdominal obesity. Children with overweight and obesity have higher concentrations of serum CRP, which supports the hypothesis of a relationship between childhood obesity and the presence of systemic inflammatory substances . InflammOur results showed that levels of hs-CRP in school children at school age are significantly higher in cases of LGA. However, in a cohort study , an inveThinness at birth and/or in infancy is associated with higher fibrinogen, hs-CRP in adulthood. Both in-utero influences and greater adiposity due to BMI gain in childhood/adolescence could be implicated consolidating the need to prevent excessive BMI gain in childhood .All anthropometric markers measured in this study  were increased in the participants who were LGA when compared to SGA. Similar results were found in the study of Rondó et al. , who desInfancy is understood as a critical period for the development of obesity for many reasons, but primarily because infants are experiencing food transitions, establishment of eating habits, and, too often, the early development of excess adiposity. Recently, more evidence has become available regarding the associations of early weight status and rapid growth with obesity and related problems in later life , 31. ForBody measures, specifically in the pediatric phase, change according to growth and development. The evaluation of the normality of these measures becomes complex but represents an important tool for evaluating the growth and nutritional status of children and adolescents. In this age group, nutritional changes usually reflect on growth, so that anthropometric parameters are important indicators for the assessment of nutritional status .High birth weight and/or in infancy is associated with higher levels of high sensitivity C-reactive protein, BMI, WC, and skinfolds. Large for gestational age altered high sensitivity C-reactive protein and promoted additional risk factor for atherosclerosis in these school children, independent of current nutritional status.