To evaluate the selenium status and oxidative stress in male infertility cases selected from a private human reproduction center in the state of Ceará, Brazil. The present study had a cross-sectional quantitative approach, carried out between January and October 2013 at a Human Reproduction Center. The studied population was composed of 49 male individuals seen at the clinic, aged between 18 and 60 years. Blood samples were collected to measure serum selenium concentrations, erythrocyte activity and glutathione peroxidase. After medical diagnosis, the participants were divided into fertile and infertile groups. Blood samples were collected for establishing Se concentrations in plasma and erythrocytes, and measurements of the enzymatic activity of glutathione peroxidase in the erythrocytes.p<0.0001, respectively). There were similarities between the groups regarding caloric intake, macronutrient and selenium intake.it resulted in 53.1% of fertile men and 46.9% of infertile men. The average age of the fertile group was 34.1 years and the infertile group was 37.3 years. Regarding the assessment of nutritional status, the scatter diagram of the infertility group showed a higher body mass index and waist circumference, showing that this group has a higher risk of global and abdominal obesity compared to the fertile group (We can conclude that the serum values of selenium, in excess and in deficiency, can be harmful to male fertility. Infertility is defined as the inability of a couple to achieve conception or to bring a pregnancy to term after one year or more of regular, unprotected intercourse, and it has been recognized as a public health problem worldwide  not only act as antioxidants but also play vital roles in multiple metabolic processes , a selenoprotein with an antioxidant function that protects the sperm membrane against oxidative stress. GPx acts as an Se reservoir, which is used in emerging needs. Due to its powerful antioxidant effect, Se in the GPx needs to be better investigated as a nutritional factor for the protection of men's health in relation to male infertility, considering that oxidative stress compromises sperm motility, vitality and function  has a Se-rich soil, the present study’s goal was to evaluate Se, nutritional status and their association with human reproduction in Fortaleza, Ceará- Brazil.The present study was a quantitative cross-sectional approach, carried out between January and October of 2013 at a Human Reproduction Center in Fortaleza, capital of the state of Ceará, Brazil. The studied population consisted of male individuals seen at the clinic, aged between 18 and 60 years without chronic diseases, non-smokers, without the use of vitamin and mineral supplements and hormonal medications. The study was conducted according to the ethical principles and guidelines for the protection of human participants in research, which was approved by the Ethics Committee for research of the State University of Ceará (protocol number 5882212.9.00005534 issued on 27/12/2012).2). Nutritional diagnosis was assessed according to the classification for adults (We collected sociodemographic data to characterize the sample. Weight (kg) and height (m) were measured according to the Frisancho methodology . We calcr adults . Waist cr adults .We assessed dietary intake using the 24-h recall method. Three non-consecutive 24-h dietary recalls were collected, which included two weekdays and one weekend day . The amoSemen analysis was completed by an accredited laboratory according to the standards set by the After medical diagnosis, the participants were divided into fertile and infertile groups. Blood samples were collected for the determination of Se concentrations in plasma and erythrocytes, and we measured their glutathione peroxidase (GPx) enzymatic activity in erythrocytes.The plasma and erythrocyte Se levels were determined by atomic absorption spectrometry using the hydride generation coupled to the quartz cell HITACHI (Z-5000 model), adapted from Paglia & Valentine (1967).We used the commercially available kit  according to the manufacturer's instructions.p<0.05.We processed the data using the free software R (version 2.15.0). To compare the mean parameters of the fertile and the infertile groups, we used the Student t-test and ANOVA, and in both cases, we obtained the p-value by the exact test via Bootstrap, ensuring the robustness against the lack of normality. To correlate dietary intake of Se and dietary energy, we used the Kolmogorov - Smirnov test and applied the Pearson’s correlation to assess whether there was a statistically significant correlation between energy and Se. After that, we ran a linear regression analysis between the energy (independent variable) and Se (dependent variable) to make the adjustment for energy. All analyses were considered statistically significant if We assessed the fertility of 50 male subjects. One participant left the study, yielding 53.1% fertile men and 46.9% infertile men. The mean age of the fertile group was 34.1 (7.6) years and the infertile group was 37.3 (8.1) years.p<0.0001, respectively)    . There wctively) .There was no significant difference for serum Se . Accordip=0.0407) at the 5% level. The higher the intake of Se, the higher the motility index (%) in the fertile group. (p=0.0456) (There was a positive correlation between Se intake and motility index (%) (e group. . However=0.0456) .p<0.0001) between the Kruger morphology (%) and serum Se in the fertile group. Thus, the higher the plasma Se levels in this group, the lower the Kruger morphology (%)  .p=0.0081), at the 5% level, with the motility index (%) in infertile men (Another result of the Kruger's strict sperm morphology (%) showed a significant positive linear correlation (tile men .p=0.0305) between ejaculate volume and GPx in the infertile group , and among the infertile, erythrocyte Se was at higher levels, revealing that serum selenium imbalance, both excess and reduction influence male fertility. GPx activity, also called GPx1, was preserved in both groups without statistical difference between them. Fertile and infertile men were studied for Se concentrations (plasm and erythrocyte).Trace elements such as selenium are involved in many vital reproductive health and performance processes. However, studies are scarce on the concentration of Se in various body fluids/tissues for optimal reproductive performance. Adequate concentrations of this mineral in the reproductive tissues are fundamental for several processes associated with fertility such as spermatogenesis, maturation and motility of spermatozoids, besides maintenance and improvement of GPx antioxidant activity. Some selenoenzymes such as selenoprotein P (SelP) and the GPx family  are involved in fertility and reproductive processes .6 also participates in the optimization of the GPx system from organic forms of selenium. Therefore, proper nutrition can contribute to fertility. Consumption and adequate concentrations of selenium are linked to testosterone biosynthesis whose mechanism is related to the expression and antioxidant action of SelP in the cells of Leydig and cytosolic GPx acting on the neutralization of H2O2 produced in this biosynthesis . These results are in agreement with Besides that, there was a positive correlation between ejaculate volume and GPx in a fertile group. This is in accordance with the study of Thus, decreased GPx activity during Se deficiency and increased lipid peroxidation, indicate increased levels of free radicals which disrupts the normal spermatogenic process and might be responsible for reduced sperm motility and viability leading to reduced fertility and fewer litters. The GPx is responsible for over 75% of antioxidant activity in spermatozoa. In Se excess, increased lipid peroxidation could be attributed to the ability of selenite to form a highly reactive species, a selenopersulfide which generates free radical, superoxide as well as other Reactive Oxygen Species .Besides these aspects, it can be verified that the nutritional status indicated higher levels of BMI and WC in the infertile group. Obesity seems to have a deleterious effect on semen quality by changes in epididymal function, reducing the biomarkers of normal accessory gland function. In addition, the ejaculated volume (mL), sperm concentration (million / mL), and total sperm count (millions / ejaculate) are inversely correlated with BMI. Obese men were 19 times more likely to have a lower total sperm count (millions / ejaculate) than eutrophic . The resOur study demonstrates the possible interferences of obesity, deficiency and excess selenium in male fertility. Thus the action of dietary selenium appears to be U-shaped with respect to reproductive capacity and its markers. Further studies are needed to clarify the mechanisms involved in this process. It also makes an important contribution by calling attention to the use of supplements with Se megadoses present in antioxidant treatments.From the above findings, we can conclude that fertile and infertile men were suitable for Se concentrations. Serum values of Se, both excess and deficiency can be detrimental to male fertility. In the fertile group, Se consumption was positively correlated with sperm motility and, in the infertile group, negatively correlated with WC.


Background: Persistent postural-perceptual dizziness (PPPD) is a persistent chronic vestibular syndrome exacerbated by upright posture/walking, active or passive motion, and exposure to moving or complex visual stimuli. PPPD has four precursors: phobic postural vertigo, space-motion discomfort, visual vertigo, and chronic subjective dizziness. These four diseases share clinical features that form the basis of the diagnostic criteria for PPPD. Semiological similarities do not necessarily mean that PPPD is a single entity. However, if PPPD is not a single disorder but just a composite of four precursors, it may be subdivided according to the characteristics of each precursor.Objective: To test whether PPPD is a single disorder, we attempted a subtyping of PPPD.Methods: One-hundred-eight untreated patients with PPPD were enrolled in the study, who filled out the Niigata PPPD Questionnaire (NPQ) that consists of 12 questions on exacerbating factors for PPPD. A factor analysis of the patients' answers to the NPQ and a subsequent cluster analysis of the patients with PPPD using factors revealed by the factor analysis were performed. To validate our cluster classification, cluster differences were assessed using analysis of variance. Multiple comparison analyses were performed on demographical data, precipitating diseases, the Dizziness Handicap Inventory, the Hospital Anxiety and Depression Scale, and several vestibular tests to characterize each cluster.Results: Factor analysis revealed three underlying factors among the exacerbating factors in the NPQ. Exacerbation by visual stimuli  accounted for 47.4% of total variance in the questionnaire. Exacerbation by walking/active motion (active-motion factor) and by passive motion/standing (passive-motion/standing factor) accounted for 12.0 and 7.67% of variance, respectively. Cluster analysis revealed three clusters: the visual-dominant subtype (n = 49); the active motion-dominant subtype (n = 20); and the mixed subtype (n = 39). The patients in the active motion-dominant subtype were significantly older than those in the visual-dominant subtype. There were no significant differences among the subtypes in other demographical data or conventional vestibular tests.Conclusions: The most common main exacerbating factor of PPPD was the visual factor. PPPD may be categorized into three subtypes. Conventional vestibular tests failed to point the characteristics of each subtype. Persistent postural-perceptual dizziness (PPPD), which has been included in the 11th revision of the International Classification of Diseases, is a persistent chronic vestibular syndrome typically preceded by acute vestibular disorders .PPPD has four precursors: phobic postural vertigo (PPV), space-motion discomfort (SMD), visual vertigo (VV), and chronic subjective dizziness (CSD) –7. TheseHere, we aimed to investigate the possible subtypes of PPPD, based on the exacerbating factors assessed by the symptom scale for PPPD, the Niigata PPPD Questionnaire (NPQ) , using ft-test, p = 0.149). The precipitating conditions for PPPD among patients are shown in In total, 108 untreated patients with PPPD who visited the Department of Otolaryngology Head and Neck Surgery at Niigata University Medical and Dental Hospital between January 2018 and August 2020 were enrolled in the study. PPPD was defined by using the Barany Society criteria , with their eyes open and closed. The foam ratio (posturography with/without foam) with eyes closed was used as an indicator for somatosensory dependence of postural control, whereas the Romberg ratio on foam was used as an indicator for visual dependence .The BCT was carried out using air at 26°C and at 45°C each for 60 s. Each external auditory canal was stimulated separately with a 5-min interval between the stimulations. Maximum slow-phase velocity was measured using electronystagmography and canal paresis % (CP%) was calculated using the Jongkee's index formula .2, and the patients' gaze fixed at a target placed 1.5 m in front of him/her. At least 7 suitable head rotational impulses to the right and left were recorded during each test.The horizontal vestibulo-ocular reflex (VOR) was evaluated by vHIT . Small-amplitude, high-acceleration, and passive head rotations were applied around the horizontal plane (yaw) at ~20° with a mean velocity of 150°/s, mean acceleration of 1000–2500°/scVEMP and oVEMP were used to assess the saccular and utricular function, respectively, using the Neuropack® system . The click (0.1-ms rarefactive square waves of 105-dB nHL) was used to induce cVEMP. For the recording of oVEMP, a hand-held electromechanical vibrator  fitted with a short bolt terminating in a plastic cap was used. The vibrator delivered a 500-Hz tone burst  on the subject's skull at the Fz (midline of the hairline). Amplitudes and latencies were measured at the response peaks, which occurred at ~13 and 23 ms for the cVEMP and 10 and 15 ms for the oVEMP, depending on the stimulus. The difference between the peak amplitudes was used to give the peak-to-peak (PP) amplitude. To compare the two ears, the asymmetry ratio (AR) was calculated using the formula (right - left) / (right + left) x 100 (%) on the raw PP amplitude .n = 0 and SD = 1.Our statistical analysis followed a three-step procedure. In the first step, exploratory factor analysis with promax rotation was used to study the factorial structure of symptoms according in the NPQ scores, which can identify latent common factors associated with the 12 questions of the NPQ. When selecting the number of factors, only factors with eigenvalues of 1.00 or higher were selected. The factor scores, which were to be used in the subsequent cluster analysis, were calculated for all patients by using regression analysis. All factor scores were transformed to mea The second step was a cluster analysis of the factors observed in the previous step to identify groups of objects that were similar to each other but different from objects in other groups. The clustering was performed based on a hierarchical method that considered the Ward clustering method based on the Euclidean distance and may be visualized in a dendrogram. To validate the cluster classification, cluster differences were assessed using the variance analysis by Tukey method.post-hoc Dann–Bonferroni test was performed on age, disease duration, DHI, HADS, and several vestibular tests to characterize the background of each cluster.Finally, the clusters observed in the previous step were characterized. A chi-square test was performed on sex differences, and Fisher's exact probability test was performed on precipitating diseases. A Kruskal–Wallis test followed by p-value < 0.05 was considered statistically significant.All statistical analyses were performed using SPSS version 26.0 for Windows. A When we first conducted a factor analysis using the 12 questions, Q6 showed a commonality estimate <1 and was observed to be an inappropriate variable for the analysis; therefore, Q6 was excluded and the factor analysis was conducted using 11 questions. The factor analysis yielded three factors underlying the associations among the 11 symptoms in the NPQ . Factor The dendrogram from the cluster analysis is presented in The basic demographic characteristics of the three subtypes are shown in The questions in the NPQ  reflect Factor 1, Factor 2, and Factor 3 accounted for 47.4, 12.0, and 7.67% of the total variance in the questionnaire, respectively. This finding suggested that exacerbation by the visual factor was the most common core characteristic in patients with PPPD, followed by exacerbation by active-motion and passive-motion/standing factors, respectively.Regarding the mechanisms of exacerbation by Factor 1  or Factor 2 (active-motion factor), increased visual or somatosensory dependence of spatial orientation, respectively, may be a possible explanation , 16. NonOur cluster analysis identified three subtypes of PPPD. As long as they were diagnosed with PPPD, the subjects should be more or less exacerbated by all factors. Among them, the visual factor score was significantly higher in cluster 1 and the active-motion factor score was significantly higher in cluster 2 ; therefoIn the comparison of the demographical characteristics by subtype, the participants with the active motion-dominant subtype were significantly older than those with the visual-dominant subtype . It has Comparisons of vestibular function tests demonstrated no differences in visual/somatosensory dependence of posture (Romberg ratio/foam ratio), horizontal canal function (CP% and vHIT), and otolith function (cVEMP and oVEMP) among the subtypes, suggesting that the differences in subtype characteristics were not derived from the type and severity of vestibular dysfunction . Since 3Under the assumption that PPPD is not a single disease, cluster analysis should reveal four clusters characterized by the four precursors of PPPD, i.e., exacerbation by upright posture (PPV), active or passive motion (SMD), complex visual pattern (VV), and motion of self or objects in the environment (CSD). Therefore, our results, which demonstrated three subtypes  with rearranged characteristics, suggest that PPPD may be a single entity, or at least, not a composite of four different diseases.There are several limitations to our study. Factor and cluster analyses may yield subjective results, rather than a unique answer, since they depend on the included variables and the selected number of factors or clusters. Our sample size was relatively small for a cluster analysis; thus, it was impossible to include other factors such as precipitating conditions and comorbid diseases into the cluster analysis. The characteristics of each subtype could not be determined based on the vestibular tests and were only proven through subjective symptoms.In conclusion, our factor analysis demonstrated that the most common core exacerbating factor of PPPD was the visual factor , followed by the active-motion factor  and the passive-motion/standing factor (sensitivity to passive motion and upright position), respectively. Our cluster analysis demonstrated that PPPD can be divided into three subtypes, namely the visual-dominant subtype, the active motion-dominant subtype, and the mixed subtype. Conventional vestibular tests failed to identify the characteristics of each subtype.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Review Board of Niigata University Medical and Dental Hospital. The patients/participants provided their written informed consent to participate in this study.CY and AH contributed to the conception and design of the manuscript. YM, MK, TY, SO, SI, and KT made substantial contributions to the conception of the work and were responsible for data collection. CY wrote the manuscript. All authors contributed to manuscript revision, read, and approved the submitted 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.


A two-stage non-random sampling was carried out from June to August of 2019. Heads of households ≥18 years and those with the ability to communicate in Spanish were recruited house by house. Structural and intermediary determinants of health were identified according to the World Health Organization Conceptual Framework and priorities were ranked using Z-scores. Being a migrant indigenous increased 1.6 times the odds of low education . In addition, the migrant indigenous status increased the odds of poor housing, unhealthy behaviour and low social cohesion (p < 0.05). Housing, behaviours and health service accessibility were top priorities for indigenous migrants and structural determinants for non-indigenous people. The findings show that the right to access the social determinants of health has not yet been guaranteed for indigenous communities.The degree to which social determinants of health differ between indigenous migrants and non-indigenous people born and raised locally is currently unknown. We compared social determinants of health between indigenous migrants and non-indigenous people from urban north-eastern Mexico. Additionally, we ranked priorities for addressing the negative social determinants of health. This was a population-based comparative cross-sectional study ( The World Health Organization has called attention to social inequalities and the social determinants of health ,2. The sTenek, Nahuas), Querétaro (Otomies), Oaxaca  and Veracruz (Nahuas), among others. Here, there are 59,196 people who speak an indigenous language (1.2% of the state’s inhabitants) and its metropolitan area has reached an annual indigenous immigration growth rate of 12% [There is a gap in the knowledge about the social determinants of health in indigenous populations that migrate from rural to urban areas. Nuevo Leon is an example of such internal migration. This north-eastern state is highly industrialized and has become a destination for indigenous migrants . They coZihuame-Mochilla organization and the non-indigenous cluster by local government authorities. The second phase consisted of recruiting, from house to house, the person that a given family recognized as the head of the household, i.e., the person who contributed the most to the family’s economy. Household heads were consecutively selected after having verified the selection criteria of minimum 18 years and being able to communicate in Spanish. If the head of the family was not available at the time of the visit, a second and third visit were scheduled. The response rate was 98% for indigenous migrants and 97% for non-indigenous people. Two eligible indigenous migrants’ household heads were excluded as they were under the influence of alcohol/psychotropic substances at the time of the interview. In a pilot study, we identified an average difference of 16 percentage points of six social determinants between indigenous migrants and non-indigenous people. We estimated 117 individuals as the minimum sample size in each group considering previous difference in the calculation with power of 80% and alpha of 0.05. We included 235 indigenous migrants and 168 non-indigenous. The protocol was approved by the Committee of Ethics and Health Research (17-FaSPyN-SA-13.TP). The corresponding informed consent was provided by all the participants and the Helsinki declaration was respected.This was a population-based comparative cross-sectional study. A two-stage non-random sampling was carried out from June to August of 2019. The first phase consisted of identification and selection of geographical areas home to indigenous migrants and non-indigenous locals (target populations). Two adjacent neighbourhoods were located (one in front of the other); the indigenous migrant cluster was endorsed by a non-profit There were three elements that defined an indigenous individual: (a) the use of an indigenous language, (b) self-ascription  and (c) belonging to a home where there is a person who speaks an indigenous language. Migrant status was defined according to place of birth. The participants were categorized as indigenous migrants and non-indigenous (non-migrant).Prospera beneficiary or non-beneficiary). Four categories of intermediary determinants of health were included: (a) housing: ownership, metal-galvanized iron sheets in walls and roofs and overcrowding ; (b) behavioural: daily tobacco smoking, excessive consumption of alcohol at least once a week, age ≤18 at first intercourse and contraceptive use at first intercourse (yes or no); (c) health service accessibility: affiliation with a public health care system, health care use in the last 12 months, has been ill ≥ 15 days without seeking health care, perceives long the traveling time between home and health care facility, perceives long the health care waiting time and work prevents from seeking health care (yes or no); (d) social cohesion: this was measured with the Neighbourhood Social Cohesion Scale Spanish version [Structural and intermediary determinants of health were distinguished as stated by the World Health Organization Conceptual Framework on the Social Determinants of Health . Structu version , which i version ,15. It cHistory of previous diagnosis of diabetes mellitus, hypertension, heart disease and dyslipidaemia was identified, as was information on any disability . Psychological distress was measured with the Kessler K–10. This is a short screening scale with easy application that is used in population-based studies ,17. It h®USA) portable digital scale , calibrated daily and a wall stadiometer. Measurements were taken without shoes and with light clothing, with feet together and heels, back and hips touching the wall. The body mass index was calculated as weight/height2 (kg/m2) and classified as follows: underweight or normal weight, <25 kg/m2; overweight, 25–29 kg/m2; obesity, ≥30 kg/m2.Age, sex, marital status, years of education, type of family and head of the family (father or mother) were all considered as sociodemographic variables. Participants were interviewed by trained personnel . Interviews ranged in duration from 15 to 20 min. At the end of an interview, height (in centimetres) and weight (in kilograms) were measured using a Taylor . Priorities were determined by social determinant of health and ranked according to Z-scores: Zi = (Xi − p > 0.05), but fewer indigenous migrants were married or had a nuclear family . They also had fewer years of education .The mother was the head of the family in 59.2% of indigenous migrant households and in 55.7% of non-indigenous homes; 42% of indigenous migrants were born in southeast Mexico and 88.2% spoke Nahuatl. Most of them had more than 20 years in the current address. There were no age differences between indigenous migrants and non-indigenous people  greater than the state-wide 25% and the nationwide 34% . A studyVarious intermediate social determinants evidenced inequality. Housing was the highest priority addressed among indigenous migrants; an indigenous migrant was 5–6 times more likely to have a house made of poor-quality materials. Noticeably, neighbourhoods were close to each other, showing ancestral gaps had not yet been overcome. Housing remediation is not easy given financial constraints and interventions should consider public–private partnerships. Smoking, sex at young age and no contraceptive protection were also high priorities to be addressed among indigenous migrants. An indigenous migrant was twice as likely to be an active smoker. Prevalence of smoking was higher among indigenous migrants (45%) than at the state and national levels  . The souSocial cohesion is the bridge between structural and intermediary determinants. Three of four aspects of social cohesion differed between indigenous migrants and non-indigenous people. Markwick et al.  identifiThe study only included urban residents. Structural issues, health service accessibility and psychological distress, among other factors, may differ between urban and rural environments. Additionally, caution is needed when generalizing these results to rural residents. Self-reported data were subject to the obtaining of socially acceptable responses, e.g., behavioural questions; to obtain inaccurate responses to sensitive topics, e.g., family income question; or to obtain inaccurate responses due to memory recall or subjective perception, e.g., traveling and waiting times questions. Consequently, underreporting may be present. However, if bias did occur, it did so in both populations. Disparities cannot be attributed solely to ethnicity or migration; there are historical, political and sociocultural backgrounds that should also be considered. It is necessary to continue studying disparities between migrant populations.Social determinants of health and their priority rankings differed between indigenous migrants and non-indigenous people from urban north-eastern Mexico. For indigenous migrants, disparities were evident in one structural social determinant (low education) and three intermediate  determinants. These findings show that the right to the social determinants of health has not yet been guaranteed for indigenous communities. Housing and behavioural factors are top priorities to be addressed among indigenous migrants. Public policies are required for reducing inequality gaps. The 2019–2024 Sectorial Health Program includes interculturality policies for fulfilling indigenous rights and guaranteeing comprehensive care ; these a


The aim of this study was to evaluate the effects of the relaxation technique with guided imagery by means of virtual reality on health-related quality of life in patients undergoing hematopoietic stem cell transplantation. A quasi-experiment conducted in a Bone Marrow Transplantation Service of a public hospital in southern Brazil. From October 2019 to October 2020, forty-two adult participants who underwent transplantation were included, 35 in the intervention group and seven in the control group. A guided imagery intervention, with audio guiding the relaxation associated with nature images in 360º, was performed during the hospitalization period. Data were collected on the first day of hospitalization, on the transplantation day, during the neutropenia stage, and at pre-hospital discharge. The Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) were used to assess health-related quality of life, fatigue and neutropenia. Data were analyzed using the Generalized Linear Mixed Model for the evolution of the health-related quality of life assessments over time, considering the groups and stages. Pearson’s correlation coefficient was adopted for the correlation analyses. Allogeneic transplantation was predominant: 28 (80%) in the intervention group and 5 (71.43%) in the control group. There were improvements in the health-related quality of life scores, although not significant. A significant difference was found among the stages (p<0.050) and a significant positive correlation (p<0.000) among the variables on general quality of life, additional concerns, fatigue and neutropenia in all stages. Patients undergoing hematopoietic stem cell transplantation suffer changes in their quality of life. Interventions based on integrative practices emerge as an option to minimize them.  Hematopoietic Stem Cell Transplantation (HSCT) is a complex and singular treatment, used for hematological and non-hematological diseases; the process requires the intervention of different health professionals. Studies in HSCT services show that the hospitalization period negatively affects the patient’s personal performance and causes additional concerns. These conditions generate an impairment in quality of life, which is conceptualized as multidimensional and includes physical, psychological and social domains .Although the complications related to HSCT are difficult to control, it is the health professional’s duty, especially the nurse’s, to offer practical options aiming to reduce anxiety and the emotional, functional and social impacts, as well as to increase treatment effectiveness, thus improving health-related quality of life (HRQoL) . It is essential to assess HRQoL especially in Oncology, since the results indicate the consequences of the disease and treatment, its cost and benefits and the patient’s preferences. HRQoL can be defined as the perceived health status, that is, how much the disease or chronic state is perceived by the individual .Integrative and Complementary Health Practices (ICHPs) are options for interventions that promote HRQoL for patients with chronic diseases. They stimulate natural mechanisms for preventing harms and recovering health, and emphasize therapeutic bond and integration of the individual with the environment and society. They can help strengthen the immune system and relieve disease symptoms and adverse effects of conventional treatments .Among the ICHPs, mind-body therapies are focused on the interaction of brain, body, mind and behavior; as well as on the way in which emotional, mental, spiritual, experiential and behavioral factors affect health . They are used to create a feeling of relaxation and stress reduction, as well as to offer psychological and health benefits, including reduced symptoms of illness, improved coping, regulation of behavior, quality of life and well-being . Guided imagery relaxation therapy is based on the mind-body connection. It is a low-cost, safe and easy-to-apply intervention that leads the individual to create mental images which bring tranquility and comfort. The person receiving the therapy is invited to mentally elaborate a sequence of images to evoke one or more senses and access physical, emotional and spiritual dimensions influencing bodily change that help them feel calm, hope, happiness, contentment and relaxation, aiming to promote mental well-being .The use of guided imagery relaxation can bring benefits in HSCT. The offer of complementary and integrative therapeutic options can contribute to the improvement of HRQoL, especially for those who are in hospital care and isolated from social activities. They can provide relief for physical and emotional symptoms, thus understanding the individual holistically.Thereby, the aim of this research was to analyze the effects of a relaxation technique with guided imagery by means of virtual reality on health-related quality of life, in reducing fatigue and neutropenia in patients undergoing hematopoietic stem cell transplantation.This is a quasi-experimental, longitudinal and analytical study, with a non-equivalent control group (CG), conducted in a Bone Marrow Transplantation Service of a public teaching hospital in southern Brazil, from October 2019 to October 2020.The sample size was calculated considering the annual mean of 52 HSCTs in adults, from 2016 to 2018. Complementing sample calculation, the mean score for Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) of 108.4 with a standard deviation (SD) of 21.04, obtained in a study  conducted in the same service, was used. The total sample was composed of 42 participants, with an error margin of 5% and a confidence level of 95%; 35 were included in the intervention group (IG) and seven in the CG, allocated in a 5:1 ratio .Patients aged 18 years old or older admitted for HSCTs were included. Those who were physically unable to complete questionnaires, see or hear were excluded, as well as those who had a history of or were being treated for vertigo, labyrinthitis and/or epilepsy with documented medical records. Patients who refused to continue receiving the intervention or to complete questionnaires, or those who stopped participating in two consecutive interventions, were discontinued.The IG received the relaxation technique with guided imagery by means of virtual reality. The participant was offered virtual reality goggles with built-in headphones, then there was the reproduction of a background sound associated with a narration that guided the relaxation, followed by the projection of nature images in 360°. The technique lasted approximately 10 minutes and was applied three times a week from admission to hospital discharge.Data collection occurred at four moments: at admission (T1); on day zero, on the transplantation day (T2); between days +5 and +8 during the neutropenia stage (T3), and at pre-hospital discharge (T4). A sociodemographic and clinical questionnaire (SDCQ), FACT-BMT version 4.0, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) version 4.0, and Functional Assessment of Cancer Therapy-Neutropenia (FACT-N) version 4.0, were used.In the Functional Assessment of Cancer Therapy-General (FACT-G), present in FACT-BMT and FACT-N, the domains on physical well-being (PWB), social/family well-being (SFWB) and functional well-being (FWB) show a variation in scores of 0-28, while the emotional well-being (EWB) domain varies from 0 to 24. The BMT subscale (BMTS) varies from 0 to 40, while the Neutropenia subscale (NS) from 0 to 76. The FACT-BMT scores vary from 0 to 148, the Trial Outcome Index - composed of the sum of the PWB, FWB and BMTS scores - varies from 0 to 96. In FACIT-Fatigue, the variation is 0-52. The higher the scores, the better the HRQoL.All answers referring to SDCQ, FACT-BMT, FACIT-Fatigue and FACT-N were coded in Microsoft® Excel spreadsheets, Office 365®. The information was scanned twice independently and then validated. The Generalized Linear Mixed Model was adopted to analyze the evolution of the HRQoL scores over time for the groups and stages, considering an autoregressive covariance matrix of order one and defining the best fit through the Akaike Information Criterion. The correlation analysis for variables on General HRQoL (FACT-G), additional concerns, fatigue and neutropenia was performed by calculating Pearson’s correlation coefficient.The research was approved by the Research Ethics Committee of the Clinical Hospital of the Federal University of Paraná, under number 3,446,872. It was registered in the Brazilian Registry of Clinical Trials, number RBR-37ymzb.Of the initial sample of 42 participants, 31 (73.81%) completed the four moments of data collection, eight  were discontinued in the IG, and three (42.86%) in the CG. In the first group, six participants became unable to continue due to treatment complications. In the CG, discontinuation was due to death. A mean of 11 interventions were performed per IG participant.The general mean age was 37.8 years old, varying from 18 to 65. There was prevalence of allogeneic transplantation in 28 (80%) cases in the IG and 5 (71.43%) in the CG .In the HRQoL assessments, the PWB scores declined between T1 and T3, hospitalization and neutropenia, with a recovery at T4, pre-discharge, for both groups without returning to baseline values. For both groups, worse scores in FWB and EWB are observed at T1, indicating impairment even before the treatment was initiated. As the discharge period approaches after hematological recovery, there is an increase in the EWB scores when compared to the first assessment. For SWB and PWB, there is recovery, but the scores are still low. For BMTS and TOI, there is greater impairment during neutropenia, indicating worse HRQoL and an increase at T4, yet with lower scores when compared to T1, demonstrating the maintenance of HRQoL impairment during this stage .For FACT-G and FACT-BMT, there was a reduction in the scores at T2 and at T3 when compared to T1, and a subsequent recovery at T4, without reaching baseline values. The CG had worse scores at T3 and T4 in these assessments .There was no significant difference between the IG and the CG in PWB (p=0.721), SWB (p=0.470) and EWB (p=0.846), FACT-G (p=0.834) and FACT-BMT (p= 0.767), despite higher scores in the IG. However, a significant difference between treatment stages T1 and T3  was found, except for EWB, for the total sample .For FACIT-Fatigue, there was no significant difference between the groups (p=0.496). Nevertheless, a significant difference was observed between stages T1 and T2 (p=0.032) and between T1 and T3 (p=0.000). It is possible to observe that the mean of the scores increases at the end of treatment at T4, with greater recovery in the IG when compared to the scores at T1, although there is no significant difference .Similarly to what was observed for fatigue, for NS there was no significant difference between the groups (p=0.469), only in the stages (p=0.000). Significant differences were observed between T1 and T2 (p=0.012) with worsening in the assessments, as well as from T1 to T3 (p=0.000) and from T2 to T3 (p=0.000), followed by an increase from T3 to T4 (p=0.001) with scores similar to T1 at pre-discharge. The scores increase at the end of treatment at T4, indicating better HRQoL. Moreover, greater recovery was observed in the IG when compared to T1 values, despite a non-significant difference between the groups .Regarding the correlation of variables for the IG, the results show a significant positive correlation, indicating an interaction among the FACT-G, FACT-BMT, FACIT-Fatigue and NS variables in all stages . It can Relaxation therapy with guided imagery is a safe intervention option, with positive evidence, and which can be part of Nursing care plans promoting comprehensive care. The research participants are relatively young and of productive age, which is in line with the findings of other Brazilian studies that show means of approximately 38 years old . International studies show higher age means of the patients undergoing HSCT. Two South Korean studies have identified means over 48 years old . An Italian study found a mean of 50 years old , and a research study conducted in the United States found a mean of 56 years old . These patients are in the productive phase of their lives and, when faced with HSCT, they find themselves distanced from family, social and work life. Such factors generate negative impacts on all domains of HRQoL; the therapeutic course of cancer or HSCT has a strong economic impact with implications for the patient’s financial toxicity, when considering the loss of the ability to provide, in addition to the costs of treatment. In this study, the IG showed higher scores in the last two assessment stages, indicating better HRQoL. Nevertheless, the differences were not significant. A reduction in scores is observed on day zero and during pancytopenia, followed by a recovery at pre-discharge without reaching baseline values. Other studies assessing HRQoL using FACT-BMT at more than two time points during the HSCT period found similar results .During hospitalization for HSCT, patients experience a series of symptoms that worsen with the progression of the treatment and a deterioration of their physical function. Pancytopenia is the most critical period, which is reflected in worse HRQoL, thus requiring more attention. After this period, hematopoiesis recovery and reduction of toxicity symptoms are related to an improvement in HRQoL scores . Nonetheless, changes in body image and in social and family relationships, as well as decreased functional capacity, do not allow the scores to return to pre-treatment values .The results found for EWB corroborate those found in another study, which assessed HRQoL in HSCT using FACT-BMT  and may be associated with the achievement of treatment goals and with hematological recovery, as well as with the prospect of hospital discharge, highlighting the importance of the patient’s emotional health during treatment. For SWB, greater impairment during pancytopenia was observed for the CG and less variation for the IG. In both groups, the scores at pre-discharge were close to the baseline. These results differ from Machado et al., (2018), who did not identify any recovery in the scores after pancytopenia, but corroborate the results of Schumacher et al., (2018).No studies using guided imagery for HRQoL in HSCT were found for comparison. Using an exergaming intervention, a study found significant differences among the treatment stages and differences between the groups, with better results in the IG without significance . Another two studies that assessed HRQoL using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and used interventions to improve HRQoL in HSCT did not find significant differences between the groups, a similar pattern to those found in the present research. The first used the Self Care Intervention in Oncology Nursing adapted for patients undergoing HSCT  and the second used music therapy .In Oncology, however, the use of mind-body techniques, such as relaxation with guided imagery, for patients in different treatment stages and survivors to improve HRQoL, has grown. Nicolussi et al., (2018) adopted guided imagery relaxation for cancer patients undergoing chemotherapy in southeastern Brazil assessing HRQoL using EORTC QLQ-C30. Significant differences were found for physical, emotional, cognitive and social function, role performance and fatigue, in addition to positive findings regarding symptoms in the assessment stages. A study conducted with Hispanic or Latino women diagnosed with cancer, using an intervention with guided imagery daily for 13 weeks, showed a significant improvement in EWB, but FWB and PWB were reduced; there was no significant difference between the groups .In a study conducted with aged individuals with breast or prostate cancer that used guided imagery twice a day for six weeks, HRQoL was assessed with EORTC QLQ-C30, and it was shown that there was a significant increase in the IG immediately and 6 six weeks after the intervention in general quality of life and functional domains .During pancytopenia, the patients experience the greatest cell depletion of all HSCT stages, combined with treatment toxicity, which is reflected in worse fatigue scores. In this research, similarly to HRQoL findings, the differences were not significant between the groups for fatigue. A significant difference was observed between the assessments at admission and pancytopenia. Nicolussi et al., (2018) found better IG fatigue scores. Differing from the results of the present research, two review studies point out that mind-body practices could reduce fatigue in cancer patients undergoing HSCT; relaxation was the best rated intervention for reducing fatigue .A randomized clinical trial using Benson’s relaxation response in HSCT showed that relaxation exercises significantly reduced the sensation of fatigue in the IG .Fatigue can also be related to erythrocyte and leukocyte changes in patients undergoing HSCT. NS underwent significant changes in the assessment stages, with the worst scores during pancytopenia, and with no difference between the groups. The period of severe leukopenia, neutropenia and thrombocytopenia that occurs shortly after HSCT infusion is expected, is the most critical in relation to the burden of symptoms for patients, and exerts a negative influence on HRQoL. In the present research, pancytopenia was the most critical period for the patients, evidenced by lower scores in all assessments. In this research, no significant differences were observed between the groups regarding HRQoL, fatigue and neutropenia using guided imagery relaxation as intervention. Cooley et al., (2013) suggest that the individual’s ability to generate and maintain mental images may interfere with the results; however, this attribute may have been mitigated with the use of virtual reality that does not depend on the participant’s imaginative capacity.The dependence of HRQoL, fatigue and neutropenia is observed with a significant positive correlation among these variables. Corroborating these results, a study with patients undergoing chemotherapy identified a significant correlation between fatigue and HRQoL . For these authors, the presence and severity of fatigue and neutropenia affect the capacity for self-care and decision-making, which influences a decline in HRQoL since it involves social, emotional and physical aspects.For Cooley et al., (2013) a greater number of intervention sessions could lead to more favorable outcomes. In contrast, Hadjibalassi et al., (2018) state that the ‘dosage’ of integrative practices may not be measurable in terms of duration and that the conceptualization of effectiveness may not be uniform. In this research, it was not possible to assess if the frequency of the intervention could change the results.Due to scarcity of studies involving guided imagery for HRQoL, in Oncology or HSCT, many of the practices adopted by researchers in the development of studies, such as script, duration, association with other techniques or number of intervention applications, show variations that make it difficult to generalize or compare the results.The heterogeneity of the sample may have been a limiting factor. Other limitations include the number of discontinued participants, especially in the CG, despite being inevitable losses due to treatment complications, and the fact that the period of intervention application may not have been enough to influence HRQoL.In conclusion, no evidence of improvement in HRQoL was observed in patients who received guided imagery relaxation. It was possible to observe that the pancytopenia stage is the most critical for patients undergoing HSCT, regarding losses in HRQoL, with significant differences in treatment stages for both groups assessed, where a positive correlation among HRQoL, fatigue and neutropenia was evidenced. The results point to the need to expand the options of ICHPs for patients undergoing HSCT in view of the impairment observed in HRQoL. In this sense, guided imagery relaxation is a safe, low cost and easy-to-apply option with the potential to help achieving the goals desired by hematological patients.Silva LAA, Santana EO and Kalinke LP conceived and designed the analysis. Guimarães PRB performed the statistical analysis. All authors discussed the results and contributed to the final manuscript.


Metabolic syndrome is a combination of cardiovascular risk factors , which entails critical issues in terms of medical management and public health. n = 1.000; body mass index, BMI >30 kg/m2; age: 18–83 yrs), subdivided into two subgroups depending on the presence (n = 630) or absence (n = 370) of metabolic syndrome. Parallelly, the percentages of treatment with hypolipidaemic drugs, hypoglycaemics, and antihypertensives and, among the treated subjects, of control of the underlying condition in accordance with the cut-offs of IDF criteria for dyslipidaemia, hyperglycaemia, and hypertension were determined over six age ranges .  The aim of the present cross-sectional study was to investigate the age-related changes of the single IDF  diagnostic criteria for metabolic syndrome  in a large population of  obese women  was detected in the whole population.  At least in an Italian context of obese females, the age-dependent worsening of glycaemia and BP exerts a fundamental pathophysiological role in the progressive increase of metabolic syndrome with advancing age, which appears to be not adequately treated in a large part of obese subjects. The results of the present study might be useful for public health decision-makers for programming future more extensive and aggressive non-pharmacological and pharmacological interventions in the obese population. Metabolic syndrome is a combination of cardiovascular risk factors, including visceral obesity, dyslipidaemia, glucose intolerance, and hypertension .Although the prevalence of obesity is pandemic , there iIndeed, body weight reduction programs allow us to reduce visceral obesity, improve glucometabolic homeostasis, and control hypertriglyceridemia and hypertension –9; moreoOne of the main reasons for this disheartening contradiction is the missing “holistic” view of any obese patient seeking for clinical help to lose body weight, which, in most patients' opinion, is primarily thought to be an “aesthetic” problem, without paying attention to the associated cardiometabolic comorbidities .Metabolic syndrome is a condition evolving over time, with a progressive increase in the number of cardiovascular risk factors in parallel with the natural history of the obese state, characterized by low-grade chronic inflammation, accelerated aging, and metabolic dysregulation .To the best of our knowledge, while epidemiological analysis of cardiovascular risk factors in large populations of children/adolescents and adults was fundamental to diagnostically define metabolic syndrome, few authors have separately and collectively investigated the age-dependent changes of IDF  diagnostic criteria for metabolic syndrome in large study populations , 14. FurBased on the previous premises, the aim of the present cross-sectional study was to collect demographic, clinical, and biochemical data from a huge number of obese women with or without metabolic syndrome and analyse the age-dependent changes of visceral obesity, dyslipidaemia, glycaemia, and blood pressure together with the prescription of specific pharmacological interventions, particularly hypolipidaemic, hypoglycaemic, and antihypertensive drugs and, within the treated group, the pharmacological control of the underlying condition .Our hypothesis is that, in a specifically Italian cohort of obese women, metabolic syndrome can be underdiagnosed, insufficiently treated, and unsuccessfully controlled. Moreover, the age-dependent increase in dyslipidaemia, hyperglycaemia, and hypertension could not be associated with a parallel prescribing of effective pharmacological interventions.2) was recruited at the Division of Metabolic Diseases, Istituto Auxologico Italiano, Piancavallo (VB), where they were hospitalized for a three-week multidisciplinary integrated body weight reduction program (BWRP), entailing hypocaloric diet, nutritional education, psychological counselling, and moderate physical activity.From January 2017 to December 2019, a population of 1.000 obese women . Metabolic syndrome was calculated by using the IDF criteria  . A very A scale with a stadiometer was used to determine height and weight . Waist circumference (WC) was measured with a flexible tape in a standing position, halfway between the inferior margin of the ribs, and the superior border of the crista. Body composition was measured by bioimpedance analysis  after 20 min of supine resting and in accordance with the international guidelines . BMI, faBlood samples (about 10 mL) were collected at around 8 : 00 AM after an overnight fast at the beginning of the BWRP. High-density lipoprotein cholesterol (HDL-C), triglycerides, and glucose were measured.Colorimetric enzymatic assays  were used to determine serum HDL-C and triglycerides levels. The sensitivities of the assays were 3.09 mg/dL (1 mg/dL = 0.03 mmol/L) and 8.85 mg/dL (1 mg/dL = 0.01 mmol/L), respectively.Serum glucose level was measured by the glucose oxidase enzymatic method . The sensitivity of the method was 2 mg/dL (1 mg/dL = 0.06 mmol/L).Blood pressure (BP) was measured on the right arm, using a sphygmomanometer with appropriate adult cuff size, with the subject in a seated position and relaxed condition. The procedure was repeated three times at 10 min intervals in between; the means of the three values for systolic BP (SBP) and diastolic BP (DBP) were recorded.According to the IDF criteria for the diagnosis of metabolic syndrome in adults , obese  was used for data analyses.Results are reported as mean ± SD (standard deviation) or percentage (as specified in tables) for six age ranges .Before applying any parametric test, the normal distribution and linearity of each variable were verified, and a log-transformation of the variable was performed, if appropriate.t-student test for unpaired data. Other parameters, such as percentages of subjects positive/negative for metabolic syndrome and for each altered IDF diagnostic criteria, of treated patients  and, within the treated groups, of controlled subjects (in accordance with the cut-offs of IDF diagnostic criteria for metabolic syndrome) were compared between obese women with or without metabolic syndrome by using a Fisher's exact test.Some parameters, such as age, BMI, BMFI, FM, FFM, WC, HDL-C, triglycerides, glucose, and BP, were compared between obese women with or without metabolic syndrome by using a Furthermore, a model of linear regression was used to analyse the age-dependence of each of the above-reported parameters.p < 0.05 was used for all data analyses.A level of significance of Using the IDF criteria for the definition of metabolic syndrome, 630 (63.0%) had metabolic syndrome and 370 were without (37.0%).A significant age-dependent increase in the prevalence of metabolic syndrome occurred (from 25.5% in the age range 18–30 yrs up to 71.0% in the range over 70 yrs). BMI and BMFI significantly decreased with advancing age in obese women with metabolic syndrome; this pattern was not recorded in those without metabolic syndrome. FM (%) and FFM (kg) decreased over time in both groups with and without metabolic syndrome .BMI was significantly higher in obese women with metabolic syndrome than in those without metabolic syndrome in the age ranges 31–40 and 51–60 yrs, while BMFI was significantly higher in obese women with metabolic syndrome aged 31–60 yrs when compared with the corresponding subgroup without metabolic syndrome. Only in the perimenopausal period, FM (%) and FFM (kg) were significantly higher in the group with metabolic syndrome than that without metabolic syndrome .WC significantly increased with advancing age only in obese women without metabolic syndrome, being an anthropometric parameter stable over time in the group with metabolic syndrome. While a significant age-dependent increase in HDL-C occurred in both groups with and without metabolic syndrome, triglycerides significantly decreased with advancing age only in obese women with metabolic syndrome. A significant worsening in glycaemia occurred over time in obese women independently of the diagnosis of metabolic syndrome. SBP significantly increased with advancing age in both patients with and without metabolic syndrome. By contrast, DBP increased with advancing age in patients without metabolic syndrome, while it reduced in patients with metabolic syndrome. An increase in the total score of altered IDF criteria for metabolic syndrome occurred age-dependently in both groups with and without metabolic syndrome .HDL-C levels were significantly higher in patients without metabolic syndrome than in those with metabolic syndrome in all age subgroups, while WC (up to the sixth decade), triglycerides, and glucose were significantly higher in obese women with metabolic syndrome than in those without metabolic syndrome. SBP was significantly higher in obese women with metabolic syndrome than in those without metabolic syndrome up to the fifth decade, while DBP up to the fourth decade. Finally, the total score of altered IDF criteria was significantly higher in the group with metabolic syndrome than in that without metabolic syndrome in all age ranges .Altered WC (ie ≥ 80 cm) was present in all subjects. The percentage of obese women with HDL-C <50 mg/dl significantly decreased with advancing age in both patients with and without metabolic syndrome. The percentage of obese women with triglycerides ≥150 mg/dl remained stable with advancing age in both patients with and without metabolic syndrome. The percentage of obese women with glucose ≥100 mg/dl significantly increased with advancing age only in the group with metabolic syndrome, the peak being reached in the age range >70 yrs, while no age-dependent changes were recorded in patients without metabolic syndrome. The percentage of obese women with SBP ≥130 mmHg and/or DBP ≥85 mmHg significantly increased in both groups, the peak being reached at 61–70 yrs in patients with metabolic syndrome and >70 yrs in those without metabolic syndrome .The percentages of obese women with altered values of HDL-C, triglycerides, glucose, and BP (in accordance with the cut-offs of IDF criteria) were significantly higher in the group with metabolic syndrome than without metabolic syndrome, the unique exception being represented by BP (age range >70 yrs) which was comparable between patients with and without metabolic syndrome .A progressive age-dependent increase in the percentage of patients pharmacologically treated for the abnormalities concurring to determinate metabolic syndrome was detected in patients with metabolic syndrome , a similar trend being also observed in patients without metabolic syndrome only for the antihypertensives (from 1.4% up to 70.0%) .Analysing the data of the treated groups, despite a significant age-dependent increase in the percentages of treated patients, a clear-cut disproportion was found between treated and adequately controlled (with pharmacotherapy) patients in the whole population (23.4% for glycaemia and 44.8% for BP), the inadequate treatment being present in all the age ranges. The only exception was in pharmacological control of hypertriglyceridemia, which increased with advancing age .The prevalence of metabolic syndrome increases with advancing age (from 25.5% in the age range 18–30 yrs up to 71.0% in patients over 70 yrs), being the age-dependent worsening of glucose and BP control the pathophysiological driver of its increaseIN the group without metabolic syndrome, an age-dependent increase in WC, glycaemia, SBP, and DBP was observed, indicating a progressive overall cardiometabolic deteriorationA progressive age-dependent increase in the percentage of patients pharmacologically treated for the abnormalities concurring to determinate metabolic syndrome is detected in patients with metabolic syndrome , a similar trend being also observed in patients without metabolic syndrome only for the antihypertensives (from 1.4% up to 70.0%)Surprisingly, among the pharmacologically treated patients, only a relatively small percentage of obese women (particularly within the group with metabolic syndrome) is successfully controlled in accordance with the cut-offs of IDF criteria A clear-cut disproportion between treated versus adequately controlled (with pharmacotherapy) patients is detected (adequately controlled in 23.4% with hypoglycaemics and 44.8% with antihypertensives in the whole population)The main results of the present cross-sectional study, carried out in a huge number of  obese women with or without metabolic syndrome, aged from 18 to 83 yrs, can be summarised in the following points:β-cell dysfunction [The age-dependent worsening of hyperglycaemia in obese patients (with or without type 2 diabetes mellitus), as demonstrated also in the present study, is related to the well-known progressive age-dependent acceleration of function . Paradoxfunction . In partAs shown in the present study, the potentially cardioprotective age-dependent increase of HDL-C in both groups with and without metabolic syndrome is of difficult interpretation. In fact, after the perimenopausal period, a reduction of the protective oestrogen effect on cholesterol is usually reported in normal weighted subjects . Since tIn the present study, the age-dependent SBP increase was comparable in patients with and without metabolic syndrome, although the latter started from higher values and were more frequently treated. A different age-dependent pattern was observed for DBP, a progressive reduction being found in patients with metabolic syndrome and an increase in those without. Although our interpretation may be speculative because of the missing normal-weight group as a control, atherosclerosis, endothelial dysfunction, and sympathetic hyperactivation are likely to play a relevant pathophysiological role in SBP increase with advancing age in obese women, more evidently in the group with metabolic syndrome than without metabolic syndrome .To the best of our knowledge, few authors have evidenced in a single study an astonishing contradiction between the natural history of metabolic syndrome, i.e., an age-dependent increase in the prevalence, and its pharmacological management, i.e., insufficient/unsuccessful control .Due to the methodological limitations of the present study, we can only tentatively explain the reasons for this evidence-based contradiction, which will require a confirmation from long-term prospective studies.First of all, in view of the unsuccessful control of obese women with metabolic syndrome, a “holistic” approach should be adopted in clinical practice when an obese patient comes to medical attention willing to lose body weight. Dyslipidemia, glucose intolerance, and hypertension should be strenuously sought, pharmacologically treated, and successfully controlled . This “hNevertheless, as demonstrated by the present study carried out in obese women seeking hospitalization in a third-level setting for obesity, the prescription of pharmacotherapy for all the abnormalities involved in the determination of the metabolic syndrome, such as dyslipidemia, hyperglycaemia, and hypertension, appears seriously insufficient and unsuccessful. This may depend on a difficulty by the general practitioner to assist obese patients (mainly those more compromised) or to manage hypoglycaemic and antihypertensive drugs (particularly when their combination is required) in severely obese patients . The obsMedical management of metabolic syndrome does not include only pharmacological interventions. In fact, the administration of a BWRP to obese patients has been demonstrated to be extremely effective in improving most of the cardiometabolic conditions underlying the metabolic syndrome, such as dyslipidemia, glucose intolerance, and hypertension , 8. In tTaking into account the contradiction between high prevalence and scarce control of metabolic syndrome, public health decision-makers are asked for the development of more effective strategies able to fight against obesity and cardiometabolic comorbidities .Before closing, some limitations of the present study should be mentioned.Although not all the subjects were successfully controlled, previous and current treatments may have certainly influenced the results of this study. In particular, the use of hypolipidaemic drugs over time could partly explain an increase in HDL-C and a decrease in triglycerides with advancing age. Moreover, the higher prevalence of treated patients with metabolic syndrome could have reduced the difference between both groups for several parameters. Anyway, due to the limitation of any clinical study with a cross-sectional design, it is statistically difficult to isolate and weigh the covariate “treatment”. Unfortunately, we do not know exactly when any treatment  has been started and, importantly, maintained over time.Apart from the cross-sectional design, which has been already highlighted above, drugs prescribed to patients (before admission to our institution) were generically classified as hypolipidaemic drugs, hypoglycaemics, and antihypertensives. Therefore, we cannot rule out that some specific pharmacological classes have been more frequently prescribed and/or could have more successfully controlled the underlying condition. Furthermore, the “correct” drug prescription by a general practitioner does not mean a “correct” drug intake by a patient due to problems of pharmacological adherence . MoreoveHypolipidaemic drugs prescribed in clinical practice (such as statins) are more effective in reducing total and LDL cholesterol rather than in elevating HDL-C . Anyway,In the present study, the effectiveness of any pharmacological treatment for dyslipidaemia, glucose intolerance, and hypertension was evaluated in accordance with the cut-offs of the IDF criteria , which fFinally, the present study was carried out in the Italian context, encompassing an obese female population with specific gender-related, demographic, anthropometric, socioeconomic, and cultural/behavioural characteristics that may be different from those of another obese population living in other European or extra-European countries. Similar considerations are valid for the national health systems, which, even among close countries within the European community, may be extremely different. Finally, subjects included in the current study might also be non-representative of other Italian obese women issued from the same population because they were recruited among women willing to be hospitalized for a 3-week BWRP. Such program is highly demanding and includes highly motivated subjects, which could have influenced the results . Therefore, based on the previous considerations, caution is necessary before extending the results of the present study in other  contexts.At least in an Italian context, glucose intolerance and systolic hypertension play a fundamental pathophysiological role in the natural history of metabolic syndrome in adulthood, and the contributions of visceral adiposity and dyslipidaemia with advancing age were less relevant. The single components determining metabolic syndrome appear to be poorly controlled. The results of the present study might be useful for public health decision-makers for programming future more extensive and aggressive non-pharmacological and pharmacological interventions in the obese population, aimed to obtain better control of the alterations determining metabolic syndrome (and the risk for cardiovascular diseases) during the different periods of adult and elderly life.


Background: Radiofrequency ablation (RFA) is a curative modality for hepatocellular carcinoma (HCC) patients who are not suitable for resection. It remains controversial whether a surgical or percutaneous approach is more appropriate for HCC.Method: A search was performed on the PubMed, Web of Science, Embase, and Cochrane Library databases from the date of database inception until April 17, 2021. Studies reporting outcomes of comparisons between surgical RFA (SRFA) and percutaneous RFA (PRFA) were included in this study. The meta-analysis was performed using the Review Manager 5.3 and Stata 12.0 software.Result: A total of 10 retrospective studies containing 12 cohorts, involving 740 patients in the PRFA group and 512 patients in the SRFA group, were selected. Although the tumor size in PRFA group was smaller than the SRFA group (p = 0.007), there was no significant difference in complete ablation rate between the SRFA and PRFA groups . However, the SRFA group showed a significantly lower local tumor recurrence than the PRFA group in the sensitivity analysis . Pooled analysis data showed that the rate of severe perioperative complications did not differ significantly between the PRFA and SRFA groups . There was no significant difference in the 1-, 3-, and 5-year overall survival rates, as well as the 1- and 3-year disease-free survival (DFS) between the PRFA and SRFA groups. The 5-year DFS of the PRFA group was significantly lower than the SRFA group .Conclusion: Based on our meta-analysis, the surgical route was superior to PRFA in terms of local control rate. Furthermore, the surgical approach did not increase the risk of major complications. Radiofrequency ablation (RFA) is recognized as a curative modality for early-stage hepatocellular carcinoma (HCC), especially in patients who are not suitable for resection and liver transplantation –4. AlthoIn this study, we performed a meta-analysis with inclusion and exclusion criteria to review the currently available published data comparing the safety and efficacy of these two therapeutic approaches in patients with HCC.The present meta-analysis was performed according to the criteria defined by the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement .A literature search on the PubMed, Web of Science, Embase, and Cochrane Library databases was performed to select relevant articles with no restrictions on regions starting from the date of database inception until April 17, 2021. The following keywords were searched in titles and abstracts: (hepatocellular carcinoma) AND [(radiofrequency) OR (ablation)] AND {[(open) OR (surgery) OR (laparoscopic) OR  OR (laparoscopy)] AND (percutaneous)}. All the retrieved articles were reviewed, with their reference lists manually screened to identify additional studies. When multiple reports described the same patient population, the most recent or complete report was included. The literature search was independently conducted by two researchers, and any disagreements were resolved by the adjudicating senior authors.Studies were included in the meta-analysis when both of the following inclusion criteria were met: 1. Comparisons of postoperative and survival outcomes between PRFA and SRFA. 2. Confirmation of HCC in study patients based on clinical diagnosis. The exclusion criteria were as follows: 1. Lack of reporting or inability to calculate relevant outcomes based on available data. 2. Non-human experimental study design. 3. Publication types, other than randomized controlled trials and observational studies, such as editorials, letters to the editor, review articles, and case reports.After the removal of duplicates, the titles and abstracts of the retrieved studies were screened and sequentially excluded according to the eligibility criteria. In the event of any uncertainties after screening the titles and abstracts, the complete text was independently assessed by two investigators, and any discrepancies were resolved by consensus. The primary outcomes were complete ablation rate, postoperative complication, and recurrence rates.p < 0.05 considered significant, and heterogeneity was quantified using the I2 statistic. In the event of significant heterogeneity among the included studies, the random-effects model was used for pooled analyses; otherwise, the fixed-effects model was used  , 15, whiwas used . PublicaThe literature search and study selection criteria are schematically illustrated in p = 0.007; p = 0.13; p = 0.33; The characteristics of the ten studies , 17–22 iStudies were evaluated for sources of bias using the mNOS. In general, the quality of all included studies was moderate . Among tp = 0.15), as well as no statistical heterogeneity . Similarly, the rate of extrahepatic metastasis in the PRFA group was not significantly different compared to the SRFA group . The indifferent rate of complete ablation resulted in no significant difference in the rates of local recurrence between the PRFA and SRFA groups . A sensitivity analysis showed that there was significantly less recurrence in the SRFA group .According to pooled analysis data from 11 cohorts of nine included studies , 18–22, p = 0.05;), and there was heterogeneity in the data reported by the included studies . Three cohorts reported that skin burn was higher in the PRFA group than in the SRFA group, with a meta-analysis showing that it was statistically significant .Among the various treatment-related complication , internap = 0.34; χ2 = 196.13; p < 0.00001, I2 = 97%). A subgroup analysis revealed that the PRFA group had a significantly reduced hospital duration compared to the open approach group , whereas the 1- and 3-year OS rates showed no heterogeneity .Eight cohorts , 20, 21 I2 = 27%, p = 0.25; Data on disease-free survival (DFS) were reported in six cohorts , 20, 21.The sensitivity analysis included eight retrospective studies that scored eight or more stars on the mNOS. There was no significant change in complete ablation rate, complication, total recurrence, intrahepatic recurrence, and extrahepatic metastasis. For local recurrence, the degree of between-study heterogeneity significantly decreased and there was significantly less recurrence in the SRFA group.p = 0.806; p = 0.917; p = 0.072; p = 0.764; According to the Begg's rank correlation test, there was no significant difference in publication bias in complete ablation rate  can be found in the article/XY, CW, and ZH contributed to the screening and data collection. TM and ZH contributed to the assessment of the included article. XB and LX contributed to the data analysis. XH and YL contributed to the writing of the manuscript. XC contributed to provide expert insight into the revision of the manuscript and being as corresponding author. All authors approved the final version of the reports and contributed to the study concept, design, data interpretation, and discussion.This research supported by Sanming Project of Medicine in Shenzhen (Nos. SZSM202011010 and SZSM201812079) and Shenzhen High-level Hospital Construction Fund.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Consequently, we carried out subgroup, sensitivity, meta-regression, trim and fill, time-trend, and meta-cumulative analyses. In this systematic review and meta-analysis, the twenty-four studies reported a total of 4,963,266 births. The pooled birth prevalence of anencephaly in Africa was 0.14% . Higher burden of anencephaly was detected in Ethiopia , Algeria , and Eritrea . The higher pooled prevalence of anencephaly was observed in the studies that included both live births and stillbirths (0.16%) and in studies done after the year 2010 (0.25%) whereas, the lower burden was detected among countries that had a mandatory folic acid fortification (0.05%). High birth prevalence of anencephaly was detected in Africa. Strong prevention and control measures should be the priority because of an increment in the magnitude of anencephaly. Helping in prevention programs, which should be the ultimate contribution of this study to the field.Anencephaly is a severe anomaly of the brain that results from the failure of the cephalic part of the neural tube to close during the fourth week. It occurs at least in one per thousand births and is the major cause of fetal loss and disabilities in newborns. The objective of this review is to determine the birth prevalence of anencephaly in Africa. We identified relevant studies via a search of databases like PubMed Central, PubMed/Medline, Science Direct, Joanna Briggs Institute, African Journals Online, Embase, Google Scholar, Web of Science, and Cochrane Library. After examining the heterogeneity of studies via the Cochran Q test and I As a result, the vault of the cranium does not form, leaving the malformed neural tissue exposed. Later, this tissue degenerates, leaving a mass of necrotic tissue due to the abnormal structure and vascularization of the embryonic exencephalic neural tissue4. Sometimes, the closure abnormality of the tube extends caudally into the spinal cord and the malformation is known as craniorachischisis3.Anencephaly is a severe defect of the brain that results from failure of the rostral neuropore to close during the fourth week of development4. It is the most common serious anomaly seen in stillborn fetuses. Newborns with this severe defect may survive after birth, but only for a short period4. Newborns delivered with anencephaly show persistent unconsciousness due to lack of functioning cerebral cortex and varying degrees of brain stem functions causing brain death4.Anencephaly, a common lethal anomaly, occurs in 1.0–4.7 per 1000 births and is more common in females  than in males1. An ossification abnormality in the bones of the cranium results in meningocele, meningoencephalocele, and meningohydroencephalocele7. The squamous part of the occipital bone is the most common malformed bone. Only meninges bulge through a small occipital bone opening, which is known as meningocele, but the part of the brain and part of the ventricle are protruding through the large defect in the skull, the defects are called meningoencephalocele and meningohydroencephalocele, respectively14. These malformations occur one in every two thousand births3.Anencephaly is always related to the absence of the calvaria16. It is associated with substantial mortality, morbidity, and psychological costs8.It is the major cause of fetal loss and disabilities in newborns and it is considered a significant public health problem3. Because anencephalic fetuses lack a swallowing reflex in the presence of a large defect , the last two months of pregnancy are characterized by polyhydramnios (excess amniotic fluid)3.Anencephaly is suspected in utero when there is an elevated level of alpha-fetoprotein in the amniotic fluid. The abnormality can be diagnosed by ultrasonography and magnetic resonance imaging because extensive parts of the brain and the vault of the skull are absent18.Anencephaly, although it is preventable, is still the major cause of death and newborn disability in the world. It can be prevented by having women take 400 µg of folic acid per day before and during pregnancyThis review is helpful to dig out the burden of anencephaly in Africa and provide valuable information to the government, policymakers, health professionals , researchers, communities, and Non-Governmental Organizations to play a role in reducing the burden, and making further research towards anencephaly. Furthermore, little is known about the magnitude of anencephaly in the region as a whole. Therefore, the aim of the present systematic review and meta-analysis is to determine the pooled birth prevalence of anencephaly in Africa.The comprehensive search of databases yielded four hundred eighteen studies about anencephaly in Africa. Of these, 99 were excluded because of duplication. Of the rest articles 319), 249 articles were excluded after reviewing the titles and abstracts. Full texts of the remaining 70 articles were screened and assessed for eligibility. Thus, twenty-four studies have fulfilled the inclusion criteria and have been included in the systematic review and meta-analysis 14, Nigeria (n = 4)23, South Africa (n = 3)31, Algeria (n = 2)28, Sudan (n = 2)33, Tunisia, Eritrea, Democratic Republic (DR) Congo, Libya, Egypt, Ghana, Tanzania, and Cameron32 were identified  and prospective cohort study design (n = 7)7 and proSurprisingly, all studies included were facility-based studies. Currently, Ethiopia has voluntary folic acid fortification whereas South Africa, Nigeria, Ghana, and Cameron have mandatory folic acid fortification with Wheat Flour, Maize Flour, and Rice. Studies considered after the implementation of mandatory folic acid fortification policy were South Africa and Nigeria Table .Table 2T33.Each study was evaluated using the JBI critical appraisal checklist for prevalence studies, it has nine questions/items with options of Yes, No, Unclear, or Not Applicable Table . The qua333, the median (per 100) value of birth anencephaly was 0.06% and the inter-quartile range was between 0.03 and 0.18. The minimum and maximum values of birth anencephaly were 0.005 and 0.78%, respectively.In the present meta-analysis, the pooled birth prevalence of anencephaly was 0.14% or 1.4 per 1000 births  , Algeria 0.24% , and Eritrea 0.19%  .The pooled birth prevalence of anencephaly for cross-sectional was 0.15%  and for prospective cohort design was 0.10%   only (contain six studies) was 0.06%  and for both live birth and stillbirths (LB + SB) (contain eighteen studies) was 0.16%  , the pooled prevalence of anencephaly for studies done after 2010 (contain nine studies) was 0.25%  and for studies done before 2010 (contain fifteen studies) was 0.07%  Fig. .Figure 4P value < 0.001, I2 = 100%), the pooled birth prevalence of anencephaly for countries that had a mandatory folic acid fortification (like Nigeria and South Africa) was lower, 0.05% , than for those free of a mandatory folic acid fortification policy, 0.15% .Even if their publication year is after the year 2010 , most of their study period were found before 2010, so we categorized them as studies done before 2010. Based on four periods, the pooled prevalence of anencephaly for the period after 2010 (contain nine studies) was 0.25% , for the period between 1991 and 2011 was 0.0% (only one study done for 20 years), for the period between 2000 and 2010 (contain seven studies) was 0.09% , and for the period before 2000 (contain seven studies) was 0.06% . Based on folic acid fortification policy , year of publication , duration of the study in month , the JBI quality score , study country , study design , folic acid fortification status , outcome status , and period prevalence  were analyzed for the source of heterogeneity. None of them was statistically significant. Nevertheless, at bivariate analysis, study country , folic acid fortification status , and period prevalence  were significant at below 0.05.Using meta-regression analysis (multivariable), sample size  to 2020 (0.14%). In this trend in Africa, the highest peak of anencephaly in prevalence was observed between 2016 and 2018  to the year 2020 (0.14%) Fig. .Figure 7Based on the Funnel plot, considerable publication bias was observed Fig. .Figure 8As a result, we conducted the trim and fill meta-analyses to adjust this bias. We analyzed thirty-seven studies (thirteen studies were filled) in the fill meta-analyses and the pooled birth prevalence of anencephaly using the random-effect model was 0.012%  . This finding is comparable with the review conducted globally that estimates the live birth prevalence of anencephaly was 0.03% with the range of 0.008 to 0.11%34. In addition, the review reported an estimate based on all pregnancies resulting in live births, stillbirths, and terminations were 0.103% for anencephaly. This review result suggested that low-and middle-income countries were mostly affected by this anomaly each year34. However, the review did not include studies from Africa except for two studies, and representativeness for Africa has decreased for this reason. A systematic review in India reported the prevalence of anencephaly, which was 0.21%, ranging from 0.16 to 0.28%15. Our finding was supported by the previous evidence that indicated anencephaly is a common lethal anomaly, occurring at least once in every thousand births35. Recent evidence proves that there is variation in the prevalence of anencephaly in time, place, and population to population16. In different times and regions, the prevalence of anencephaly ranges from one in every thousand births to one in every five thousand births. Income level and instituted folic acid fortification are the main factors that determine the prevalence of anencephaly in one country. A significant difference in the birth prevalence of anencephaly across countries was detected in this review. A very high (0.37%) birth prevalence of anencephaly was detected in Ethiopia for example, the prevalence in Algeria was 0.24%, and in Eritrea was 0.19%. The lowest prevalence was detected in Tunisia (0.005%). Maybe this difference among countries comes due to the levels of knowledge of mothers about folic acid supplementation, the country’s health policies regarding folic acid fortification, and other preventive measures. Furthermore, the difference in prevalence estimate among countries may be due to the difference in the presence of robust surveillance systems that track all pregnancy outcomes . These variations may underestimate the overall burden of anencephaly in Africa. The prevalence estimates were also affected by the difference of countries having access to antenatal screening and terminations. If the terminated cases of anencephaly during pregnancy are very high in one country, it is less likely to have high prevalence estimates at birth. Studies reported that the presence of wide geographical variation in prevalence estimates between the countries16. In Tunisia, the lowest prevalence may be related to the detection methods used, reporting and recording system, and the issue of terminated cases. Moreover, the adequacy of the sample size (extremely high sample size in Tunisian study) may affect the estimated report. In the present review, time trend analysis displayed that there was variation in different periods. The highest burden of anencephaly was observed between 2016 and 2018. This finding was also supported by a subgroup analysis of the period prevalence . The increment in the prevalence of anencephaly in this duration may be due to a change in detection methods, an increment of the practices in documenting and reporting cases, an increase of the demands for fetal pathological examinations over these years, or a real increase in disease. The prevalence estimate in live births (0.06%) was lower than estimates from both live births and stillbirths (0.16%). Besides, the prevalence estimate is affected by the status of a mandatory folic acid fortification policy. Because all studies in the current review were hospital-based studies, an underestimation of the prevalence estimates should be noted, as the review did not consider many stillbirths and home births that are delivered in the community setting.The present systematic review and meta-analysis were carried out to determine the pooled birth prevalence of anencephaly in Africa. The burden of anencephaly seems to become decreasing due to different preventive measures and folic acid fortifications in high-income countries. In Africa, the hidden burden of anencephaly was very high and the primary data research, as well as systematic review and meta-analysis that show this burden, were so scarce. Even in the global estimation of the burden, the inclusion of studies from Africa was a few to represent the whole continent due to different reasons. Nevertheless, the effects of the anomaly correlate with mortality, disability, and psychological costs. It is an important public health problem that can be prevented with folic acid supplementation and fortification of staple foodsThis review finding will help to improve the prevention and control programs in African countries. The severity of the defect, the observed differences in prevalence estimate among countries, may inform to modify the clinical and policy guidelines in the prioritization of interventions in Africa. It is remarkable if the next step will be that all African countries should adopt and implement a mandatory folic acid fortification policy. Besides, there should be started/improved robust surveillance systems in each country to track all pregnancy outcomes, particularly birth defects. Notably, this review highlight the birth prevalence of anencephaly in African countries, providing crucial evidence for policymakers, clinicians, and the concerned bodies who neglected the burden of this defect. The high burden detected in this review may initiate the policymakers to apply effective prevention strategies and may use their ultimate potential in reducing the burden of the anencephaly and making further research possible .As many strengths of the review as it is, the outputs of the present review should be interpreted based on some limitations; the estimate did not include the terminated pregnancy/cases of anencephaly and this may decrease the prevalence estimates. Furthermore, the variability of the sample size in the included studies might influence the pooled birth prevalence estimates. Besides, the presence of significant variation across countries may underestimate the overall burden in Africa. Further, English-written articles were included in order to meticulously examine the quality of the articles. The review represented the studies from the twenty-four African countries due to limited available data about anencephaly.The present systematic review and meta-analysis showed that a high birth prevalence of anencephaly was detected in Africa.The birth-pooled prevalence of anencephaly was very high in Ethiopia and Algeria.The higher pooled prevalence of anencephaly was observed in the studies included both live births and stillbirths and in studies done after the year 2010 whereas, the lower burden of anencephaly was detected among countries that had a mandatory folic acid fortification.Therefore, we would like to inform policymakers that the pooled birth prevalence estimates are possible underestimates due to the lack of robust surveillance systems in Africa. The meta-analysis should not impact policy decisions on folic acid-based prevention efforts in Africa negatively where policymakers may feel that this is not a big enough problem for prioritizing prevention funds. Moreover, strong prevention and control measures should be the priority because of an increment in the magnitude of anencephaly, and limited available data on anencephaly in Africa informs the need for additional primary research that would improve the estimated prevalence of anencephaly and recommend favorable aid policies through maternal education on preventive measures. Helping in prevention programs, which should be the ultimate contribution of this study to the field.19  from the total number of births (live births and/or stillbirths) during the study period (denominator). Remarkably, we performed this review in accordance with the PRISMA 2020  guidelinesStudies were eligible for inclusion if they reported the birth prevalence (live births and/or stillbirths) of anencephaly in Africa, studies in any setting, published and unpublished full-text studies in any period, studies reported in the English language, and study designs that reports the birth prevalence/incidence. All newborns with visible congenital neural tube anomaly/defect, anencephaly, identified through clinical evaluation  by physicians, and/or diagnosed based on ICD-10 classifications, at the time or following the delivery after the twenty-eight weeks of gestation were considered anencephaly cases. Meanwhile, we excluded anonymous reports, conferences, editorials, case reports, and studies without full access (after contacting the author two times through email) from the review. Moreover, studies that did not contain appropriate prevalence data, for instance, review papers or studies providing only calculated estimates (without reporting appropriate numerator/denominator) were excluded. The Endnote Version 7.2 Software was used to import citations following the search of the databases. The three authors , independent of each other, selected all articles.36. The checklist of studies reporting the prevalence data was considered to evaluate studies (it contains nine items)  extracted all essential qualitative and quantitative data independently using a standardized, pre-specified, data abstraction template. The data abstraction format included main author, study design, publication year, sample size, study country, study setting, study duration, period prevalence, folic acid fortification policy, and birth prevalence  of anencephaly. In this review, all studies’ prevalence reports in the different denominators have been converted into per hundred births to maintain uniformity and we used per hundred estimates to report the findings. This was calculated directly from data when the appropriate number of cases and denominator were given.2 test statistics37. Due to the significant heterogeneity , it was decided that estimating a weighted average  was the best approach to obtaining the pooled prevalence estimates39. Furthermore, meta-analyses were carried out separately for each sub-group: birth prevalence based on the study country, study design, birth outcome, period prevalence, and folic acid fortification status. In subgroup analysis, if significant heterogeneity across the sub-groups was detected, the Der Simonian and Laird’s (D + L) pooled prevalence method was considered because it is more conservative (can lead to reliable estimates) than the inverse variance method (I–V). The Forest plot was used to display the presence of heterogeneity among the studies. Meta-regression analysis, sensitivity analysis, time-trend analysis, and meta-cumulative analysis were performed as well. To assess the publication bias, funnel plot asymmetry was used. Essentially, the trim and fill analyses were considered to mitigate the publication bias.After extraction of the data in Microsoft Excel and we exported it into STATA Version 14 Statistical Software for further analyses. In addition to the main analysis, we estimated the median value and interquartile range for all included studies. The heterogeneity between the studies was examined using the Cochran Q test and ISupplementary Information.