BackgroundEpilepsy is a neurological disorder that presents with recurrent seizures associated with erratic brain activity which can be measured through EEG in addition to other neurological investigations. However, EEG may show abnormal patterns and waveforms while the patient is having a seizure which is crucial for making an accurate diagnosis.ObjectiveThis study aims to evaluate the spectrum of EEG findings in newly diagnosed epileptic patients as part of a neurological investigation.Material and methodsThis cross-sectional study was carried out at the Department of Paediatric Neurology, the Children's Hospital, and the Institute of Child Health, Lahore for six months. A sample of 122 patients was enrolled in this study with an age range of >1 month and <18 years, with a diagnosis of epilepsy based upon ≥2 unprovoked seizures that occurred ≥ 24 hours apart. After obtaining informed consent from the patients, a one-time EEG was carried out and details were noted such as type and frequency of the discharge, site of maximum amplitude, paroxysm morphology, and onset and offset  of the discharges. The data was analyzed using SPSS v.25 .ResultsThe mean age of children enrolled in this study was 5.58 ± 3.46 years. There were 70 (57.4%) males and 52 (42.6%) females. The mean age at the onset of seizures was 4.85 ± 3.16 years. Out of 122 children, focal onset aware epilepsy type was noted in 8 cases, focal onset impaired awareness was noted in 19 cases and generalized onset motor type of epilepsy was noted in 95 cases. Furthermore, EEG findings were normal in 41 (33.61%) patients; however, 81 (66.39%) EEG findings of the patients place them in the abnormal range. On EEG, paroxysm morphology was typical in 78 (96.3%) patients while atypical in 3 (3.7%) patients. Discharge spectrum was generalized in 46 (56.8%) patients, localized in 19 (23.5%) patients, bilateral independent in 1 (1.2%) patient and multifocal in 15 (18.5%) patients. Discharge pattern was periodic in seven (8.6%) cases, rhythmic delta activity was noted in 4 (4.9%) cases, spike and wave pattern was noted in 68 (84.0%) cases and sharp and wave pattern was observed in 36 (44.4%) patients.ConclusionOur study concluded that EEG findings were abnormal in 81 (66.39%) patients. Thus to make the recommendations locally and nationally, we observed that EEG can highlight the abnormal pattern and discharges in newly diagnosed individuals with epilepsy. Our findings could be instrumental to identify the type of EEG discharges in a timely fashion while making diagnoses and treatment plan protocols accordingly. This study finding recommends the early application of EEG after the presentation of epileptic symptoms by the patient. We further recommend that further similar studies be conducted in multiple tertiary care settings to reach a firm and valuable conclusion.  Epilepsy is a neurological condition, characterized by frequent seizures and abnormal brain behavior. Epilepsy requires urgent medical attention and, in many cases, long-term treatment. In various world societies, the frequency is about 0.3-0.5 percent, with a prevalence rate of 5-10 per 1000 people .The primary aim of electroencephalography (EEG) is to identify the exact type of seizure and epilepsy syndrome so that care can be provided accordingly and also detect unexplained paroxysmal spells that could be seizures . The ranA bilateral, symmetrical, and synchronous spike-wave behavior on a normal basis is the classic EEG irregular reading of hereditary generalized epilepsy. Generalized polyspikes, generalized polyspike-wave discharges, photoparoxysmal response, eye-closure sensitivity, fixation-off sensitivity, and occipital intermittent rhythmic delta activity are other common EEG anomalies identified in the literature . AtypicaDue to inconsistency in previous studies, it is hard to generalize the findings of the EEG abnormalities while making a diagnosis of epilepsy. The rationale of this study is to evaluate the wide spectrum of EEG abnormalities in children with epilepsy. This would help to get an estimate of the prevalence of the vast spectrum of EEG findings in epileptic patients; consequently, leading us to identify any atypical EEG findings in patients presenting with seizures which could have otherwise potentially led to inaccurate diagnosis and inappropriate choice of antiepileptic drug therapy. Therefore, we conducted this study to make some recommendations locally and nationally as there are limited relative studies published in Pakistan about newly diagnosed epilepsy cases highlighting abnormal patterns and discharges.statistics.co.uk/calculators/) where the confidence level was 95%, and margin of error was 5.5%, prevalence of epilepsy was 9.99 per 1000 population [This cross-sectional study was carried out at the Department of Paediatric Neurology, the Children's Hospital, and the Institute of Child Health, Lahore for six months (22/07/2020 to 21/01/2021). The sample size was calculated by using Select Statistics sample size calculator  as when “at least two or more unprovoked seizures occurring more than 24 hours apart” or “one unprovoked seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years”. ChildreEthical approval from the institutional ethical review committee 2020-123-CHICH) was attained prior to the study. After obtaining informed consent from the patients, a one-time encephalography (EEG) was conducted. Clinical and demographic information was collected. The gathered information like current age of child, sex of child, type of seizure, age at the time of first episode of seizures and duration of recent seizure. An expert EEG reader reviewed all the EEGs readings. Detailed evaluation of all abnormal epileptiform readings was done. Details of each discharge was noted in the proforma. The details of discharges listed type and frequency of the discharges, site of the maximum amplitude, paroxysm morphology and onset and offset  and pattern  of the discharges. The spectrum of EEG findings was defined as "the various epileptiform both typical and atypical patterns that are whether generalized, focal or multifocal and (i) spikes (<70msec duration), (ii) spike and wave, (iii) sharp and wave (70-200ms duration), (iv) rhythmic delta activity, (v) periodic discharges” [-CHICH waOut of 122 children, focal onset aware epilepsy type was noted in 8 cases, focal onset impaired awareness was noted in 19 cases, and generalized onset motor type of epilepsy was noted in 95 cases. For additional details, see Tables EEG was performed within 24 hours of fits in 59 (72.8%) patients, within 24-48 hours in 15 (18.5%) patients, within 48-72 hours in 19 23.5%) patients and after 72 hours in 29 (35.8%) patients. On EEG, paroxysm morphology was typical in 78 (96.3%) patients while atypical in 3 (3.7%) patients. Discharge spectrum was generalized in 46 (56.8%) patients, localized in 19 (23.5%) patients, bilateral independent in 1 (1.2%) patient and multifocal in 15 (18.5%) patients. Discharge pattern was periodic in 7 (8.6%) cases, rhythmic delta activity was noted in 4 (4.9%) cases, spike and wave pattern was noted in 68 (84.0%) cases and sharp and wave pattern was observed in 36 (44.4%) patients as given in Table .5% patieData was stratified for age and gender of children. In children aged ≤5 years, EEG was abnormal in 39 patients, in children aged 6-9 years, EEG was abnormal in 32 patients and in children aged ≥10 years, EEG was abnormal in 10 patients. The difference was insignificant (p>0.05). In male children, EEG was abnormal in 49 patients while in females, EEG was abnormal in 32 patients. The difference was insignificant (p>0.05) in both genders as given in Table Out of 122 children, EEG was overall normal in 41 (33.61%) patients, while EEG was abnormal in 81 (66.39%) patients as given in Figure Apart from clinical history and neurological examination, an EEG is a common investigation used in the diagnosis of epilepsy. The EEG is the recording of the electrical impulses produced by the nerve cells in the brain, and it is a very useful therapeutic instrument for epilepsy diagnosis and treatment . To diagIt is usual for epileptic patients to have normal EEG readings. However, EEG may show abnormal patterns and waveforms while the patient is having a seizure  which is crucial for making an accurate diagnosis . These fIn our study, the mean age of children enrolled in this study was 5.58 ± 3.46 years. There were 70 (57.4%) males and 52 (42.6%) females. The mean age at the onset of seizures was 4.85 ± 3.16 years. Out of 122 children, focal onset aware epilepsy type was noted in eight cases, focal onset impaired awareness was noted in 19 cases and generalized onset motor type of epilepsy was noted in 95 cases. EEG was overall normal in 41 (33.61%) patients, while abnormal in 81 (66.39%) patients. On EEG, paroxysm morphology was typical in 78 (96.3%) patients while atypical in three (3.7%) patients. Discharge spectrum was generalized in 46 (56.8%) patients, localized in 19 (23.5%) patients, bilateral independent in one (1.2%) patient and multifocal in 15 (18.5%) patients. Discharge pattern was periodic in seven (8.6%) cases, rhythmic delta activity was noted in four (4.9%) cases, spike and wave pattern was noted in 68 (84.0%) cases and sharp and wave pattern was observed in 36 (44.4%) patients.Rajper et al. conducted a study in Karachi and found that generalized seizures were observed in 86.7% of cases while 13.3% of cases had focal seizures. In about 45.3% of cases, the EEG was done within the first 24 hours of presentation, which was almost similar as we observed in our study (48.4%). They further observed that EEG was abnormal in 55.2% cases, while in our study, EEG was abnormal in 66.39% cases. A history of abnormalities was observed in 15.6% of patients, interictal epilepticus discharges in 20.9%, and interictal epilepticus discharges with background slowing in 18.7% .However, in another study, Samra et al. found that the frequency of epileptiform EEG abnormality was 40% in all children presenting with seizures, and the overall frequency of confirmed epilepsy was about 30%. Thus EEG abnormality was 13.3% associated with the diagnosis of epilepsy . AnotherInterictal discharges were seen in the first EEG in about 18-56% of patients with new-onset epilepsy, but when a second sleep-dependent EEG was conducted, the percentage increased to 61%, according to a report by Wirrell et al.  EEG has The presence of epileptiform EEGs also in the absence of epilepsy has recently piqued researchers' attention. Some researchers believe that these anomalies may play a causal role in the autism phenotype, claiming that rates as high as 60% have been registered. The care effects are becoming extremely significant, considering the fact that this syndrome is still not fully known and risk factors are yet to be determined .Hypsarrhythmia in infantile spasm, burst suppression in early infantile epileptic encephalopathy, generalized 3 Hz pulse wave discharges in absence seizures, and intermittent complexes in subacute sclerosing panencephalitis are all common classic epileptiform patterns seen in infancy . For theWhen compared to children with regular EEG, people with focal epileptiform discharges have a greater chance of recurrence . These hIn our study, we conclude that EEG findings were abnormal in 81 (66.39%) patients. Thus to make the recommendations locally and nationally, we observed that EEG can highlight the abnormal pattern and discharges in newly diagnosed individuals with epilepsy. Our findings could be instrumental to identify the type of EEG discharges in a timely manner while making appropriate diagnoses and treatment plan protocols accordingly. The findings of this study recommend the early application of EEG after the presentation of epileptic symptoms by the patient. We further recommend that further similar studies be conducted in multiple tertiary care settings to reach a firm and valuable conclusion.


CEP104, CROCC, NEK1, TOM1L2, and TSTD2 predicted as damaging were found to be shared between the four tall family members. Three of the five genes  belong to the ciliary gene family. All genes are expressed in mouse growth plate. Pathway and network analyses indicated close functional connections. Together, these data expand the spectrum of genes with a role in linear growth and tall stature phenotypes.Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing was carried out in a tall male (height 3.5 SDS) and his parents. Filtered damaging variants with high CADD scores were validated by Sanger sequencing in the trio and three other affected and one unaffected family members. Network analysis was carried out to assess links between the candidate genes, and the transcriptome of murine growth plate was analyzed by microarray as well as RNA Seq. Heterozygous gene variants in  Human height is a highly polygenic complex trait, largely determined by genetics. Most of our understanding of the genetic architecture of height has derived from children with abnormal growth patterns and single gene defects (rare variants of large effect) , 2. At twww.icped.org). In families with multiple affected individuals, genetic top hits can be compared between individuals sharing the same phenotype and those who are unaffected, thereby subtracting the common genetic background. If multiple gene variants are identified that may contribute to a specific phenotype, it can be of interest to determine how these genes interact in networks. Connected genes within a pathway can provide useful insights on the biology and function. Lastly, expression analysis in growth plates may provide further indications on functionality.Normal growth requires signaling through many different pathways at the growth plate. Multiple hormones, growth factors, and cytokines as well as paracrine factors regulate growth plate function and thereby linear growth. We have studied the genetic profile of a family with a son with extremely tall stature, a very tall father and normal statured mother by exome sequencing and extended the analysis to other family members. Tall stature is defined as height of more than two standard deviations (SDs) above the mean for a defined population (Birth weight and length were expressed as standard deviation score (SDS) for Swedish references . Height Sitting height, leg length, and sitting height/height ratio were expressed as SDS for age and sex based on the 1997 Dutch reference . Arm spaTo analyze growth data in a multigenerational family is a challenge because of the downward course of height in anybody’s lifetime (due to shrinking) and the phenomenon of secular trend in the mean height of a given population that has been prominent in most countries in the past century. Therefore, for a proper analysis of height in a multigenerational family, it is necessary to obtain information about the approximate age at which the height measurement was taken so that the height in young adulthood can be estimated, followed by a comparison with the reference data in the year that the person was 21 years of age. Fortunately, good longitudinal data on shrinking by age have been published, and for the Netherlands detailed information is available about mean (SD) height of the population over the last century . This enThis study was part of the research protocol (P06.118) “Genetic diagnosis of very tall stature”, Leiden University Medical Center. Written informed consent was received from all participants prior to their inclusion in the study. The study was also part of the Research Program “Whole exome genetic analyses in rare hereditary diseases” of Heidelberg University. The study was conducted in accordance with the guidelines of the WMA Declaration of Helsinki and the Department of Health and Human Services Belmont Report.Agilent SureSelect Human All Exon V4 was used to capture the exons. Sequencing was done using the Illumina HiSeq 2000 system. Raw sequence data was mapped to the 1,000 genomes phase II reference genome (GRCh37 version hs37d5) using BWA 0.6.2, and duplicates were removed using PICARD. The three samples (parents and index case) showed an average coverage of 176×, and >99% of bases in the autosomal chromosomes of the target regions have >=10× coverage and >=20 QUAL score  with primers indicated in https://digitalinsights.qiagen.com/) was applied to predict functional connections, and their interpretation was carried out in the context of protein networks that comprise protein–protein interactions and related biological functions, and canonical signaling pathways.QIAGEN IngenuityPathway Analysis ; GnomAD (https://gnomad.broadinstitute.org/); CADD score (https://cadd.gs.washington.edu); dbSNP (https://www.ncbi.nlm.nih.gov); GTEx database ; PROVEAN/SIFT (http://provean.jcvi.org/index.php); Polyphen2 (http://genetics.bwh.harvard.edu/pph2/); Mutation Taster (http://www.mutationtaster.org/); GWAS (www.ebi.ac.uk); IPA Ingenuity Systems .TGP  using microarray  croarray . (2) spa RNA-Seq ; and (3) RNA-Seq .The index case . A duplication of the SHOX gene region was excluded by MLPA (MRC Holland). At follow-up, full pubertal development (testes ˃16 ml) was reached at 14.4 years, and at 14.9 years, height was 197.8 cm (3.0 SDS) and predicted adult height 208.6 cm (3.5 SDS). Epiphysiodesis was performed at 15.1 years of age and at 16.7 years his adult height was 202.8 cm (3.0 SDS). His growth curve is shown in At the age of 10.5 years, the proband was referred to the pediatric endocrine clinic because of tall stature. Previous growth data included a birth weight of 3.8 kg (0.5 SDS) and length of 54 cm (1.8 SDS). During the first year, length increased to 2.0 SDS, weight-for-age remained close to 2.0 SDS, and head circumference decreased from 2.2 to 1.3 SDS. During childhood, his height gradually increased to 3.5 SDS. At age 10.5, his height was 172 cm (3.8 SDS), sitting height 89.5 cm (4.1 SDS), leg length 82.3 cm (4.3 SDS), sitting height/height ratio 0.5203 (0.2 SDS), arm span 169.5 cm (3.7 SDS), arm span/height ratio 0.7 SDS, head circumference 56 cm (1.5 SDS), and weight 60.0 kg (BMI 1.5 SDS). Shoe size was 43. He had no hyperlaxity or arachnodactyly, and established causes of tall stature  were excluded by karyotype, serum  and candidate gene analysis (The boy’s sister was born with a weight of 3.6 kg (0.4 SDS) and a length of 52 cm (1.2 SDS). During the first year, her length increased to 2.5 SDS, weight remained at 1.3 SDS and the head circumference was −0.5 SDS. During childhood, her height SDS was approximately 2.2 SDS. At 13.2 years of age, height was 177.2 cm (2.3 SDS), sitting height 88.4 cm (1.2 SDS), sitting height/height ratio −1.2 SDS, arm span 180.8 cm (2.7 SDS), arm span/height ratio 1.1 SDS, weight 64.0 kg (BMI 0.7 SDS), pubertal stages B5, P3, A3, blood pressure 118/61 mm Hg. Menarche occurred at 14.0 years. Adult height was 187 cm (2.6 SDS) (CEP104), Rootletin (CROCC), Serine/threonine-protein kinase (NEK1), Thiosulfate Sulfurtransferase-like Domain containing 2 (TSTD2) and Target Of Myb1-Like 2 (TOM1L2), suggesting that these were potentially relevant for the phenotype . All identified missense variants were predicted to be damaging or probably damaging  are members of the ciliary gene family.Exome sequencing was carried out in the index case (adjusted adult height 3.5 SDS), his father (height 3.2 SDS), and his mother (height 0.9 SDS) , while the NEK1 and TSTD2 variants were likely transmitted from the maternal grandfather (I.1) or de novo . Top hit for molecular and cellular function was cell morphology (1.49 × 10−5–1.49 × 10−5). Using the Ingenuity pathway analysis, close network links between the highlighted genes could be revealed. Direct interaction between NEK1 and CEP104 was previously experimentally demonstrated (via the Embryonic Ectoderm Development (EED) Polycomb protein with the other candidate gene, CROCC . Stature is determined by the growth of long bones, which occurs at the growth plate, a cartilage structure with three principal layers, the resting, proliferative, and hypertrophic zones. To explore possible biological functions of the implicated genes in the growth plate, we assessed mRNA expression of the candidate genes in the growth plates of mice. For this purpose, we evaluated microarray data generated from growth plates of 1-week old mice and RNA-Seq data generated specifically from the proliferative and hypertrophic zones of 1- and 4-week old mouse proximal tibial growth plates . We found that all five candidate genes are expressed in mouse growth plate. Three of the five genes  showed expression differences between the proliferative and hypertrophic zones with downregulation of Crocc and Nek1 and upregulation of Tstd2 during hypertrophic differentiation. These differences between proliferative and hypertrophic zones were replicated in a different set of 1-week old mouse growth plate RNA-Seq data containing all three zones (including resting zone) generated independently . Finally, we looked for changes in gene expression in the mouse growth plate with age, as bone growth slows from 1 to 4 weeks of age, but found little temporal regulation of gene expression with only a decline in expression of Crocc in the proliferative zone from 1 to 4 weeks of age.All candidate genes are expressed ubiquitously according to the genotype-tissue expression GTEx database , Drosophila (in the case of NEK1 and TOM1L2) and C. elegans (TOM1L2). Three of these five genes  are members of the ciliary gene family. Three genes, CROCC, TOM1L2, and TSTD2 were found to be associated with height in GWAS studies (www.ebi.ac.uk)  , 18. PatCrocc and Nek1 were found to be downregulated, and Tstd2 was found to be upregulated during hypertrophic differentiation, suggesting a possible role of these genes in growth plate chondrocyte differentiation and therefore a possible mechanism to explain the tall stature.Longitudinal bone growth occurs at the growth plate by endochondral ossification, where cartilage is formed and then remodeled into bone tissue. This process involves chondrocyte proliferation and hypertrophy and extracellular matrix secretion, orchestrated by complex networks of local paracrine factors and modulated by endocrine factors. All five candidate genes were found to be expressed in mouse growth plate. Expression was also analyzed for temporal and spatial regulation in growth plate cartilage. NEK1 is the only one of the five genes which has been associated with a phenotype related to height, while CROCC, TOM1L2, and TSTD2 were found to be associated with height in GWAS   , 22. SinCEP104 and CROCC) or TSTD2 has not been reported to be associated with a growth disorder, although CROCC has been detected at genome-wide significance for adult height. CROCC (Rooletin) is a structural component of the centrosomes, the main microtubule organizing centre as well as regulator of cell cycle progression. A biallelic defect of CEP104 causes Joubert syndrome, but no clinical syndrome has been discovered caused by a CROCC or TSD2 variant. However, an interesting observation is that CROCC interacts with RUNX3  have been discovered in individuals with growth hormone deficiency  a loss of function is associated with tall stature , and gain of function with short stature  (DNMT3A)  , while g(DNMT3A) .In summary, the identified genes in this study encode mechanistically distinct proteins, but their function converges on shared pathways and growth plate-related features. In future studies on genetic causes of stature or skeletal growth, specific attention to these five genes is warranted.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The studies involving human participants were reviewed and approved by Leiden University Medical Center (P06.118) “Genetic diagnosis of very tall stature”. Written informed consent to participate in this study was provided by the participants’ or their legal guardian/next of kin prior to their inclusion in the study. Written informed consent was obtained from the individual(s) and/or minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.Conceptualization, JW and GR. Investigation, BW, BE, and JL. Software, NP. Patient resources, CB, HD, and JW. Methodology and supervision, JB and GR. Data analysis, BW, BE, JW, and GR. Writing and editing, JB, JW, and GR. All authors contributed to the article and approved the submitted version.This work was funded by the University of Heidelberg, Medical Faculty.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.


Chemical transport models, such as the Community Multiscale Air Quality (CMAQ) model, are valuable tools for exploring policy options for improving air quality but are computationally expensive. Here, we statistically fit an efficient polynomial function in a response surface model (pf-RSM) to CMAQ simulations over the eastern U.S. for January and July 2016. The pf-RSM predictions were evaluated using out-of-sample CMAQ simulations and used to examine the nonlinear response of air quality to emission changes. Predictions of the pf-RSM are in good agreement with the out-of-sample CMAQ simulations, with some exceptions for cases with anthropogenic emission reductions approaching 100%. NOX emission reductions were more effective for reducing PM2.5 and ozone concentrations than SO2, NH3, or traditional VOC emission reductions. NH3 emission reductions effectively reduced nitrate concentrations in January but increased secondary organic aerosol (SOA) concentrations in July. More work is needed on SOA formation under conditions of low NH3 emissions to verify the responses of SOA to NH3 emission changes predicted here. Overall, the pf-RSM performs well in the eastern U.S., but next-generation RSMs based on deep learning may be needed to meet the computational requirements of typical regulatory applications.Reducing PM Air qironment –5. Air qironment .2.5 and ozone to precursor emission changes is nonlinear and depends on hundreds of chemical reactions. For instance, ozone concentrations decrease in response to NOx emission reductions when NOx is the limiting precursor for oxidant formation but increase under NOx-saturated conditions, where NOx inhibits oxidant production [2.5 nitrate can also increase or decrease in response to NOx emission reductions depending on oxidant levels and other factors, such as aerosol pH, temperature, and relative humidity [2.5 to NOx emission reductions in the U.S. for retrospective periods [2.5 and its components for multiple precursors under recent conditions in the U.S. Consideration of relatively recent conditions is important because NOx emissions declined by 57% and SO2 emissions by 85% between 2000 and 2017 .Air quality modeling is important for effective air quality management because the response of PModuction . PM2.5 nhumidity –12. Prev periods ,14. Howe2.5 over wide ranges of precursor emission changes. RSMs are developed by statistically modeling the results of multiple CTM simulations with a set of explanatory variables based on the emission inputs for each simulation compared to a baseline simulation. After fitting, RSMs can provide predictions of the air quality response to emission changes in near real-time. RSMs have been developed to provide the air quality response to emission changes rather than changes in other variables  because pollutant emissions are the key modifiable factors in air quality management applications.A challenge in using CTMs to explore hypothetical policy options is computational expense. The runtime for CTM simulations (days to weeks) typically prevents direct modeling of the dozens to hundreds of possible emission scenarios that may be of interest to policymakers –17. As a2.5 and ozone to emission changes [http://www.abacas-dss.com, accessed on 11 August 2021) project, and applications of recent RSMs have been limited to regions in Asia. The performance and applicability of recent RSM methods for the U.S. and other regions needs to be established for these approaches to gain broader use.Early-generation RSMs required large numbers of CTM simulations to produce a statistical fit to capture the complex pollutant responses simulated by CTMs ,23,28,29 changes . Recentl changes  has been changes . Much of2.5, nitrate, sulfate, and organic matter (OM) concentrations to emission changes of NOx, SO2, NH3, and traditional volatile organic compounds (VOCs). The pf-RSM also simulates the response of PM2.5 concentrations to primary PM2.5 emissions and is available for download.In this study, we fit a one-region pf-RSM  to CTM s2.2.1.https://zenodo.org/record/3585898#.YRXGeEARWUk, accessed on 11 August 2021) model on a domain covering the eastern U.S. with 12 km grid spacing and 35 vertical layers. January and July were selected to be representative of winter and summer conditions, respectively. Gas-phase chemistry was parameterized according to the Carbon Bond 2006 mechanism (CB6r3) [CTM simulations were performed for January and July 2016 with version 5.3.1 of the Community Multiscale Air Quality  , the dep (CB6r3) ,33. Chem (CB6r3) . The sta (CB6r3)  were not (CB6r3) , and emi (CB6r3)  were sim (CB6r3) .2.5, PM2.5 components, and MDA8 ozone  module [In addition to the base-case simulation, 22 simulations were conducted for model fitting with domain-wide changes in U.S. anthropogenic emissions of NOM2.5 see . For 19 ) module . Version2.5, PM2.5 components, and MDA8 ozone to changes in NOx, SO2, VOC, NH3, and primary PM2.5 emissions across the domain. The following optimized polynomial functions developed in the previous work [2.5,spc refers to the change from the base case in the concentration of PM2.5, PM2.5 nitrate, PM2.5 sulfate, or PM2.5 organic matter; ΔE refers to the ratio of the difference in emissions between the base and emission perturbation cases to the base emissions /EBase); and X1–12 and Y1–7 are the polynomial coefficients determined by least-squares error fitting.Polynomial functions were fit in each grid cell to provide the nonlinear response of monthly average PMous work ,45 were x, SO2, NH3, and VOC emissions.The pf-RSM was evaluated by comparison with 30 OOS CMAQ simulations that were not used in model fitting . The OOS2.5 and its components in the eastern U.S. in winter and summer. The RSM-VAT software is available with cases preloaded for exploration of additional scenarios.The strength of the RSM is the ability to conduct interactive exploratory analyses on air quality impacts for an unconstrainted number of emission cases using the RSM-VAT software. Below, we focus on comparisons of pf-RSM and CMAQ OOS predictions to demonstrate the performance of the pf-RSM. We also use the OOS simulations to illustrate features of the nonlinear response of ozone and PM3.2.5 and MDA8 ozone to reductions in U.S. anthropogenic emissions. Average monitored concentrations of PM2.5, PM2.5 components, and MDA8 ozone in the region are provided in Predictions of the pf-RSM are compared with CMAQ results for the 30 OOS runs in this section. The comparisons illustrate the performance of the pf-RSM as well as the nonlinear response of PM3.1.x emission reductions . These overestimates are associated with cases of SOmissions . For pf-missions . These rmissions .x emission reduction case   . This be3, NOx, SO2, and VOC emissions. The response patterns for the pf-RSM and CMAQ are in good agreement in all cases. NOx emission reductions in January lead to increases in MDA8 ozone over much of the domain  and over Florida, likely due to the lower NOx emissions and inflow of marine air. For VOC, the 60% emission reductions reduce MDA8 ozone concentrations broadly over the eastern U.S. (CMAQ mean reduction: 1.1 ppb).In e domain , especian winter ,46,47. B3 and NOx emissions reduce nitrate concentrations in the northern part of the domain and demonstrate the sensitivity of nitrate to both precursors there (3 emission reductions in areas of elevated NH3 concentration [3) and thereby reducing the fraction of total nitrate in the particle phase [x emission reductions reduce nitrate through direct removal of the nitrate precursor, which outweighs the effect of increased NOx-to-nitrate conversion efficiency from increased ozone/oxidant concentrations. For reducing nitrate in January, NH3 emission reductions (mean nitrate reduction: 0.62 μg m−3) are more effective than NOx emission reductions (mean nitrate reduction: 0.46 μg m−3). SO2 and VOC emission reductions have relatively small influence on nitrate, with some nitrate disbenefits for SO2 reductions in the northern part of the domain .The 60% reductions in NHrs there . NH3 emintration  can redule phase ,49,50. N3 emissions lead to small decreases in sulfate concentrations in the northern part of the domain  to S(VI) conversion . Shah eathways,  reportedx emission reductions reduce OM concentrations throughout the southeast but increase concentrations slightly in the northeast. In winter, both monoterpene [x emissions lower the concentrations of monoterpene nitrate precursors in the southeast [x emission reductions are consistent with more efficient conversion of SOA precursors to OM due to increased oxidant  concentrations. In addition, reducing NOx shifts aromatic oxidation to higher-yield SOA pathways [The response of OM concentrations to 60% emission reductions is shown in oterpene  and aromoterpene  oxidatiooutheast  and reduoutheast . In the pathways .x emissions increase MDA8 ozone by 9% (about 2.5 ppb) in NY and Chicago and a smaller amount in Atlanta  and Houston . NOx emission reductions reduce nitrate by 29% (0.6 μg m−3) in NY, 39% in Chicago (1.2 μg m−3), 52% in Atlanta (0.6 μg m−3), and 47% in Houston (0.3 μg m−3). Decreases in NH3 emissions also reduce nitrate in the CBSAs: 51% (1.1 μg m−3) in NY, 46% in Chicago (1.4 μg m−3), 57% in Atlanta (0.6 μg m−3), and 44% in Houston (0.3 μg m−3). SO2 emission reductions reduce sulfate concentrations by 0.11 to 0.18 μg m−3 but increase nitrate concentrations by 0.02 to 0.1 μg m−3 in the CMAQ simulations. In contrast to the slight nitrate disbenefits predicted by CMAQ, the pf-RSM predicted small nitrate reductions in Atlanta and Houston for the SO2 emission reductions. NH3 emission reductions produce the greatest reductions in PM2.5 concentrations in January in all CBSAs except Houston.In x emission reductions transition to benefits for larger reductions. For instance, MDA8 ozone increased over the CBSAs by 0.7 ppb for the 40% NOx emission reduction but decreased by 2.8 ppb for the 100% NOx reduction in the CMAQ simulations.Comparisons of mean absolute concentrations predicted by the pf-RSM and CMAQ over all CBSAs in the domain for 0% to 100% emission reductions in January 2016 are provided in x emissions ; −1.61 μg m−3 ; and −0.19 μg m−3 . The PM2.5 concentration reductions associated with 100% NOx emission reductions overcome a 0.07 μg m−3 sulfate disbenefit, and the PM2.5 concentration reductions for 100% SO2 emission reductions overcome a 0.15 μg m−3 nitrate disbenefit (about 50% of the sulfate reduction in that case).The trend of increasing sulfate with decreasing NOmissions  is consi fitting , althoug3.2.x emission reductions with large (>30 ppb) MDA8 ozone decreases  throughout the eastern U.S.  and subsequent in-particle reaction involving nucleophile addition to the parent hydrocarbon. This SOA formation pathway is enhanced under conditions of greater acidity and increased nucleophile (water and sulfate) concentration  . The 60to 0.84) , which cmissions  and aeromissions .x emissions decrease OM concentrations in the southern U.S. where biogenic SOA is relatively high  due to the low nitrate concentrations in summer. In response to 60% NOx emission reductions, MDA8 ozone concentrations decreased from 16% (5 ppb in Houston) to 28% (12 ppb in Atlanta) in the CMAQ simulations. NOx emission reductions also caused decreases in OM concentrations in the CBSAs, with the greatest reduction in Atlanta , where biogenic SOA is prominent. NOx emission reductions caused large percent reductions in nitrate concentrations (up to 36% in Chicago), but the absolute concentration changes are small . NH3 emission reductions lead to decreases in nitrate concentrations and increases in OM concentrations in July. The OM increases are greater than the nitrate decreases in absolute terms . Anthropogenic VOC reductions have a small effect on concentrations in July due to the high levels of biogenic VOC, although this study did not consider intermediate and semi-volatile VOC beyond what is included in the NEI.Good agreement exists between pf-RSM and CMAQ predictions of the percent change in concentrations over the four CBSAs in 2 emission reductions reduce sulfate (up to 0.42 μg m−3) and OM (up to 0.16 μg m−3) concentrations but increase nitrate concentrations (up to 0.13 μg m−3). In contrast to January, NOx emission reductions reduce MDA8 ozone and sulfate concentrations for all NOx emission reduction levels due to the greater oxidant abundance in July. NOx emission reductions also decrease OM concentrations (up to 0.93 μg m−3). NH3 emission reductions lead to increases in OM concentrations (up to 0.51 μg m−3), with increases growing nonlinearly with a decreasing emission level. As discussed above, the fact that OM concentration increases with decreasing NH3 emissions could be related to biogenic SOA formation associated with IEPOX uptake. Additional investigation of this SOA formation pathway under low NH3 and SO2 (and water content) conditions would be worthwhile. Riva et al. [2 and NH3 emissions.Comparisons of mean absolute concentrations predicted by the pf-RSM and CMAQ over all CBSAs in the domain for 0% to 100% emission reductions in July 2016 are shown in a et al.  reported2.5 concentrations for 100% reductions in anthropogenic emissions are −1.09 μg m−3 (−15.4%) (NOx emissions); −0.54 μg m−3 (−7.67%) (SO2 emissions); −0.072 μg m−3 (−1.02%) (VOC emissions); and +0.30 μg m−3 (+4.3%) (NH3 emissions). The PM2.5 concentration decreases associated with 100% NOx emission reductions include a small decrease in sulfate concentration of 0.09 μg m−3 (in contrast to January when sulfate concentrations increased with NOx emission reductions). The PM2.5 concentration decreases for 100% SO2 emission reductions overcome a 0.13 μg m−3 increase in nitrate concentration . The predicted change in MDA8 ozone concentration for 100% reduction in NOx emissions is −15.0 ppb (38%), and for 100% reduction in VOC emissions, it is 0.25 ppb.Predicted changes in PM4.2.5 and ozone concentrations is important to protect human health and the environment. CTMs are valuable tools for exploring policy options for improving air quality, but CTMs are computationally expensive and statistical models are therefore developed to approximate CTMs in some applications. Recent developments in RSM technology have reduced the number of CTM simulations needed for model fitting and provide an opportunity to evaluate RSM performance in the U.S.Reducing PMPredictions of the pf-RSM developed here are in good agreement with OOS CMAQ simulations in the eastern U.S., with some exceptions for cases with anthropogenic emission reductions approaching 100%. These extreme conditions may have limited relevance in typical applications. Furthermore, previous work  suggestsx emission reductions were more effective for reducing PM2.5 concentrations than SO2, NH3, and traditional VOC emission reductions. In January, NOx emission reductions decreased nitrate concentrations in the north and OM concentrations in the south. NOx emission reductions did cause some disbenefits for sulfate concentrations in January, but the decreases in other PM2.5 components overcame the disbenefits. In July, NOx emission reductions led to substantial decreases in OM concentrations by reducing biogenic SOA formation in the south. NH3 emission reductions were effective for reducing nitrate concentrations in January but increased OM concentrations in July. As a result, the effectiveness of NH3 emission reductions for reducing PM2.5 concentrations was less than for NOx emission reductions overall. More work should be done to understand IEPOX SOA formation under conditions of low NH3 emissions to verify the OM responses predicted here. VOC emission reductions had a smaller effect on PM2.5 concentrations than NOx and NH3 in part due to high levels of biogenic VOC in the eastern U.S. Moreover, our study did not include emissions of intermediate and semi-volatile VOC [NOtile VOC  beyond wx emissions are needed to avoid disbenefits in northern and urban areas in January. In July, all levels of NOx emission reductions are effective for reducing MDA8 ozone due to the abundance of oxidants in summer. VOC emission reductions caused small decreases in MDA8 ozone concentrations in January and had little effect in July due to the high levels of biogenic VOC.For MDA8 ozone concentrations, large reductions (>80%) in NO2.5 emissions on PM2.5 concentrations. However, PM2.5 concentrations are generally more responsive to reductions in primary PM2.5 emissions than the precursors for secondary PM2.5 discussed here. Some components of primary PM2.5 emissions  can also influence concentrations of secondary PM2.5 [x and SO2 emissions in the eastern U.S. in recent decades have reduced the concentrations of secondary inorganic aerosol and increased the importance of primary PM2.5 emissions and organic aerosol. Improved representations of the emissions and chemistry of organic aerosol are increasingly important in this context.Since our study focused on the nonlinear response of pollutant concentrations, we did not discuss the influence of primary PMry PM2.5 ,61. LargSupplement1


After six months, mean IOP was 10.2 ± 4.3 mmHg (p = 0.005), and after one year ± 4.7 mmHg (p = 0.0117). To obtain the target pressure, the sutures had to be removed in one patient, and medical therapy was undertaken in three patients. Mean decimal best-corrected visual acuity (BCVA) before the sutures was 0.18 ± 0.13 and increased to 0.53 ± 0.25 (p = 0.0004) after one month, to 0.46 ± 0.31 (p = 0.005) after six months, and to 0.31 ± 0.22 (p = 0.025) after one year. In one case, leakage from the bleb was observed after the procedure and bleb revision was required. CONCLUSIONS: transconjuctival compressive sutures seem to be an efficient and safe technique for managing hypotony maculopathy after glaucoma surgery.PURPOSE: The aim of the study was to assess the efficacy and safety of compressive sutures in patients with hypotony maculopathy after glaucoma surgery. METHODS: This retrospective case series analyzes the clinical outcomes of conjunctival compressive sutures in 17 patients with hypotony maculopathy developed after glaucoma surgery. Compressive Nylon 10–0 single sutures were used in all patients; in two patients, the procedure was repeated. All patients underwent ophthalmic evaluation and macular OCT scanning before the surgery, one month, six months, and one year after the procedure. RESULTS: Mean intraocular pressure (IOP) before suturing was 2.3 ± 1.57 mmHg and increased to 14.2 ± 7.03 mmHg ( Glaucoma, one of the leading causes of irreversible blindness worldwide , is a prAfter trabeculectomy, a standard surgical glaucoma procedure, aqueous humor flows into the surgically created filtering bleb . The finClinical hypotony is defined as a level of IOP that is too low to maintain the shape of the eyeball and results in structural and functional changes ,9. If leThe clinical characteristics of hypotony maculopathy were first described by Dellaporta in 1954 as “creasing of retina in hypotonia” , but theTreatment options for hypotony after glaucoma surgery mainly caused by overfiltrating blebs include conservative management of topical autologous serum , bleb inTransconjunctival compressive sutures were introduced to the management of post-surgical hypotony as a simple and effective technique . The aimThe studied group consisted of 17 Caucasian patients with hypotony maculopathy after glaucoma surgery treated in the Department of Diagnostics and Microsurgery of Glaucoma, Medical University of Lublin, Poland, between 2015 and 2017. During this period, every patient who met inclusion criteria participated in the study.Age at glaucoma diagnosis of over 18 years;At least 6 months after the antiglaucoma procedure;Clinically significant hypotony: intraocular pressure (IOP) lower than 6 mmHg, associated with the BCVA decreased by at least 2 lines on Snellen charts in comparison to pre-trabeculectomy results;Features of hypotony maculopathy with macular folds;No progression of the cataract;No leakage from the bleb;No kissing choroidal effusion.The inclusion criteria was as follows:Clinical and demographic characteristics of the studied group are presented in The information about patients’ medical history was obtained from their clinical records. At the inclusion visit, patients underwent ophthalmic examination with BCVA , Goldman applanation tonometry, slit lamp examination, eye fundus assessment by ophthalmoscopy, and OCT  measurements assessing the thickness of the macula and the presence of choroidal folds.During the surgical procedure, 5–7 single Nylon 10–0 sutures were placed transconjunctivally in the area of the bleb as described earlier . In brieIn the post-surgical period, only fixed combination of dexamethasone/tobramycine was used in decreasing doses . Some patients needed to have installed the preservatives free lubricant drops.The patients were controlled one day after the procedure, as well as 7 days, 1 month, 3 months, 6 months, and 12 months after the procedure. During the check-ups, ophthalmic examination was performed including BCVA testing , Goldman applanation tonometry, slit lamp examination, eye fundus assessment by ophthalmoscopy, and OCT measurements assessing the thickness of the macula and the presence of choroidal folds. All patients were present at all time-point visits. However, in 2 cases at 6 months, OCT was not performed because of technical problems. Additionally, the study eye was examined at every visit to look for possible complications.IOP over 6 mmHg;BCVA improvement of at least 2 lines on a Snellen chart.Two criteria of success were defined:p-value lower than 0.05 was considered statistically significant. Normal distribution was assessed with the Shapiro–Wilk test. The Mann–Whitney test was used for non-normally distributed data.Changes in the assessed values (BCVA and IOP) were measured at each control visit planned in the study by subtracting the preoperative value from the postoperative value. Statistic evaluation of the data was performed using Statistica 13.1 . The results were reported mainly as mean ± SD or percentage values. A p = 0.00065) at 1 month post-op. After 6 months, mean IOP was 10.2 ± 4.3 mmHg (p = 0.005); and after one year ± 4.7 mmHg (p = 0.0117) (Mean IOP before suturing was 2.3 ± 1.57 mmHg and increased to 14.2 ± 7.03 mmHg ( 0.0117) . On day Success criterion 1 (IOP over 6 mmHg) at 7 days post-procedure was achieved in 15 (88%) patients, after 3 months in 10 (59%) patients, and after 6 months in 9 (53%) patients (and remained stable during the first and second year of follow-up).p = 0.0004) after 1 month; to 0.46 ± 0.31 (p = 0.005) after 6 months; and to 0.31 ± 0.22 (p = 0.025) after one year (Mean BCVA before applying the sutures was 0.18 ± 0.13 and increased to 0.53 ± 0.25 (one year .Success Criterion 2 (BCVA improvement of at least 2 lines) was fulfilled in the whole studied group at 3 months post-procedure, in 14 patients (82%) at 6 months, in 12 (71%) at 1 year, and in 11 (65%) at 2 years.p = 0.0314), and to 279.77 μm at 1 year (p = 0.0322)  . Macularp = 0.1050; R = −0.61). Interestingly, we could not find any significant correlations between the change in macular thickness in OCT and the change in BCVA .No significant correlations were found between the change in IOP and the change in mean subfoveal macular thickness in OCT, except for the tendency to a negative correlation between these results obtained at 6 months . Assessing the influence of the time since the primary procedure on the final BCVA, we observed negative tendencies at 3 and 6 months  and a significant negative correlation at 1 year .The mean time between the primary surgery and compression suturing was 3.08 years. The time between the primary surgery and suturing did not correlate with postoperative IOP . The initial IOP did not differ the groups . However, the IOP seemed to be higher in early group with statistical tendency at 1 year  and statistical significance at 2 years .When our group was divided into 2 subgroups: with time from the primary surgery shorter than one year (early group: 8 patients) and longer than a year (late group: 9 patients), no differences in BCVA were found . Tight suturing with the attachment to the superficial parts of the sclera in case of extensively hyperfiltarating and elevated blebs may also be problematic. Additionally, it is possible that after MMC application during primary procedure the scleral tissues are weakened and melted which makes transconjunctival suturing not enough for limitation of the outflow. In such cases, the revision with opening of conjunctiva and direct suturing of the sclera may be beneficial. Finally, after antiglaucoma procedure prolonged ciliary body hypoperfusion and hyposecretion is possible.Clinical assessment had led us to the assumption that a shorter time since the primary procedure may enable obtaining a more prominent increase in the IOP level, which was not confirmed by our results: in this study, at no time-point was IOP correlated with the time since the primary surgery, which was also observed by other authors . HoweverIn general, the highest IOP during the follow-up period was measured on postoperative Day 7. Furthermore, this spike in IOP seemed to be beneficial for expediting the resolution of any preexisting serous choroidal detachments  and causExcept for the observed IOP spikes, transconjunctival sutures seem to be a safe procedure. In the course of the study, we observed only one patient with avascular thin bleb who suffered from bleb leakage and needed bleb revision, which involved covering it with the mobilized conjunctiva.To sum up, transconjunctival sutures seem to be an effective and safe method to treat hypotony maculopathy after glaucoma surgery. In the study, the improvement in BCVA started with the elevation of IOP at the early postoperative period and remained stable during the observation time. Our results also provide an argument for an earlier intervention in case of clinical hypotony after glaucoma surgery.


Persistent infection with high-risk (HR) papillomavirus (HPV) genotypes plays a central role in the pathogenesis of invasive cervical cancer.This study aimed to determine the prevalence and distribution of HR-HPV among women with or without cervical lesions at VIA/VILI in Togo.Cervical samples were collected from 238 women with or without cervical lesions at VIA / VILI and[c3] DNA [c4]was extracted and analyzed by real-time multiplex PCR. Logistic regression analysis was used to determined risk factors associated with HPV infection.inPietro Annigoni Biomolecular Research Center (CERBA / LABIOGENE) in Burkina Faso.The age of the women ranged from 17 to 61 years old, and most were married (73.5%). The prevalence of HRHPV was 35.71% and this was higher in the age range 35–39 years. The six most common genotypes were HPV 31 (18.7%), HPV 52 (13.82%), HPV 68 (13.01%), HPV 66 (9.76%), HPV 58 (8.13%) and HPV 56 (8.13%). Genotypes HPV 18 (4.07%) and HPV 16 (0.81%) were less frequent.[c5] Married or living with a partner was associated with HPV infection .This study allowed characterizing for the first time in Togo, HR-HPV genotypes. This will help mapping-HR-HPV genotypes circulating in West Africa. Humanpapillomavirus infection is a necessary (but not sufficient) risk foctor [c6]of cervical cancerThis population based cross-sectional study was conducted in women with or wthout cervical lesions aged between 17 and 61 years from Kara in north Togo. All women gave their written informed consent before participating in the study. For minors (under 18 years old), the consent of a parent or tutor was required in additional to their own informed consent. From December 27, 2016 to January 06, 2017, we recruited238 women by random sampling after mass sensitization and those coming for gynecology consultation at the gynecology department of the «Hippocrates cabinet». The virgin or pregnant women or during menstrual period or having undergone total hysterectomy were not included in thisstudy. Midwifes administered a questionnaire to each woman in order to get information on their socio-demographiccharacteristics and sexual behavior. Endocervical samples were collected by gynecologist by swabbing. Samples was introduced into a transport medium (Transport medium from the Sacace kit) and stored at −20°C. At the end of collection, the frozen samples were introduced into coolers fitted with ice and carried to Pietro Annigoni Biomolecular Research Center (CERBA / LABIOGENE) in Burkina Faso.sequentially or concurrently by visual inspection after acetic acid and Lugol applications (VIA/VILI).DNA extraction was carried out using SACACE biotechnologies ® DNA-Sorb-A kit . The main steps of extraction are: lysis of cells membranes, fixation of DNA on columns, washing and elution.Lyse step: Add 300µl of lysis solution to 100µl of sample. Mix by vortexing, incubate at 65°C for 5min and centrifuge at 12000g for 10min. Transfer the supernatant into eppendorf tube.DNA fixation step: Add 20µl of Sorbent, incubated for 3 min at room temperature (repeat the step). Centrifugate for 30 sec at 5000 g. Remove the supernatant with micropipette into another tubeWashing step: Add 500µl of washing solution. Vortex and centrifuge at 10000g for 30sec. Discard the supernatant (repeat this step). Dry the pellet for 5–10 min at 65°CElution step: Add 100µl of DNA-eluent. Incubate for 5 min at 65°C and vortex and centrifuge. Stored the supernatant at - 20°C for DNA amplificationThe genotyping was performed by real-time multiplex PCR, using the SACACE biotechnologies® HPV Genotypes 14 Real-TM Quant V67-100 FRT kit, according to the manufacturer's instruction. For amplification, prepare 4 tubes for each clinical sample, 4 tubes for standards K1, 4 tubes for standards K2, 4 tubes for Negative control. The final reaction volume was 25µl containing: 10µl of specific primers , 5µl of mix-PCR-Buffer-FRT and DNA-polymerase, 10 µl of extracted DNA sample. For control and standards add, 10 µl of Negative control into control tube, 10 µl of each K1 et 10 µl of each K2 into standards tubes.[c14]The data was processed and analyzed using Excel database, SPSS 21 and Graph Pad 6. The Chi-square test and the exact Fisher test were used to compare the proportions and univariate regression analysis were used to study the risk factor associated with HPV infection. [c15][D16]The p-value threshold for the Chisquare test and the exact Fisher test was 0.05 and 0.2 for the univariate regression analysis.Of a total of 238 women included in our study, 13 (5.46%) came for gynecological consultation purpose and 225 (94.54%) came only for cervical cancer screening after mass sensibilization. For those who came for gynecological consultation purpose, the main motifs of their consultation: was dysmenorrhea (1.7%); desire for a child (0.42%); leucorrhoea (0.8%); pruritus (0.42%); dysuria (0.42%); pelvic ultrasound (0.42%); vaginal infection (1.3%).As recorded in the As it is shown in 233 women out of 238 were screened at VIA/VILI. The raisons why the test was not performed in five other women was bleeding and discomfort. The prevalence of cervical lesions diagnosed by VIA and VILI were 0.86%.β-globin gene. The estimated HR-HPV prevalence among 238 women was 35.71% (85/238). As shown in In our study, all samples tested were positive for The results in Univariate logistic regression revealed that married or women living with a partner were more exposed to HPV infection than women living alone .VIA/VILI and smoking did not allow analysis of associations with HR-HPV infection. Eight women did not give information about number of sexual partners and condom use.This study which allow to identify HR-HPV among women in Kara region, is for our knowledge one of the first study in Togo. Even though our sample size is not sufficient to generalize the conclusions for all of the population of Togo, these results remain valid for study populations. The average age of the women in our study was 34.67 ± 9.44 years. The average age of women at first sexual intercourse was 18.50 ± 2.86 years. These results are similar to those of Traoré et al. who found 35.3 ± 8.1 years for the average age and 18.57 ± 2.2 years for mean age at first intercourse, in Bobo-DioulassoThe prevalence of cervical lesions diagnosed with VIA / VILI was 0.86%. This prevalence is lower than that found in Bobo-Dioulasso (5.0%) by Traore et al.The prevalence of HR-HPV infection among women in this study was high (35.71%) compared to the adjusted global HPV prevalence in western Africa region (17%) as reported by de Sanjose et al. The six most common genotypes found in this study was, HPV 31 (18.7%), HPV 52 (13.82%), HPV 68 (13.01%), HPV 66 (9.76%), HPV 56 (8.13%) and HPV 58 (8.13%). Similar genotypes have been reported by many other authors, such as HPV39 and 52 in Bobo DioulassoAccording to age, the prevalence of HR-HPV infection showed two picks; the first 22.4%) between 25–29 years old and the second (21.2%) between 40–44 years old . Sanjose% betweenOur study also reveals that the 7 HR-HPV genotypes included in the Gardasil-9 vaccine represent 55% whilethose included in Gardasil-4 and Cervarix represent only 5%.All these results suggest that both Gardasil-4 and Cervarix vaccines confer limited protection against HR-HPV infection in our population. However, the Gardasil-9 could be suitable for our population.Several Many risk factors are reported to be associated to HR-HPV infection such as: age; marital status; condom use, age at first intercourse, number of sexual partners, parity, oral contraception; cervical cancer screening participationThis study identified fourteen genotypes among women in Kara. The high prevalence of HPV infection shows that women are exposed continuously to high risk of transmission. The most common genotypes found in our study does not have vaccines available. The HPV16 and 18 genotypes that have vaccines are rare. These results provide new directions on the strategy to adopt to fight against cervical cancer in this population and also direct the choice of the suitable vaccine for our populations. Although the study has shown that the most common genotypes are other than genotypes 16 and 18, the role that play these genotypes in the development of cervical neoplasia and cancer remains unknown.


We conducted a second nationwide severe acute respiratory syndrome coronavirus 2 seroprevalence study in the Faroe Islands during November 2020. We found crude seroprevalence was 0.3% and prevalence was 0.4% after adjusting for test sensitivity and specificity. This low seroprevalence supports the prevention strategies used in the Faroe Islands. Early in the coronavirus disease (COVID-19) pandemic, the World Health Organization recommended close surveillance and abundant testing at the regional level . After excluding 2 newborns, we invited 1,498 persons by letter to provide blood samples at 1 of 6 study sites around the islands during November 21–30, 2020. We offered home visits to those unable to attend. Nonresponders received a follow-up phone call. All participants provided oral and written informed consent. The study was approved by the Faroese Ethical Committee and Data Protection Agency and is methodologically aligned with the World Health Organization generic protocol for population-based seroepidemiologic COVID-19 studies , which has a sensitivity of 94.4% (95% CI 90.9%–96.8%) and specificity of 100% (95% CI 98.8%–100.0%). We estimated 95% CI for crude seroprevalence by using exact binomial models and used bootstrap methods to adjust seroprevalence for test performance  persons participated in the serosurvey ; mean ag+23.4) years of age for nonparticipants versus 48.1 (SD +20.5) years of age for participants (p<0.0001). Persons 0–29 years of age were underrepresented and persons 50–79 years of age overrepresented. The study sample was geographically representative of the population but had minor differences in sex and age distribution. More men and younger persons comprised nonparticipants than participants: 41.3 . After adjusting for test sensitivity and specificity, we estimated a seroprevalence of 0.4% (bootstrap 95% CI 0.1%–1.0%). Including cases previously confirmed by RT-PCR, seroprevalence in the sample was 1.5%.We found only a few undetected cases, underpinning the effectiveness of the prevention strategies in the Faroe Islands. Among the 3 seropositive cases, 1 was a child who had experienced symptoms at the beginning of the epidemic. Subsequent serologic analyses revealed that both parents and the child’s siblings were seropositive. The other 2 seropositive cases were in adults who did not recall any symptoms.>500 participants noted infection rates ranging from 0.02% to 53.4% by September 9, 2020, but reported large variations in sampling, clustering, and adjustment for test performance . Nonetheless, our results show that prevention strategies effectively managed the COVID-19 epidemic in the Faroe Islands and that the country effectively reacted to timely information of the contagion.In May 2020, we estimated 0.6% seroprevalence in the Faroe Islands (


Background and Objectives: The main reason for Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) is to prevent adrenal insufficiency that can lead to life-threatening conditions. On the other hand, screening programs are not always sensitive and effective enough to detect the disease. We aimed to evaluate impact of the national NBS on the clinical presentation of patients with CAH in Lithuania. Materials and Methods: A retrospective study was performed on data of 88 patients with CAH from 1989 to 2020. Patients with confirmed CAH were divided into two groups: (1) 75 patients diagnosed before NBS: 52 cases with salt-wasting (SW), 21 with simple virilising (SV) and two with non-classical (NC) form; (2) 13 patients diagnosed with NBS: 12 cases with SW and 1 case with SV form. For the evaluation of NBS effectiveness, data of only male infants with salt-wasting CAH were analysed . Data on gestational age, birth weight, weight, symptoms, and laboratory tests (serum potassium and sodium levels) on the day of diagnosis, were analysed. Results: A total of 158,486 neonates were screened for CAH from 2015 to 2020 in Lithuania and CAH was confirmed in 13 patients , no false negative cases were found. The sensitivity and specificity of NBS program for classical CAH forms were 100%; however, positive predictive value was only 4%. There were no significant differences between unscreened and screened male infant groups in terms of age at diagnosis, serum potassium, and serum sodium levels. Significant differences were found in weight at diagnosis between the groups . Conclusions: The sensitivity and specificity of NBS for CAH program were 100%, but positive predictive value—only 4%. Weight loss was significantly lower and the weight SDS at diagnosis was significantly higher in the group of screened patients. CYP21A2 gene that encodes the enzyme 21-hydroxylase (21OH) [CYP21A2 mutations and range from mild to a life-threatening condition—adrenal insufficiency. As a result of impaired reverse negative feedback of cortisol to the pituitary gland, the secretion of adrenocorticotropic hormone (ACTH) is increased which stimulates testosterone hypersecretion, causing virilized genitalia in female newborns [Congenital adrenal hyperplasia (CAH) is one of the life-threatening disorders in neonates. The term CAH refers to a group of autosomal recessive disorders that result from impaired steroidogenesis in the adrenal cortex. The estimated prevalence of CAH is 1:10,000 and annual incidence ranges from 1: 5000 to 1: 20,000 [e (21OH) ,4. Due tnewborns . The difnewborns . In ordenewborns .Since 2015, a national Newborn screening (NBS) program for CAH has been introduced in Lithuania. The aim of our study was to summarize the results of the past six years of NBS for CAH in Lithuania. Specifically, we wished to evaluate the efficiency of CAH screening and the prevalence/incidence of CAH in Lithuania.Newborn screening (NBS) program for phenylketonuria, congenital hypothyroidism, congenital adrenal hyperplasia, and galactosemia in Lithuania is performed nationwide. NBS is managed by the Ministry of Health of Lithuania and funded by the National Health Insurance Fund under the Ministry of Health.NBS tests are conducted by the single NBS laboratory at the Vilnius University Hospital Santaros Klinikos.NBS for CAH in Lithuania started in 2015. Since then, more than 158,000 newborns have been screened in NBS laboratory, managing approximately 26,000 samples per year. Coverage of the NBS is 99.3–99.7% of newborns, despite the fact that NBS is not mandatory in Lithuania.The dried blood spot (DBS) samples were collected from the infants on Whatman 903 filter paper on the 3–5th day of life at the time of the routine hospital newborn screening heel prick. DBS was requested to be delivered to the NBS laboratory within 72 h of collection by courier or regular post.The level of 17-hydroxyprogesterone (17OHP) in the DBS was measured by fluorometric enzyme immunoassay . As false-positive results are common with premature infants, a fixed cut-off level, based on gestational age (GA), was used to identify newborns at risk for CAH . When elA case is considered true positive when laboratory tests are evaluated together with the clinical assessment of the child and data are consistent with the CAH diagnosis. Criteria of a positive screening test as true were elevated serum 17OHP >30 nmol/L  measured by radioimmunoassay (RIA) method. Hyperkalemia is defined as >6.9 mmol/L, hyponatraemia <136 mmol/L according to the reference range for neonatal age.CYP21A2 gene and CYP21A1P pseudogene copy number analysis was performed using quantitative multiplex ligation-dependent probe amplification (MLPA) with SALSA® MLPA® probemix P050-C1 CAH ; reference sample—SD039-S02 Reference DNA (MRC-Holland). Detection of sequence changes of CYP21A2 gene was performed using Sanger sequencing after selective long-range PCR with primers specific for CYP21A2 and/or CYP21A1P [All diagnosed patients and cases with uncertain diagnoses were genotyped for confirmation of the diagnosis. CYP21A1P .Data were collected retrospectively on 88 newborns diagnosed with CAH and followed up at the Lithuanian University of Health Sciences Kaunas Clinics Endocrinology department from 1989 to 2020.Data collected for each patient included the birth date, sex, diagnosis , age at diagnosis and weight, symptoms, and laboratory tests  on the day of admission to pediatric endocrinology department.For the evaluation of NBS effectiveness, data of only male infants with SW CAH were analyzed whereas during the prenatal period, testosterone hypersecretion does not result in any visible signs for male infants and adrenal insufficiency occurs at 2 to 3 weeks of age with severe hyperkalemia, hyponatremia, and hypovolemic shock.(1)Before NBS: 75 patients; 52 cases with SW form, 21-with SV, and 2-with NC form.(2)After NBS: 13 patients; 12 cases with SW, and 1 case with SV form .Patients with confirmed CAH were divided into 2 groups:For the evaluation of NBS effectiveness, data of only male infants with SW CAH were analyzed.Statistical data analyses were performed using Statistical Package for Social Sciences . Birth weight was converted to standard deviation score according to gestational age while the weight at the day of diagnosis was converted to standard deviation score according to sex and age at the determination of CAH. Quantitative variables were described as a mean and standard deviation (M ± SD), nominal values were given in frequencies. The Mann—Whitney test was used for non-normal data distribution.p < 0.05.The differences were considered statistically significant when The study was approved by the local and national ethical committees (No. BE-2-29), and all patients and their parents or legal guardians gave their informed consent. The study was carried out in accordance with the 1964 Helsinki declaration and its later amendments.There were 158,987 live births registered in Lithuania between the 1st of January 2015 and 31st of December 2020. Of these, 158,486 (99.7%) were screened for CAH. The overall results of the screening for CAH from 2015 to 2020 are shown in The predictive value of a positive test for classical CAH forms was 0.04. The sensitivity was 1.0 as no false-negative cases were found, and the specificity was 0.998. Calculated incidence of classical CAH—1:12,190.However, we cannot confirm the sensitivity of NBS for non-classical CAH form due to conditionally high cut-off of 17OHP serum concentrations in DBS, because the basal 17OHP concentration for NC CAH can be lower than the NBS cut-off (>6 nmol/L) .In total, 320 infants required further testing: 204 newborns were recalled for a second sample and 116 newborns with abnormal 17-OHP levels on first DBS were referred for urgent medical evaluation, 2 newborns were referred for medical evaluation after 17OHP was repeatedly found elevated in the second sample. CAH was confirmed in 13 newborns. Gender as indicated on DBS cards: 9 males, 1 female, and 2 with ambiguous genitalia . Twelve cases of the patients identified in the screening had the SW form of the disease, and 1 had SV with a mild clitoriomegaly but without any other clinical symptoms.The median gestational age and birth weight of the true-positive CAH cases was 40 weeks (range: 38–41 weeks) and 3525 g (range: 3100–4088 g). On average, the screening DBS samples of confirmed CAH cases were collected on day 3 (median) (range: 2–4) and reached the screening laboratory by mail or courier on day 9 (range 3–19), and the 17OHP result was available on day 13 (range: 7–23 days). On receipt DBS, 17OHP results were available on 2nd or 4th day, as 17OHP assay with overnight incubation was performed twice per week. Three patients were suspected of having CAH on the first day of life: two newborns had ambiguous genitalia and one was the male sibling of a previously confirmed CAH patient. The median day of CAH diagnosis confirmation by pediatric endocrinologist was 15 . The median screening value of 17-OHP in patients with SW CAH was 115 ng/mL (range: 29.19–651 ng/mL).n = 52) and after NBS (screened n = 12) were compared. There were 34 male newborns  and 31 female newborns . The gestational age average of the unscreened cohort was 39.36 ± 1.25 weeks, that of screened cohort—39.75 ± 0.87 weeks, p = 0.329. The birth weight of unscreened patients was 0.11 ± 1.04 SDS and screened patients—0.077 ± 0.62 SDS, p = 0.922.Patients with CAH SW form before NBS (unscreened p = 0.048).Data of demographic and laboratory findings of all infants  with diagnosed SW CAH are presented in p = 0.78. There were significant differences in weight SDS at the diagnosis between unscreened and screened newborns in the whole cohort . In addition, significant differences in weight at diagnosis between male newborn groups were observed .Time (median) from birth to the day of SW CAH diagnosis in the unscreened cohort was 15.7 (0–42) days, screened cohort—13.25 (1–32) days, r = −0.44, p = 0.782. Importantly, unscreened  infants lost 6.2 ± 6.9% of weight from their birth to the day when CAH was confirmed and screened infants with SW CAH gained 6.7 ± 1.3% of weight, p = 0.007 (p = 0.22).There was no significant correlation between weight and age (in days) when CAH was confirmed,  = 0.007 . The difp = 0.79 and 7.7 ± 1.5 mmol/L versus 6.89 ± 1.5 mmol/L, p = 0.33 respectively). Hyperkalemia (>6.9 mmol/L) occurred in 63.6% of patients in the unscreened males’ cohort and in 55.5% of screened males, p = 0.65. No significant correlation was observed between serum potassium levels and days when CAH was confirmed . Serum sodium levels were 124.5 ± 9.7 mmol/L (102–138) in the unscreened males and 126.31 ± 8.99 mmol/L (111–135.8) in screened males, p = 0.64; hyponatremia (<130 mmol/L) was determined in 72% and 55% of unscreened and screened newborn’s males, respectively, p = 0.59.On the day of diagnosis, serum potassium levels in unscreened all cohort and separately in males’ group were higher, although not statistical significantly, than in screened cohort , clinical symptoms at the diagnosis were: vomiting in 21 (67.7%), jaundice in 9 (29%), hypotonia in 11 (35.5%) and hypovolemic shock in two (6.5%) patients. Three patients (9.7%) had hypoglycemia and 22 (70.9%)-hyperkalemia. Clinical signs and symptoms distribution in males’ groups (unscreened and screened) are shown in Over a 6-year period (2015–2020), all screened patients were genotyped as part of the clinical follow-up and 12 patients had SW  form and one female of CAH.CYP21A2 gene. One girl without clinical manifestation of CAH had 17OHP levels above the normal range (39.8 nmol/L) on NBS, and a benign compound heterozygous mutation was identified. In another girl with mild clitoriomegaly  with and basal 17OHP level of 697 nmol/L during NBS and stimulated 17OHP of 580 nmol/L, molecular analysis of CYP21A2 gene revealed a pathological mutation in only one allele.Six patients with blood levels of 17OHP less than 300 nmol/L (30.8–180) during NBS, were re-examined with ACTH (Synacten) stimulation test, and SW CAH form was confirmed for five patients and for one girl was confirmed SV CAH at the 71 days of age. Two cases were twin brothers with 17-OHP levels above 30 nmol/L (46.3 and 32.2 nmol/L) during NBS, but no clinical signs were observed. During ACTH stimulation tests maximal stimulated 17OHP levels were 31.0 and 28.2 nmol/L and genetic analysis confirmed pathogenic mutation (c.293-13C > G) only in one allele of CYP21A2 genes comprised 41% of CAH alleles in our group. Three novel pathogenic variants in CYP21A2 gene were identified.Molecular genetic analysis was available for 52 unrelated individuals in the study group . The divCYP21A2 gene were 30 kb deletion and c.293-13C > G, accounting for 21% and 19% of all pathogenic variants, respectively. Large deletions involving several exons of CYP21A2 gene accounted for as much as 41% of all pathogenic variants of CYP21A2 gene. Two novel pathogenic variants c.329T>A (p.(Leu110Ter) and c.525C > A(p.(Tyr175Ter)) not derived from the pseudogene and both generating a premature termination codon were identified in the compound heterozygous state for a male patient with salt-wasting CAH. Novel frameshift variant c.916del ) was identified in the compound heterozygous state with pathogenic variant c.518T>A (p.(Ile173Asn)) for two brothers both manifesting with SW CAH.The most common pathogenic variants of the n = 12; 92%) as compared to only one case of SV CAH (8%) was detected. The different distribution of SW and SV incidence rates was described in other population-based studies, namely in Japan 73:14 and in New York State 90:8, respectively [CAH belongs to the group of rare diseases and its prevalence in Lithuania is similar to other countries of the world. Annelieke A A van der Linde and co-authors indicated a worldwide prevalence of CAH to be approximately 1:10,000 to 1:20,000 . It was ectively . A relatp = 0.003) [p = 0.077) [The NBS program is performed in many developed countries, however, there are only a few published studies that evaluated the NBS program effectiveness. In a study by Heather et al. in New Zealand, the time of diagnosis of CAH was compared before and after the introduction of NBS (11 ± 3.0 0–26) days versus 8.5 ± 3.2 3–16) days, respectively, 6 days ve days, re= 0.077) , and in = 0.077) . The med= 0.077) , 13 days= 0.077)  and 17 d= 0.077) . In LithAdrenal crisis is a life-threatening medical emergency, and 55% of screened and as much as 72% of unscreened male newborns had hyponatremia <130 mmol/L at the day of diagnosis. Severe adrenal crisis during the neonatal period may cause permanent neurological comorbidities. Studies in Japan before the NBS and in the UK showed that up to 20% of patients with the SW form of 21OHD developed learning difficulties and intellectual disabilities ,22,23. TThe possibility of developing severe salt-wasting is extremely low without weight loss, which in our cohort was significantly greater in the unscreened group of newborns, even if there were no significant differences in sodium levels at the diagnosis in screened and unscreened newborns. Change in weight from birth to the day of diagnosis is an important indicator of the newborn’s health status. Physiological weight loss in neonates is found to be up to 10% of birthweight  and weigThe sensitivity of NBS program for CAH in Lithuania in 2015–2020 was 100% as no false-negative cases were found and the specificity—>99.9%, which were comparable to previously published results from other countries . HoweverCYP21A2 gene mutation in a single allele or benign compound mutation in CYP21A2. Italian study describes three girls with slightly elevated 17OHP levels (18.2–35.3 nmol/L) detected during NBS and transient clitoromegaly were later identified as heterozygous cases . In these cases, spontaneous regression of clitoromegaly was observed during the follow-up through the first six months of life [CYP21A2 mutation presented with premature pubarche and late-onset hyperandrogenemia [Interestingly, we documented elevated basal and stimulated 17OHP concentrations in three carriers of a  of life . In otheels 18.2–.3 nmol/Logenemia ,37.We did not evaluate the cost-efficacy of NBS, and the data from the literature are rather controversial. Earlier studies reported CAH screening would be either unlikely to be cost-effective or cost-effective only if a single test is performed ,38. WhilThe main strength of this study is that we analyzed all cases of CAH after NBS implementation and almost whole unscreened patients’ cohort in Lithuania. On the other hand, the main drawback of this study is the low number of CAH patients confirmed by NBS, which limits the statistical power of data analyses.The introduction of the NBS program for CAH in Lithuania resulted in a more favorable clinical presentation of affected male infants compared to those diagnosed before NBS, despite the non-significant difference in time of diagnosis, which should definitely be shortened by timely DBS shipment from maternity departments to NBS laboratory. The long–term effects of NBS and the consequences of hyponatremia in the neonatal period on neurological development, intellectual functioning, and quality of life should be explored in future studies. Discrepancies in genotype and biochemical and clinical profiles described in our patients confirm earlier published data in CAH patients.


This study investigated patients who underwent more than one operation for a meningioma, a type of brain tumor. Currently, there is little evidence available for this specific patient group. The purpose of this study was to determine if patients had an improvement or deterioration following a second operation for a recurrent meningioma, and to identify any factors that may influence this change. The results demonstrated that following a second operation for meningioma, patients have poorer outcomes. The findings of this study provide supporting information for surgeons and patients, thereby informing decisions related to patient care and re-operation. p = 0.002). An increased number of post-operative complications following the second operation was associated with a poorer performance status following that procedure (odds ratio 2.2 [95% CI 1.1–4.6]). The second operation complication rates were higher than after the first surgery . The median OS was 312.0 months (95% CI 257.8–366.2). The median PFS following the first operation was 35.0 months (95% CI 28.9–41.1). Following the second operation, the median PFS was 68.0 months (95% CI 49.1–86.9). The patients undergoing a second operation for meningioma had higher rates of post-operative complications, which is associated with poorer clinical outcomes. The decisions surrounding second operations must be balanced against the surgical risks and should take patient goals into consideration.The outcomes following re-operation for meningioma are poorly described. The aim of this study was to identify risk factors for a performance status outcome following a second operation for a recurrent meningioma. A retrospective, comparative cohort study was conducted. The primary outcome measure was World Health Organization performance. Secondary outcomes were complications, and overall and progression free survival (OS and PFS respectively). Baseline clinical characteristics, tumor details, and operation details were collected. Multivariable binary logistic regression was used to identify risk factors for performance status outcome following a second operation. Between 1988 and 2018, 712 patients had surgery for intracranial meningiomas, 56 (7.9%) of which underwent a second operation for recurrence. Fifteen patients (26.8%) had worsened performance status after the second operation compared to three (5.4%) after the primary procedure ( Meningiomas account for 38.3% of primary brain tumors ,2. TheirfRT), or stereotactic radiosurgery (SRS) .,18.17,183) [Clinical characteristics were collected and recorded at the time of the primary surgery. Patient sex, age, presenting clinical features, the WHO performance status, and Age-Adjusted Charlson Comorbidity Index (ACCI) were included ,20. The 3) ,25. The 3) ,7,16. AdA comparative cohort of meningioma patients treated with a single operation was generated from the overall database. For the patients that underwent a single operation, the following variables were collected: the Simpson grade of resection, the WHO grade ,7, recurp-value ≤ 0.2 were included in the multivariable model. A multivariable binary logistic regression model was used to identify risk factors, and a p-value ≤ 0.05 was considered statistically significant. The Kaplan Meier analysis was used to assess overall and progression free survival, along with log rank tests where applicable. Chi-Squared tests were used to assess the differences in categorical variables. A statistical analysis was conducted using SPSS version 26 (IBM Corp.). The R version 4.1.0 was used for graphical analysis. The continuous variables were subject to a Kolmogorov-Smirnov test of normality. The normally distributed variables are presented using mean and standard deviation (SD); the skewed variables are presented using median and interquartile range (IQR). Descriptive statistics were used to compare variables between the re-operated and non-re-operated cohorts. A univariate analysis was conducted using binary logistical regression to identify factors associated with worsened performance status following a second operation. The variables with a n = 28). The most common tumor location at diagnosis was convexity , and peri-tumoral signal change was identified in 19 patients (33.9%). Tumor hyperintensity was identified in 20 (35.7%) patients. The mean tumor volume at diagnosis was 38.2 cm3 (SD = 32.6). Multiple meningiomas were identified in eight (14.3%) patients. Between 1988 and 2018, 712 meningioma patients were treated with surgery, 56 (7.8%) of which had a second operation for recurrent meningioma. The mean age at initial diagnosis was 50.1 years , and the mean age at the second operation was 56.1 years . Two patients (3.6%) had a history of previous cranio-spinal radiation and no other risk factors were identified. The most common presenting symptom was a headache . There were 200 (30.5%) Simpson grade 1, 248 (37.8%) Simpson grade 2, and 30 (4.6%) Simpson grade 3 resections in the non-re-operated group. Simpson grades following a first operation for the re-operated cohort are presented in The proportion of Simpson grade 4 resections following a first operation was lower in the 656 non-re-operated patients compared to the re-operated cohort (n = 31). The median residual tumor volume was 1.9 cm3 (IQR = 0.5–4.6). Adjuvant radiation was administered to seven (12.5%) patients . Three patients received 54Gy in 30 fractions, and four received 60Gy in 30 fractions. The surgical details for the first operation in the re-operated cohort are included in On a post-operative MRI, residual tumors were present in 55.4% of cases (n = 40) and 21.4% recurring radiologically and clinically (n = 12). One patient recurred only clinically, having developed worsening symptoms with no changes to the residual tumor on an MRI. For three patients, there was incomplete data due to the historic nature of the cases. Of the 40 patients with tumor recurrence on MRI, 62.5% (n = 25) fulfilled RANO criteria for radiological progression. All patients with symptomatic progression fulfilled the RANO criteria. The more common symptoms at recurrence were optic neuropathy  and headaches . The management of meningioma recurrence after a primary operation included surgery , surgery and fRT , SRS , surgery and SRS , and fRT .The median time to the first recurrence was 35.5 months (IQR = 18.5–71.5), with 71.4% recurring radiologically (n = 18) achieved a Simpson grade 1 or 2 resection. The majority of tumors were grade 1 , while grade 2 and 3 tumors accounted for 44.6% (n = 25) and 5.3% (n = 3), respectively. Following a second operation, 10 patients (17.9%) had a change in the WHO tumor grade; three decreased to a lower WHO grade, while seven increased to a higher grade. The residual tumors were present in 34 cases (60.7%). The median residual volume after a second operation was 0.9 cm3 (IQR = 0.4–4.0). Adjuvant radiation was administered to 23 patients . Two patients had SRS (12.5Gy to the 80% isodose). The remaining 21 patients received adjuvant fRT over 30 fractions; 11 patients were given 54Gy and 10 were given 60Gy. Further details are included in At the second operation, 32.1% . The performance status decreased in more patients following the second operation when compared to the first , time to first recurrence (p = 0.02), and number of post-operative complications (p = 0.01) were included in the multivariable model. The multivariable analysis demonstrated that an increased number of post-operative complications  and increased time to recurrence  were associated with a deterioration in performance status after a second operation  in the re-operated cohort had a complication. A CSF leak was seen in five cases (8.9%) and two patients suffered a post-operative stroke (3.6%). The complication rates following a second operation were higher than those following a first surgery . After a second operation, four patients had a CSF leak (7.1%), while three patients suffered a post-operative hemorrhage (5.4%). The frequency and grade of both Landriel-Ibañez and Clavien-Dindo complications following a first and second operation are presented in Following the first operation, 32.1% of patients (p = 0.006) (n = 21). The median tumor volume at the recurrence was 1.5 cm3 (IQR 1–6.6). The most common presenting symptom at the time of the second recurrence was cranial nerve palsy ; there were three cases of optic neuropathy and one case of oculomotor nerve palsy. The second recurrence meningiomas were treated with surgery , fRT , SRS , and surgery with fRT . After a second recurrence, 12 more patients had a third, four patients had a fourth, three had a fifth, and one patient had a sixth recurrence. Eleven patients had three surgeries and 3 patients had four surgeries , and 68.0 months (95% CI 49.1–86.9) following a second surgery. There was a statistically significant difference between the median PFS of patients when comparing the first and second surgery (= 0.006) . After turgeries .n = 30). The median follow up time was 128.5 months (IQR = 73–194.5). The median OS was 312 months (95 % CI 257.8–366.2)  and 10 patients had died (17.9%). Eight of the deaths were attributed to disease progression. The majority of patients under follow-up were monitored clinically with interval MRI surveillance  .In this study, over a period of 30 years, out of 712 patients treated surgically for intracranial meningioma, only 56 patients underwent second surgery for a recurrence. A significant worsening of performance status after a second surgery was observed compared to the first operation. The complication rates were higher following a second operation. A multivariable analysis identified increased complications and a longer time to a first recurrence as significant factors associated with a poorer performance status outcome. The median overall survival was 312 months, and although a second operation improved the control of the meningioma, 26.8% of patients had a poorer performance status following the procedure. The known factors associated with meningioma recurrence have the greatest influence over the likelihood of requiring a second operation and adjuvant treatment. Meningioma recurrence following a gross total resection is uncommon, and undergoing a second operation for a recurrent tumor is equally rare ,27. The The risk profile associated with undergoing a second operation for intracranial meningioma is not comparable to the first. The complication rates following a second operation for meningioma were reported to range from 30% and 47.7%, depending on anatomical location ,12. AddiThis study is the first to investigate functional performance status outcomes following repeated operations for a recurrent intracranial meningioma. WHO performance status provides a clinical perspective on the functional capabilities of patients, with a degree of correlation to patient quality of life . The patDespite the risks associated with a second operation, there is a quantifiable benefit to pursuing repeated resection. Previous studies have demonstrated that re-operated patients tend to have excellent overall survival rates ,12. The This study had several limitations. Firstly, undergoing a second operation for recurrent meningioma is a low frequency event; this cohort included only 56 out of 712 meningioma patients over a 30-year period. Secondly, there was a high degree of treatment strategy heterogeneity. Thirdly, WHO tumor grade was classified based on the WHO criteria in use at the time of surgery; this may result in an under-reporting of grade 2 meningiomas. Finally, Ki-67 may be an explanatory variable for changes in progression free survival . HoweverThe decision to pursue a second operation for recurrent intracranial meningioma should be made in the context of patient symptoms, extent of the meningioma as shown on an MRI, WHO grade, and patient-oriented care goals. Caution is advised when immediately offering repeat surgical treatment for a patient with radiological recurrence in the absence of any change in neurological symptoms. A period of monitoring should also be considered to assess the tempo of any recurrence. The choice of treatment for recurrence should be discussed within a multi-disciplinary team with an acknowledgement of the potential increased risk in post-operative complications and worsened long term performance status. Additional large-scale, multi-center studies are needed to delineate the outcomes following repeat operation in recurrent meningiomas.