Several studies reported the increased risk of second primary pancreatic ductal adenocarcinoma (2nd PDAC) in cancer survivors. However, data on the characteristics of 2nd PDAC are insufficient.This retrospective cohort study included 1759 patients with PDAC. They were classified as having 2nd PDAC or first primary PDAC (1st PDAC) according to a prior diagnosed cancer of different origin, at least 6 months before PDAC diagnosis.There were 110 patients (6.4%) with 2nd PDAC and 1606 (93.6%) patients with 1st PDAC. Patients with 2nd PDAC presented with older age  and higher rate of resectability  at diagnosis than those with 1st PDAC. Multivariate analysis without considering resectable status showed that 2nd PDAC  was associated with better overall survival. After adjusting for resectable status, however, 2nd PDAC  was no longer associated with overall survival. When subgroups were separately analyzed according to initial treatment modality, the effectiveness of surgery and chemotherapy were similar between 2nd and 1st PDAC .The proportion of resectable cases was significantly higher in 2nd PDAC. When surgery with curative aim was possible, the overall survival was increased even in patients with 2nd PDAC. These results suggest the importance of screening for second primary cancer in cancer survivors. Second primary cancer is a new neoplasm that is biologically independent of a prior cancer. The secoPancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer-related deaths and known to have an extremely poor prognosis, with a 5-year survival rate of <6%. The onlySimilar to patients with other second primary malignancies, there have been patients with PDAC who developed another primary tumor in another organ or with a different histology. To date, there are only a few studies about second primary PDAC (2nd PDAC). A study about 2nd PDAC with pooled analysis of international multicenter cancer registries reported that the prevalence of 2nd PDAC among all patients with PDAC was about 6.3%. There haA retrospective patient cohort from Severance Hospital, Seoul, Korea, was examined. A total of 1759 patients with PDAC, diagnosed as having ductal adenocarcinoma of the pancreas according to histopathological findings between 2006 and 2014, were included in this study. The age of the participants ranged from 44 to 91 years old.The patients in the cohort were classified as having 2nd PDAC or first primary PDAC (1st PDAC) according to the history of a prior cancer. Patients who met the following criteria were considered as having 2nd PDAC: 1) the histological type of the prior cancer was not adenocarcinoma; 2) if the histological type of the previous tumor was adenocarcinoma, the possibility of primary pancreatic cancer should be higher than that of metastasis or recurrence of the previous tumor based on specific immunohistochemical staining or a reliable review by an experienced pathologist; and 3) PDAC was diagnosed at least 6 months after the diagnosis of the prior cancer to exclude synchronous PDAC. If the patient had a history of more than one prior cancer, the time of diagnosis of the first cancer was applied into the criteria.The following clinical characteristics of patients were collected: sex, age, smoking status, alcohol consumption, history of diabetes and hypertension, CA19-9 level at diagnosis, primary location of pancreatic cancer, resectability at diagnosis, initial treatment modality, origin of another primary tumor, period between the time of diagnosis of another primary tumor and that of the 2nd PDAC, and OS.2, Fisher’s exact, and Student’s t-tests to compare variables between the groups, and a p-value of <0.05 was considered statistically significant. The OS and cumulative incidence rate of the 2nd PDAC after the diagnosis of other tumors were calculated and analyzed by using Kaplan-Meier analysis with a log-rank test. Hazard ratios (HRs), 95% confidence intervals (95% CIs), and p-values were calculated with a univariate Cox proportional hazards model for OS, by using the variables that were statistically significant. A multivariate Cox proportional hazards model was built to evaluate possible significant factors, taking into account the possible influence of confounding clinical variables. Only those variables that were significant in univariate analysis were entered into the multivariate analysis. Statistical analyses were carried out with Predictive Analytics Software statistics version 23.Data were analyzed by using the χAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. As a retrospective analysis, Yonsei University Health System, Severance Hospital, Institutional Review Board approval was obtained and the need for informed consent was waived.A total of 1759 patients with PDAC were included in the cohort. Forty-three patients were classified as having synchronous 2nd PDAC and excluded from the analysis. There were 1606 patients (93.6%) with 1st PDAC and 110 patients (6.4%) with 2nd PDAC in the study population . Six patThe OS was slightly longer in patients with 2nd PDAC; however, the difference was not significant . Multivariate analysis without resectable status showed that 2nd PDAC , age at diagnosis , and alcohol consumption  were significantly related to OS . When reTo exclude the confounding effect of the resectability of PDAC on OS, we divided the whole cohort according to the initial treatment modality for PDAC: 1) patients who received curative surgery and 2) patients who received chemotherapy. Then, the OS of patients with 1st PDAC and those with 2nd PDAC was compared with Kaplan-Meier analysis according to treatment modality . In the To compare differences according to the follow-up modality that might be different depending on the location of the prior cancer, we divided patients with 2nd PDAC into those with a prior cancer originating from the abdomen and those with prior cancer of non-abdominal origin . The oriIn addition, we analyzed ratios of incidental findings on abdominal follow-up diagnostics in comparison to symptomatic 2nd primary PDAC, which led to scan-diagnostics in the first place. There were 47 patients who were diagnosed with 2nd PDAC on follow-up abdominal CT/MRI scans and 63 patients who were diagnosed with 2nd PDAC by symptoms. Comparing the two groups, the rate of resectable disease was significantly higher in the patients who were diagnosed by follow-up abdominal CT/MRI scans than those diagnosed by symptoms presentation .The median interval between the diagnosis of the 2nd PDAC and the diagnosis of the prior cancer was 8.4 years (range 0.7–31.4 years) in the 2nd PDAC group . Among pet al reported features of patients with PDAC and history of extrapancreatic malignancy compared to patients with PDAC as only tumor, however, the results of the study were limited to patients who underwent surgery for PDAC.[Previously, there were a few studies about 2nd PDAC with a population-based analysis. These studies reported that cancer survivors have an increased risk of developing 2nd PDAC., 12, 13 for PDAC. ConsiderIn this study, there were 110 patients with 2nd PDAC among a total of 1716 patients with PDAC. The proportion of patients with 2nd PDAC was about 6.4%, and this percentage was compatible with that reported in a previous study. The consIn our results, the patient age at diagnosis of 2nd PDAC was older than that of 1st PDAC . Similarly, in a previous report, there were more patients >75 years old (46% vs. 32%) and fewer patients <65 years old (22% vs. 37%) in the 2nd PDAC group than in the 1st PDAC group. This resThe rate of alcohol consumption  was lower in the 2nd PDAC group in our results. This might be because of the tendency of patients to stop drinking alcohol upon the diagnosis of cancer. Like our study, a previous study reported that the onset of cancer was significantly associated with cessation of alcohol consumption, based on cohort data from 9001 Korean patients.In the multivariate analysis after adjusting for confounding factors such as older age at diagnosis of 2nd PDAC, 2nd PDAC was significantly associated with a longer OS compared with 1st PDAC . However, after adjusting for resectability at diagnosis, 2nd PDAC was no longer significantly associated with OS. In fact, the rate of resectability of 2nd PDAC was significantly higher than that of 1st PDAC . Furthermore, more patients with 2nd PDAC could receive curative surgery, which could potentially increase their OS. When the whole cohort was divided into subgroups according to initial treatment modality (curative surgery or chemotherapy), there was no difference in OS between 2nd PDAC and 1st PDAC in both subgroups. These results suggest that the OS of the 2nd PDAC group seemed to be longer because there were more resectable cases at the time of diagnosis. Concerning the treatment, it can be presumed that that the nature of 2nd PDAC and 1st PDAC was not much different. When surgery of curative aim was possible, the OS was increased even in patients with 2nd PDAC. This result suggests the need to develop screening programs for detecting resectable pancreatic cancer in cancer survivors.To identify the effect of follow-up methods that might be different depending on the anatomical distribution of the prior cancer, we compared the subgroups divided according to the location of prior cancer in the 2nd PDAC group. When comparing cancers of abdominal origin, which were closer to the pancreas, and those of non-abdominal origin, there were no significant differences between subgroups in terms of resectability (p = 0.864) or OS (p = 0.212). It seems that the origin of prior cancer was not related to the tendency of early detection of 2nd PDAC. Interestingly, the rate of resectable disease was significantly higher in the patients who were diagnosed by follow-up abdominal CT/MRI scans than those diagnosed by presentation of symptomatic 2nd PDAC, which led to scan-diagnostics in the first place. It seemed that there was a correlation between early detection and follow-up methods, which suggested the necessity of developing screening programs for 2nd PDAC. However, there were only 110 patients with 2nd PDAC in this study, and follow-up intervals and methods were heterogeneous. A larger study with subgroup analysis according to the cell types or common etiologies shared by prior cancers should be conducted in the future. Most importantly, an optimal follow-up program for 2nd PDAC should be developed and evaluated.The cumulative curve of diagnosis of 2nd PDAC is presented in This study has several limitations. The number of patients with 2nd PDAC was small compared with those with 1st PDAC, although the proportion of 2nd PDAC in the total cases of PDAC was compatible with a previous study. In addition, we did not consider the possibility of multicancer syndromes accompanied with genetic disorders and the presence of premalignant lesions of PDAC such as intraductal papillary mucinous tumor. To overcome such limitations, larger prospective studies are needed in the future.Second primary pancreatic cancer had a higher rate of resectability, and there was no difference in the effectiveness of curative surgery and chemotherapy between 2nd and 1st PDAC. Therefore, when curative surgery for 2nd PDAC is possible, it should be conducted similarly to curative surgery for 1st PDAC. Considering the increased risk of 2nd PDAC in cancer survivors and the fact that surgery is the only curative treatment for this fatal cancer, more efforts are needed to develop screening programs for second primary pancreatic cancer in cancer survivors.


To investigate morphological differences of the hard palate in infants with Down syndrome (DS) compared with a volumetric-matched control group (CG).Trial design: retrospective case control study. Based on inclusion and exclusion criteria, plaster casts of edentulous maxillae of 40 DS infants  and 40 CG infants  were digitized and converted into 3-dimensional stereolithography data. An automated landmark- and investigator-independent method for assessing two-dimensional measurements such as width, depth, and length of palate, as well as palatal index and the 3-dimensional volume, were used.Matching DS and healthy CG infants by age, we found reduced sizes in all linear and volumetric measurements in the DS group. Matching both groups by palatal volume, we found no differences between the groups according to palatal width (p = .93), palatal depth (p = .32), and palatal index (p = .31). Control infants with the same palatal volume compared with the DS infants were about 151 days younger, 95%-CI =  (Hodges-Lehmann estimator). Except for palatal length and palatal volume, the growth pattern of DS palates decreased irregularly at age 6 to 9 months.The palate of DS infants in the first 6 to 9 month of life is of normal shape but considerably smaller compared with healthy normals. From 6 to 9 months onward, the growth pattern of the hard palate in DS infants decreases irregularly. High-arch-constricted palates could, therefore, be interpreted as secondarily acquired in later life. We therefore speculate that it could be advantageous to begin oral muscular stimulating therapy between 6 and 9 months of age which may prevent palatal shape alterations and enhance oral function which also contributes to maxillary development. Various cranio- and orofacial conditions have been described in patients with Down syndrome (DS). Despite nuchal thickness, maxillary hypoplasia may play an important role in prenatal ultrasonographic diagnostics , 2 becauThere is disagreement which orofacial features are caused by the genetic disorder and which are secondarily acquired in later life. Knowing which features are epigenetic  is essenNot only the jaw position but also morphological distortion can impair orofacial function. The hard palate of DS adolescents is often described as high arched and constricted or narrow , 11, 12,Tongue sucking habits or deep tongue pressure at rest would be both leading to a narrowing of the maxilla, the first by enhancing the buccal pressure, leading to compression tones on the alveolar process, the second by generating a missing counter force of the tongue from inside while pressure from the buccal side remains the same.The majority of studies assessed adolescent or adult DS palates, but measurements on infants are missing. Moreover, only few studies used control groups, and some were matched by sex and age. It can be shown that palatal volume and palatal surface are robust against shape differences and deformities of the palate compared with linear measurements , 19. TheEdentulous maxillary casts of infants treated with a stimulating plate  were retInclusion criteria for the DS group were (1) known trisomy 21, (2) plaster cast of the edentulous upper jaw prior to treatment, (3) the whole alveolar process with tubera maxillae and palatal vault perceivable on the plaster cast. Exclusion criteria were (1) other pathological conditions than trisomy 21, especially clefts, trisomy 18, and other syndromes, (2) poor quality of the cast, (3) erupting teeth.Of 233 selected infants treated with a stimulating plate 57 remained for inclusion in this study. During the matching process, an additional 17 patients were excluded because of lack of comparable cast from the healthy infant group. Finally, 40 DS infants  aged 221.3 ± 132.4 days remained for analysis. A control group of healthy term-born infants  was established by using digital plaster casts from a clinical trial registered under clinicaltrials.gov (NCT00408746).Permission to conduct this study was given by the Ethics Committee of the General Medical Council Westfalen-Lippe and the Medical Faculty of the Westphalian University of Münster, Germany. An informal request for using retrospective, anonymised data of DS infants was approved on September 4, 2013, prior to the study. Written informed consent was not obtained on retrospective data. Data from term-born infants (control group) were taken from a clinical trial registered under clinicaltrials.gov (NCT00408746). Prior to this study written informed consent was obtained from parents of term-born infants.3) were assumed as nearly identical concerning 3-dimensional growth.Edentulous upper jaw casts of healthy infants are not routinely available to match the DS group by age. We therefore relied on digital casts of a study where healthy term and preterm infant palates were compared . BecauseAll plaster casts of the DS group were digitized with the ATOS II system  and were exported as stereolithography (STL) files for further processing. Software was developed to extract linear and 3-dimensional measurements from the STL files. Detailed processing and theoretical background are clearly pointed out by . The relU test, and Hodges-Lehman estimator additionally 95%-confidence intervals (CI). Inferential statistics are intended to be exploratory (hypotheses generating), not confirmatory, and are interpreted accordingly. The comparisonwise type-I error rate is controlled instead of the experimentwise error rate. Local significance level is set at 0.05. No adjustment for multiple testing is performed. Therefore, an overall significance level is not determined and cannot be calculated.Descriptive statistics were performed using the software SPSS . Differences in measurements between the 2 groups were assessed by the Mann-Whitney The DS group was on average 221.3 ± 132.4 days old—an age range in which parents normally seek treatment for proper oral development of their DS-affected children. Plaster casts of healthy infants are not available in this age range; therefore, the groups could not be matched by age. The parameter “palatal volume” was used for the matching process because it represents a 3-dimensional measurement and could be seen as a better representation of growth and development compared with linear measurements. Results of the matching process are presented in The measurements obtained are presented in To assess the parameters in relation to age we followed the methodology of Hohoff et al. . TherefoThe curve pattern of the DS group was also different from that of the healthy controls . The DS The present study compares the morphometric findings of the hard palate between a group of infants with Down syndrome and a matched healthy control group. The following limitations of the study have to be taken into account when interpreting the results. Ethnicity has an influence on the morphology of the head and face. The DS group consisted of Caucasians only, therefore the results could not be extrapolated to other ethnic groups. DS individuals were taken from a patient group that was intended to treat with a stimulating plate . This crIn the literature, a small maxilla in the anteroposterior or transverse dimension is often considered as maxillary hypoplasia . The meaMaxillary hypoplasia is of diagnostic interest in different stages of growth. During prenatal evaluation, the occurrence of maxillary hypoplasia may lead to the detection of structural abnormalities, genetic disorders, or syndromes . During We found that in the first year of life, palatal dimensions of the younger control group were consistently greater than those of the older DS group. No differences in measurements were observed after matching the groups by palatal volume, meaning that the hard palate of DS infants had a normal shape relative to width, length, and depth at this particular age. Fischer-Brandis  observedFurther studies are available only for adolescent and adult DS patients. Bhagyalakshmi et al.  investigHypodontia is seen as a contributing factor in maxillary hypoplasia in DS patients , but it It was stated that palatal volume is a reliable indicator of growth . If the 3 to 3306.6 ± 647.1 mm3 [Only few studies have investigated the volume. Primožič et al.  observed47.1 mm3 . These v47.1 mm3  measuredIt is apparent from the literature that high-arched and narrow palates are a characteristic feature in adult DS subjects. The DS palate develops differently in each plane of space in a wavelike overall growth pattern. DS infants may present maxillary hypoplasia but with normal shape of the palatal vault and alveolar ridges. It could be shown that growth patterns change at approximately quarter 3 at 6 to 9 month (≥183 days <274 days). Fischer-Brandis  observedAssuming that shape alterations start around these ages, it would be advantageous to begin oral muscular stimulating treatment between 6 and 18 months (183–548 days) of age. This is in accordance with recommendations to treat hypotonicity of the perioral and masticatory muscles, as well as lips, and a possible protruding tongue . TreatmeThe hard palate of infants with Down syndrome is of normal shape in the first 6 to 9 months of age but considerably smaller in all 3 dimensions compared with healthy normals. From the age of 6 to 9 months onward, the growth pattern of the hard palate varies in the various planes of space. Anatomical distortions such as high-arched, narrow shapes could therefore be interpreted as secondarily acquired in later life. To prevent palatal shape alterations and enhance oral function which also contributes to maxillary development it could be advantageous to begin oral muscular stimulating therapy between 6 and 9 months of age.S1 Table(CSV)Click here for additional data file.


Participants in each group will be randomly assigned, equally, to one of the following interventions: (1) active tDCS + active PES; (2) active tDCS + sham PES; (3) sham tDCS + active PES; and (4) sham tDCS + sham PES. Active tDCS intervention will consist of 20 min 2 mA anodic stimulation over the primary motor cortex contralateral to the most painful hip. Active PES intervention will consist of 30 min sensory electrical stimulation at 100 Hz over the most painful hip. The main study outcome will be pain intensity, measured by a Visual Analogue Scale. In addition, electroencephalographic power density, cortical maps of the gluteus maximus muscle elicited by Transcranial Magnetic Stimulation (TMS), serum levels of Brain-derived Neurotrophic Factor (BDNF), and Tumor Necrosis Factor (TNF) will be assessed as secondary outcomes. Data will be analyzed using ANOVA of repeated measures, controlling for confounding variables.Chronic pain in Sickle Cell Disease (SCD) is probably related to maladaptive plasticity of brain areas involved in nociceptive processing. Transcranial Direct Current Stimulation (tDCS) and Peripheral Electrical Stimulation (PES) can modulate cortical excitability and help to control chronic pain. Studies have shown that combined use of tDCS and PES has additive effects. However, to date, no study investigated additive effects of these neuromodulatory techniques on chronic pain in patients with SCD. This protocol describes a study aiming to assess whether combined use of tDCS and PES more effectively alleviate pain in patients with SCD compared to single use of each technique. The study consists of a one-session double blind, block-randomized clinical trial (NCT02813629) in which 128 participants with SCD and femoral osteonecrosis will be enrolled. Stepwise procedures will occur on two independent days. On day 1, participants will be screened for eligibility criteria. On day 2, data collection will occur in four stages: sample characterization, baseline assessment, intervention, and post-intervention assessment. These procedures will last ~5 h. Participants will be divided into two groups according to homozygous for S allele (HbSS) ( Sickle-cell disease (SCD) refers to the group of hemoglobinopathies in which hemoglobin S plays a relevant role. The most prevalent genotypes are homozygous for S allele (HbSS) and heterozygous for S and C alleles (HbSC). Severity of SCD depends on different genotype, being the HbSS genotype the most severe  is involved in neural regulation, maintenance, and synaptic formation, having an important role in the central nervous system plasticity  in this population.Currently, pharmacologic interventions are the main treatment for management of chronic pain in subjects with SCD  compared to individual or sham use of these techniques.gluteus maximus muscle, and serum levels of BDNF and TNF;Evaluate the effect of a single session of anodic tDCS associated with sensory PES on the following neurophysiological variables: electroencephalographic power density, TMS cortical mapping of the Evaluate whether therapeutic response varies according to genotypes HbSS and HbSC.A single session of anodic tDCS associated with sensory PES provides greater analgesic effect compared with single use of the techniques;gluteus maximus cortical representation compared to the individual use of the techniques;The association of anodic tDCS and sensory PES causes greater decrease on serum levels of BDNF and TNF and greater increase on the muscle A session combining anodic tDCS and sensory PES leads to greater decrease of electroencephalographic low frequency  power density compared to the individual use of the techniques in participants with SCD.www.randomization.com) creating four groups for each SCD genotype (HbSS and HbSC), totaling eight experimental groups. Allocation concealment will be enforced using sealed opaque envelopes listed in ascending order, and the allocation secrecy will be maintained until the end of the analyses. The allocation envelope will be opened on the day of the intervention according to the order of inclusion of the study participant. The envelope will contain one of the following interventions: (1) active tDCS + active PES (n = 16); (2) active tDCS + sham PES (n = 16); (3) sham tDCS + active PES (n = 16); (4) sham tDCS + sham PES (n = 16) , and HbSC (n = 64) groups, totalizing 128 participants.This is a clinical, parallel, controlled, block-randomized, double blind trial. The study will occur in 2 days at the Clinical Electrophysiology Laboratory of the Federal University of Bahia, Brazil. An assistant researcher not involved in any other stage of the study will generate an allocation sheet  and in Reference Centers for treatment of SCD in the municipalities of Salvador and Feira de Santana, the two largest cities in the State of Bahia, Northeastern Brazil. SCD is more prevalent in this region of the country. Enrollment of participants will take place between March 2016 and December 2019. The study will be advertised in the SCD reference centers and health care facilities in the two cities. To improve adherence to the intervention protocol, all participants will receive financial aid for round-trip transportation, as well as a meal voucher. In addition, they will receive SCD care recommendations. At the end of the study, all participants will be offered the most effective intervention.To homogenize the sample, only participants with SCD of HbSS and HbSC genotypes suffering from chronic pain secondary to femoral head osteonecrosis will participate in this study. Theses genotypes were chosen because they are more prevalent, and both have a higher prevalence of femoral head osteonecrosis in adult individuals ;Individuals from both sexes, between 18 and 50 years of age.Any contraindication to use TMS and tDCS such as: cochlear implant, cardiac pacemaker or metal implantation in the skull/brain; drug treatment that modifies the threshold of neuronal activation ; history of seizure or epilepsy; and pregnancy;Douleur Neuropathique 4 questionnaire (DN-4)  or severe  during neurophysiological evaluation or intervention;Participant withdraws consent at any stage of the study.2) electrodes embedded in saline solution (0.9%). The anodic pole will be placed in the motor cortex region (M1) contralateral to the painful hip  . The cathodic pole will be placed over the contralateral supra-orbital region . The 2 mA stimulation will last 20 min, ramped up and down for 30 s at the initial and final stages of stimulation. A clinical pulse generator  will be used to administer PES using 35 cm2 dischargeable electrodes located on the side of the most painful hip. The stimulation will start together with tDCS and will be held for 30 min. The intensity will be maintained at the sensory level, characterized as a comfortable intensity just under motor threshold, with pulse rate of 100 Hz and pulse duration of 200 μs.An experienced physical therapist will manage the intervention protocols. During the intervention, participants will be comfortably seated in a chair, in silence. They will be encouraged to make no cognitive effort, such as mathematical calculations or complex reading. tDCS will be applied with a proper device  connected with two silicon-sponge 5 × 7  and clinical data (anxiety/depression symptoms and disability index related to pain). Socio-demographic data will be collected by self-report questionnaire designed specifically for this study. Clinical data will be collected using the following instruments:Hospital anxiety and depression scale (HADS): HADS comprises two seven-items subscales. Subjects will rate each item using an ordinal scale varying from zero (non-existent symptom) to three (very severe symptom) : PDI is composed of seven items to assess how pain interfere in daily activities, including: family and domestic obligations, recreation, social activities, profession, sexual life, autonomy, and elementary activities indispensable to life. Subjects will rate each item using an ordinal score ranging from zero (no disability) to 10   with 30 electrodes arranged according to the international system of electroencephalography 10/10 will be used in the following electrode locations: F7 T3 T5 Fp1 F3 C3 P3 O1 F8 T4 T6 Fp2 F4 C4 P4 O2 Fz Cz Pz Oz FT7 FT8 TP7 CP3 FC3 CPz FCz CP4 FC4 TP8. EEG data will be collected at a sampling rate of 600 Hz and referenced to Cz channel. Impedance will be maintained below 5 kΩ for all electrodes. The recording environment will be kept in subdued light and protected by a Faraday cage. Participants will be instructed to sit comfortably in a chair, keeping their eyes closed during EEG recording, which will occur in the two conditions described below.a. Resting state: This condition will last 4 min, and the participant will be asked to not focus on any specific cognitive activity;Kinesthetic–MI of a movement in the non-painful region of the body: After 10 s of recording, participants will hear a standardized command requesting to mentally simulate closing and opening the contralateral hand to the most painful hip side. The command to each mental simulation will be repeated eight times, being 5 s of closing movements and 10 s of opening movements of the hand, totaling 120 s. (2) Kinesthetic–MI of a movement in the painful region of the body: The same protocol described above will be repeated, but this time the command will be to mentally simulate the abduction and adduction of the most painful hip. Electromyographic (EMG) data of the gluteus medius muscle on the most painful side and flexor muscles of the fingers contralateral to the hip will be also recorded to ensure absence of real movement. After each recording, the quality of the Kinesthetic–MI will be assessed by the kinesthetic and visual imagery questionnaire (KVIQ) : Kinesthetic–MI will follow the resting state recorded, divided into two distinct stages. (1) toolbox version 14. The signals will be filtered offline with a bandpass between 0.5 and 45 Hz. EEG data will be segmented into epochs of 1.71 s to allow an analysis of power densities at frequencies ranging from 1.2 to 30 Hz. EEG artifacts with minimum amplitude below −750 or maximum amplitude above 750 μV will be rejected using a semi-automated protocol. EEG data with more than 33% of rejected epochs will be excluded from further analyses. After the artifact rejection protocol, all EEG data will be adjusted to have the same number of epochs.Pre-processing of EEG data will be done using the MATLAB software version 2015 and EEGlab Power density will be calculated by fast Fourier transform in each epoch and electrodes, separately for each participant. The average power densities will be grouped in delta (1.2–3.5 Hz), theta (4–7 Hz), alpha (8–12 Hz), and beta (13–30 Hz) frequency bands. Regions of interest (ROI) chosen for analysis will be computed by averaging power densities for the following groups of electrodes: frontal , central , parietal  temporal , and occipital . After obtaining absolute power densities, the relative power density will be calculated dividing electrode's values in each one of the analyzed frequencies by their values in the total power spectrum.B. TMS cortical mappinggluteus maximus muscles. A figure-of-eight coil will be positioned with the handle oriented backwards and aligned to the sagittal suture, inducing a postero-anterior flow of current. One cap marked with an 8 × 7 cm grid and oriented to the vertex will be placed on the participant's head and regularly checked to guarantee placement consistency. The vertex will be marked on the intersection of interaural and nasion to inion lines according to the 10/20 international EEG system.Cortical mapping will be assessed pre- and post-intervention. After EEG recording, each participant will be asked to lie down comfortably in a supine position on an examination table, with head and neck resting on a support. The TMS cortical mapping will be performed using a single-pulse TMS apparatus  delivered over M1 to cover the representation of both gluteus maximus muscle. AMT will be the minimum intensity at which a TMS stimulus evokes a response of 200 μV while the gluteus maximus muscle is contracted under a comfortable bridge position in supine. Then, the AMT will be determined using the adaptive TMS motor threshold assessment tool (MTAT 2.0). The TMS pulse will be applied every 6 s, with a total of five stimuli at each site on the 8 × 7 cm grid.The stimulus intensity for mapping will be set at 120% of Active Motor Threshold (AMT) for the gluteus maximus muscles, bilaterally. The two registering electrodes will be placed at 50% on the line between the second sacral vertebrae (S2) and the hip greater trochanter. The positioning of the electrode will be determined after palpation of the gluteus maximus muscle during a moderate voluntary contraction. The reference electrode will be placed over the hip greater trochanter or S2  will be used to record EMG activity at the gluteus maximus muscles will be used as dependent variables. These parameters will be calculated, respectively, by the sum of normalized MEP amplitudes at each site and by the formula:TMS map volume and center of gravity (CoG) of both i = mean MEP amplitude at each site with the coordinates Xi, YiWhere, VC. Serum levels of BDNF and TNFSerum levels of BDNF and TNF will be measured pre- and post-intervention. Approximately 5 mL of blood will be collected from each study participant and stored in test tubes with anticoagulant EDTA (0.03%). This procedure will last <5 min. The blood sample will be centrifuged at 2,500 rpm for 10 min and the plasma stored at a temperature of −40°C.At a later time, serum levels of BDNF and TNF will be quantified using enzyme-linked immunosorbent assay kits . A volume of 100 μL of monoclonal antibody-based capture will be added to a 96-well plate, which will be incubated for 12 h at room temperature (RT). The wells will be washed with wash buffer (PBS/Tween) and incubated with a blocking solution (300 μL) containing PBS and bovine serum albumin (BSA) for 1 h at RT. Samples and standards will be plated and incubated for 2 h at RT. After washings, the detection monoclonal antibody will be added to the plate and incubated for 2 h at RT. Then, a streptavidin-peroxidase solution will be added and incubated for 1 h at RT.2O2 and TMB tetramethylbenzidine) will be added to the plate and a blue color will develop within a period of 20 min. The staining reaction will be stopped by adding H2SO4 2N, and the reading will be made on a microplate reader at 450 nm. Levels of BDNF and TNF will be expressed in pg/mL and calculated from the reference values obtained with a standard curve built with known concentrations of recombinant BDNF and TNF. Concentrations of BDNF and TNF in plasma will be quantified using commercially available antibody pairs and recombinant cytokine standards , using sandwich enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions.Finally, the substrate solution  to evaluate differences among intervention groups , genotypes (HbSS and HbSC), and time (pre- and post-intervention). For most of the secondary outcomes  the repeated measures ANOVA will have the same three factors listed above. Relative EEG power will further include in the ANOVA the factors ROI  and EEG condition . All analysis will be controlled for anxiety/depression symptoms. Bonferroni test will be used to correct for multiple comparisons. An α-value of 5% (P < 0.05) will be used to accept statistically significant differences for all analyses.To ensure impartiality of the results, researchers who do not participate in any stage of data collection will perform the statistical analysis. Descriptive statistic will be used to summarize demographic and clinical sample characteristics. Shapiro–Wilk test will be performed to test normality of the data. Chi-square test will be used to compare frequency distributions and one-way ANOVA or Kruskal–Wallis Volunteers will receive explanation regarding their participation and the freedom to remove consent at any time during the study. They will read and receive answers to any questions before signing an Informed Consent Form (ICF), prepared according to Resolution 466/2012 of the Brazilian National Council of Health. This study has been approved by the Ethics and Research Committee (ERC) of the Adventist Institution of Bahia (CAAE No. 31237514.1.0000.0042). The study is registered at the Protocol Registration and Results System (PRS), trial number NCT02813629. Any changes in the study protocol will be informed to both the ERC and the PRS.Study procedures will occur in 2 independent days . Eligible subjects will receive the ICF to read. The assistant research will read aloud the ICF if requested by the subject. All doubts will be clarified and the ICF will be filled out and signed. Participants will be scheduled for data collection in the Clinical Electrophysiology Laboratory at the Federal University of Bahia.Day 2: Data collection. Procedures will begin in the morning. Upon arrival of participant at the study room, an allocation envelope will be opened to determine participant's intervention group. Data collection will be divided into four stages .Stage 1 (Sample characterization) will last ~40 min. The researcher will explain to the participant why and how to fill the socio-demographic and clinical questionnaires. The researcher will be available to clarify any doubts and help participant, if requested;Stage 2 (Baseline assessment). EEG data will be collected during resting and Kinesthetic–MI conditions. Subsequently, in another room, the participant will receive instructions for the TMS cortical mapping. Following these electrophysiological assessments, a blood sample will be collected for BDNF and TNF serum level analysis. Finally, the pain intensity will be assessed. This stage may last up to 1 h and 30 min;Stage 3 (Intervention). At this stage, the participant will be seated and the researcher will position the tDCS electrodes on the scalp according to the 10/20 EEG system. Electrodes will be fixed with an elastic band, comfortably adjusted. The PES electrodes will be positioned at the most painful hip. This stage will last around 40 min;Stage 4 (Post-intervention assessment). In the last part of the study, the sequence of assessments will be slightly different from Stage 2. First, pain intensity will be measured. Then, a blood sample will be collected. Blood sample must be collected earlier in this stage to reduce circadian cycle effect on BDNF and TNF serum levels (Pan et al., Participants may take 5–10 min-breaks between all stages. During their time in the laboratory room, participants will have snacks and light beverage available at breaks. Participants will be reimbursed for transportation costs and receive a food voucher at the end of data collection.This protocol was designed with the main purpose of answering the question “Does tDCS combined with PES have an additive effect in the control of osteonecrosis joint pain associated with SCD?” As in any clinical trial, risk of bias and errors exist. Several strategies will be used to reduce them:The development of this protocol involved several experts to carefully design the interventions in order to reduce systematic errors. To minimize human errors, all personnel involved in data collection will be thoroughly trained on how to use study questionnaires and instruments.According to the Ficat classification Ficat, , the femStimulation duration in this study will differ between neuromodulatory techniques, being 20 min for tDCS and 30 min for PES. The choice for a longer time of PES stimulation was based on studies demonstrating that 30 min provides significant improvement on cortical excitability (McKay et al., Gluteus maximus muscle TMS mapping may be difficult because of its small and deep representation in the primary motor cortex. We aim to counteract this problem using active motor threshold and contraction during TMS assessment, a method successfully used by others (Lepley et al., gluteus maximus muscle used a system similar to the one available for this study (Fisher et al., A. Pain intensityEmotional aspects such as anxiety and depression are commonly associated with chronic pain (Keefe et al., B. Serum level BDNF and TNFCircadian rhythm has influence on BDNF and TNF serum levels. A study with healthy subjects evaluated BDNF levels every 4 h and identified a continuous decrease throughout the day (Begliuomini et al., To be included as an author in the articles from this study, individuals should meet the following criteria of authorship (Petroianu, Contribute substantially to the study conception and design; or to the acquisition, analysis, or interpretation of study data;Participate in the writing of this manuscript or critically examine its intellectual content.TL, AB, WS, and SR were involved in all aspects of study design and conception. TL drafted the introduction, while AB, PM, and FQC critically reviewed it. All authors contributed with the design of study methodology. WS and CF contributed with data collection and design of methodology and analysis of serum BDNF and TNF levels. FQC contributed with the calculation of sample size and designed the statistical analysis. FQC, PM, and AV reviewed the English. RL and SR contributed with conception and design of tDCS data collection and safety aspects. PM and GD contributed with selection of clinical questionnaires in the study design. PM and FQC contributed with the conception and design of the EEG data collection, pre-processing, and analysis. All authors contributed with the drafting of the work. TL, AB, PM, FQC, and CF revised the manuscript critically for important intellectual content. All authors gave final approval of the version to be published. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.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.


Hypoglycemia is the most common side effects for most glucose-lowering therapies. It constitutes a serious risk that faces diabetic patients who fast during Ramadan . New glucose-lowering classes like dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 receptor agonist (GLP-1 RA), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are efficacious in controlling blood glucose level with less tendency to induce hypoglycemia and thus may constitute a good choice for diabetic patients during Ramadan. This study reviews the safety and efficacy of newer glucose-lowering therapies during Ramadan. This study was accomplished through a careful literature search about studies that assess the benefit and side effects of these new glucose-lowering therapies during Ramadan during September 2015. Vildagliptin, sitagliptin, liraglutide, exenatide, and dapagliflozin were the only studied glucose-lowering therapies. All of the studied newer glucose-lowering therapies except dapagliflozin were associated with reduced risk to induce hypoglycemia. Gastrointestinal upset was common with the usage of liraglutide while increased thirst sensation was common with dapagliflozin. In conclusion DPP-4 inhibitors such as vildagliptin and sitagliptin may form a suitable glucose-lowering therapy option for Ramadan fasting patients. Fasting during Ramadan, the 9th month in the Islamic calendar, is not mandatory for patients with diabetes mellitus (DM), but many insist on fasting. This can create many health problems, especially if the fast is prolonged . GlucoseThis study was accomplished during September 2015 through a careful literature search using  for studies from 2005 to 2015 with the one or more of following keywords in English language: diabetes DPP-4 inhibitor , GLP-1 RA , and SGLT-2 inhibitors , in combination with the essential keyword (Ramadan). EMBASE was not searched because of funding limitations. All study types  that examined the efficacy and side effects of these classes of glucose-lowering therapy on patients with type 2 DM during the fasting month of Ramadan were included. Reviews were excluded. Information from these studies were summarized in relation to study design, duration of study, number of participating patients, medications used, assessment criteria for medication safety and effectiveness, and final conclusions.A total of 16 studies were included as shown in 1c) without causing weight gain [The dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of oral glucose-lowering therapies for type 2 DM treatment. They act by inhibiting the breakdown of GLP-1, increasing its systemic concentration which leads to a significant increase in endogenous insulin secretion and a decrease in glucagon secretion. They have a glucose dependent mechanism of action, leading to a lower incidence of hypoglycemia. In clinical practice DPP-4 inhibitors are associated with 0.6–0.7% reductions in glycosylated hemoglobin  Vildagliptin as Monotherapy. There are only few studies that assess the benefits of vildagliptin as monotherapy for type 2 DM patients maybe because of its unlicensed use as monotherapy. In nonfasting patients vildagliptin has nearly similar effectiveness to SU in lowering HbA1c but with less risk to induce hypoglycemia [p = 0.104). HbA1c was decreased in vildagliptin group while there was a slight increase in SU group . More patients in the vildagliptin group achieved HbA1c < 7.0% than in the SU treated group . Additionally, there was a significant difference in weight loss. Patients in the vildagliptin group lost an average of 1.2 kg while those in SU group lost an average of 0.03 kg (p < 0.001). Although vildagliptin was shown to be safer than SU in this study, this superior safety was lacking statistical significance, perhaps due to the small sample size. In another large, multiregional, observational study [1c than SU . Also, vildagliptin was associated with significantly fewer episodes of hypoglycemic events  in comparison with the SU therapy . This large study confirmed that vildagliptin had significantly higher effectiveness and safety when compared to SU. These two studies showed that the risk of hypoglycemia in patients using vildagliptin is around one-third to that in patients using SU.glycemia . In Ramaglycemia  for 97 Ial study  that was1c reduction) and body weight. It is also safer than SU by its less risk to induce hypoglycemia.In summary, the use of vildagliptin 50 mg twice daily as monotherapy for Ramadan fasting patients is more effective than SU to control blood glucose level (through HbA(2) Vildagliptin as Add-On Therapy. There are many studies examining vildagliptin as add-on therapy for both fasting and nonfasting patients. In nonfasting patients it was found that vildagliptin when used as add-on therapy to metformin has comparable efficacy to different SU (glimepiride and gliclazide) but with less risk to induce hypoglycemia [p ≤ 0.001). The effect of both gliclazide and vildagliptin was similar on HbA1c and body weight. The lack of significant difference in the effectiveness between vildagliptin and gliclazide in this study may be due to short period (24 days) of follow-up besides the small sample size which further compromises statistical significance. Another small prospective, 16-week, multicenter study [1c reduction for those taking vildagliptin; however this higher effectiveness may be attributed to higher adherence rate by patients using vildagliptin than for those using gliclazide [glycemia , 16. In glycemia  that waser study  was condiclazide . On the 1c. The incidence of hypoglycemia, which was confirmed by measuring blood glucose level, during Ramadan was higher in the SU group . The number of patients who had medication noncompliance because of fasting discomfort was higher in the SU than in the vildagliptin group.In 2014 a randomized, open-label, clinical trial [All the previously discussed small scale studies , 18, 20 1c ≤ 8.0%. 83 patients were in the metformin-sulfonylurea/glinide (IS) cohort and 115 patients were in the metformin-vildagliptin cohort. Hypoglycemic episodes  were confirmed in 30.8% of the IS cohort and 23.5% in the vildagliptin cohort (p > 0.05), while severe hypoglycemia and/or unscheduled medical visit due to hypoglycemia occurred in 10.4% of the IS cohort and in 2.6% of vildagliptin cohort (p = 0.0029). Glycemic control remained stable in both cohorts. Compliance with fasting was higher, as well as adherence to drug therapy in vildagliptin cohort, with ≥5 missed doses for 15.4% of IS, compared to 8.5% only in patients using vildagliptin. In this study the nonsignificant difference in the total hypoglycemic episodes between vildagliptin and SU/glinide which was different from the finding of previous studies at which vildagliptin was less likely to induce hypoglycemia than SU, maybe due to the usage of glinide in some patients but unfortunately their number was vague which keeps the final conclusion about the hypoglycemic risk of glinide in comparison with vildagliptin unknown.Another large study was a prospective, observational, 14-week study design  for 198 n = 121) or SU  as add-on to metformin or as monotherapy for at least 4 weeks. Patients in the vildagliptin group experienced at least one episode of hypoglycemia  less frequently than patients in the SU group . The reduction in HbA1c was greater with vildagliptin than in SU . A reduction of 0.3 kg in body weight was seen with vildagliptin treatment versus 0.2 kg weight gain in the SU group. Overall adverse events  were less frequently reported in vildagliptin cohort than in the SU group . Hypoglycemic events were significantly less common in vildagliptin than in SU group . GIT side effects including abdominal pain, nausea, and vomiting are more common in vildagliptin than in SU group ; these side effects may be symptoms for acute pancreatitis which is a rare but serious side effect of vildagliptin therapy [Another study, VIRTUE study  was a mu therapy .However, large, multiregional, randomized studies are required to confirm the safety of vildagliptin on GIT system and/or pancreatitis when used as add-on therapy to metformin for Ramadan fasting patients since this study was just an observational study on a limited number of Pakistani patients only.p = 0.039). There was a nonsignificant difference in effectiveness of vildagliptin versus gliclazide according to the adjusted mean change in HbA1c (p = 0.165). Also there was a nonsignificant difference between vildagliptin and gliclazide on body weight change (p = 0.987). Overall safety  was similar between the treatments. The randomized design of this study and its large sample size lead to a less biased conclusions and a thus form a strong evidence for the lower risk of hypoglycemia with comparable safety of vildagliptin when compared to gliclazide. This finding occurs in contrast to the findings of VIRTUE study which assume that GIT upset is higher by vildagliptin than in SU (the majority of patients were on glimepiride) while in STEADFAST study vildagliptin has similar incidence of GIT side effects to gliclazide and since the incidence of GIT side effects is higher by glimepiride than gliclazide [More recently a STEADFAST study  was a muiclazide ; then itIn summary, the usage of vildagliptin in fasting patients as add-on therapy to metformin has comparable safety and effectiveness to SU but with a lower tendency to induce hypoglycemia.(1) Sitagliptin as Add-On Therapy. There is a complete absence for studies that evaluate the effect of sitagliptin as monotherapy for patients with type 2 DM during Ramadan but there are many studies on the usage of sitagliptin as add-on therapy to other glucose-lowering therapies, specifically metformin. In a pilot prospective study [ve study  involvinn = 507) or remain on their prestudy treatment (n = 514). There was a nonsignificant difference in the incidence of symptomatic hypoglycemia  for patient in the gliclazide group when compared with those in the sitagliptin  group, while a significant difference in the incidence of hypoglycemia occurs between patients using sitagliptin and those using glibenclamide and glimepiride. Furthermore, sitagliptin appeared to induce side effects to a lesser extent than SU ; all the side effects in sitagliptin group were not serious and include constipation, vomiting, or hyperglycemia, while three patients in SU group developed serious problems like ischemic stroke, acute pancreatitis, and urinary tract infection. In this study although there was a nonsignificant difference in the incidence of hypoglycemia between gliclazide and sitagliptin, gliclazide was associated with lower risk of hypoglycemia when compared to sitagliptin; unfortunately authors in that study did not classify patients who are using gliclazide according to the used dosage form (sustained and immediate release), so it is difficult to conclude that whether this lower incidence of hypoglycemia by gliclazide when compared to sitagliptin is related to specific dosage form of gliclazide or due to gliclazide itself.Sitagliptin had been also studied in large, randomized, open-label multinational study  that was1c ≤ 10%. Patients were divided into two groups: 421 patients were switched from SU to sitagliptin 100 mg once daily and 427 patients remained on SU. The proportion of patients who recorded ≥1 symptomatic hypoglycemic event during Ramadan was lower for patients in sitagliptin than in SU group . The incidence of symptomatic hypoglycemia was the lowest in patients using gliclazide (1.8%), then sitagliptin (3.8%), then glibenclamide (5.2%), and finally glimepiride (9.1%). The proportion of patients experiencing adverse effects other than hypoglycemia was 10.0% versus 7% in the sitagliptin and SU group, respectively. The major limitation for this study was the absence of medication efficacy assessment through measuring glycemic control and body weight. The assumption of this study in that sitagliptin is safer than SU in regard to hypoglycemia was not accurate since incidence of hypoglycemia is lower in gliclazide than in sitagliptin. The finding of this study may provide confirmatory evidence to the finding of Al Sifri et al. [Another multicenter, randomized study  is involi et al. –28.In summary, the studies that evaluate the usage of sitagliptin for patients with diabetes during Ramadan found that it is associated with reduced risk of hypoglycemia when used as add-on therapy to metformin compared to two SUs (glimepiride and glibenclamide) and a slightly higher risk of hypoglycemia than gliclazide; this difference may be attributed to the higher degree of selectivity in pancreatic receptor stimulation by gliclazide  while inOther rare side effects including gastrointestinal (GIT) side effects  and central nervous system (CNS) side effects  appeared to occur at higher percent in sitagliptin than in SU treated patients. One of the major limitations in all of these studies about the usage of sitagliptin during Ramadan is that they did not focus on sitagliptin effect to control blood glucose level, so further studies are needed in this regard to find out whether sitagliptin benefit is limited to less risk of hypoglycemia or extends beyond that to include a better glycemic control than SU for patients with type 2 DM during Ramadan.Till the time of collecting the data for this review there are no any study (2005–2015) that had been evaluating the effect and side effects of using DPP-4 other than vildagliptin and sitagliptin like linagliptin, saxagliptin, and alogliptin during Ramadan. It seems that the differences are negligible regarding efficacy and incidence of hypoglycemia among all DPP-4 inhibitors . So it mGlucagon-like peptide-1 receptor agonists (GLP-1 RA) act by binding to and activating the GLP-1 receptor, resulting in glucose dependent increase in insulin secretion and decrease secretion of glucagon, so they are effective in decreasing blood glucose levels associated with reduced risk of hypoglycemia. They also act to delay gastric emptying and increase satiety; thereby they are effective in reducing body weight for diabetic patients. The approved agents in this class include exenatide, liraglutide, albiglutide, and lixisenatide. All of these agents are administered by subcutaneous injections with mainly GIT side effects such as nausea, vomiting, and diarrhea in addition to injection-site reaction , 32. Exe1c with less hypoglycemic risk, only few studies examined exenatide usage for Ramadan fasting patients. One pilot study [Although there are many studies that examine the effect of exenatide as add-on therapy in nonfasting patients , 34, whiot study  for 34 pot study  was assoIn above 2 studies regular exenatide was assessed while the usage of sustained release exenatide during Ramadan was not assessed.In summary, regular exenatide is not associated with hypoglycemia when used for type 2 DM patients during Ramadan; however it is difficult to recommended the use of exenatide for fasting patients until further studies performed because the current studies are small scaled studies, with major focus on hypoglycemic side effects without focusing on the efficacy of exenatide to control blood glucose level during Ramadan.1c but with less risk of hypoglycemia when used in nonfasting patients [Liraglutide was shown to have comparable efficacy to SU in lowering HbApatients , 38.1c . Liraglutide resulted in greater and significant reductions in both weight and diastolic blood pressure (BP) for patients with DM than SU. Self-recorded episodes of hypoglycemia  were significantly lower with liraglutide (p < 0.0001). The major limitation in this study was the reliability of the method that was used to calculate hypoglycemia (patient self-record method).During Ramadan many studies assess the benefits and drawbacks for liraglutide usage; one of the earliest studies in this regard was the Treat 4 Ramadan trial, which was a randomized, controlled clinical trial  comparin1c 7–10%, and being treated with a combination of metformin and SU (at maximum tolerated dose). Study participants were randomized to either switch from SU to liraglutide 1.8 mg once daily or continue pretrial SU. Patients in liraglutide group were more likely to achieve HbA1c target of <7% with no confirmed hypoglycemic events  compared with SU . Moreover, people treated with liraglutide experienced significantly greater weight loss (p < 0.0001) and greater improvements in HbA1c  than those treated with SU. The incidence of patients experiencing adverse events (AE) during Ramadan was similar in the liraglutide and SU groups ; meanwhile gastrointestinal side effects  occurred more commonly with liraglutide treatment (10.5% versus 3.7%). The results of this study were more reliable and add a confirmation to the findings of Treat 4 trial because of its randomized design with larger sample size at which in both studies liraglutide showed a significantly better efficacy than SU with a lower incidence of hypoglycemia.LIRA- Ramadan study was longer and larger than the previous Treat 4 trial. LIRA study was an open-label, multinational randomized clinical trial  involvinIn summary, liraglutide usage during Ramadan for patients with type 2 DM may be reasonable because it is associated with better glycemic control, improved body weight, and less hypoglycemic episodes when compared with SU; however, it should be used with caution because of its GIT side effects, which may negatively affect a fasting patient, since GIT problems may occur more frequently during Ramadan .Studies for other GLP-1 RA like albiglutide and lixisenatide during Ramadan were lacking which may be attributed to their recent approval by FDA and it may be possible to find such trials in the near future.Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are the most recent class of oral glucose-lowering therapies that are used for treating patient with type 2 DM. Medications of this class include dapagliflozin, canagliflozin, ipragliflozin, and empagliflozin. These drugs act to lower blood glucose level by decreasing renal glucose threshold through their effect to induce a competitive inhibition on the SGLT-2 in the kidney which is responsible for reabsorption of 90% of filtered glucose by the kidneys and thus block the reabsorption of glucose. The risk of inducing hypoglycemia is low with SGLT-2 inhibitors because of their insulin-independent action and hence forms an attractive class for managing patients with type 2 DM during Ramadan. However, caution is recommended while using these medications because of their ability to cause dehydration, especially in the setting of absence of fluid intake, which occurs during fasting hours of Ramadan , 43. RecThere are some studies that assess dapagliflozin as add-on therapy in nonfasting patients; in all of these studies dapagliflozin was shown to have comparable efficacy to SU with lower hypoglycemic risk .p = 0.258); this may be because already most of Ramadan fasting persons without regard to their disease or medication status suffer from dehydration due to long period (12–22 hour) of abstinence from foods and water during Ramadan [To date, there is only one study that evaluates dapagliflozin during Ramadan which was a 12-week, randomized, open-label study  for 110  Ramadan .p = 0.026) than in SU group complained from thirst sensation. Additionally, there was a significantly higher mean for haematocrit level (p = 0.009), urine osmolarity (p = 0.001), and blood ketone (p = 0.002) in dapagliflozin group; however, there was a lack of information regarding the development of ketoacidosis in participated patients of this study. Furthermore, there was a significantly lower mean of urinary sodium (p < 0.005) in dapagliflozin group when compared to SU group; however authors of that study postulated that dapagliflozin does not pose a higher risk of dehydration during Ramadan. Assessment of dapagliflozin effectiveness to reduce HbA1c and its risk to induce hypoglycemia was the major limitation in this study which may be because the main aim of this study was to assess the safety of dapagliflozin on excessive water excretion.There were significantly more patients in the dapagliflozin group  have been studied during Ramadan. The hypoglycemic risk was assessed for all of the above medications except dapagliflozin; nearly all of the assessed medications were associated with reduced risk of hypoglycemia when compared with SU when used during Ramadan. DPP-4 inhibitors such as vildagliptin and sitagliptin may form a suitable glucose-lowering therapy option for Ramadan fasting patients, since they are unlike liraglutide less likely to cause GIT upset, and unlike SGLT-2 inhibitors are not associated with increased thirst sensation. Effectiveness of sitagliptin to control blood glucose level for Ramadan fasting patients was not assessed in any study in contrast to vildagliptin which was shown to be effective to control blood glucose level and body weight when used as monotherapy or even as add-on therapy to metformin; accordingly vildagliptin seems to be the most suitable glucose-lowering therapy choice for diabetic patients who are wishing to fast during Ramadan. Further studies on the use of other new glucose-lowering therapies during Ramadan are recommended; furthermore it is recommended to do studies that directly compare the advantages and disadvantages between these new glucose-lowering therapies.