Interruptions in infliximab therapy are associated with the development of antibodies to infliximab (ATI), infusion reactions (IRs), and loss of response. Despite these challenges, recent observational studies suggest that reinitiating infliximab after a drug holiday can be safe and effective. We assessed the utility of our protocol for restarting infliximab using early serum infliximab and ATI measurements.A retrospective cohort study of patients restarted on infliximab after at least a 6-month drug holiday. The cohort was divided into 2 groups: a “therapeutic drug monitoring (TDM) group,” those who had serum infliximab and ATI measured 1–3 weeks after first reinduction dose, and a “non-TDM group.” Outcomes included results of TDM, occurrence of immediate IR (IIR) and delayed hypersensitivity reactions, and medication persistence at 14 weeks and 1 year.About 76 patients were included: 49 in the TDM group and 27 in the non-TDM group. Of 76, 67 (88%) patients tolerated the first reinduction dose without IR. Formation of ATI was seen in 17 of 49 (35%) patients and was associated with longer drug holidays. Most did not experience IR during the entire therapy course—in 26 of 32 (81%) without ATI and 20 of 27 (74%) in the non-TDM group. Infliximab persistence at 14 weeks and 1 year was 76% and 57% for the cohort, respectively.Infliximab can be safely and effectively restarted after a drug holiday. We suggest performing TDM with a drug-tolerant assay 1–3 weeks after the first reinduction infusion as a means to identify patients at risk for severe IIR at the second dose. Infliximab (IFX), a chimeric IgG1 monoclonal antibody against TNF, is highly effective in the treatment of luminal and fistulizing CD as well as UC.9 Multiple studies have demonstrated an association between the presence of antibodies to IFX (ATI) and LOR, as well as infusion reactions (IRs).11 The HLA-DQA1*05 allele has been associated with increased immunogenicity to IFX and adalimumab.12 Other risk factors for development of ATI include episodic exposure to IFX compared to scheduled maintenance therapy.10 Long drug holidays have been associated with a high risk for immediate IR (IIR) and delayed hypersensitivity reactions (DHRs).14 However, recent studies evaluating IFX restart following a drug holiday have suggested that it may be performed safely and effectively, even for patients who previously discontinued IFX therapy due to LOR.15–18Among patients with LOR to IFX, one important mechanism is immunogenicity, that is, host antibodies against IFX.We sought to clarify the role of proactive assessment of therapeutic drug levels and ATI in the setting of restarting IFX therapy in patients who were previously exposed but who had a treatment interruption. We hypothesized that screening for ATI after the first reinduction dose could be used to identify those patients at risk for a subsequent hypersensitivity reaction to IFX. Our study proposes an algorithm for safely reinitiating IFX in select patients.This was a retrospective cohort study performed at 2 IBD centers in the United States: The University of Chicago Medicine Inflammatory Bowel Disease Center and The Crohn’s and Colitis Center at the University of Miami Miller School of Medicine. Through a systematic review of our medical records from January 2014 onward, we identified all patients with IBD who had previously received IFX treatment, had a drug interruption/holiday of minimum 6 months, and who were subsequently restarted on IFX. At the treating clinician’s discretion, some patients followed the outlined protocol  and had The patients were premedicated at the time of infusions. All patients received intravenous diphenhydramine and oral acetaminophen. Most patients also received intravenous corticosteroids. Patients received their second infusion dose between 2 and 4 weeks from the first infusion. All but 2 patients had a minimum follow-up period of 1 year at the time of the last data analysis.19 IIRs are defined as those during the infusion or within 1–2 hours of its completion and DHRs first manifest more than 24 hours post-infusion, usually producing serum sickness-type symptoms. The reactions were further determined to be mild, moderate, or severe. Mild and moderate reactions subside after pausing the infusion and allow for the completion of the infusion after a break, with or without intravenous corticosteroids, or at a slower infusion rate. Severe reactions are those which necessitate cessation of therapy due to significant cardiovascular or respiratory symptoms.For this analysis, we used the World Health Organization nomenclature for the classification of IRs to immunoglobulins into 2 types—immediate and delayed.Analysis of serum samples for TDM was performed by several different laboratories. At The University of Chicago Medicine Inflammatory Bowel Disease Center, most samples were analyzed using solid-phase detection techniques (electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay) performed by LabCorp, Mayo Clinic Laboratories, Quest Diagnostics, and Inform Diagnostics. About half of the patients had ATI measured as a “reflex” only if the IFX level was under a predefined threshold. At The Crohn’s and Colitis Center at the University of Miami Miller School of Medicine, all but one patient had TDM performed using the PROMETHEUS Anser IFX homogeneous mobility shift assay. Regardless of the assay used, any level of detectable antibodies was considered ATI positive.The medical records were reviewed retrospectively to obtain standard demographic data, smoking status, IBD clinical characteristics , reason for initial discontinuation of IFX treatment , duration of drug holiday, and other IBD therapies used prior to restarting IFX therapy.We also collected the following information on the IFX restart period: age at restart, therapy used (IFX vs the biosimilar IFX-dyyb), concomitant immunomodulator , reason for stopping therapy , duration on therapy, and characteristics of any IIR or DHR. Additionally, for the TDM group, serum IFX level, ATI level, and the laboratory performing the testing were recorded.The co-primary endpoints were persistence of IFX therapy, noted at 14 weeks and 1 year, and safety of restarting the therapy. We used persistence of therapy as an indicator for response to therapy and we defined safety as the absence of IIR.P values are 2-sided. Descriptive statistics were reported as percentages, mean values, and standard errors of the mean. Univariate analysis was performed to compare baseline characteristics between patients under TDM and patients without TDM by using chi-square tests for categorical variables and analysis of variance (ANOVA) for continuous variables. Logistic regression analysis was used to assess the relationship between the class of TDM and clinical outcome of interests, which include initial IR, subsequent IR, DHR, ATI formation, 14-week medication persistence, and 1-year medication persistence. ANOVA was used to compare the length of drug holidays and 1-year medication persistence. A Kaplan–Meier curve was used to compare the cumulative probability of medication persistence between ATI-negative TDM and non-TDM groups.Statistical analyses were performed using the Statistical Analysis Systems (SAS) Software program . The α-error was set at 0.05 and reported A total of 76 patients were included, 49 patients in the TDM group and 27 in the non-TDM group. Patient baseline characteristics are given in The reason for discontinuation of the first therapeutic course with IFX was LOR or insufficient response to IFX in nearly half (45%) of our cohort. The specifics regarding the nature of the first therapy course, such as the schedule of administration (episodic vs continuous), whether dose optimization was attempted and whether evaluation for disease activity and presence of ATI prior to discontinuation were assessed, were not available to us due to the retrospective nature of this study. Importantly, patients who had reported previous IRs to IFX were not offered an attempt at IFX reinitiation.−1 through Prometheus and 64 ng mL−1 through LabCorp) following the first restart infusion. In these 3 patients, the IIRs were non-life-threatening and they were able to complete the first dose after a pause in the infusion and additional diphenhydramine. The specific reactions were jaw pain in the patient with ATI of 100 U mL−1 (Prometheus), pruritis and throat discomfort during the infusion in the patient with ATI of 64 ng mL−1 (LabCorp), and sensation of body warmth in the non-TDM group patient.Our protocol measured ATI after the first reinduction dose which risks missing patients who have preexisting ATI. The cohort had a total of 3 patients (4%) who experienced an IIR during the first restart dose: 2 were in the TDM group and 1 in the non-TDM group. Both patients in the TDM group were found to have ATI (100 U mL−1 through Prometheus) and the others were continued with further infusions. The incidence of IIR with the first dose was similar between the 2 groups (P = .94). IRs are summarized in One had discontinuation of therapy following the first infusion (patient with ATI of 100 U mL−1 through LabCorp). The other 3 had ATI of 907 U mL−1 (Mayo), 309 µg mL−1 (Arup), and 24.5 U mL−1 (Prometheus). The patient in the non-TDM group developed a rash and hypotension more than 24 hours after the infusion for which he was admitted to another hospital. Unfortunately, the patient was lost to follow-up after this event and no further information could be obtained.Our cohort identified 7 patients (9%) who experienced a DHR with the first restart dose—6 were in the TDM group, 4 with positive ATI. One of these patients also experienced an IIR with the first dose , 208 ng mL−1 (LabCorp), 64 ng mL−1 (LabCorp), and 8.8 U mL−1 (Prometheus). The patient with an ATI level of 220 ng mL−1 (LabCorp) was admitted for the second dose so that it could be given in a more controlled setting and she could be observed thereafter. Two of the 4 (those with ATI levels of 220 ng mL−1 through LabCorp and 8.8 U mL−1 through Prometheus) responded well to therapy, without any immune-related adverse events and were still receiving IFX at their last follow-up . The patient with an ATI level of 208 ng mL−1 (LabCorp) developed an IIR with the second restart dose (flushing and tachycardia). He was able to complete the infusion with additional medications and a pause but further therapy was discontinued. The patient with an ATI level of 64 ng mL−1 (LabCorp) who had throat discomfort and pruritis with the first infusion developed bothersome classic serum sickness-like DHR prompting discontinuation of IFX after 4 doses. This was surprising as this level of ATI is generally considered low and thus expected to be clinically insignificant.Four of the patients with ATI continued with further therapy at the discretion of the treating physician, with the rationale being that ATI levels were considered low and/or due to the necessity of the therapy. The levels of ATI in these 4 patients were 220 ng mL−1 (Quest), 13 mcg mL−1 (Mayo), and 19 mcg mL−1 (Mayo). The patient with serum IFX of 13 mcg mL−1 (Mayo) had TDM following the IIR (pruritis and urticaria) with the second infusion and was found to have a serum IFX level of 1.3 μg mL−1 with ATI of 705 U mL−1 (Prometheus). The patient who had an IIR at 9 months from restart  continued therapy until a year from restart. She has Crohn’s disease and had a good response to re-therapy, with normalization of C-reactive protein and calprotectin. Interestingly, her therapy was discontinued because she was found to have high ATI with no IFX level on TDM at 1 year from restart  and was transitioned to adalimumab.The remaining 32 patients did not have detectable ATI ; these patients were allowed to continue with the treatment course. Three patients without ATI developed subsequent IIR—2 during the second infusion and 1 after a maintenance infusion 9 months from restart (developed urticaria). All 3 IIRs were mild to moderate in severity. The patients were able to complete the infusion following a pause, with restart at a slower rate and an additional dose of intravenous diphenhydramine; however, IFX therapy was discontinued thereafter. Their serum IFX levels following the first restart dose were 2.09 mcg mL−1 every 6 weeks, with clinical response to therapy, without any immune-related adverse events, and was still receiving IFX at her last follow-up (67 months from restart).One patient had no detectable serum IFX but also no ATI at first TDM (performed at Mayo). Subsequent TDM tests, done through various laboratories , showed detectable IFX levels without ATI. She required dose intensification over the course of therapy, most recently receiving 10 mg kgIn addition to the 6 patients in the TDM group who developed DHR with the first dose, another patient without ATI developed a DHR 6 months from restart.−1 and 100.0 U mL−1 (both through Prometheus).Five patients in the non-TDM group developed moderate-to-severe IIR; 4 of these patients required immediate termination of the infusion and treatment with intravenous steroids and diphenhydramine. In all cases, this was during the second restart infusion and further IFX therapy was discontinued. Two of these patients had serum IFX and ATI measured prior to the second dose; however, the results were not available at the time of the second infusion. They both had high levels of ATI—47.7 U mLP = .31) or DHR (P = .79). However, IRs were more severe in the non-TDM group.When comparing rates of IR between the ATI-negative TDM group and the non-TDM group, there was no statistical difference in rates of IIR  remained on IFX at 14 weeks and 18 of 30 (60%) remained at 1 year from restart. Two patients were excluded from the 1-year persistence analysis as they did not reach the 1-year mark at the time of analysis.P = .64 for 14 weeks and .35 for 1 year). Results are summarized in Of 27 patients in the non-TDM group, 18 (67%) were on IFX at 14 weeks and 14 (54%) had IFX persistence at 1 year. One patient did not reach the 1-year follow-up mark from restart. The rate of medication persistence at either time point was not statistically different from that of the ATI-negative patients in the TDM group (P = .83), age at IFX restart (P = .76), smoking status (P = .72), duration of drug holiday (P = .35), or the use of concomitant IMM at restart (P = .49).We next looked at the relationship between clinical parameters and IR. Univariate logistic regression analysis showed that IR rates were not associated with age at IBD diagnosis (P = .0385). There was no association with prior concomitant IMM use .In the TDM group, the presence of ATI 1–3 weeks following the first restart dose was associated with a longer drug holiday , younger age at restart of IFX , a shorter drug holiday , and the concomitant use of an IMM at restart .IFX persistence at 14 weeks was associated with a younger age at IBD diagnosis  and a shorter drug holiday . There was no association with concomitant IMM use  or the reason for discontinuation of the first course of IFX therapy.IFX persistence at 1 year was associated with a younger age at restart of IFX  and retrospectively analyzed their bio-banked serum samples for IFX trough levels and ATI. They demonstrated that measuring ATI prior to the first restart dose was not helpful in predicting response or safety of reinitiation as all patients had undetectable ATI. However, the absence of ATI in an early sample after reexposure to IFX was associated with both short-term responses and decreased risk of IR.18 Ours is the first study to examine this proactively and in real-life practice.We examined the use of TDM in a consecutive cohort of patients with IBD who were being retreated with IFX following a drug holiday to identify patients who are at risk of serious IR and unlikely to benefit from IFX retreatment. Patients with IBD who develop ATI have double the risk of developing any IIR and nearly a 6-fold risk of serious IRs,We show that assessing serum concentrations of drug and antidrug antibody status after the first restart infusion can identify patients who develop ATI and are thus at risk for early IIR as well as serious IIR. The logic of such a protocol is that after a long dose interruption, memory B cells that recognize IFX have not been stimulated by cognate antigen and thus the ATI measurement will be negative if done prior to the first restart dose. Yet once a patient with memory B cells specific for IFX is rechallenged with antigen, they then generate ATI. We therefore reasoned that measurement of ATI after the first restart dose would be better than before restart.24 Findings of these previous studies are summarized in Previous studies on reinitiation of IFX therapy have reported IR in 0%–39% of patients.14In the non-TDM group, 5 patients developed IIR during the second dose, 4 of which were severe. Thus, although the absolute number of IIR with the first 2 infusions did not significantly differ between the TDM and non-TDM groups, qualitatively the IIRs were more severe in the non-TDM group. All severe IIRs occurred during the second restart dose, which is concordant with the findings by Steenholdt et al.20 assessing the risk of IR according to patients’ ATI status, there was not a difference in risk of DHR between ATI-positive and ATI-negative patients in 710 patients who experienced DHR. These findings suggest that patients should be warned, especially if the ATI assay is not drug-tolerant, that they may still develop a DHR, albeit the risk is low.DHR occurred in 12% of the cohort, 4 of 9 (44%) of them occurred in patients who were found to have positive ATI following the first restart dose and 3 of 9 (33%) in patients who had no ATI. In a meta-analysis by O’Meara et al18 Brandse et al17 included a cohort of 29 patients with CD who had been reinduced after sequential use of IFX and adalimumab. At the end of their 18-month follow-up period, 62% of the patients remained on IFX and 72% at 1 year. Another study published by Gagniere et al15 included 61 patients with CD who had also been reinduced with IFX after failing treatment with both IFX and adalimumab. The probabilities of remaining on IFX after reintroduction were 60% and 51% at 1 and 2 years, respectively. As in our study, short-term IFX persistence and long-term IFX persistence were associated with a shorter drug holiday. Furthermore, our study also showed that short-term IFX persistence and long-term IFX persistence were associated with a younger age at restart, which has not been previously described.In this study, we were able to demonstrate that restarting IFX following a drug holiday is clinically effective, as over half of the patients who were restarted on IFX had medication persistence at 1 year. Younger age at restart of IFX and a shorter drug holiday were both associated with IFX persistence at 14 weeks and at 1 year. Additionally, we found that a longer drug holiday was associated with the presence of ATI. Concomitant use of an IMM at restart was only associated with short-term (14 weeks) IFX persistence. In agreement with our results, several studies have shown that IFX reintroduction is clinically effective and that patients with prior LOR to IFX can be recaptured with retreatment. Baert et al. studied a cohort of 128 patients . They reported an 84.5% response at week 14, 70% at 1 year, and 61% at more than 4 years.26 as well as improve the efficacy of IFX therapy,2 potentially due to the observed reduction in ATI formation with their use.27Concomitant use of IMM at restart has also been explored. It has been shown to have a protective role in reducing IR with IFX therapyIn our study, we did not find an association between IMM and ATI formation, IR or long-term IFX persistence, but we did find an association between the use of IMM and short-term IFX persistence (OR 3.5). However, as less than half of our cohort was started on IMM at the time of IFX restart, we likely did not have sufficient patients to reach firm conclusions about the effects of concomitant IMM use.One of the limitations of this study is the small sample size. However, this is the first study that assesses proactive TDM in the setting of IFX reintroduction in real-life practice. Another limitation is the retrospective study design and lack of detailed historical data related to their first time on IFX. This also reflects that both our centers are tertiary referral centers wherein most patients have been on multiple therapies previously. Additionally, we used the persistence of IFX therapy as a surrogate marker of response, with the assumption that each treating physician is assessing their patients for response and not continuing therapy if the patient is not showing improvement on it. Having had disease activity scores pre-restart and during therapy as well as objective markers of biochemical response would have provided a better assessment of response to therapy. We did not include these in the study design as there was no standardization in how clinical assessments were performed by the different treating physicians, which is another limitation of this study. A prospective study, with a standardized assessment of disease activity after IFX restart, would be of value to better study this therapeutic option.28A strength of our study is provided by the different practices employed at each center which provides some range of approaches to this common clinical scenario. For example, we employed different premedication protocols and used different laboratories for TDM. Because different laboratories were used, we cannot set an ATI threshold above which patients should not be retreated. In general, the presence of ATI in the absence of detectable IFX should lead to IFX discontinuation, especially if measured only a few weeks after a dose. However, ATI threshold that should preclude continuation of therapy in the presence of detectable IFX is less clear. It has been demonstrated that drug-sensitive assays can underestimate ATI as they do not detect ATI in the presence of a drug. In our patient cohort, approximately half of the patients had TDM with drug-sensitive, rather than drug-tolerant, assays. As such, it is likely that additional patients in the TDM group had ATI that was not reported by the laboratory due to the type of assay, thus limiting the ability to flag patients who are at risk for IR or are less likely to benefit from retreatment with IFX. On the other hand, drug-tolerant assays have increased ATI detection which may incorrectly deter use of IFX, as it is known that low levels of transient, nonneutralizing ATI may be treated through with a low risk of IR and are clinically insignificant.29 The increased use of IMM in the non-TDM group may have also decreased IR in that group and in general should be considered in patients restarting IFX. This study challenges the previous dogma of “once exposed to infliximab, if you stop, you cannot go back.” Given the need for additional therapies and options for patients with IBD, reintroduction of IFX should be considered in appropriate patients.In summary, IFX can be safely and effectively restarted in patients with IBD who have had a drug holiday and who have failed multiple subsequent intervening therapies. A prospective study looking at markers of clinical response  and rates of remission is needed to study the specific efficiency of this treatment option. Based on our experience, we suggest that TDM be performed 1–3 weeks after the first IFX restart infusion as a means to identify patients at risk for IR at the second dose. Patients should be warned, especially if the ATI assay is not drug-tolerant, that they may still develop an IR and that they are at risk, albeit low (12%) of developing a DHR. It is a good idea to explain to patients typical signs and symptoms of a DHR including migrating polyarthralgia and jaw pain.


A significant proportion of pregnant women and women in the early postpartum period suffer from mental health problems. The COVID-19 pandemic represents a unique stressor during this period and many studies across the world have shown elevated rates of postpartum depression (PPD).In this multicenter two-phase observational prospective cohort study, we aim to assess the prevalence of anxiety prior to labor , as well as PPD at 6–8 weeks postpartum using the Edinburgh Postnatal Depression Scale (EPDS).Of the 330 women analyzed, 13.2% reported symptoms of depression using EPDS cut-off score ≥13. High antenatal levels of anxiety (24.8% scored ≥10 in GAD-7) were documented. A significant proportion of postpartum women reported a decrease in willingness to attend antenatal education courses (36%) and fewer antenatal visits to their obstetrician (34%) due to pandemic. Higher antenatal anxiety increased the odds of being depressed at 6–8 weeks postpartum (EPDS ≥13).Compared to reported prevalence of PPD from previous studies before the COVID-19 era in Greece, we did not find elevated rates during the first wave of the pandemic. High anxiety levels were observed indicating that there is a need for close monitoring in pregnancy during the pandemic and anxiety screening to identify women who need support in the pandemic era. A well-planned maternity program should be employed by all the associated care providers to maintain the proper antenatal care adjusted to the pandemic strains as well as a follow-up after labor. This is not unprecedented since there is previous experience of mental onus in recent outbreaks3 and all clinical manifestations are exaggerated during lockdown periods, by the fear of forthcoming socioeconomic crisis and loss of employment4.COVID-19 viral pandemic has imposed a great worldwide psychological burden attributed to the fear of wellbeing and to an immediate threat to human life per se. The SARS-CoV-2 virus is associated with profound psychological implications ranging from stress and generalized anxiety disorder to depression and suicidal tendencies7. In the context of the COVID-19 pandemic, emotions of fear seem to be more prevalent (49%) than before (7.5%) and joyful expectations are overclouded by the pandemic (63% before vs 17% after)8.Pregnancy is a period of conflicting emotions ranging from joyful expectations of the forthcoming baby to the fear of childbirth, trait anxiety and distress over the couple’s adjustment, while diagnosis of clinical depression intensifies the previous conditions9. In a recent study of Centers for Disease Control and Prevention, women were strongly advised to self-isolate regardless of quarantine periods10.COVID-19-related concerns surfaced because this viral infection is considered to be a state of increased risk of severe illness, as was reported in previous outbreaks and in a study from Italy during the COVID-19 pandemic11.In this framework, pregnant women are reported to have higher levels of anxiety augmented by the protective measures taken relevant to perinatal care and labor. In most countries women are forced to separate from their supportive network due to a strict visitation policy system and present alone in the prenatal appointments and even in labor. Loss of social support and prolonged exposure of pregnant women to stressful events could be a leading pathway to postpartum depression (PPD)14, and the first meta-analysis15 suggests that the pooled prevalence of PPD is 22%, representing a higher rate than before the pandemic16. Studies assessing PPD at 6 weeks postpartum revealed a prevalence of PPD up to 34%18.PPD is defined as a major depression episode with perinatal onset; its prevalence ranges between 6.5% and 12.9%. Several studies regarding PPD in the pandemic have already been published20. In Greece, the reported levels of anxiety, as recorded during the first lockdown period, were >50% with a decreasing tendency towards the end of the restrictive measures reaching 34–40%, probably due to the efficacious control of the pandemic21.According to a recent meta-analysis, the overall prevalence of perinatal anxiety has almost tripled during the COVID-19 pandemic from 15% to 40%Concerning PPD, however, to the best of our knowledge there are no studies assessing its prevalence during COVID-19 pandemic in Greece. Given this gap in the literature, we aim to assess the prevalence of PPD and anxiety symptoms in the Greek puerperal women and to evaluate the association of COVID-19 related concerns with antenatal anxiety and PPD symptoms.This is a multicenter two-phase observational prospective cohort study conducted from June 2020 (one month after the first lockdown in Greece) to August 2020, involving 5 hospitals, throughout Greece. The study was approved by the ethics committees of all hospitals, and it was registered on clinicaltrials.gov. All procedures were in accordance with the World Medical Association Helsinki Declaration and signed informed consent was obtained from all participants.In the first phase of the study, all parturients presenting for labor during June 2020, were asked to participate. Exclusion criteria were inability to read and write in Greek, history of an acute psychotic episode, intoxication or confusion. Each local investigator explained the aims of the study and a written informed consent was signed. The set of Phase 1 questionnaires  was administered to all parturients. Demographic and medical variables were also recorded from the medical records. The second phase was conducted at 6–8 weeks postpartum by telephone and all women were asked to complete the Edinburgh Postnatal Depression Scale (EPDS). This is because PPD usually manifests at 6–8 weeks postpartum and in order to avoid the confounding impact of maternity blues (30–80% during the first 15 days postpartum). If a woman recorded suicidal ideation or a high score in the study tools, she was referred to a mental health service. Also, they were informed about the healthcare services and help lines operated during the pandemic.25. Two parturients that were not included in the study sample were involved in this research by means of assisting in developing these research questions and in their prioritization in this structured questionnaire. Reliability analysis revealed a good strength of associations .Sociodemographic and pregnancy variables were collected through a questionnaire and medical records. COVID-19 related concerns were collected using a 38-items structured questionnaire grouped in 5 domains . Fourteen items were dichotomous (Y/N) or with multiple responses  and 24 items were scored on a 10-point Likert scale . The questionnaire was developed specifically for this study after careful examination of the available regarding common concerns and anxieties among pregnant women. Subsequently all items were reviewed by all authors based on their expertise, specialty, and empirical knowledge at the first wave of pandemic in Greece, and consensus was established26, which is a 10-item self-report tool. Mothers were asked to check the response that is closest to how they have been feeling in the last 7 days in a 4-point Likert scale . PPD was defined as an EPDS score of ≥13. The reliability of the scale was high .PPD was assessed with the EPDS27.Anxiety symptoms were assessed by the Greek version of GAD-7 which rates the frequency of anxiety symptoms in the last 2 weeks on a Likert scale ranging from 0–3  with a standard cut-off point of ≥10 indicating moderate to severe anxiety symptomsAll statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 26 for Mac. Summary statistics for all variables were calculated using means and standard deviation for continuous variables and frequency and proportions for categorical variables. The primary outcome variable was the EPDS score at 6–8 weeks postpartum. To assess the association of COVID-19 related concerns with anxiety and depressive symptoms, Pearson’s correlations tests were carried out, followed by partial correlations adjusted for age, demographic and obstetric variables. To assess the independent associations of COVID-19 related concerns with anxiety and depression, two separate binary logistic regression analyses were performed with dependent variable the GAD-7 score (<10 and ≥10) and EPDS score (<13 and ≥13), respectively. Independent variables in each analysis were the most significant associations of COVID-19-related concerns derived from the correlation analysis.In total, 339 parturients enrolled in the study. There was a 2.65% dropout rate between the first and second phase of the study (9 participants were not located at 6 weeks). Finally, the sample consisted of 330 women with a mean age of 32.3 years (SD: 5.6) , at a gestational age of 38 weeks (SD: 1.9). The majority were married , 63.1% were employed (n=209) and 85.5% (n=282) had completed secondary education (high school). Labor was conducted via caesarean  or vaginal  delivery. Preterm deliveries accounted for 10% of the study sample (n=33) and term deliveries for 90% (n=297).In total, 43 mothers scored 13 or above in EPDS indicating that the prevalence of MDD (Major Depressive Disorder) was 13.2%. As far as anxiety symptoms are concerned, the mean score of GAD-7 before delivery was 6.3±5.0 indicating mild anxiety for parturients, while one-fourth  could be identified as having probable, generalized anxiety disorder, when a cut-off point of ≥10 was used.In univariate analysis , a numbeSeparate univariate analysis  showed tSubsequent regression analysis  showed tUnivariable analysis in 30. Gonidakis et al.29 found that the prevalence of PPD one month after delivery was 12.5% using the cut-off point of 12. Similarly, Koutra et al.30, using the same cut-off with our study (≥13), found that the prevalence of PPD was 13.6% at 8 weeks postpartum. Moreover, Leonardou et al.28 used the cut-off point of 11/12 and found that the prevalence of PPD was 12.4%. Vivilaki et al.31 in 2007–2008, in a sample of postpartum women, reported that 6.7% of mothers diagnosed with major depression, 11.7% with moderate and 31.7% with mild depression according to BDI-II scores. Therefore, the prevalence of PPD during the first phase of COVID-19 pandemic was not increased, most probably because Greece was not hit hard by the first pandemic wave. Confirmed cases during the study period (June 2020–August 2020) ranged from 2.937 on 1 June to 10.757 on 1 September; the latter represents a rate near to 1% of the total population. Moreover, the number of deaths were low compared to other countries (n=271 on 1 September 2020). Moreover, our study was conducted over a period where no strict restrictive measures were implemented. Although a number of studies report an increase in PPD, a recent meta-analysis showed that even though the EPDS score was higher in the pandemic compared to the nonpandemic period, it did not reach the level of statistical significance32. In contrast, parturients reported high antenatal levels of anxiety, since 24.8% of them scored ≥10 in GAD-7. A recent meta-analysis, before the pandemic showed that self-reported anxiety symptoms prevalence was 24.6% in the third trimester and the overall prevalence of any anxiety disorder was 15.2%19. During the pandemic, two studies using GAD-7 reported lower rates compared to our study, of moderate anxiety (14% and 21.6%) in countries hit hard by COVID-1933. Similarly, in a multinational study of 3097 pregnant women, 11% scored ≥10 in GAD-713. Exception to these rates is the study of Preis et al.33 which revealed substantial levels of moderate to severe anxiety up to 43.3%. Evidence suggests that prenatal anxiety increases with the severity of the measures imposed. Interestingly, our recruitment was undertaken in a period where strict restrictive measures were not applied since Greece was not hit so hard in the first pandemic wave. One explanation is that family and social support during pregnancy in Greek families is very high and this was disrupted during lockdown, right before recruitment. Additionally, parturients were not allowed to have companions in the antenatal visits and in the hospital before delivery. By tradition, in Greece parturients have frequent visits to the hospital, and social support is associated with increased mental health and emotional well-being34. Still, we cannot ignore that anxiety measurement (even if GAD refers to the last 2 weeks) was undertaken right before delivery and this per se represents a stressful moment.In our study, the prevalence of PPD at 6 weeks postpartum was 13.2%. Data from Greece regarding the prevalence of PPD prior to the pandemic have revealed similar rates35. However, even if the evidence was against transmission, parturients could be influenced by the so-called infodemic phenomenon. Moreover, antenatal care was correlated with GAD-7 scores probably because of the fear of transmission. Finally, anxiety symptoms were associated with the decreased contact with the partner, probably due to lack of emotional support.Our findings suggest that parturients were more anxious when they believed that SARS-CoV-2 virus could be transmitted by them to their baby. Anxiety could be due to lack of solid scientific evidence about transplacental transmission at the time the study was conducted37. In general, little is known about predictive risk factors for anxiety disorders in pregnancy and postnatal period, being a neglected area of research42. In our study during the pandemic, parturients being at higher risk for generalized anxiety disorder were those whose family relations were affected the most. This is indicative of the importance of marital and social support during pregnancy that a woman calls on during stressful events43.In our study, anxiety of advanced maternal age mothers was correlated with the belief that the virus could be transmitted to the baby, something that was not observed in the younger group. Advanced maternal age and the fear of related complications in pregnancy could be the explanation. In contrast, younger mothers were anxious when they have lost their daily contact with their husband. Anxiety of preterm pregnancy mothers (in contrast with term pregnancies) is not associated with beliefs about transmission to the baby probably because their primary source of anxiety is the survival or the complications to the newborn due to the preterm pregnancy itself44. Additionally, women who experience higher levels of support from their partners during the second trimester of pregnancy present lower levels of psychological implications postnatally44. Therefore, it comes as no surprise that COVID-19 outbreak preventive measures related to partners’ distancing implemented in our study population could predispose to PPD. Moreover, anesthesiologists who come in close contact with severely ill patients are exposed to airborne viral transmission and are among the medical professionals of highest risk of infection45. Furthermore, their contribution to the current pandemic management is vastly praised by the social media and the public46. Considering that the public is overexposed to social media and TV news as a source of information during this pandemic47, parturients were directly exposed to the infodemic phenomenon. However, concerning predictive factors, in our study only high levels of anxiety were associated with postnatal depression, a finding consistent with the literature50.Depressive symptoms were correlated with various COVID-19 concerns. The PPD was positively associated with the reduced daily contact with the husband and with the fear that anesthesiologists could be a possible source of transmission. Previous studies related to SARS outbreak showed that the relationship with the partner was compromised due to interruption of intimacy and fear of transmission51. Finally, the study was conducted during the first pandemic wave where COVID-19 confirmed cases and deaths were not high in Greece. However, to the best of our knowledge, this is the first study in Greece assessing the prevalence of PPD during the COVID-19 pandemic.Our study has some limitations that need to be addressed. One lies in its cross-sectional nature. Yet it involves 5 centers throughout Greece . Moreover, it assesses depressive symptoms at 6 weeks postpartum in order to avoid the ‘baby blues’ period. Although we used the most common PPD tool, we did not confirm the diagnosis using a structured interview. Another limitation is the fact that the 6 weeks’ postpartum assessment was performed by telephone contact where women underreport their symptoms. However, there are reports that EPDS administration over the telephone has high reliabilityUnfortunately, the pandemic is still on the rise and new mutations appear that may be a trigger for psychological distress for the population and of course for pregnant women. Future longitudinal research is needed to better identify high risk parturients and to provide the best maternal and child care both prenatal and postnatal. Future research should focus on psychosocial features such as the general support to pregnant women, e.g. marital and social support during pregnancy as well as medical staff support just after the labor, with well validated tools. Finally, since countries do not have the same infection rate throughout their region (and in different times this was the case in Greece), it is important to conduct further prevalence and longitudinal studies (throughout pregnancy) with larger samples in different regions to identify the effect of covid-infection rate in maternal psychological distress.52, especially in those with high antenatal anxiety which should be screened during pandemic in pregnancy as well as before labor.PPD rates according to our results did not increase during the first phase of the pandemic in Greece. It is known that many people do not develop psychopathology soon after a traumatic event and this may be the case in our sample. On the other hand, anxiety levels seem to be increased, indicating that there is a need for close monitoring and anxiety screening in order to identify women who need support in the pandemic era. Maternity care providers should employ an informative well-structured antenatal program in respect to the parturients’ concerns related to this pandemic. If restrictive measures are implemented, telephone contacts, video calls with the specialists or online antenatal courses could be applied. In such antenatal programs, enhancement of social support of pregnant women (e.g. involvement of husband and other close relatives) should be included. It is important to call attention to the need for close monitoring of antenatal care during the pandemic since a significant proportion of women were forced to skip the usual prepartum care appointments, like in previous outbreaks. Decreased antenatal care not only poses a medical danger to the mother and the fetus but also relates to PPD symptoms. Additionally, anesthesiologists should address parturients concerns. Safe emotional contact with their partners should be always advocated. Finally, a follow-up using teleconference in the first weeks of labor should be established by midwives in order to identify symptoms of PPD


Urgency urinary incontinence (UUI) is characterized by involuntary urine leakage immediately after reporting of sudden, compelling desire to void. Electrostimulation and non-invasive neuromodulation have been considered as the first and third line of UUI treatment but there is a lack of consensus on which parameters are more efficient. Thus, this study aims to compare the effect of low versus medium frequency currents on urinary incontinence severity and quality of life in women with UUI complains.It will be a randomized controlled trial with 5 arms, double-blinded (outcome assessor and statistician). The study was approved by the Research Ethics Committee (CAAE: 11479119.9.0000.5406) and has been prospectively registered on the Brazilian Registry of Clinical Trials (RBR-8bkkp6). Concerning, double-blind process, the blinded assessor will be responsible for evaluate primary and secondary outcomes at baseline and follow-up without information about allocation and the statistician will perform analyses without information about group codification. One hundred and five participants will be randomized to receive: (1) Transcutaneous tibial nerve stimulation-low frequency, (2) Transcutaneous tibial nerve stimulation-high frequency, (3) Aussie median frequency, (4) Interferencial median frequency or (5) High voltage stimulation. The application will be performed during 20 sessions of 45-minutes, twice a week for 10 weeks, in groups of maximum 5 participants. The participants will be evaluated before treatment (baseline- 0 week), during the treatment (5 weeks) and after the last treatment session (10 weeks). The primary outcomes measures will be UI severity and quality of life, and the secondary outcome will be pelvic floor strength. Statistical analysis will be performed using SPSS software version 24.0 for Windows . The variables will be described by the mean and 95% confidence interval. The distribution of normality will be analyzed by the Shapiro-Wilk test. ANOVA for repeated measures will be performed. Mauchly’s test the hypothesis of sphericity and when if this violated the hypotheses, the analyses will be based on the Greenhouse-Geisser test. Peer-to-peer comparisons will be performed using the Bonferroni Post-Hoc test. The significant level adopted will be 5% (p ≤ 0.05).This study will enhance knowledge about effect of different neuromodulation currents in the improvement of UUI. Urinary incontinence (UI) is a public health problem and affects millions of women worldwide . DefinedAlthough the electrostimulation of pelvic floor muscles (PFM) has been considered as the first line of treatment for UUI , neuromoThe most therapeutic neuromodulation TENS parameters used for urgency symptoms treatment are low pulse width (200 μs) and low frequency (10 Hz) , but othThe Aussie current has been suggested as an option due to its comfort during application, as well as reducing the impedance of the skin ensuring that the pulse of the current reaches deeper tissues . The IntDespite the neuromodulation options described in the literature for improving UUI, the evidence is not conclusive, mainly because is still not clear whether the improvement in symptoms occurs due to the application of a specific type of electric current or if the parameters applied are responsible for the improvement. Therefore, the objective of the study will be to compare the effects of applying low frequency currents versus medium frequency currents on severity and quality of life at before treatment (baseline- 0 week), during the treatment (5 weeks) and after the last treatment session (10 weeks) in women with UUI. Our hypothesis is that medium frequency currents may be more effective in UUI treatment when compared to low frequency currents, considering that higher frequencies reduces skin’s impedance which implies delivery of the electrical current to deeper tissues and promotes more assertive stimulation to the tibial nerve which is involved on bladder activity modulation.A five-arm, parallel randomized controlled trial, double-blinded (outcome assessor and statistician), will be performed. All personal data will be confidential. The study follows the TIDieR (Template for Intervention Description and Replication) checklist , the 201The study was approved by the Research Ethics Committee (CAAE: 11479119.9.0000.5406). All participants will be informed about the research and will sign a consent form. The protocol of this study has been prospectively registered on the Brazilian Registry of Clinical Trials (RBR-8bkkp6). Participants will be informed about all study procedures and asked to sign the Informed Consent Form prior to their enrollment in the study.Women with UUI will be recruited from a waiting list from the Specialized Center for Women’s Health Rehabilitation of the São Paulo State University, Marília, São Paulo, Brazil.Potential participants will be eligible for the study if they are between 18 to 80 years old with complaints of UUI. Potential participants will be ineligible for the study if they have cognitive impairment, psychiatric disorders, pregnancy, diagnosis of neurogenic bladder, pelvic organ prolapse greater than grade II, ongoing signs and symptoms of urinary tract infections, use of anticholinergic drugs, antagonists calcium, beta-antagonists, and dopamine antagonists, cannot commit to participating for the duration of treatment and those who do not sign the consent form.Potential participants who fulfil the eligibility criteria undergo baseline assessments. The protocol will include anamnesis and physical assessment, the clinical screening will be carried out at São Paulo State University and will take approximately 30 minutes.A registered physiotherapist with 8 years of experience on urogynecological examination, and who has a Master in Gynecology and Obstetrics field supervised by physiotherapist that has more than 30 years of urogynecological assessment experience will perform the evaluation. Both assessors will not be enrolled on the screening, randomization and/or treatment routine to ensure blinding assessment regardless the treatment type.The first step of data collection will be related to anthropometric data , personal information, demographic partner  and pathological and clinical history. The personal data of the participants will be numerically coded and stored in a database.The second step of data collected will be the physical examination. PFM function will be assessed through the PERFECT scheme  and willThe same blinded assessor will evaluate the participants before treatment (baseline- 0 week), during the treatment (5 weeks) and after the last treatment session (10 weeks).n2) of 0.03. Considering that we selected 5 therapies with potential treatment effects and we expect minimal differences between them, we considered the small effect size calculated by this appropriated method. In addition, we selected a power of 0.85, α error probability of 0.05, number of groups 5, number of measures 3, correlation among repeated measures of 0.5 and nonsphericity correction of 1 and a 10% dropout rate which estimated the recruitment of 105 participants, 21 per group.A priori sample size calculation was performed using the G* Power 3.1 software. As the innovative comparisons methodology of this trial did not allow us to state our sample calculation on literature data, we calculated our sample size, based on F tests, ANOVA: repeated measures, within-between interactions, an effect size f of 0.17 were calculated considering a direct method using a small partial eta square .If all inclusion criteria are fulfilled and if the presence of UUI is determined, the participants will be randomly assigned to receive: (1) Transcutaneous Tibial Nerve Stimulation—Low Frequency (TTNS–LF), (2) Transcutaneous Tibial Nerve Stimulation—High Frequency (TTNS–HF), (3) Aussie Median Frequency (AMF), (4) Interferencial Median Frequency (IMF) and (5) High Voltage Stimulation (HVS). To ensure homogeneous distribution between groups, the participants will be randomly allocated to five therapeutic arms using permuted, block-randomization to balance the number of participants allocated to each group. The permuted block (with 15 participants per block) randomization sequence will be done through the website The intervention will be performed during 20 sessions of 45-minutes, twice a week for 10 weeks. All participants will carry out the treatment in groups of maximum 5 participants in the same room. They will remain seated comfortably during the entire treatment session. All participants will have their tibial nerve stimulated, with the current intensity adjusted to the highest possible sensory level, modified according to their habituation to the current, without reaching the motor threshold or causing pain .TTNS-LF: Symmetrical biphasic pulsed current with 10Hz frequency, a pulse width of 200μs ..21].Before placing the electrodes, the skin will be cleaned with 70% alcohol. All groups will receive transcutaneous electrical stimulation through the tibial nerve for 30 minutes. However, on the high voltage group a third dispersive electrode of 13x9 centimeters will be positioned above the popliteal fossa to ensure the direction of the electrical current from tibial nerve directed to the sciatic nerve .The primary outcomes will be: 1) UI severity and 2) quality of life.1) ISI is a validated questionnaire to Portuguese, that classify UI according to severity by multiplying two simple and brief questions about incontinence frequency and volume. The severity score is stratified into mild (one to two points), moderate (three to six points), severe (eight to nine), or very severe  . The ISI1) Voiding diary is a self-real-life-assessment of voiding habits . The 24-2) The ICIQ-SF is a brief self-administered questionnaire combined severity and bother-score through 4 questions about incontinence frequency, volume, impact of UI in daily life and self-diagnosis questions about mechanism reasons. The higher the score obtained is, the worse the quality of life related to that domain is . The ICI2) The OAB-V8 will be used to assess the impact of overactivity bladder symptoms on quality of life. It is a questionnaire composed of 8 questions about the discomfort caused by the symptoms. The responses range from 0 to 5 points and in the sum of the results, if the total is ≥ 8, it will be considered as a probable diagnosis for UUI . The OAB2) The ICIQ-OAB questionnaire provides an assessment measure for voiding frequency, urgency, nocturia, and UI. It is composed of six specific questions about voiding symptoms correlating with quality of life, and the higher the score the worst the impairment . The ICIThe study will have one secondary outcome: 1) Assessment of the strength of the pelvic floor muscles (PFM) by PERFECT scheme.The PFM assessment will be held before treatment (baseline- 0 week), and after the last treatment session (10 weeks). The first step bladder emptying will be requested to participant. After, the participant will be instructed to lay-down in supine position, with the lower limbs flexed, and the feet on the stretcher . Prior tThe study will be run as a superiority trial. The statistical analysis will follow the per-treatment concept. Statistical analysis will be performed using SPSS software version 24.0 for Windows . The variables will be described by the mean and 95% confidence interval (95% CI). The distribution of normality will be analysed by the Shapiro-Wilk test. To analyse the effect of group and currents, ANOVA for repeated measures will be performed. The Mauchly’s test will be performed to test the hypothesis of sphericity and when if this violated the hypotheses, the analyses will be based on the Greenhouse-Geisser test. Peer-to-peer comparisons will be performed using the Bonferroni Post-Hoc test. The significant level adopted will be 5% (p ≤ 0.05).This study was designed to compare the use of low and medium frequency currents by transcutaneous electrical nerve stimulation for UUI treatment. Concerning the instruments that will be applied during time-points assessments, the questionnaires are widely used to screening and diagnosis of UI and more over to quantify severity and impact on quality of life .The use of TTNS–LF current is common in the literature and widely used in clinical practice to treat urgency related symptoms , althougMedium frequency currents have the advantage of producing smaller pulses during a period, reducing the impedance of the skin, which can generate greater current absorption through deeper tissues, besides, offer more comfortable sensation , 27. StuThe currents that will be used in the study were chosen due to their wide use in clinical practice in several areas of physiotherapy, moreover, to the characteristics of the currents  and the The IMF differential is the production of two medium frequency currents that interfere with each other, which allows the tissue to absorb more deeply  and can In order to maintain the highest level of methodological quality, this RCT will be based on the CONSORT checklist. Participants will be randomized by a blinded assessor and will not receive information about the differences between the treatments offered. The assessors and statistician will not have contact with the participants during the intervention period and will not have knowledge about the group composition.This study arose from the intention to cover the knowledge about electrotherapy for UUI treatment. Stimulation of the tibial nerve with TTNS is a treatment with favorable results, but many gaps on the knowledge remains .The study results will be circulated to peer-reviewed journals, lectures and scientific meetings.This study will help determine which parameters are more efficient in electrical stimulation for the improvement of UUI.S1 Checklist(DOC)Click here for additional data file.S1 Protocol(PDF)Click here for additional data file.S2 Protocol(PDF)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.


Both therapies significantly decreased both CME and SFCT, independent of factors such as age, sex, previous intravitreal therapy, antidiabetic treatment, and the time of diabetes progression. There were no changes in the mean values of CME and SFCT in the untreated eyes. Conclusions: SFCT significantly decreased in response to intravitreal therapy with anti-VEGF or corticosteroids, irrespective of age, sex, previous intravitreal therapy, antidiabetic treatment, and the time of diabetes progression. There was a correlation between the changes in CME and SFCT after intravitreal therapy with aflibercept or dexamethasone implantation. SFCT was not a good predictor of the CME response but could be used to monitor the response to treatment. Local intravitreal therapy only affected the treated eye.Objective: This study aimed to analyze the variation in subfoveal choroidal thickness (SFCT) and its relationship with the variation in central macular thickness (CME) in response to intravitreal therapy with an antiangiogenic (anti-VEGF) drug or corticosteroid in type 2 diabetic patients with diabetic macular edema (DME). Material and methods: This retrospective study included 70 eyes of 35 patients: 26 eyes received 4−5 intravitreal injections of aflibercept, 26 eyes were treated with a single intravitreal implant injection of dexamethasone, and 18 eyes without DME did not receive intravitreal therapy. SPECTRALIS® optical coherence tomography (OCT)  was used to measure the SFCT and CME before and at the end of the follow-up period. Results: The mean reductions in CME were 18.8 +/− 14.7% (aflibercept) and 29.7 +/− 16.9% (dexamethasone). The mean reductions in SFCT were 13.8 +/− 13.1% (aflibercept) and 19.5 +/− 9.6% (dexamethasone). The lowering effects of both parameters were significantly greater in the group treated with the dexamethasone implant ( Diabetes mellitus (DM) is a major public health problem. This is due to the high prevalence rate of diabetes mellitus (DM), the severe health complications DM can cause, and the resulting increase in healthcare costs. The retina is the body structure that most frequently presents microvascular alterations in DM . Of the Diabetic macular edema (DME) is the main cause of blindness in diabetic patients of working age . Up to 1The main risk factors associated with the development of DME are the duration of diabetes, poor glycemic control, and hypertension, with Afro-American heritage and dyslipidemia being potentiating factors .Sustained hyperglycemia activates a number of intracellular metabolic pathways, including the hexosamine and polyol pathways, C-reactive protein, and free radical formation. Crucial elements in the development of DME are glycation end products and increased levels of inflammatory mediators such as cytokines, chemokines, prostaglandins, adhesion molecules, and matrix metalloproteinases. Leukocyte chemotaxis contributes to the disruption of the BHR, leading to endothelial dysfunction and decreased vascular perfusion ,5,6,7. TOptical coherence tomography (OCT) has become the gold standard test for the diagnosis and follow-up of DME ,9 and ovOn the other hand, based on the response to intravitreal therapy with vascular endothelial factor (VEGF) inhibitors or corticosteroids, numerous articles have been published describing OCT imaging biomarkers that are predictive of responses or prognostic to improve the management of patients with DME ,12,13.The thickness of the choroid in a healthy eye is variable depending on the location, with a minimum value of 100 µm in the ora serrata and a maximum value of 250–300 µm at the level of the fovea. Histological examinations have revealed that in diabetic patients the choroid undergoes pathological changes such as increased tortuosity of the vessels and the appearance of areas of fibrosis ,15. MetaOne parameter that is studied in relation to DME is the subfoveal choroidal thickness (SFCT), although results have been inconsistent and even contradictory. Some studies have concluded that DME correlates with a thinning of the GCSF ,19,20,21SFCT is a parameter for which no consistent results have been obtained with regards to its relationship with DME and the response of both to intravitreal therapy. The present work studies changes in choroidal thickness and its relationship with DME in response to intravitreal therapy in order to assess its usefulness as a biomarker.The main objective is to study SFCT variation and its correlation with CMT variation in response to intravitreal therapy with anti-VEGF or corticosteroids in type 2 diabetic patients with DME.To demonstrate whether there are differences in the variation in macular and choroidal thicknesses in patients treated with anti-VEGF compared to patients treated with corticosteroids.To analyze whether there is a variation in CMT and GCSF in untreated eyes after intravitreal treatment in the contralateral eyes.-Age;-Gender;-Previous intravitreal therapy;-Type of antidiabetic treatment;-Time course of type 2 diabetes.To evaluate the influence of the following variables on the response to intravitreal therapy with anti-VEGF or corticosteroids:Secondary objectives:This was a retrospective study that was conducted in patients with type 2 DM with subfoveal macular edema who were treated with intravitreal therapy, either anti-VEGF or corticoid, in the Ophthalmology Department of the Hospital Universitario y Politécnico la Fe in Valencia from January 2020 to July 2021.In total, 70 eyes of 35 type 2 diabetic patients were included, 52 eyes with DME (treatment group) and 18 eyes without edema (control group); of the 52 eyes with DME, 26 eyes were treated with anti-VEGF (aflibercept) and 26 eyes were treated with corticosteroids (dexamethasone implant).The inclusion criteria for the treatment group included patients over 18 years of age diagnosed with type 2 DM with DME in at least one eye treated by intravitreal therapy with anti-VEGF or corticosteroids with a minimum follow-up of 2 months in the corticosteroid group and 6 months in the anti-VEGF group from the first intravitreal injection and all eyes with availability of volume scan (high-speed resolution and 20º × 20º scan pattern), with follow-up performed in the same OCT SPECTRALIS®  and sufficient quality to measure morphological changes in the retina and choroid at baseline and at the end of the study period.The measured parameters were the central macular thickness (CMT) and subfoveal choroidal thickness (SFCT), and all tomographic parameters were analyzed by a single observer (CMM). To measure the central macular thickness (CMT), the retinal thickness map analysis protocol was selected. On the other side, the SFCT was measured manually using the fundus image analysis window and the manual measurement tool; three measurements of the vertical distance between the outer boundary of the hyper-reflective line of the RPE and the sclerochoroidal interface at the subfoveal level were taken, and the mean was calculated .The main variables included the intravitreal treatment and the pretreatment and post-treatment CMT and SFCT.Other variables included age, gender, previous intravitreal therapy , the type of systemic antidiabetic treatment , and the time course of type 2 diabetes (years).p = 0.05).The Sigmaplot v14 software for Windows  was used for the statistical analysis. For descriptive statistics, the arithmetic mean was used as the index of central tendency, and the standard deviation and the range, with its maximum and minimum values, were used as indices of dispersion. The level of statistical significance was set at 5%  and no (there was not) groups.-▪50 μm;▪50–100 μm;▪>100 μm.The variable “Thinning in CMT or SFCT after treatment” was categorized into three levels:The chi-square test was used to compare the variables prior to the intravitreal treatment. Since the chi-square test may not be sufficiently robust due to the sample size and the stratification into several pretreatment groups, the variables were categorized as follows to reapply the chi-square test:-▪INS (insulin);▪ANI (non-insulin antidiabetic);▪COM (combined treatment with insulin and non-insulin antidiabetics).The variable “Antidiabetic treatment” was categorized into three levels:The chi-square test was used to study the possible influence of the antidiabetic treatments  on the improvement (thinning) in SFCT and CMT after intravitreal treatment in each of the two treatment groups. The variables were categorized as follows:t-test (age), Fisher’s exact test , chi-square (systemic treatment for diabetes), and the Mann–Whitney test (time course of diabetes).To determine whether the populations of both treatment groups were homogeneous and that no biases were introduced that could invalidate the response analysis, the following statistical tests were employed: The Mann–Whitney test was used to detect pre- and post-treatment differences in SFCT or CMT between the two intravitreal treatment groups.The non-parametric Kruskall–Wallis test (non-parametric test corresponding to the one-way ANOVA) was employed to detect statistically significant differences in CMT or SFCT before and after treatment between the aflibercept, dexamethasone, and untreated oleander eye groups. Dunn’s multiple comparisons post hoc test was used to locate these differences between groups in the case of significant differences in the Kruskall–Wallis test.p = 0.782).Of the 26 eyes that were included in this group, 12 eyes (46%) had received some previous intravitreal treatment, while 14 eyes (54%) had not been treated before . A paired t-test found statistically significant differences between the pre- and post-treatment values   .2 = 2.465, p = 0.292).When applying the chi-square test on these data, no relationship was found between having received pretreatment and improvement or thinning in CMT after intravitreal treatment with aflibercept .There was no difference in CMT changes according to the type of systemic treatment . A paired t-test found statistically significant differences between the pre- and post-treatment SFCT . The correlation between the SFCT before and after aflibercept treatment was high and statistically significant, with an R2 value of 0.814 . The change in SFCT was also independent of the time of diabetes progression and systemic treatment for DM .When applying the chi-square test on the categorized data, no relationship was found between the change in SFCT and having received previous intravitreal treatment  and 13 males (50%). In this group, 16 eyes (62%) had received some previous intravitreal treatment, while 10 eyes (38%) had not been treated before.The mean CMT went from 480.1 ± 97.3 μm to 328.0 ± 72.2 μm after treatment. The mean reduction in CMT after treatment with dexamethasone was 29.7 ± 16.9%.p < 0.05), so the non-parametric Wilcoxon rank test was used, which revealed statistically significant differences between CMT before and after treatment   . The medp = 0.407) and pooling both into one group  and categorizing the variable CMT thinning after treatment into three levels: <50 μm, 50–100 μm, and >100 μm .The CMT thinning achieved after dexamethasone treatment was not different between eyes with and without prior intravitreal treatment, both analyzing two groups separately .As in the aflibercept group, the time of diabetes progression was not an important factor in the CMT change after dexamethasone treatment, although there was a slight trend towards greater improvements in eyes with less time of diabetes progression. There was no difference according to previous systemic treatment , so the paired t-test was employed, which revealed statistically significant differences between the pre- and post-treatment values   . In contp = 0.394). The duration of diabetes and the systemic treatment received by the patients also did not influence the SFCT results, although there was a discrete tendency for greater post-treatment thinning in eyes with shorter durations of diabetes.As with the CMT changes, no difference in SFCT change was found between pretreated and naïve eyes  or in the SFCT  between the two groups.Before starting treatment, there were no significant differences in the CMT  or in the SFCT,  between the two groups. Although the mean pre- and post-treatment values were similar in both groups, the weight loss in the CMT achieved with treatment was greater and was statistically significant in the dexamethasone-treated group . The improvement in the SFCT after treatment with dexamethasone was also significantly higher compared to treatment with aflibercept   .In the untreated/control eye group, there were no significant differences in the mean SFCT or CMT values at baseline or at the end of the follow-up period. The mean reductions in CMT and SFCT were −1.7 ± 9.9% and −1.6 ± 11.3%, respectively. There was no reduction effect for both parameters in eyes not treated with intravitreal therapy.The present study evaluated and attempted to correlate the variation in choroidal thickness with the improvement in macular edema in response to intravitreal therapy with anti-VEGF (aflibercept) or corticosteroids (dexamethasone) in type 2 diabetic patients. Our results indicate that both intravitreal therapies significantly decrease both choroidal thickness and macular edema, independent of factors such as age, sex, previous intravitreal therapy, the systemic treatment of diabetes, and the time of diabetes evolution, and that the choroidal and macular thickness reduction effects were greater in the dexamethasone-treated group than in the aflibercept-treated group. The central macular thicknesses achieved in the dexamethasone-treated group were very similar to those in the group of eyes without macular edema. The subfoveal choroidal thicknesses (SFCT) of both treatment groups decreased to the same values as those of the oleophilic eyes without macular edema. A relevant finding of the present study is that baseline choroidal thicknesses (determined by the SFCT marker) are not predictive of the macular edema response to intravitreal treatment.Monitoring the response to treatment using biomarkers is important for decision making. OCT allows the measurement of different anatomical parameters with high reproducibility to assess the degree of response to different treatments . The choThe decrease in choroidal thickness after intravitreal therapy demonstrated in the present study is consistent with previously published results. Campos et al. analyzed 126 eyes with newly diagnosed DME and demonstrated a significant reduction in SFCT after therapy with loading doses of aflibercept or ranibizumab for 3 months . LikewisThe present study shows a correlation between the improvement in macular edema and the decrease in central choroidal thickness, as determined by the SFCT in response to intravitreal therapy with anti-VEGF or corticosteroids. Therefore, SFCT is a biomarker that can be used to monitor the response to treatment. Previous studies have reported significant increases in the SFCT during exudative recurrences of DME . In addiOur results indicate that it is not possible to use the baseline SFCT as a predictive parameter of the DME response to intravitreal treatment with anti-VEGF or corticosteroids. The decrease in CMT after treatment with aflibercept or dexamethasone did not correlate significantly with the SFCT values before intravitreal therapy. One possible explanation is that the state of the choroid in diabetic patients is highly variable, depending on the stage of DR, so its baseline central thickness before treatment could be found to be increased or decreased depending on whether an inflammatory or ischemic pathogenic mechanism prevails, respectively. Therefore, the value of SFCT as a biomarker acts more as a parameter in monitoring the response of DME to intravitreal treatment based on its variation than as a predictor of a possible good or bad response to treatment.When comparing the variations in choroidal and macular thicknesses between the two treatment groups, the improvements were statistically superior in the dexamethasone-treated group. The mean reductions in CMT and SFCT after intravitreal treatment with aflibercept were 18.8 ± 14.7% and 13.8 ± 13.1%, while the mean reductions in CMT and SFCT after intravitreal treatment with dexamethasone were 29.7 ± 16.9% and 19.5 ± 9.6%. Intravitreal treatment with dexamethasone improved the macular thickness to levels comparable with eyes without DME, while aflibercept achieved macular thinning but without reaching the values of normal eyes without DME.The secondary variables of age and gender were not shown to influence choroidal or macular thinning. Similarly, variations in both parameters after treatment with aflibercept or dexamethasone did not differ between eyes with and without previous intravitreal treatments. Patients who had received an intravitreal therapy other than the one studied in the last 6 months were excluded in order to exclusively assess the effect of the therapy under study . The durIn the control group of untreated eyes, there were no significant differences in the mean choroidal or macular values at baseline or at the end of the follow-up period.The limitations of this work are those inherent to retrospective studies. Although the populations of the two study groups were homogeneous, the individual eyes presented different conditions. They differed, for example, in the number of previous injections and the history of eye surgery, although eyes operated on within the last two years were excluded. It has been shown that choroidal thickness may decrease after panretinal photocoagulation . To miniTo conclude, an intravitreal treatment with anti-VEGF or corticosteroids in type 2 diabetic patients with macular edema decreases choroidal and macular thicknesses. According to our results, the SFCT is not a good biomarker of response (predictive biomarker), but it can be useful to assess the response to treatment, together with the CMT, and can be used in monitoring the response to DME treatment.


Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma that slowly progresses over a period of years to decades. In some cases, lesions that spread to the scalp, neck, or facial skin can have a significant impact on cosmetic appearance and a patient's quality of life. Among the various treatments, radiation therapy is one of the most effective treatment modalities for patients with symptomatic cutaneous lesions. We report on an MF patient who had gradually increasing patches and plaques on the scalp, face, and neck and who underwent irradiation with 20 Gy administered in 10 fractions using volumetric modulated arc therapy. After undergoing this highly conformal technique, the patient obtained prolonged local control and significant alleviation of symptoms with acceptable adverse events. This technique constitutes a promising approach for treating a complex target due to its ability to provide homogeneous coverage of irregularly shaped target volumes along with its ability to preserve organs at risk. In addition, we systematically reviewed clinical reports on the management of extensive cutaneous lesions in MF patients undergoing other irradiation techniques. Although mycosis fungoides (MF) is a rare disease with a relatively good prognosis when treated at an early stage, extensive cutaneous lesions can impair a patient's quality of life (QOL) -4. RadiaAn 82-year-old man presented with a tumor in the posterior auricular region and a three-year history of erythematous patches and plaques on the trunk, extremities, and face. A skin biopsy from a cutaneous chest lesion was performed and a histological evaluation of the specimen revealed the infiltration of atypical lymphocytes into the epidermis, which was positive for CD3, CD4, and CD5, and negative for CD79a, CD8, and CD20 (L26). Atypical lymphocytes were not seen in the peripheral blood. The serum level of the soluble interleukin-2 receptor was elevated at 848 U/mL, and anti-human T-cell leukemia virus 1 and 2 antibodies were not detected.The patient was diagnosed with MF T3N0M0B0 Stage2B according to the International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer (ISCL/EORTC) revised classification system. Although he was treated with chemotherapy (bexarotene) and skin-directed therapies such as topical agents and phototherapy, the cutaneous lesions became resistant to these therapies and the side effects such as renal impairment and hypertriglyceridemia made it difficult to administer adequate doses of chemotherapy. Patches and plaques gradually increased, most prominently on the facial skin and scalp, and this appearance of cutaneous lesions such as erythema and alopecia impaired the QOL of the patient Figure , 1B. TheComputed tomography (CT) simulation was performed in the supine position at a slice thickness of 2 mm. After immobilization of the subject using a type S shell (Toyo Medic), a 0.5 cm bolus was placed to fit the patient, with a second type S shell then immobilized over the bolus Figure , 1D. TwoMF is a peripheral T-cell lymphoma that primarily affects the skin and which is often treated using local electron beam irradiation or TSEBT -7. HowevFurthermore, some authors have reported good outcomes for cutaneous T-cell lymphoma of the scalp when using IMRT treatments, in conjunction with clinically acceptable adverse events -15. WhilFurthermore, it has also been reported that MF patients developed bone marrow suppression including grade 4 thrombocytopenia after TSHT despite receiving bone marrow mean doses (arms not included) that were as low as 1.66 and 2.3 Gy, respectively . In our The advantages of treating our current case with VMAT were the shorter treatment times, the less laborious setup, and the high dose homogeneity to the target. These results suggest that this approach can be utilized for treating patients with other cutaneous malignancies that include the extensive spread of lesions on the scalp and face. MF is a highly radiosensitive disease and radiation therapy plays an important role in the management of patients with all stages of MF. VMAT can deliver a highly conformal dose to the target with complex shapes, while minimizing the dose delivered to the organs at risk. For MF with extensive lesions that ranged over an area from the skin of the scalp to the face and neck, low-dose radiation therapy with VMAT was found to be very useful and led to excellent local control with little toxicity.