Early Initiation and Long-Term Use of Vaginal Progesterone may Cause Gestational Diabetes Mellitus.

BACKGROUND: Preterm birth (PTB) is an important cause of neonatal mortality and morbidity. Spontaneous PTB (sPTB) is the most common cause of PTB. In patients with a singleton pregnancy, progesterone treatment appears to reduce the rate of spontaneous preterm birth in those with a previous history of spontaneous preterm labor and/or cervical shortening in the current pregnancy. Progesterone therapies used for the prevention of sPTB may increase the risk of gestational diabetes mellitus (GDM) towards the end of pregnancy owing to their effects on carbohydrate metabolism. AIM: We aimed to show the effects of vaginal progesterone use, starting time, and duration of treatment on GDM. METHODS: A retrospective cohort study was carried out in pregnant women 18 to 39 years old who came to our hospital between January 1, 2021, and August 31, 2021, and who had a 2-hour 75-g oral glucose tolerance test (OGTT) at 24 to 28 weeks of gestation. In a total of 540 patients, 68 were diagnosed with GDM based on at least one abnormal plasma glucose value at screening. The remaining 472 patients with normal plasma glucose levels were considered as the control group. The groups were compared in terms of age, parity, pre-pregnancy body mass index (BMI), smoking, gestational age, and vaginal progesterone use. Patients using vaginal progesterone with and without GDM were then compared again in terms of indications for vaginal progesterone use, initiation time of progesterone therapy, duration of progesterone use, and cervical length. RESULTS: The incidence of GDM in our study group was 12.5%. Despite the use of vaginal progesterone at a higher rate in the GDM group than in the control group (23.5 vs. 13.9%; p=0.07), it was not statistically significant. When we examined patients using progesterone as a subgroup analysis, the mean time to start vaginal progesterone treatment was 19.8±2.6 (14-24), and it was significantly earlier in the GDM group (18.1±2.0 vs. 20.2±2.6; p=0.007). Initiation of vaginal progesterone before 20 weeks of gestation was statistically significantly more frequent in the GDM group than the control group (68.8 vs. 39.4%; p=0.050 OR :3.3, 95%CI: 1.0-10.8). The mean duration of vaginal progesterone use was 50.0±15.6 days (28-90) and it was longer in the GDM group (57.8±13.4 vs. 48.1±15.6; p=0.027). CONCLUSION: Since the duration of vaginal progesterone use will be prolonged, there may be a risk of GDM, especially in patients who started vaginal progesterone before the 20th week of pregnancy. Even if the OGTT test performed between 24-28 weeks is normal, it should be kept in mind that these patients may have GDM in the later weeks of pregnancy, and repeating the OGTT test should be considered if necessary.

The impact of bariatric surgery on eustachian tube dysfunction.

PURPOSE: We aimed to evaluate the relationship between acute loss of weight after 6 months of bariatric surgery and the occurrence of tubal dysfunction symptoms METHODS: We recruited 76 patients who had undergone bariatric surgery between 2018 and 2019. It was planned to see if the change in Body Mass Index (BMI) caused changes in the Eustachian Tube Dysfunction Questionnaire (ETDQ-7) scores of individuals. Regardless of the questionnaire, patients were also asked for 3 symptoms (autophony, fullness in the ear, hearing their own breath in the ear) before and 6 months after bariatric surgery. RESULTS: The mean age of the study group was 39.32 ± 11.09 years and 80.3% percent of the patients were female. The mean weight loss of the patients at the 6th month was 44.67 ± 13.10 kg, and mean weight loss rate was % 35.06 ± 8.01. The incidence of hearing their own breath, autophony and fullness of the ear were 25%, 22.4% and 11.8%, respectively. The proportion of those experiencing any of these three complaints was 30.3% (n = 23). The ETDQ scores of the cases ranged from 7 to 27, with an average of 9.38 ± 4.28. There are 10.5% (n = 8) paints with a score of ≥ 14.5 as regarded as patients with Eustachian tube dysfunction (ETD). The mean age of patients with ETD was significantly higher (p < 0.05) than patients without ETD. Gender distributions, weight loss rates, smoking, previous operation and additional disease distributions do not show statistically significant differences between patients with and without ETD (p > 0.05). CONCLUSION: Present study indicated a 10.5% ETD incidence after bariatric surgery. ETDQ questionnaire can be used for ETD screening in patients who underwent bariatric surgery, which will be an overlooked complication in this group of subjects.

Graphical data mining of cancer mechanisms with SEMA.

MOTIVATION: An important goal of cancer genomics initiatives is to provide the research community with the resources for the unbiased query of cancer mechanisms. Several excellent web platforms have been developed to enable the visual analyses of molecular alterations in cancers from these datasets. However, there are few tools to allow the researchers to mine these resources for mechanisms of cancer processes and their functional interactions in an intuitive unbiased manner. RESULTS: To address this need, we developed SEMA, a web platform for building and testing of models of cancer mechanisms from large multidimensional cancer genomics datasets. Unlike the existing tools for the analyses and query of these resources, SEMA is explicitly designed to enable exploratory and confirmatory analyses of complex cancer mechanisms through a suite of intuitive visual and statistical functionalities. Here, we present a case study of the functional mechanisms of TP53-mediated tumor suppression in various cancers, using SEMA, and identify its role in the regulation of cell cycle progression, DNA repair and signal transduction in different cancers.SEMA is a first-in-its-class web application designed to allow visual data mining and hypothesis testing from the multidimensional cancer datasets. The web application, an extensive tutorial and several video screencasts with case studies are freely available for academic use at https://sema.research.cchmc.org/. AVAILABILITY AND IMPLEMENTATION: SEMA is freely available at https://sema.research.cchmc.org. The web site also contains a detailed Tutorial (also in Supplementary Information), and a link to the YouTube channel for video screencasts of analyses, including the analyses presented here. The Shiny and JavaScript source codes have been deposited to GitHub: https://github.com/msolmazm/sema. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

High-Volume, Low-Concentration Intraperitoneal Bupivacaine Study in Emergency Laparoscopic Cholecystectomy: A Double-Blinded, Prospective Randomized Clinical Trial.

Background. Laparoscopic cholecystectomy (LC) often results in postoperative pain, especially in the abdomen. Intraperitoneal local anesthesia (IPLA) reduces pain after LC. Acute cholecystitis-associated inflammation, increased gallbladder wall thickness, dissection difficulties, and a longer operative time are several reasons for assuming a benefit in pain scores in urgent LC with IPLA application. The aim was to determine the postoperative analgesic efficacy of high-volume, low-dose intraperitoneal bupivacaine in urgent LC. Materials and Methods. Fifty-seven patients who were American Society of Anesthesiologists physical status I or II were randomly assigned to receive either normal saline (control group) or intraperitoneal bupivacaine (test group) at the beginning or end of urgent LC. The primary outcome was the postoperative pain score of the Visual Analogue Scale (VAS). The secondary outcomes included Visual Rating Prince Henry Scale (VRS), patient satisfaction, and analgesic consumption. Results. Postoperative VAS scores at the first and fourth hours were significantly lower in the test group than in the control group (P < .001). Postoperative VRS scores at the first, fourth, and eighth hours were significantly lower in the test group than in the control group (P < .001, P = .002, P = .004, respectively). Analgesic use was significantly higher in the control group at the first postoperative hour (P < .001). Shoulder pain was significantly lower, and patient satisfaction was significantly higher in the test group relative to the control group (both P < .001). Conclusion. High-volume, low-concentration intraperitoneal bupivacaine resulted in better postoperative pain control and reduced incidence of shoulder pain and analgesic consumption in urgent LC.

Early effect of the fear of terrorism on a hospital's emergency department use and on the incidence of cardiovascular events: A Turkish multicenter study.

BACKGROUND: To our knowledge, the early effect of the fear caused by terrorism on human health, especially its effect on the number of visits to medical emergency departments (EDs), has not yet been studied. OBJECTIVES: To observe the effect of fear from terrorist alerts on the use of EDs and on the rate of cardiovascular (CV) and/or cerebrovascular events. SETTING: In Istanbul, Turkey, there was a terror alert on the weekend of 19 and 20 March 2016. In this multicenter retrospective study, we compared the data of patients from that weekend with those from the preceding and following weekends. PATIENTS: A total of 12 324 adult patients' records were included in this study: 4562 patients in the first weekend, 3627 patients in the second, terror alert weekend, and 4135 patients in the third weekend. MEASUREMENTS: The ED, CV, and cerebrovascular incidence rates of the above three groups were compared. RESULTS: The rate of ED use was the least in the weekend of the terror alert; the highest rate occurred during the weekend prior to it (female applications decreased more [P = 0.03]). The medical center that was the farthest from the crowded central places of the city and from the place where suicide bombing occurred was less affected by the decrease in use. CONCLUSIONS: Fear associated with terrorism may affect human health indirectly by preventing patients from reaching the necessary emergency healthcare facilities. This finding may be a pathfinder to decision-makers in such extraordinary emergency conditions. Further studies are needed in this field.

Colonic mucosal pseudolipomatosis: Are we aware of it?

OBJECTIVE: Colonic mucosal pseudolipomatosis is rare, and its pathogenesis is controversial. A number of mechanisms, including mechanical injury during an endoscopic procedure or chemical injury by disinfectant, seem to contribute to its pathogenesis. MATERIAL AND METHODS: This retrospective study examined the colonic biopsies of 1370 patients. These biopsies were preserved at the Department of Pathology of Istanbul Training and Research Hospital between January 2012 and June 2013. RESULTS: We found pseudolipomatosis in 14 of 1370 colonoscopy cases (1.02%). Of these 14 patients, 8 were male and 6 were female. The male patients were between 24 and 66 years, with a mean of 39; the female patients were between 26 and 58 years, with a mean of 42. CONCLUSION: Many endoscopists are unaware of the lesion, and the diagnosis is generally possible only after pathological assessment of multiple biopsies taken from suspect lesions. Here we report and discuss colonic pseudolipomatosis incidentally found in a series of patients undergoing routine colonoscopy, and we underline the endoscopic pattern and diagnostic difficulties.

Serum levels of carcinoembryonic antigen (CEA) in patients with bipolar disorder.

OBJECTIVE: Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein that is widely used as a tumour marker in adenocarcinomas. However, several non-neoplastic conditions, including acute and chronic inflammation and other inflammation-related conditions, are characterised by increased CEA concentrations. Bipolar disorder (BD) ranks seventh among the worldwide burden of non-fatal diseases. Inflammatory biomarkers have been considered as one of the main key pillars of a multifactorial approach for prediction of BD in an at-risk population. BP is accompanied by activation of inflammatory, cell-mediated and negative immunoregulatory cytokines. METHODS: We measured the levels of CEA in serum samples from 44 individuals with euthymic BP out-patients and 45 healthy controls. Patients were diagnosed according to the DSM-IV criteria. CEA was measured by an electrochemiluminescence immunoassay. RESULTS: The mean serum CEA concentration was 2.36±1.52 and 1.77±0.98 µg/l in patients and controls, respectively. CEA levels were significantly increased in euthymic BP patients when compared with controls (p=0.031). CONCLUSIONS: This study suggests that CEA is increased in BD and supports a role for immune activation in the core pathological mechanisms of BP. CEA levels may be a secondary marker for diagnosing BP.

The relationship between oxidative stress markers and 1H-Magnetic resonance spectroscopy findings in obsessive compulsive disorder.

INTRODUCTION: The purpose of this study was to examine N-acetyl aspartate (NAA)/creatine (Cr) and glutamate, glutamine, and gamma-aminobutyric acid complex (Glx)/Cr levels in patients with obsessive compulsive disorder (OCD) and healthy controls' orbitofrontal cortex (OFC) and caudate nucleus (CN) by proton magnetic resonance spectroscopy (1H-MRS) method and to investigate their relationship with oxidative stress markers glutathione peroxidase (GPx) and superoxide dismutase (SOD). METHODS: This study included patients with OCD (n = 25) and healthy controls (n = 25) ranging in age from 18 to 65. We used the ELISA method to evaluate serum SOD and GPx levels. Levels of NAA/Cr and Glx/Cr in the orbitofrontal cortex and caudate nucleus were measured using the 1H-MRS method. RESULTS: Our study did not detect statistically significant differences in the orbitofrontal cortex Glx/Cr and NAA/Cr levels between the OCD patients and the control group. OCD patients exhibited a decrease in NAA/Cr levels, consistent with impaired neuronal integration, and an increase in Glx/Cr levels, consistent with hyperactivation, in the caudate nucleus compared to the control group. We observed a negative correlation between NAA/Cr levels in the caudate nucleus and the levels of SOD and GPx. CONCLUSIONS: Our study is the first to assess CN and OFC together in OCD patients using 3 T MR, investigating the relationship between neurometabolite concentrations and oxidative stress parameters. The negative correlation we observed between NAA/Cr levels and SOD and GPx in the caudate nucleus suggests that increased oxidative stress in this brain region in OCD patients may contribute to impaired neuronal integration and functionality.

Morphological characterization of cherry rootstock candidates selected from Central and East Black Sea Regions in Turkey.

The use of rootstocks particularly for sweet cherry cultivars is of great importance for successful and sustainable production. Choosing the right cherry rootstocks is just as important as choosing the right cultivar. In this study, 110 sweet cherry, 30 sour cherry, and 41 mahaleb types displaying rootstock potential for sweet cherry cultivars were selected from Central and East Black Sea Regions in Turkey. The morphologic characteristics of the studied genotypes were compared with the standard clonal rootstocks PHL-A, MaxMa 14, Montmorency, Weiroot 158, Gisela 5, Gisela 6, and SL 64. A total of 42 morphological UPOV characteristics were evaluated in the selected genotypes and clonal rootstocks. The obtained data were analyzed by using principal component analysis and it revealed that eigenvalues of the first 3 components were able to represent 36.43% of total variance. The most significant positive correlations of the plant vigor were determined with leaf blade length and petiole thickness. According to the diversity analysis of coefficients, the 05 C 002 and 08 C 039 genotypes were identified as being similar (6.66), while the 05 C 002 and 55 S 012 genotypes were determined as the most distant genotypes (325.84) in terms of morphology.

Mechanical performance improvement of super absorbent polymer-modified concrete.

In this study, a method has been developed to reduce the negative effects of superabsorbent polymers on concrete mechanical properties. The method involves concrete mixing and curing, with the concrete mixture being designed using a decision tree algorithm. Instead of the standard water curing approach, air curing conditions were used during the curing process. In addition, heat treatment was applied to reduce any possible negative effects of the polymers on the concrete's mechanical properties and to enhance their performance. The details of all these stages are presented in this method. Various experimental studies were conducted to demonstrate the validity of this method, which proved to be effective in reducing the negative effects of superabsorbent polymers on concrete mechanical properties. •The method can be used to eliminate the negative effects of superabsorbent polymers.•The proposed method yielded promising results, demonstrating that the expected level of compressive strength, modulus of elasticity and toughness in concrete can be achieved in 5-10 days instead of 28 days•The widespread use of superabsorbent polymers in the concrete industry and reinforced concrete systems can be attributed to their many benefits.

CoronaVac vaccine does not affect ovarian reserve.

OBJECTIVES: In this study, our aim is to investigate the effect of CoronaVac vaccine on ovarian reserve in female patients followed up for infertility. MATERIAL AND METHODS: Our study is a retrospective study. Forty-six infertile patients who received two doses of CoronaVac vaccine one month apart and had not had a previous Covid 19 infection were included in the study. Anti-müllerian hormone (AMH) and folliculometry of 46 patients one month before CoronaVac vaccine and one month after the second dose of vaccine were compared. RESULTS: There was no statistically significant difference in the change of AMH level and follicle number before and after vaccination (respectively p = 0.366; 0.610). CONCLUSIONS: Considering that having a COVID-19 infection has a negative effect on female fertility and causing ovarian damage in recent studies, vaccination is a rational and cost-effective approach to protect ovarian reserve. Knowing that the vaccine does not have a negative effect on fertility may increase the application of the vaccine in women of reproductive age.

Mineral Addition and Mixing Methods Effect on Recycled Aggregate Concrete.

This paper presents influence of treatment and mixing methods on recycled aggregate concretes (RAC) designed regarding various techniques. Absolute Volume Method (AVM) according to TS 802, Equivalent Mortar Volume Method (EMV), silica fume (SF) as a mineral addition were considered in the design of concretes. In total, four groups of concretes were produced in the laboratory: (1) natural aggregate concrete (NAC) designed with AVM as control concrete, (2) RAC designed with AVM as control RAC, (3) RAC with SF as a mineral addition designed with AVM as treated RAC and (4) RAC designed with EMV as treated RAC. The tests were performed at 28th days and the statistical analysis were made on the test results. According to the results, EMV and SF increased the compressive strength of concretes and this resulted an increase in the strength class of concrete. A significant statistical difference between the concretes were determined. According to multiple comparison analysis, it was found that especially there was a significant relationship among NAC, RAC and RAC-EMV. In addition, it was recommended that EMV and AVM with 5% SF could be used in the design of RAC rather than AVM only to achieve the target strength class C30/37.

Prediction of Match Outcomes with Multivariate Statistical Methods for the Group Stage in the UEFA Champions League.

The aim of this study was to analyse the win, draw, and loss outcomes of soccer matches with situational variables and performance indicators. Data from group stage matches spanning the ten years between the 2010/2011 and 2019/2020 seasons in the European Champions League, were used. One-way analysis of variance (ANOVA) and Tukey HSD (honestly significant difference) tests indicated performance indicators which affected the outcome of matches. K-mean clustering, with statistically significant variables, categorized the quality of the opposition into three clusters: weak, balanced, and strong. Multidimensional scaling (MDS) and decision tree analysis were applied to each of these clusters, highlighting that performance indicators of the teams differed according to the quality of their opponent. Furthermore, according to the decision tree analysis, certain performance indicators, including scoring first and shots on target, increased the chances of winning regardless of the quality of the opposition. Finally, particular performance indicators increased the chance of winning, while others decreased this, in accordance with the quality of the opposition. These findings can help coaches develop different strategies, before or during the match, based on the quality of opponents, situational variables, and performance indicators.

Generation of 2-mode scale-free graphs for link-level internet topology modeling.

Comprehensive analysis that aims to understand the topology of real-world networks and the development of algorithms that replicate their characteristics has been significant research issues. Although the accuracy of newly developed network protocols or algorithms does not depend on the underlying topology, the performance generally depends on the topology. As a result, network practitioners have concentrated on generating representative synthetic topologies and utilize them to investigate the performance of their design in simulation or emulation environments. Network generators typically represent the Internet topology as a graph composed of point-to-point links. In this study, we discuss the implications of multi-access links on the synthetic network generation and modeling of the networks as bi-partite graphs to represent both subnetworks and routers. We then analyze the characteristics of sampled Internet topology data sets from backbone Autonomous Systems (AS) and observe that in addition to the commonly recognized power-law node degree distribution, the subnetwork size and the router interface distributions often exhibit power-law characteristics. We introduce a SubNetwork Generator (SubNetG) topology generation approach that incorporates the observed measurements to produce bipartite network topologies. In particular, generated topologies capture the 2-mode relation between the layer-2 (i.e., the subnetwork and interface distributions) and the layer-3 (i.e., the degree distribution) that is missing from the current network generators that produce 1-mode graphs. The SubNetG source code and experimental data is available at https://github.com/netml/sonet.

Laparoscopic Lavage Versus Aspiration Alone in Perforated Acute Appendicitis: A Prospective Randomized Controlled Study.

The optimal method for preventing abscesses in perforated appendicitis is unclear. We compared the efficacy of lavage versus aspiration for periappendicular collections/abscesses in perforated appendicitis. Our study included 286 patients. After the removal of the appendectomy material, those who underwent aspiration without prior lavage were assigned to Group I, whereas those who underwent aspiration after lavage with 500 mL physiological saline were assigned to Group II. The primary outcome measure was postoperative complications. Secondary outcome measures were intraoperative complications, morbidity, and mortality. Group I comprised 174 patients (60 female and 114 male; mean age 34.47±17.40 y), whereas Group II comprised 112 patients (39 female and 73 male; mean age 36.22±18.60 y). The 2 groups were not significantly different in age, hospitalization duration, sex, abscess formation, morbidity, or mortality. Our results demonstrate that aspiration of the surgery area without prior lavage is sufficient and can be safely applied in perforated appendicitis.

Colonic Stent Use in Patients With Malignant Flexure Tumors Presenting With Obstruction.

BACKGROUND AND OBJECTIVE: Colonic stenting in left-sided tumor is being commonly used. However, placing a stent in the flexure tumors is rare because it is technically more difficult. In this study, we aimed to retrospectively screen patients with flexure tumors admitted to our clinic who were treated using a colonic stent and discuss our findings. METHODS: Patients admitted to the emergency department for obstructive colonic tumors between 2012 and 2017 were retrospectively evaluated, and 21 patients treated using stents were included in the study. The expandable metal stent (Wallflex®, Boston Scientific, Marlborough, MA, USA) was placed at the obstruction through the lead wire. RESULTS: The mean age of the patients was 62 years, and the ratio of females to males was 3:18. Splenic flexure tumors were detected in 18 patients and hepatic flexure tumors in 3 patients. Seven of the patients were stented for palliative purposes. Fourteen of the cases underwent surgery. Three of them underwent laparoscopic surgery and eleven underwent open surgery. CONCLUSIONS: Preoperative stenting in colonic flexura tumors is associated with faster healing, less postoperative complications, lower rates of colostomy, and higher rates of minimally invasive surgery, and can be safely used at experienced centers.

Evaluation of serum inflammatory markers in treatment-resistant manic patients and adequate responder manic patients.

Mania is accompanied with immune activation as indicated by increased pro-inflammatory cytokines, acute phase proteins; and carcinoembryonic antigen (CEA) is known to accompany signs of immune-inflammatory responses in bipolar disorder (BD) and medical disorders. In this study, it was aimed to compare high sensitivity C-reactive protein (hsCRP), CEA levels and white blood cells (WBCs) counts in the treatment-resistant BD (Group 3), the treatment-responsive BD patients (Group 2), and the healthy control group (Group 1). The sociodemographic data form, the Young Mania Rating Scale (YMRS), the Hamilton Depression Rating Scale (HDRS), and the Clinical Global Impression Severity of Illness (CGI-S) Scale were applied to the patients. In Group 3, the WBCs counts, and CEA levels were significantly higher than the other two groups. There was a positive correlation between WBCs counts and YMRS and CGI-S scores in all manic patients. There was a positive correlation between CEA levels and YMRS, HDRS and CGI-S in manic patients. This study shows that there is an activation of the immune-inflammatory response system in treatment resistant manic patients; and, WBCs counts and CEA levels are associated with severity of disease in manic patients.

False-Positive 68Ga-DOTATATE PET/CT in Active Chronic Prostatitis.

A 66-year-old man with neuroendocrine tumor originating from midgut was referred to Ga-DOTATATE PET/CT imaging for restaging postoperatively. No suspicious uptake regarding residual primary tumoral involvement was seen. But there was diffuse high uptake in prostate gland suggestive of prostatitis or secondary primary tumoral lesion. Concurrent prostate-specific antigen level was 5.02 ng/mL (range, 0-4 ng/mL), C-reactive protein level was 8.25 mg/L (range, <5 mg/L), and white blood cell count was 6.83 × 10/µL (range, 3.9-10.9 × 10/µL). Diagnosis of active chronic prostatitis was achieved by core biopsy, which is identified as potential cause for false-positive diffuse uptake on Ga-DOTATATE PET/CT.

Small bowel prolapse from anus: Atypical presentation of rectal perforation.

Non-traumatic rectum perforation is rarely seen if there is no underlying tumor formation. The perforations in the middle and lower parts of the rectum that are under the peritoneal reflex are asymptomatic unless there is intraabdominal infection or inflammation. In this study, we aim to present a patient who referred to the emergency surgery clinic with the small bowel prolapse from the anus.

Evaluation of Risk Factors for ADHD and Co-Morbid Psychiatric Disorders Among the Parents of Children With ADHD.

OBJECTIVE: The aim of this study is to investigate the presence of ADHD and other psychiatric disorders among parents with at least one child with ADHD relative to parents with children who do not have ADHD. METHOD: Eighty five parents of children with ADHD with 68 control parents who had healthy children without ADHD were interviewed for participation in present study. Each parent was evaluated for co-existing psychiatric disorders using the Structured Clinical Interview for the DSM IV Axis I Disorders (SCID I). RESULTS: We found that ADHD and co-morbid psychiatric symptoms were increased in the parents of children with ADHD in comparison with the healthy control group. CONCLUSION: Psychiatric co-morbidity was more common among the parents of patients with inattentive and combined presentations. Adult ADHD is associated with psychiatric co-morbidities including anxiety disorders, mood disorders, and somatoform disorders as well as substantial role impairment.