• Molecular epidemiology of sexually transmitted human papillomavirus in a self referred group of women in Ireland.

      Menton, John F; Cremin, Suzanne M; Canier, Lydie; Horgan, Mary; Fanning, Liam J; Molecular Virology Research and Diagnostic Laboratory, Department of Medicine, Cork University Hospital & University College Cork, Cork, Ireland.j.menton@ucc.ie (2009)
      BACKGROUND: Human papillomavirus (HPV) causes cervical cancer and external genital warts. The purpose of this study is to document the genotype distribution of HPV in females aged between 18 and 34 who self-referred to an STI clinic with visible external genital warts (EGW). Scrapings were taken from visible external genital warts (EGW). These scrapings were analysed by PCR for the presence of HPV DNA. Positive samples were then genotyped by means of a commercially available assay (LiPA). A comparison of genotyping results determined by the LiPA assay and direct amplicon DNA sequencing was also performed. RESULTS: Ninety-two patients out of 105 samples (88%) had detectable levels of HPV DNA. The majority of individuals with EGW (66%) showed the presence of two or more genotypes. The most common HPV genotypes present in the study population were HPV-6, HPV-11, HPV-16, HPV-18, HPV-33 and HPV-53. Potential effects of vaccination on HPV molecular epidemiology indicate that 40% of the patients could have been protected from the high risk genotypes HPV-16 and HPV-18. CONCLUSION: This is the first report of the molecular epidemiology of external genital warts in women aged between 18 and 34 from Ireland based on results from a LiPA assay. The study shows that most individuals are infected with multiple genotypes including those with high oncogenic potential and that the newly available HPV vaccines could have a significant impact on prevalence of the most common HPV genotypes in this study population.
    • An outcome analysis of seventeen patients treated surgically for intractable extratemporal epilepsy.

      Mulholland, D; Ali, Z; Delanty, N; Shahwan, A; O'Brien, D F; Department of Neurosurgery and Neurology, Beaumont Hospital, Beaumont, Dublin 9. (2010-07)
      We studied the outcomes of seventeen patients treated surgically for extratemporal lobe epilepsy. A retrospective case review of medical charts was performed. Seizure freedom post surgery was appraised using the Engel classification system. Post-operatively seven patients (41%) were seizure free (Engel class I), four patients were class II (23.5%), two in class III (11.76%) and four in class IV (23.5%). Three patients (17.6%) suffered traumatic injuries due to seizures. The mean duration of epilepsy prior to surgery was 12.2 years and the mean number of anti-epileptic medications given was 6.5. Seizure freedom rates for surgical treatment of extratemporal epilepsy in this centre are similar to those of other centres. Post-operative morbidity in this centre was similar to other centres. Any complications resolved with no lasting impairment.
    • Phenotypic characterization of lymphocytes in HCV/HIV co-infected patients.

      Roe, Barbara; Coughlan, Suzie; Dean, Jonathan; Lambert, John S; Keating, Shay; Norris, Suzanne; Bergin, Colm; Hall, William W; Centre for Research in Infectious Diseases, University College Dublin, Ireland. (2009-02)
      While hepatitis C virus (HCV)-specific immune responses are attenuated in HCV/HIV co-infected patients compared to those infected with HCV alone, the reasons for this remain unclear. In this study, the proportions of regulatory, naïve, and memory T cells, along with chemokine receptor expression, were measured in co-infected and mono-infected patients to determine if there is an alteration in the phenotypic profile of lymphocytes in these patients. HCV/HIV co-infected patients had increased proportions of CD4(+) naïve cells and decreased proportions of CD4(+) effector cells when compared to HCV mono-infected patients. The proportions of CD4(+) Tregs and CD4(+) CXCR3(+) T cells were also significantly lower in co-infected patients. A decrease in CD4(+) Tregs and subsequent loss of immunosuppressive function may contribute to the accelerated progression to liver disease in co-infected individuals. Dysregulation of immune responses following reduction in the proportions of CD4(+) CXCR3(+) Th-1 cells may contribute to the reduced functional capacity of HCV-specific immune responses in co-infected patients. The findings of this study provide new information on the T-cell immunophenotype in HCV/HIV co-infected patients when compared to those infected with HCV alone, and may provide insight into why cell-mediated immune responses are diminished during HCV infection.
    • A postal survey of data in general practice on the prevalence of Acquired Brain Injury (ABI) in patients aged 18-65 in one county in the west of Ireland.

      Finnerty, Fionnuala; Glynn, Liam; Dineen, Brendan; Colfer, Finbarr; Macfarlane, Anne; Department of Medical and Social Care Education Medical School, Leicester, LE 1 9HN, UK. ff21@leicester.ac.uk (2009)
      BACKGROUND: Very little is known about the prevalence of acquired brain injury (ABI) in Ireland. ABI prevalence has previously been obtained from Belgian general practitioners using a postal survey. We attempted to ascertain the prevalence of ABI in County Mayo through a postal survey of all general practitioners in the county.The specific objectives of this project were to:1. identify whether general practitioners are a. aware of patients with ABI aged 18-65 in their practices b. able to provide prevalence data on ABI in patients aged 18-65 c. able to provide data on age, gender and patient diagnosis 2. analyse prevalence of ABI from any available data from general practitioners. METHODS: A pilot postal survey was performed initially in order to assess the feasibility of the study. It was established that general practitioners did have the necessary information required to complete the questionnaire. A main postal survey was then undertaken. A postal questionnaire was administered to all general practices in County Mayo in the west of Ireland (n = 59). The response rate was 32.2% (n = 19). RESULTS: General practitioners who replied on behalf of their practice could provide data on patient age, gender and diagnosis. In the nineteen practices, there were 57 patients with ABI. The age-specific prevalence of ABI in the area surveyed was estimated at 183.7 per 100,000. The mean patient population per practice was 2,833 (SD = 950). There were found to be significantly more patients with ABI in rural areas than urban areas (p = 0.006). There were also significant differences in the ages of patients in the different ABI categories. Patients whose ABI was of traumatic origin were significantly younger than those patients with ABI of haemorrhagic origin (p = 0.002). CONCLUSION: Although this is a small-scale study, we have ascertained that general practitioners do have data on patients with ABI. Also, some prevalence data now exist where none was available before. These can be used to form the basis of a more substantial programme of university/community partnership research which could provide medical and psychosocial benefits for people with ABI and their families.
    • Pregnancy-specific stress, fetoplacental haemodynamics, and neonatal outcomes in women with small for gestational age pregnancies: a secondary analysis of the multicentre Prospective Observational Trial to Optimise Paediatric Health in Intrauterine Growth Restriction.

      Levine, Terri A; Grunau, Ruth E; Segurado, Ricardo; Daly, Sean; Geary, Michael P; Kennelly, Mairead M; O'Donoghue, Keelin; Hunter, Alyson; Morrison, John J; Burke, Gerard; et al. (BMJ Open, 2017-06-21)
      To examine associations between maternal pregnancy-specific stress and umbilical (UA PI) and middle cerebral artery pulsatility indices (MCA PI), cerebroplacental ratio, absent end diastolic flow (AEDF), birthweight, prematurity, neonatal intensive care unit admission and adverse obstetric outcomes in women with small for gestational age pregnancies. It was hypothesised that maternal pregnancy-specific stress would be associated with fetoplacental haemodynamics and neonatal outcomes.
    • Preterm birth and reduced birthweight in first and second teenage pregnancies: a register-based cohort study.

      Khashan, Ali S; Baker, Philip N; Kenny, Louise C; Anu Research Centre, Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland. a.khashan@ucc.ie. (2010)
      BACKGROUND: Higher risks of preterm birth and small for gestational age babies have been reported in teenagers. The aim of this study was to investigate the relationship between first and second teenage pregnancies and preterm birth, birthweight and small for gestational age (SGA). METHODS: All women aged 14 to 29 yrs who gave birth to live singletons in the North Western Region of England between January 1st 2004 and December 31st 2006 were identified. Women were classified in three groups; 14-17 yrs, 18-19 yrs and 20-29 yrs (reference group). The outcome measures were preterm birth, very preterm birth, birthweight, SGA (< 5th percentile), very SGA (VSGA< 3rd percentile). We compared these outcome measures in teenagers' first and second pregnancies with those of mothers aged 20 to 29 yrs. RESULTS: The risk of preterm birth was increased in first (OR = 1.21, [95% CI: 1.01-1.45]) and second (OR = 1.93, [95% CI: 1.38-2.69]) time mothers aged 14-17 yrs compared to the reference group. Birthweight was reduced in the first (mean difference = -24 g; [95% CI: -40, -7]) and second (mean difference = -80 g; [95% CI: -115, -46]) time mothers aged 14-17 yrs compared to the reference group. There was some evidence of a protective effect against VSGA in 14-17 yr old first time mothers (OR = 0.79, [95% CI: 0.63-0.99]). CONCLUSIONS: Teenage mothers are at increased risk of preterm birth compared to adult mothers and this risk is further increased in second time teen pregnancies. This study highlights the importance of ensuring pregnant teenagers have appropriate antenatal care. A first pregnancy may be the first and only time a pregnant teenager interacts with health services and this opportunity for health education and the promotion of contraception should not be overlooked.
    • Prevalence and predictors of alcohol use during pregnancy: findings from international multicentre cohort studies.

      O'Keeffe, Linda M; Kearney, Patricia M; McCarthy, Fergus P; Khashan, Ali S; Greene, Richard A; North, Robyn A; Poston, Lucilla; McCowan, Lesley M E; Baker, Philip N; Dekker, Gus A; et al. (BMJ Open, 2015-07)
      To compare the prevalence and predictors of alcohol use in multiple cohorts.
    • Proton pump inhibitors: potential cost reductions by applying prescribing guidelines.

      Cahir, Caitriona; Fahey, Tom; Tilson, Lesley; Teljeur, Conor; Bennett, Kathleen; HRB Centre for Primary Care Research, Division of Population Health Science, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland. caitrionacahir@rcsi.ie (2012)
      There are concerns that proton pump inhibitors (PPI) are being over prescribed in both primary and secondary care. This study aims to establish potential cost savings in a community drug scheme for a one year period according to published clinical and cost-effective guidelines for PPI prescribing.
    • Public knowledge of head and neck cancer.

      O'Connor, T E; Papanikolaou, V; Keogh, I J; Department of Otolaryngology, Galway University Hospitals, Newcastle Rd, Galway. antoconnor@ireland.com (2010-04)
      Studies show 60% of patients with newly diagnosed Head & Neck Squamous Cell Cancer in Ireland, present with advanced disease. A poor level of knowledge and awareness among the public of Head & Neck Cancer, is an important consideration in the often delayed presentation for medical attention in many of these cases. Our study surveyed 200 members of the public to assess their knowledge and awareness of Head & Neck Cancer. One hundred and forty (70%) of respondents had never encountered the term "Head & Neck Cancer". One hundred and forty six (73%) failed to identify excessive alcohol consumption as a risk factor. Less than 100 (50%) would have concern about persisting hoarseness or a prolonged oral ulcer. An urgent need exists to raise awareness of Head & Neck Cancer among the public in Ireland.
    • Quality of life of palliative chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction treated with irinotecan combined with 5-fluorouracil and folinic acid: results of a randomised phase III trial.

      Curran, Desmond; Pozzo, Carmelo; Zaluski, Jerzy; Dank, Magdalena; Barone, Carlo; Valvere, Vahur; Yalcin, Suayib; Peschel, Christian; Wenczl, Miklós; Goker, Erdem; et al. (2009-09)
      PURPOSE: The quality of life (QL) of advanced gastric cancer patients receiving irinotecan, folinic acid and 5-fluorouracil (5-FU) (IF arm) or cisplatin with 5-FU (CF arm) is presented. METHODS: Patients with measurable or evaluable advanced gastric cancer received IF weekly for 6/7 weeks or CF q4 weeks. QL was assessed using the EORTC QLQ-C30 at baseline, subsequently every 8 weeks until progression and thereafter every 3 months until death. The QL data were analysed using several statistical methods including summary measures and pattern-mixture modelling. RESULTS: A total of 333 patients were randomised and treated (IF 170, CF 163). The time-to-progression for IF and CF was 5.0 and 4.2 months (P = 0.088), respectively. The overall compliance rates for QL questionnaire completion were 60 and 56% in the IF and CF arms, respectively. Significant treatment differences were observed for the physical functioning scale (P = 0.024), nausea\vomiting (P = 0.001) and EQ-5D thermometer (P = 0.020) in favour of the IF treatment arm. CONCLUSION: There was a trend in favour of IF over CF in time-to-progression. The IF group also demonstrated a better safety profile than CF and a better QL on a number of multi-item scales, suggesting that IF offers an alternative first-line platinum-free treatment option for advanced gastric cancer.
    • Remission in psoriatic arthritis: is it possible and how can it be predicted?

      Saber, Tajvur P; Ng, C T; Renard, Guillaume; Lynch, Bernadette M; Pontifex, Eliza; Walsh, Ceara A E; Grier, Alexia; Molloy, Marian; Bresnihan, Barry; Fitzgerald, Oliver; et al. (2010)
      Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFalpha) therapy and to examine possible predictors of response.
    • The role of thyrotropin suppression in patients with differentiated thyroid carcinoma.

      Deasy, J; Prichard, R S; Evoy, D; McDermott, E W; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4. (2010-07)
      Thyroid carcinoma is the commonest endocrine malignancy. The majority of these are differentiated thyroid carcinomas, which have a good overall prognosis. Treatment includes surgical excision, radio-iodine ablation and long-term thyrotropin suppression. The degree and length of suppression required, as well as the potential side-effect remain controversial. Therefore, the aim of this study was to establish the degree of thyrotropin suppression achieved in a cohort of patients with differentiated thyroid carcinoma. A retrospective review was performed of a prospectively maintained database. All patients with a diagnosis of differentiated thyroid carcinoma between January 1998 and January 2008 were identified. Demographic data, pathological stage and the treatment that the patient received was documented. TSH and free T4 levels were identified at specific time points post-operatively. Eighty-eight patients with differentiated thyroid carcinoma were identified. Seventy patients (79.5%) were female. The mean age was 55, with a range of 18 to 79 years. The majority of patients underwent a total thyroidectomy (n=79; 89.7%) and of those 29 (32.9%) had an associated modified neck dissection. Accurate follow-up was available on forty-nine patients. TSH and free T4 were measured at 3 and 6 months, as well as at 1 and 2 years post-operatively. Adequate TSH suppression was taken at a level < 0.1 mU/L. The majority of patients (69.5%) had achieved adequate TSH suppression at 2 years. However, 65% of these same patients had a high free T4 at 2 years indicating a degree of hyperthyroidism. This study has demonstrated that TSH suppression is being adequately achieved in the majority of patients with differentiated thyroid carcinoma. However, this must be carefully weighed against the potential detrimental side-effects of long-term sub-clinical hyperthyroidism.
    • Smoking characteristics of Polish immigrants in Dublin.

      Kabir, Zubair; Clarke, Vanessa; Keogan, Sheila; Currie, Laura M; Zatonski, Witold; Clancy, Luke; Research Institute for a Tobacco Free Society (RIFTFS), The Digital Depot, Thomas Street, Dublin, Ireland. (2008)
      BACKGROUND: This study examined two main hypotheses: a) Polish immigrants' smoking estimates are greater than their Irish counterparts (b) Polish immigrants purchasing cigarettes from Poland smoke "heavier" (>/= 20 cigarettes a day) when compared to those purchasing cigarettes from Ireland. The study also set out to identify significant predictors of 'current' smoking (some days and everyday) among the Polish immigrants. METHODS: Dublin residents of Polish origin (n = 1,545) completed a previously validated Polish questionnaire in response to an advertisement in a local Polish lifestyle magazine over 5 weekends (July-August, 2007). The Office of Tobacco Control telephone-based monthly survey data were analyzed for the Irish population in Dublin for the same period (n = 484). RESULTS: Age-sex adjusted smoking estimates were: 47.6% (95% Confidence Interval [CI]: 47.3%; 48.0%) among the Poles and 27.8% (95% CI: 27.2%; 28.4%) among the general Irish population (p < 0.001). Of the 57% of smokers (n = 345/606) who purchased cigarettes solely from Poland and the 33% (n = 198/606) who purchased only from Ireland, 42.6% (n = 147/345) and 41.4% (n = 82/198) were "heavy" smokers, respectively (p = 0.79). Employment (Odds Ratio [OR]: 2.89; 95% CI: 1.25-6.69), lower education (OR: 3.76; 95%CI: 2.46-5.74), and a longer stay in Ireland (>24 months) were significant predictors of current smoking among the Poles. An objective validation of the self-reported smoking history of a randomly selected sub-sample immigrant group, using expired carbon monoxide (CO) measurements, showed a highly significant correlation coefficient (r = 0.64) of expired CO levels with the reported number of cigarettes consumed (p < 0.0001). CONCLUSION: Polish immigrants' smoking estimates are higher than their Irish counterparts, and particularly if employed, with only primary-level education, and are overseas >2 years.
    • Study protocol. ECSSIT - Elective Caesarean Section Syntocinon Infusion Trial. A multi-centre randomised controlled trial of oxytocin (Syntocinon) 5 IU bolus and placebo infusion versus oxytocin 5 IU bolus and 40 IU infusion for the control of blood loss at elective caesarean section.

      Murphy, Deirdre J; Carey, Michael; Montgomery, Alan A; Sheehan, Sharon R; Obstetrics & Gynaecology, Coombe Women and Infants University Hospital, Trinity College Dublin, Dublin 8, Ireland. deirdre.j.murphy@tcd.ie (2009)
      BACKGROUND: Caesarean section is one of the most commonly performed major operations in women throughout the world. Rates are escalating, with studies from the United States of America, the United Kingdom, China and the Republic of Ireland reporting rates between 20% and 25%. Operative morbidity includes haemorrhage, anaemia, blood transfusion and in severe cases, maternal death. The value of routine oxytocics in the third stage of vaginal birth has been well established and it has been assumed that these benefits apply to caesarean delivery as well. A slow bolus dose of oxytocin is recommended following delivery of the baby at caesarean section. Some clinicians use an additional infusion of oxytocin for a further period following the procedure. Intravenous oxytocin has a very short half-life (4-10 minutes) therefore the potential advantage of an oxytocin infusion is that it maintains uterine contractility throughout the surgical procedure and immediate postpartum period, when most primary haemorrhages occur. The few trials to date addressing the optimal approach to preventing haemorrhage at caesarean section have been under-powered to evaluate clinically important outcomes. There has been no trial to date comparing the use of an intravenous slow bolus of oxytocin versus an oxytocin bolus and infusion. METHODS AND DESIGN: A multi-centre randomised controlled trial is proposed. The study will take place in five large maternity units in Ireland with collaboration between academics and clinicians in the disciplines of obstetrics and anaesthetics. It will involve 2000 women undergoing elective caesarean section after 36 weeks gestation. The main outcome measure will be major haemorrhage (blood loss >1000 ml). A study involving 2000 women will have 80% power to detect a 36% relative change in the risk of major haemorrhage with two-sided 5% alpha. DISCUSSION: It is both important and timely that we evaluate the optimal approach to the management of the third stage at elective caesarean section. Safe operative delivery is now a priority and a reality for many pregnant women. Obstetricians, obstetric anaesthetists, midwives and pregnant women need high quality evidence on which to base management approaches. The overall aim is to reduce maternal haemorrhagic morbidity and its attendant risks at elective caesarean section. TRIAL REGISTRATION: number: ISRCTN17813715.
    • Successful outcome of sphincterotomy and 7 French pigtail stent insertion in the management of post-cholecystectomy bile leaks.

      Donnellan, Fergal; Zeb, Faisal; Courtney, Garry; Aftab, Abdur R; Department of Gastroenterology, St. Luke's Hospital, Kilkenny, Ireland. fdonnellan77@hotmail.com. (2009-06)
      BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is widely used to manage post-cholecystectomy bile leaks. However, the best endoscopic intervention remains controversial. We investigated the success of a 7 French double pigtail stent following sphincterotomy in the management of such bile leaks. METHODS: Between July 1998 and June 2008, 48 patients were referred for ERCP for presumed post-cholecystectomy bile leaks. Leaks were confirmed at ERCP and managed by a combination of sphincterotomy and stent insertion unless contraindicated. RESULTS: Bile duct cannulation was successful in 44 (91.7%) patients. A leak of the cystic duct was demonstrated in 19 (43.2%) patients, the duct of Luschka in 11 (25.0%), and the common hepatic duct in 5 (11.4%). Complete transection of the common bile duct occurred in 4 patients. The remaining patients had no cholangiographic evidence of a leak. Sphincterotomy was performed in 34 patients. A 7 French double pigtail plastic stent was placed in all 35 patients with cholangiographic evidence of a bile leak. No bile leaks were demonstrated at a follow-up of 8-16 weeks and all stents were removed successfully. CONCLUSION: The combination of sphincterotomy and insertion of a 7 French double pigtail stent results in excellent outcomes in the management of post-cholecystectomy bile leaks.
    • Survey of the provision of crowns by dentists in Ireland.

      Rath, Claire; Sharpling, Bill; Millar, Brian J; London Dental Education Centre, King's College London Dental Institute, London SE1 9NH. (Irish Dental Association, 2010-08)
      The literature is limited on the detailed description of the practice of Irish general dentists in the provision of crowns.
    • Undergraduate medical research: the student perspective.

      Burgoyne, Louise N; O'Flynn, Siun; Boylan, Geraldine B; School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland. l.burgoyne@ucc.ie (2010)
      Research training is essential in a modern undergraduate medical curriculum. Our evaluation aimed to (a) gauge students' awareness of research activities, (b) compare students' perceptions of their transferable and research-specific skills competencies, (c) determine students' motivation for research and (d) obtain students' personal views on doing research.
    • The use of complementary and alternative medicine by patients with diabetes mellitus in Bahrain: a cross-sectional study.

      Khalaf, Abeer J; Whitford, David L; Department of Family & Community Medicine, Royal College of Surgeons in Ireland - Medical University of Bahrain, PO Box 15503, Busaiteen, Kingdom of Bahrain. dwhitford@rcsi-mub.com (2010)
      CAM use is widespread, especially among patients with diabetes. The Gulf States have a high prevalence of diabetes, alongside a long tradition of CAM use. The aim of this study is to establish the prevalence of CAM use among patients with diabetes mellitus in Bahrain and to examine the characteristics of the CAM users.
    • Visual sensory processing deficits in patients with bipolar disorder revealed through high-density electrical mapping.

      Yeap, Sherlyn; Kelly, Simon P; Reilly, Richard B; Thakore, Jogin H; Foxe, John J; The Cognitive Neurophysiology Laboratory, St. Vincent's Hospital, Richmond Road, Fairview, Dublin, Republic of Ireland. (2009-11)
      BACKGROUND: Etiological commonalities are apparent between bipolar disorder and schizophrenia. For example, it is becoming clear that both populations show similar electrophysiological deficits in the auditory domain. Recent studies have also shown robust visual sensory processing deficits in patients with schizophrenia using the event-related potential technique, but this has not been formally tested in those with bipolar disorder. Our goal here was to assess whether early visual sensory processing in patients with bipolar disorder, as indexed by decreased amplitude of the P1 component of the visual evoked potential (VEP), would show a similar deficit to that seen in those with schizophrenia. Since the P1 deficit has already been established as an endophenotype in schizophrenia, a finding of commonality between disorders would raise the possibility that it represents a measure of common genetic liability. METHODS: We visually presented isolated-check stimuli to euthymic patients with a diagnosis of bipolar disorder and age-matched healthy controls within a simple go/no-go task and recorded VEPs using high-density (72-channel) electroencephalography. RESULTS: The P1 VEP amplitude was substantially reduced in patients with bipolar disorder, with an effect size of f = 0.56 (large according to Cohen's criteria). LIMITATIONS: Our sample size was relatively small and as such, did not allow for an examination of potential relations between the physiologic measures and clinical measures. CONCLUSION: This reduction in P1 amplitude among patients with bipolar disorder represents a dysfunction in early visual processing that is highly similar to that found repeatedly in patients with schizophrenia and their healthy first-degree relatives. Since the P1 deficit has been related to susceptibility genes for schizophrenia, our results raise the possibility that the deficit may in fact be more broadly related to the development of psychosis and that it merits further investigation as a candidate endophenotype for bipolar disorder.