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"text": "\n120288\nGenome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.\n\nEstrada, K\n\nStyrkarsdottir, U\n\nEvangelou, E\n\nHsu, YH\n\nDuncan, EL\n\nNtzani, EE\n\nOei, L\n\nAlbagha, OM\n\nAmin, N\n\nKemp, JP\n\nKoller, DL\n\nLi, G\n\nLiu, CT\n\nMinster, RL\n\nMoayyeri, A\n\nVandenput, L\n\nWillner, D\n\nXiao, SM\n\nYerges-Armstrong, LM\n\nZheng, HF\n\nAlonso, N\n\nEriksson, J\n\nKammerer, CM\n\nKaptoge, SK\n\nLeo, PJ\n\nThorleifsson, G\n\nWilson, SG\n\nWilson, JF\n\nAalto, V\n\nAlen, M\n\nAragaki, AK\n\nAspelund, T\n\nCenter, JR\n\nDailiana, Z\n\nDuggan, DJ\n\nGarcia, M\n\nGarcia-Giralt, N\n\nGiroux, S\n\nHallmans, G\n\nHocking, LJ\n\nHusted, LB\n\nJameson, KA\n\nKhusainova, R\n\nKim, GS\n\nKooperberg, C\n\nKoromila, T\n\nKruk, M\n\nLaaksonen, M\n\nLacroix, AZ\n\nLee, SH\n\nLeung, PC\n\nLewis, JR\n\nMasi, L\n\nMencej-Bedrac, S\n\nNguyen, TV\n\nNogues, X\n\nPatel, MS\n\nPrezelj, J\n\nRose, LM\n\nScollen, S\n\nSiggeirsdottir, K\n\nSmith, AV\n\nSvensson, O\n\nTrompet, S\n\nTrummer, O\n\nvan Schoor, NM\n\nWoo, J\n\nZhu, K\n\nBalcells, S\n\nBrandi, ML\n\nBuckley, BM\n\nCheng, S\n\nChristiansen, C\n\nCooper, C\n\nDedoussis, G\n\nFord, I\n\nFrost, M\n\nGoltzman, D\n\nGonzález-Macías, J\n\nKähönen, M\n\nKarlsson, M\n\nKhusnutdinova, E\n\nKoh, JM\n\nKollia, P\n\nLangdahl, BL\n\nLeslie, WD\n\nLips, P\n\nLjunggren, Ö\n\nLorenc, RS\n\nMarc, J\n\nMellström, D\n\nObermayer-Pietsch, B\n\nOlmos, JM\n\nPettersson-Kymmer, U\n\nReid, DM\n\nRiancho, JA\n\nRidker, PM\n\nRousseau, F\n\nSlagboom, PE\n\nTang, NL\n\nUrreizti, R\n\nVan Hul, W\n\nViikari, J\n\nZarrabeitia, MT\n\nAulchenko, YS\n\nCastano-Betancourt, M\n\nGrundberg, E\n\nHerrera, L\n\nIngvarsson, T\n\nJohannsdottir, H\n\nKwan, T\n\nLi, R\n\nLuben, R\n\nMedina-Gómez, C\n\nPalsson, ST\n\nReppe, S\n\nRotter, JI\n\nSigurdsson, G\n\nvan Meurs, JB\n\nVerlaan, D\n\nWilliams, FM\n\nWood, AR\n\nZhou, Y\n\nGautvik, KM\n\nPastinen, T\n\nRaychaudhuri, S\n\nCauley, JA\n\nChasman, DI\n\nClark, GR\n\nCummings, SR\n\nDanoy, P\n\nDennison, EM\n\nEastell, R\n\nEisman, JA\n\nGudnason, V\n\nHofman, A\n\nJackson, RD\n\nJones, G\n\nJukema, JW\n\nKhaw, KT\n\nLehtimäki, T\n\nLiu, Y\n\nLorentzon, M\n\nMcCloskey, E\n\nMitchell, BD\n\nNandakumar, K\n\nNicholson, GC\n\nOostra, BA\n\nPeacock, M\n\nPols, HA\n\nPrince, RL\n\nRaitakari, O\n\nReid, IR\n\nRobbins, J\n\nSambrook, PN\n\nSham, PC\n\nShuldiner, AR\n\nTylavsky, FA\n\nvan Duijn, CM\n\nWareham, NJ\n\nCupples, LA\n\nEcons, MJ\n\nEvans, DM\n\nHarris, TB\n\nKung, AW\n\nPsaty, BM\n\nReeve, J\n\nSpector, TD\n\nStreeten, EA\n\nZillikens, MC\n\nThorsteinsdottir, U\n\nOhlsson, C\n\nKarasik, D\n\nRichards, JB\n\nBrown, MA\n\nStefansson, K\n\nUitterlinden, AG\n\nRalston, SH\n\nIoannidis, JP\n\nKiel, DP\n\nRivadeneira, F\n\nBeiträge in Fachzeitschriften\nISI:000303416300007\n22504420.0\n10.1038/ng.2249\nPMC3338864\nBone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32, 61 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50, 33 independent subjects and for association with risk of low-trauma fracture in 31, 16 individuals with a history of fracture (cases) and 102, 44 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.\n\nObermayer-Pietsch, Barbara\n\nTrummer, Olivia\n\n\n"
},
{
"text": "\n64533\nWhen should the doctor order a spine X-ray? Identifying vertebral fractures for osteoporosis care: results from the European Prospective Osteoporosis Study (EPOS).\n\nKaptoge, S\n\nArmbrecht, G\n\nFelsenberg, D\n\nLunt, M\n\nO'Neill, TW\n\nSilman, AJ\n\nReeve, J\n\nEPOS Study Group\n\nBeiträge in Fachzeitschriften\nISI:000225341700008\n15537441.0\n10.1359/JBMR.040901\nNone\nVertebral fractures are common but usually remain unrecognized in primary care. Data from 2908 women and 2653 men in the EPOS study were used to derive algorithms to indicate the need for a spine X-ray to identify a fracture using easily elicited determinants. At a sensitivity of 50% for identifying cases, the specificity was increased from 50% to 78% in women and from 50% to 72% in men compared with a random allocation of X-rays. Use of X-rays can be optimized by selecting patients at high risk using a short screening procedure. INTRODUCTION: Previous osteoporotic fracture is an independent risk factor for further fractures and an indication for treatment. Vertebral fractures are the most common osteoporotic fractures before age 75, accounting for 48% of all fractures in men and 39% in women over 50. They usually remain unrecognized, so many patients requiring treatment are denied it, doubling their risk of a further fracture. Our objective was to develop an efficient algorithm indicating the need for an X-ray. MATERIALS AND METHODS: Data from 2908 women and 2653 men >or=50 years of age in the European Prospective Osteoporosis Study (EPOS) were analyzed. Lateral thoracic and lumbar spine radiographs were taken at baseline and at an average of 3.8 years later. Prevalent fractures were qualitatively diagnosed by an experienced radiologist. Fracture risk was modeled as a function of age, statural height loss since age 25, gender, and fracture history including limb fractures in the last 3 years using negative binomial regression. Receiver operating characteristic (ROC) curves were used to summarize a model's predictive ability, and a prediction algorithm was devised to identify those most likely to have a fracture. RESULTS: In a multivariate model for women, the risk of prevalent vertebral fracture significantly increased with age (RR, 1.67 [95% CI, 1.46, 1.93] per decade), statural height loss (1.06, [1.03, 1.10] per centimeter decrease), self-reported history of spine fracture (7.52 [5.52, 10.23]), and history of other major fracture (1.83 [1.46, 2.28]). Higher body weight reduced risk (0.86 [0.79, 0.95] per 10-kg increase). In men, the respective RR estimates were as follows: age (1.32 [1.18, 1.49]); height loss (1.06 [1.04, 1.09]); self-reported spine fracture (5.05 [3.69, 6.90]); other major fracture (1.42 [1.12, 1.81]); and weight (0.86 [0.79, 0.94]). Using algorithms based on these easily elicited determinants, specificity was increased from 50% to 78% in women and from 50% to 72% in men at a sensitivity of 50% compared with a random allocation of X-rays. At a sensitivity of 75%, the specificity was 50% in women and 40% in men. Inclusion of hip BMD (femoral neck or trochanter), measured in 1360 women and 1046 men, significantly improved the area under the ROC curves by 4% in women (p < 0.002) but not in men (p > 0.350). Spine BMD, measured in 982 women and 847 men, produced a significant 5% AUC improvement in women (p = 0.007) but not in men (p = 0.554). CONCLUSION: A woman 65 years of age with one vertebral fracture has a one in four chance of another fracture over 5 years, which can be reduced to one in eight by treatment. Positive treatment decisions are often contingent on identifying a vertebral fracture. Selective use of lateral vertebral X-rays can be optimized using a 2-minute screening procedure administered by a nurse.\n\nWeber, Kurt\n\n\n"
},
{
"text": "\n153404\nShort-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus.\n\nFullerton, B\n\nSiebenhofer, A\n\nJeitler, K\n\nHorvath, K\n\nSemlitsch, T\n\nBerghold, A\n\nPlank, J\n\nPieber, TR\n\nGerlach, FM\n\nBeiträge in Fachzeitschriften\nISI:000381106800044\n27362975.0\n10.1002/14651858.CD012161\nNone\nShort-acting insulin analogue use for people with diabetes is still controversial, as reflected in many scientific debates.\n To assess the effects of short-acting insulin analogues versus regular human insulin in adults with type 1 diabetes.\n We carried out the electronic searches through Ovid simultaneously searching the following databases: Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to 14 April 2015), EMBASE (1988 to 2015, week 15), the Cochrane Central Register of Controlled Trials (CENTRAL; March 2015), ClinicalTrials.gov and the European (EU) Clinical Trials register (both March 2015).\n We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues with regular human insulins in the treatment of adults with type 1 diabetes who were not pregnant.\n Two review authors independently extracted data and assessed trials for risk of bias, and resolved differences by consensus. We graded overall study quality using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. We used random-effects models for the main analyses and presented the results as odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes.\n We identified nine trials that fulfilled the inclusion criteria including 2693 participants. The duration of interventions ranged from 24 to 52 weeks with a mean of about 37 weeks. The participants showed some diversity, mainly with regard to diabetes duration and inclusion/exclusion criteria. The majority of the trials were carried out in the 1990s and participants were recruited from Europe, North America, Africa and Asia. None of the trials was carried out in a blinded manner so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the trials. Furthermore, several trials showed inconsistencies in the reporting of methods and results.The mean difference (MD) in glycosylated haemoglobin A1c (HbA1c) was -0.15% (95% CI -0.2% to -0.1%; P value < 0.00001; 2608 participants; 9 trials; low quality evidence) in favour of insulin analogues. The comparison of the risk of severe hypoglycaemia between the two treatment groups showed an OR of 0.89 (95% CI 0.71 to 1.12; P value = 0.31; 2459 participants; 7 trials; very low quality evidence). For overall hypoglycaemia, also taking into account mild forms of hypoglycaemia, the data were generally of low quality, but also did not indicate substantial group differences. Regarding nocturnal severe hypoglycaemic episodes, two trials reported statistically significant effects in favour of the insulin analogue, insulin aspart. However, due to inconsistent reporting in publications and trial reports, the validity of the result remains questionable.We also found no clear evidence for a substantial effect of insulin analogues on health-related quality of life. However, there were few results only based on subgroups of the trial populations. None of the trials reported substantial effects regarding weight gain or any other adverse events. No trial was designed to investigate possible long-term effects (such as all-cause mortality, diabetic complications), in particular in people with diabetes related complications.\n Our analysis suggests only a minor benefit of short-acting insulin analogues on blood glucose control in people with type 1 diabetes. To make conclusions about the effect of short acting insulin analogues on long-term patient-relevant outcomes, long-term efficacy and safety data are needed.\n\nBerghold, Andrea\n\nHorvath, Karl\n\nJeitler, Klaus\n\nPieber, Thomas\n\nSemlitsch, Thomas\n\nSiebenhofer-Kroitzsch, Andrea\n\n\n"
},
{
"text": "\n177279\n[The impact of capsular repair on the dislocation rate after primary total hip arthroplasty: a retrospective analysis of 1972 cases].\n\nPrietzel, T\n\nHammer, N\n\nSchleifenbaum, S\n\nAdler, D\n\nPretzsch, M\n\nKöhler, L\n\nPetermann, M\n\nFarag, M\n\nPanzert, S\n\nBauer, S\n\nvon Salis-Soglio, G\n\nBeiträge in Fachzeitschriften\nISI:000337692500013\n24760453.0\n10.1055/s-0034-1368209\nNone\nDislocation is the second most frequently encountered complication in primary total hip arthroplasty (THA) and occurs more commonly in the early postoperative rehabilitation phase. Sir Charnley recommended the "avoidance of resection of the capsule" and emphasised its contribution to hip joint stability in THA. Several authors, however, doubted its significance and considered resection of the capsule to be essential. Since 2002, some surgeons increasingly adopted a modified, less invasive technique of THA via Bauer approach, including the preservation and repair of the hip joint capsule with focus on maintaining its acetabular origin. Another group of surgeons applied the traditional technique including the resection of the joint capsule via an anterolateral approach. In this case-control study we investigated whether the dislocation rate can be reduced through joint capsule reconstruction and whether any negative impact on patient satisfaction, functional results or revision rate is observed.\n All cases of primary THA performed in our institution in a timeframe between 2002 and 2009 were included with the only exceptions of resurfacing arthroplasty, dual mobility and tumour hip replacements. Joint capsule repair cases were gathered in the study group (SG), capsule resection cases in the control group (CG). Additional patient-related data were taken from the anaesthesia records. The WOMAC score and a questionnaire focusing on detection of dislocations and revision surgeries was sent out for each case. Further targeted research was conducted that included requesting records and reports from external hospitals. In the case of non-responding patients, all available data (operating room documentation, electronic files, archive, X-rays) were reviewed for incidents of dislocation and revision surgery. Groupings and classifications were exclusively performed by senior surgeons. SG and CG were compared regarding epidemiologic, implant-associated and surgery-specific data. Statistical evaluations were performed using the Chi-squared test and the Mann-Whitney U test.\n 1972 cases of primary THA were included: 992 in the SG and 980 in the CG. The follow-up rates were 92.7 % in the SG and 76.4 % in the CG, the mean follow-up times 33.5 months and 73.4 months, respectively, with a follow-up of at least 12 months in all cases. In the SG, the dislocation rate was 0.3 % (n = 3) and thus significantly lower than the 2.55 % in the CG (n = 25, p < 0.001). Both the WOMAC score (SG: 1.46 ± 1.73; CG: 1.53 ± 1.80; p > 0.05) and the revision rate (SG: 5.24 %; CG: 6.84 %; p = 0.139) showed no significant differences.\n Preservation and repair of the hip joint capsule causes an 88-%-reduction of the dislocation rate in primary THA in this large series including 1972 cases, operated via the Bauer or the anterolateral approach. Several authors reported comparable results after THA using similar techniques of soft tissue and capsular repair through the posterior or posterolateral approach. Sparing and reconstructing the hip joint capsule therefore seems to reduce the dislocation rate after primary THA by one order of magnitude regardless of the surgical approach and, especially, if the acetabular origin is preserved. Capsule-related specific complications such as an increased revision rate, malfunction or pain were neither recorded in our study nor by others. Thus, careful preservation and reconstruction of the hip joint capsule may be expressly recommended in primary THA.\n Georg Thieme Verlag KG Stuttgart · New York.\n\nHammer, Niels\n\n\n"
},
{
"text": "\n181791\nAssociation of polygenic score for major depression with response to lithium in patients with bipolar disorder.\n\nAmare, AT\n\nSchubert, KO\n\nHou, L\n\nClark, SR\n\nPapiol, S\n\nCearns, M\n\nHeilbronner, U\n\nDegenhardt, F\n\nTekola-Ayele, F\n\nHsu, YH\n\nShekhtman, T\n\nAdli, M\n\nAkula, N\n\nAkiyama, K\n\nArdau, R\n\nArias, B\n\nAubry, JM\n\nBacklund, L\n\nBhattacharjee, AK\n\nBellivier, F\n\nBenabarre, A\n\nBengesser, S\n\nBiernacka, JM\n\nBirner, A\n\nBrichant-Petitjean, C\n\nCervantes, P\n\nChen, HC\n\nChillotti, C\n\nCichon, S\n\nCruceanu, C\n\nCzerski, PM\n\nDalkner, N\n\nDayer, A\n\nDel Zompo, M\n\nDePaulo, JR\n\nÉtain, B\n\nJamain, S\n\nFalkai, P\n\nForstner, AJ\n\nFrisen, L\n\nFrye, MA\n\nFullerton, JM\n\nGard, S\n\nGarnham, JS\n\nGoes, FS\n\nGrigoroiu-Serbanescu, M\n\nGrof, P\n\nHashimoto, R\n\nHauser, J\n\nHerms, S\n\nHoffmann, P\n\nHofmann, A\n\nJiménez, E\n\nKahn, JP\n\nKassem, L\n\nKuo, PH\n\nKato, T\n\nKelsoe, JR\n\nKittel-Schneider, S\n\nKliwicki, S\n\nKönig, B\n\nKusumi, I\n\nLaje, G\n\nLandén, M\n\nLavebratt, C\n\nLeboyer, M\n\nLeckband, SG\n\nTortorella, A\n\nManchia, M\n\nMartinsson, L\n\nMcCarthy, MJ\n\nMcElroy, SL\n\nColom, F\n\nMitjans, M\n\nMondimore, FM\n\nMonteleone, P\n\nNievergelt, CM\n\nNöthen, MM\n\nNovák, T\n\nO'Donovan, C\n\nOzaki, N\n\nÖsby, U\n\nPfennig, A\n\nPotash, JB\n\nReif, A\n\nMajor Depressive Disorder Working Group of the Psychiatric Genomics Consortium\n\nReininghaus, E\n\nRouleau, GA\n\nRybakowski, JK\n\nSchalling, M\n\nSchofield, PR\n\nSchweizer, BW\n\nSeverino, G\n\nShilling, PD\n\nShimoda, K\n\nSimhandl, C\n\nSlaney, CM\n\nSquassina, A\n\nStamm, T\n\nStopkova, P\n\nMaj, M\n\nTurecki, G\n\nVieta, E\n\nVeeh, J\n\nWitt, SH\n\nWright, A\n\nZandi, PP\n\nMitchell, PB\n\nBauer, M\n\nAlda, M\n\nRietschel, M\n\nMcMahon, FJ\n\nSchulze, TG\n\nBaune, BT\n\nBeiträge in Fachzeitschriften\nISI:000519671200001\n32203155.0\n10.1038/s41380-020-0689-5\nNone\nLithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135, 58 cases and 344, 01 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.\n\nBengesser, Susanne\n\nBirner, Armin\n\nDalkner, Nina\n\nReininghaus, Eva\n\n\n"
},
{
"text": "\n50104\nFine needle capillary cytology versus fine needle aspiration cytology--a comparison of quality between puncture techniques in the ENT area\n\nBraun, H\n\nWalch, C\n\nBeham, A\n\nMoinfar, F\n\nBeiträge in Fachzeitschriften\nISI:A1997XJ70800005\n9333280.0\n10.1055/s-2007-997442\nNone\nBACKGROUND: Needle aspiration is currently a widely used technique in the diagnosis of unclear lesions in the head and neck region. We present a modified technique of fine needle biopsy in ENT, "fine needle capillary technique". The basics of this technique were developed by Zajdela and coworkers (1987) as a cytological method of fine needle biopsy in benign and malignant mammary tumors. Fine needle capillary technique does not require aspiration of cell samples via negative pressure created by a syringe. A thin 25 G needle (outer diameter 0.50 mm, length 25 mm) is introduced into the lesion with one hand. The cells are detached by the cutting edge of the needle and are conducted into the lumen by capillary force. The needle is removed and the cellular material is expelled onto a glass slide, spread, and immediately fixed. METHOD: In a series of 166 patients with unclear lesions in the head and neck region, we compared the fine needle capillary technique with the classic fine needle aspiration technique in each patient. Regarding quality and assessment of the cytological smear the fine needle capillary technique proved clearly superior in most of the cases. Lymph nodes, tumors of the salivary glands, thyroid glands, branchiogenic cysts, one atheroma, one lipoma, and one skin metastasis of a squamous cell carcinoma were punctured. RESULTS: In our study fine needle capillary technique showed a very good quality of the cytological smear in 24.7% of all cases, while fine needle aspiration technique reached 12.1% only. A good quality was obtained in 51.2% with fine needle capillary technique and in 51.8% with fine needle aspiration technique, poor quality in 24.1% with fine needle capillary technique and in 36.1% with fine needle aspiration technique. Nondiagnostic cytology was obtained in 21.7% with fine needle capillary technique and in 32.5% with fine needle aspiration technique. Both techniques together showed insufficient material in 10.8%. The quality of the cytological smear in each region was always better with fine needle capillary techniques than with fine needle aspiration technique except five punctures of the submandibular gland. Of 166 patients 113 (68.1%) underwent surgery, and a correlation of the cytologic report to the surgical specimen showed agreement in 95.7% with fine needle capillary technique and in 90.5% with fine needle aspiration technique. In 17.7% with fine needle capillary technique and in 25.7% with fine needle aspiration technique it was not possible to compare the cytological smear with the histological results because of poor quality of the cytological smear. In four cases (4.3%) with fine needle capillary technique the cytological diagnosis was wrong. With fine needle aspiration technique, a wrong diagnosis occurred eight cases (9.5%). CONCLUSIONS: Fine needle capillary technique offers several advantages. Without aspiration trauma to cells and tissues is reduced. Less blood in the samples results in higher quality of the cytological smear. These circumstances make it easier for the pathologist to comment the cytological findings. The handling of the needle is practiced with a wrist movement and not from the shoulder joint as in aspiration method using the Cameco syringe holder. This allows for a more sensitive puncture technique touching the lesion during sampling with the finger tips. The puncture causes less pain than the aspiration technique. Our results demonstrate that fine needle capillary technique is the better method of fine needle biopsy in the head and neck region.\n\nBraun, Hannes\n\nMoinfar, Farid\n\nWalch, Christian\n\n\n"
},
{
"text": "\n87977\nShort acting insulin analogues versus regular human insulin in patients with diabetes mellitus.\n\nSiebenhofer, A\n\nPlank, J\n\nBerghold, A\n\nNarath, M\n\nGfrerer, R\n\nPieber, TR\n\nBeiträge in Fachzeitschriften\nNone\n15106199.0\n10.1002/14651858.CD003287.pub2\nNone\nBACKGROUND: In short acting insulin analogues the dissociation of hexamers is facilitated, achieving peak plasma concentrations about twice as high and within approximately half the time compared to regular human insulin. According to these properties this profile resembles the shape of non-diabetic patients more than that of regular human insulins. Despite this theoretical superiority of short acting insulin analogues over regular human insulin, the risk-benefit ratio of short acting insulin analogues in the treatment of diabetic patients is still unclear. OBJECTIVES: To assess the effect of treatment with short acting insulin analogues versus regular human insulin. SEARCH STRATEGY: A highly sensitive search for randomised controlled trials combined with key terms for identifying studies on short acting insulin analogues versus regular human insulin was performed using the Cochrane Library (issue 1, 2003), MEDLINE and EMBASE. Date of last search was December 2003. SELECTION CRITERIA: We included randomised controlled trials with diabetic patients of all ages that compared short acting insulin analogues to regular human insulin. Intervention duration had to be at least 4 weeks. DATA COLLECTION AND ANALYSIS: Trial selection as well as evaluation of study quality was done by two independent reviewers. The quality of reporting of each trial was assessed according to a modification of the quality criteria as specified by Schulz and Jadad. MAIN RESULTS: Altogether 7933 participants took part in 42 randomised controlled studies. Most studies were of poor methodological quality. In patients with type 1 diabetes, the weighted mean difference (WMD) of HbA1c was estimated to be -0.1% (95% CI: -0.2% to -0.1%) in favour of insulin analogue, whereas in patients with type 2 diabetes the WMD was estimated to be 0.0% (95% CI: -0.1% to 0.1%). In subgroup analyses of different types of interventions in type 1 diabetic patients, the WMD in HbA1c was -0.2% (95% CI: -0.3% to -0.1%) in favour of insulin analogue in studies using continuous subcutaneous insulin injections (CSII) whereas for conventional intensified insulin therapy (IIT) studies the WMD in HbA1c was -0.1% (95% CI: -0.2% to -0.0%). The WMD of the overall mean hypoglycaemic episodes per patient per month was -0.2 (95% CI: -1.2 to 0.9) and -0.2 (95%CI: -0.5 to 0.1) for analogues in comparison to regular insulin in patients with type 1 diabetes and type 2 diabetes, respectively. For studies in type 1 diabetic patients the incidence of severe hypoglycaemia ranged from 0 to 247.3 (median 20.3) episodes per 100 person-years for insulin analogues and from 0 to 544 (median 37.2) for regular insulin, in type 2 the incidence ranged from 0 to 30.3 (median 0.6) episodes per 100 person-years for insulin analogues and from 0 to 50.4 (median 2.8) for regular insulin. No study was designed to investigate possible long term effects (e.g. mortality, diabetic complications), in particular in patients with diabetes related complications. REVIEWERS' CONCLUSIONS: Our analysis suggests only a minor benefit of short acting insulin analogues in the majority of diabetic patients treated with insulin. Until long term efficacy and safety data are available we suggest a cautious response to the vigorous promotion of insulin analogues. Due to fears of potentially carcinogenic and proliferative effects, most studies to date have excluded patients with advanced diabetic complications. For safety purposes, we need a long-term follow-up of large numbers of patients who use short acting insulin analogues. Furthermore, we need well designed studies in pregnant women to determine the safety profile for both the mother and the unborn child.\n\nBerghold, Andrea\n\nPieber, Thomas\n\nSiebenhofer-Kroitzsch, Andrea\n\n\n"
},
{
"text": "\n100460\nNeo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study.\n\nIssels, RD\n\nLindner, LH\n\nVerweij, J\n\nWust, P\n\nReichardt, P\n\nSchem, BC\n\nAbdel-Rahman, S\n\nDaugaard, S\n\nSalat, C\n\nWendtner, CM\n\nVujaskovic, Z\n\nWessalowski, R\n\nJauch, KW\n\nDürr, HR\n\nPloner, F\n\nBaur-Melnyk, A\n\nMansmann, U\n\nHiddemann, W\n\nBlay, JY\n\nHohenberger, P\n\nfor the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG)\n\nthe European Society for Hyperthermic Oncology (ESHO)\n\nBeiträge in Fachzeitschriften\nISI:000279019500028\n20434400.0\n10.1016/S1470-2045(10)70071-1\nPMC3517819\nBackground The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is undear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallelgroup randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy. Methods Patients were recruited to the trial between July 21, 997, and November 30, 006, at nine centres in Europe and North America. Patients with localised high-risk STS (>= 5 cm, Federation Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade 2 or 3, deep to the fascia) were randomly assigned to receive either neo-adjuvant chemotherapy consisting of etoposide, ifosfamide, and doxorubicin (EIA) alone, or combined with regional hyperthermia (EIA plus regional hyperthermia) in addition to local therapy. Local progression-free survival (LPFS) was the primary endpoint. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT 00003052. Findings 341 patients were enrolled, with 169 randomly assigned to EIA plus regional hyperthermia and 172 to EIA alone. All patients were included in the analysis of the primary endpoint, and 332 patients who received at least one cycle of chemotherapy were included in the safety analysis. After a median follow-up of 34 months (IQR 20-67), 132 patients had local progression (56 EIA plus regional hyperthermia vs 76 EIA). Patients were more likely to experience local progression or death in the EIA-alone group compared with the EIA plus regional hyperthermia group (relative hazard [RH] 0.58, 95% CI 0.41-0.83; p=0.003), with an absolute difference in LPFS at 2 years of 15% (95% CI 6-26; 76% EIA plus regional hyperthermia vs 61% EIA). For disease-free survival the relative hazard was 0.70 (95% CI 0.54-0-92, p=0.011) for EIA plus regional hyperthermia compared with EIA alone. The treatment response rate in the group that received regional hyperthermia was 28-8%, compared with 12.7% in the group who received chemotherapy alone (p=0.002). In a prespecified per-protocol analysis of patients who completed EIA plus regional hyperthermia induction therapy compared with those who completed EIA alone, overall survival was better in the combined therapy group (HR 0.66, 95% CI 0.45-0.98, p=0.038). Leucopenia (grade 3 or 4) was more frequent in the EIA plus regional hyperthermia group compared with the EIA-alone group (128 of 165 vs 106 of 167, p=0.005). Hyperthermia-related adverse events were pain, bolus pressure, and skin burn, which were mild to moderate in 66 (40.5%), 43 (26.4%), and 29 patients (17.8%), and severe in seven (4.3%), eight (4.9%), and one patient (0.6%), respectively. Two deaths were attributable to treatment in the combined treatment group, and one death was attributable to treatment in the EIA-alone group. Interpretation To our knowledge, this is the first randomised phase 3 trial to show that regional hyperthermia increases the benefit of chemotherapy. Adding regional hyperthermia to chemotherapy is a new effective treatment strategy for patients with high-risk STS, including STS with an abdominal or retroperitoneal location.\n\n\n"
},
{
"text": "\n61340\nSerum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features.\n\nBerna, MJ\n\nHoffmann, KM\n\nLong, SH\n\nSerrano, J\n\nGibril, F\n\nJensen, RT\n\nBeiträge in Fachzeitschriften\nISI:000242251500002\n17108779.0\n10.1097/MD.0b013e31802b518c\nNone\nIn two-thirds of patients with Zollinger-Ellison syndrome (ZES), fasting serum gastrin (FSG) levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES. Whereas numerous gastrin provocative tests have been proposed, only the secretin, calcium, and meal tests are widely used today. Many studies have analyzed gastrin provocative test results in ZES, but they are limited by small patient numbers and methodologic differences. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of gastrin provocative tests in 293 patients with ZES and compare these data with those from 537 ZES and 462 non-ZES patients from the literature. In 97%-99% of gastrinoma patients, an increase in serum gastrin post secretin (Delta secretin) or post calcium (Delta calcium) occurred. In NIH ZES patients with <10-fold increase in FSG, the sensitivity/specificity of the widely used criteria were as follows: Delta secretin > or =200 pg/mL (83%/100%), Delta secretin >50% (86%/93%), Delta calcium > or =395 pg/mL (54%/100%), and Delta calcium >50% (78%/83%). A systematic analysis of the sensitivity and specificity of other possible criteria for a positive secretin or calcium test allowed us to identify a new criterion for secretin testing (Delta > or =120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Delta > or =395 pg/mL) (62%/100%). This analysis further showed that the secretin test was more sensitive than the calcium test (94% vs. 62%).Our results suggest that secretin stimulation should be used as the first-line provocative test because of its greater sensitivity and simplicity and lack of side effects. In ZES patients with a negative secretin test, 38%-50% have a positive calcium test. Therefore the calcium test should be considered in patients with a strong clinical suspicion of ZES but a negative secretin test. Furthermore, we found that some clinical (diarrhea, duration of medical treatment), laboratory (basal acid output), and tumoral (size, extent) characteristics correlate with the serum gastrin increase post secretin and post calcium. However, using the proposed criteria, the result of these provocative tests (that is, positive or negative) is minimally influenced by these factors, so secretin and calcium provocative tests are reliable in patients with different clinical, laboratory, and tumor characteristics. A systematic analysis of meal testing showed that 54%-77% of ZES patients have a <50% postprandial serum gastrin increase. However, 9%-20% of ZES patients had a >100% increase post meal, causing significant overlap with antral syndromes. Furthermore, we could not confirm the usefulness of meal tests for localization of duodenal gastrinomas. We conclude that the secretin test is a crucial element in the diagnosis of most ZES patients, the calcium test may be useful in selected patients, but the meal test is not helpful in the management of ZES. For secretin testing, the criterion with the highest sensitivity and specificity is an increase of > or =120 pg/mL, which should replace other criteria commonly used today.\n\nHoffmann, Karl Martin\n\n\n"
},
{
"text": "\n139776\nLarge-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.\n\nScott, RA\n\nLagou, V\n\nWelch, RP\n\nWheeler, E\n\nMontasser, ME\n\nLuan, J\n\nMägi, R\n\nStrawbridge, RJ\n\nRehnberg, E\n\nGustafsson, S\n\nKanoni, S\n\nRasmussen-Torvik, LJ\n\nYengo, L\n\nLecoeur, C\n\nShungin, D\n\nSanna, S\n\nSidore, C\n\nJohnson, PC\n\nJukema, JW\n\nJohnson, T\n\nMahajan, A\n\nVerweij, N\n\nThorleifsson, G\n\nHottenga, JJ\n\nShah, S\n\nSmith, AV\n\nSennblad, B\n\nGieger, C\n\nSalo, P\n\nPerola, M\n\nTimpson, NJ\n\nEvans, DM\n\nPourcain, BS\n\nWu, Y\n\nAndrews, JS\n\nHui, J\n\nBielak, LF\n\nZhao, W\n\nHorikoshi, M\n\nNavarro, P\n\nIsaacs, A\n\nO'Connell, JR\n\nStirrups, K\n\nVitart, V\n\nHayward, C\n\nEsko, T\n\nMihailov, E\n\nFraser, RM\n\nFall, T\n\nVoight, BF\n\nRaychaudhuri, S\n\nChen, H\n\nLindgren, CM\n\nMorris, AP\n\nRayner, NW\n\nRobertson, N\n\nRybin, D\n\nLiu, CT\n\nBeckmann, JS\n\nWillems, SM\n\nChines, PS\n\nJackson, AU\n\nKang, HM\n\nStringham, HM\n\nSong, K\n\nTanaka, T\n\nPeden, JF\n\nGoel, A\n\nHicks, AA\n\nAn, P\n\nMüller-Nurasyid, M\n\nFranco-Cereceda, A\n\nFolkersen, L\n\nMarullo, L\n\nJansen, H\n\nOldehinkel, AJ\n\nBruinenberg, M\n\nPankow, JS\n\nNorth, KE\n\nForouhi, NG\n\nLoos, RJ\n\nEdkins, S\n\nVarga, TV\n\nHallmans, G\n\nOksa, H\n\nAntonella, M\n\nNagaraja, R\n\nTrompet, S\n\nFord, I\n\nBakker, SJ\n\nKong, A\n\nKumari, M\n\nGigante, B\n\nHerder, C\n\nMunroe, PB\n\nCaulfield, M\n\nAntti, J\n\nMangino, M\n\nSmall, K\n\nMiljkovic, I\n\nLiu, Y\n\nAtalay, M\n\nKiess, W\n\nJames, AL\n\nRivadeneira, F\n\nUitterlinden, AG\n\nPalmer, CN\n\nDoney, AS\n\nWillemsen, G\n\nSmit, JH\n\nCampbell, S\n\nPolasek, O\n\nBonnycastle, LL\n\nHercberg, S\n\nDimitriou, M\n\nBolton, JL\n\nFowkes, GR\n\nKovacs, P\n\nLindström, J\n\nZemunik, T\n\nBandinelli, S\n\nWild, SH\n\nBasart, HV\n\nRathmann, W\n\nGrallert, H\n\nDIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium\n\nMaerz, W\n\nKleber, ME\n\nBoehm, BO\n\nPeters, A\n\nPramstaller, PP\n\nProvince, MA\n\nBorecki, IB\n\nHastie, ND\n\nRudan, I\n\nCampbell, H\n\nWatkins, H\n\nFarrall, M\n\nStumvoll, M\n\nFerrucci, L\n\nWaterworth, DM\n\nBergman, RN\n\nCollins, FS\n\nTuomilehto, J\n\nWatanabe, RM\n\nde Geus, EJ\n\nPenninx, BW\n\nHofman, A\n\nOostra, BA\n\nPsaty, BM\n\nVollenweider, P\n\nWilson, JF\n\nWright, AF\n\nHovingh, GK\n\nMetspalu, A\n\nUusitupa, M\n\nMagnusson, PK\n\nKyvik, KO\n\nKaprio, J\n\nPrice, JF\n\nDedoussis, GV\n\nDeloukas, P\n\nMeneton, P\n\nLind, L\n\nBoehnke, M\n\nShuldiner, AR\n\nvan Duijn, CM\n\nMorris, AD\n\nToenjes, A\n\nPeyser, PA\n\nBeilby, JP\n\nKörner, A\n\nKuusisto, J\n\nLaakso, M\n\nBornstein, SR\n\nSchwarz, PE\n\nLakka, TA\n\nRauramaa, R\n\nAdair, LS\n\nSmith, GD\n\nSpector, TD\n\nIllig, T\n\nde Faire, U\n\nHamsten, A\n\nGudnason, V\n\nKivimaki, M\n\nHingorani, A\n\nKeinanen-Kiukaanniemi, SM\n\nSaaristo, TE\n\nBoomsma, DI\n\nStefansson, K\n\nvan der Harst, P\n\nDupuis, J\n\nPedersen, NL\n\nSattar, N\n\nHarris, TB\n\nCucca, F\n\nRipatti, S\n\nSalomaa, V\n\nMohlke, KL\n\nBalkau, B\n\nFroguel, P\n\nPouta, A\n\nJarvelin, MR\n\nWareham, NJ\n\nBouatia-Naji, N\n\nMcCarthy, MI\n\nFranks, PW\n\nMeigs, JB\n\nTeslovich, TM\n\nFlorez, JC\n\nLangenberg, C\n\nIngelsson, E\n\nProkopenko, I\n\nBarroso, I\n\nBeiträge in Fachzeitschriften\nISI:000308491200010\n22885924.0\n10.1038/ng.2385\nPMC3433394\nThrough genome-wide association meta-analyses of up to 133, 10 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.\n\nMärz, Winfried\n\n\n"
},
{
"text": "\n149148\nLoci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.\n\nNINDS Stroke Genetics Network (SiGN)\n\nInternational Stroke Genetics Consortium (ISGC)\n\nBeiträge in Fachzeitschriften\nISI:000368116000015\n26708676.0\n10.1016/S1474-4422(15)00338-5\nPMC4912948\nThe discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.\n To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.\n We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10-8; joint OR 1·19, 1·12-1·26, p=1·30 × 10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10-19; joint OR 1·37, 1·30-1·45, p=2·79 × 10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10-7; joint OR 1·17, 1·11-1·23, p=2·29 × 10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10-8; joint OR 1·24, 1·15-1·33, p=4·52 × 10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10-8; joint OR 1·17, 1·11-1·23, p=2·92 × 10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.\n Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.\n US National Institute of Neurological Disorders and Stroke, National Institutes of Health.\n Copyright © 2016 Elsevier Ltd. All rights reserved.\n\nSchmidt, Helena\n\nSchmidt, Reinhold\n\n\n"
},
{
"text": "\n170431\nInterdisciplinary Diagnosis, Therapy and Follow-up of Patients with Endometrial Cancer. Guideline (S3-Level, AWMF Registry Nummer 032/034-OL, April 2018) - Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer.\n\nEmons, G\n\nSteiner, E\n\nVordermark, D\n\nUleer, C\n\nBock, N\n\nParadies, K\n\nOrtmann, O\n\nAretz, S\n\nMallmann, P\n\nKurzeder, C\n\nHagen, V\n\nvan Oorschot, B\n\nHöcht, S\n\nFeyer, P\n\nEgerer, G\n\nFriedrich, M\n\nCremer, W\n\nPrott, FJ\n\nHorn, LC\n\nPrömpeler, H\n\nLangrehr, J\n\nLeinung, S\n\nBeckmann, MW\n\nKimmig, R\n\nLetsch, A\n\nReinhardt, M\n\nAlt-Epping, B\n\nKiesel, L\n\nMenke, J\n\nGebhardt, M\n\nSteinke-Lange, V\n\nRahner, N\n\nLichtenegger, W\n\nZeimet, A\n\nHanf, V\n\nWeis, J\n\nMueller, M\n\nHenscher, U\n\nSchmutzler, RK\n\nMeindl, A\n\nHilpert, F\n\nPanke, JE\n\nStrnad, V\n\nNiehues, C\n\nDauelsberg, T\n\nNiehoff, P\n\nMayr, D\n\nGrab, D\n\nKreißl, M\n\nWitteler, R\n\nSchorsch, A\n\nMustea, A\n\nPetru, E\n\nHübner, J\n\nRose, AD\n\nWight, E\n\nTholen, R\n\nBauerschmitz, GJ\n\nFleisch, M\n\nJuhasz-Boess, I\n\nSigurd, L\n\nRunnebaum, I\n\nTempfer, C\n\nNothacker, MJ\n\nBlödt, S\n\nFollmann, M\n\nLanger, T\n\nRaatz, H\n\nWesselmann, S\n\nErdogan, S\n\nBeiträge in Fachzeitschriften\nISI:000447951900008\n30364388.0\n10.1055/a-0713-1218\nPMC6195426\nSummary The first German interdisciplinary S3-guideline on the diagnosis, therapy and follow-up of patients with endometrial cancer was published in April 2018. Funded by German Cancer Aid as part of an Oncology Guidelines Program, the lead coordinators of the guideline were the German Society of Gynecology and Obstetrics (DGGG) and the Gynecological Oncology Working Group (AGO) of the German Cancer Society (DKG). Purpose The use of evidence-based, risk-adapted therapy to treat low-risk women with endometrial cancer avoids unnecessarily radical surgery and non-useful adjuvant radiotherapy and/or chemotherapy. This can significantly reduce therapy-induced morbidity and improve the patient's quality of life as well as avoiding unnecessary costs. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimal surgical radicality together with the appropriate chemotherapy and/or adjuvant radiotherapy where required. The evidence-based optimal use of different therapeutic modalities should improve survival rates and the quality of life of these patients. The S3-guideline on endometrial cancer is intended as a basis for certified gynecological cancer centers. The aim is that the quality indicators established in this guideline will be incorporated in the certification processes of these centers. Methods The guideline was compiled in accordance with the requirements for S3-level guidelines. This includes, in the first instance, the adaptation of source guidelines selected using the DELBI instrument for appraising guidelines. Other consulted sources include reviews of evidence which were compiled from literature selected during systematic searches of literature databases using the PICO scheme. In addition, an external biostatistics institute was commissioned to carry out a systematic search and assessment of the literature for one area of the guideline. The identified materials were used by the interdisciplinary working groups to develop suggestions for Recommendations and Statements, which were then modified during structured consensus conferences and/or additionally amended online using the DELPHI method with consent being reached online. The guideline report is freely available online. Recommendations Part 1 of this short version of the guideline presents recommendations on epidemiology, screening, diagnosis and hereditary factors, The epidemiology of endometrial cancer and the risk factors for developing endomentrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer including the pathology of the cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer.\n\nPetru, Edgar\n\n\n"
},
{
"text": "\n179979\nEAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort: under the auspices of the EAU and ESMO Guidelines Committees\n\nHorwich, A\n\nBabjuk, M\n\nBellmunt, J\n\nBruins, HM\n\nDe Reijke, TM\n\nDe Santis, M\n\nGillessen, S\n\nJames, N\n\nMaclennan, S\n\nPalou, J\n\nPowles, T\n\nRibal, MJ\n\nShariat, SF\n\nVan der Kwast, T\n\nXylinas, E\n\nAgarwal, N\n\nArends, T\n\nBamias, A\n\nBirtle, A\n\nBlack, PC\n\nBochner, BH\n\nBolla, M\n\nBoormans, JL\n\nBossi, A\n\nBriganti, A\n\nBrummelhuis, I\n\nBurger, M\n\nCastellano, D\n\nCathomas, R\n\nChiti, A\n\nChoudhury, A\n\nComperat, E\n\nCrabb, S\n\nCuline, S\n\nDe Bari, B\n\nDe Blok, W\n\nDe Visschere, PJL\n\nDecaestecker, K\n\nDimitropoulos, K\n\nDominguez-Escrig, JL\n\nFanti, S\n\nFonteyne, V\n\nFrydenberg, M\n\nFutterer, JJ\n\nGakis, G\n\nGeavlete, B\n\nGontero, P\n\nGrubmuller, B\n\nHafeez, S\n\nHansel, DE\n\nHartmann, A\n\nHayne, D\n\nHenry, AM\n\nHernandez, V\n\nHerr, H\n\nHerrmann, K\n\nHoskin, P\n\nHuguet, J\n\nJereczek-Fossa, BA\n\nJones, R\n\nKamat, AM\n\nKhoo, V\n\nKiltie, AE\n\nKrege, S\n\nLadoire, S\n\nLara, PC\n\nLeliveld, A\n\nLinares-Espinos, E\n\nLogager, V\n\nLorch, A\n\nLoriot, Y\n\nMeijer, R\n\nMir, MC\n\nMoschini, M\n\nMostafid, H\n\nMuller, AC\n\nMuller, CR\n\nN'Dow, J\n\nNecchi, A\n\nNeuzillet, Y\n\nOddens, JR\n\nOldenburg, J\n\nOsanto, S\n\nOyen, WJG\n\nPacheco-Figueiredo, L\n\nPappot, H\n\nPatel, MI\n\nPieters, BR\n\nPlass, K\n\nRemzi, M\n\nRetz, M\n\nRichenberg, J\n\nRink, M\n\nRoghmann, F\n\nRosenberg, JE\n\nRoupret, M\n\nRouviere, O\n\nSalembier, C\n\nSalminen, A\n\nSargos, P\n\nSengupta, S\n\nSherif, A\n\nSmeenk, RJ\n\nSmits, A\n\nStenzl, A\n\nThalmann, GN\n\nTombal, B\n\nTurkbey, B\n\nLauridsen, SV\n\nValdagni, R\n\nVan der Heijden, AG\n\nVan Poppel, H\n\nVartolomei, MD\n\nVeskimae, E\n\nVilaseca, A\n\nRivera, FAV\n\nWiegel, T\n\nWiklund, P\n\nWilliams, A\n\nZigeuner, R\n\nWitjes, JA\n\nBeiträge in Fachzeitschriften\nISI:000507594800008\nNone\n10.1093/annonc/mdz296\nNone\nBackground: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), 7-9 (agree). A priori (level 1) consensus was defined as >= 70% agreement and <= 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach.\n\nZigeuner, Richard\n\n\n"
},
{
"text": "\n133228\nEffectiveness and cost-effectiveness of traditional and new partner notification technologies for curable sexually transmitted infections: observational study, systematic reviews and mathematical modelling.\n\nAlthaus, CL\n\nTurner, KM\n\nMercer, CH\n\nAuguste, P\n\nRoberts, TE\n\nBell, G\n\nHerzog, SA\n\nCassell, JA\n\nEdmunds, WJ\n\nWhite, PJ\n\nWard, H\n\nLow, N\n\nBeiträge in Fachzeitschriften\nISI:000329915500001\n24411488.0\n10.3310/hta18020\nPMC4780998\nPartner notification is essential to the comprehensive case management of sexually transmitted infections. Systematic reviews and mathematical modelling can be used to synthesise information about the effects of new interventions to enhance the outcomes of partner notification.\n To study the effectiveness and cost-effectiveness of traditional and new partner notification technologies for curable sexually transmitted infections (STIs).\n Secondary data analysis of clinical audit data; systematic reviews of randomised controlled trials (MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials) published from 1 January 1966 to 31 August 2012 and of studies of health-related quality of life (HRQL) [MEDLINE, EMBASE, ISI Web of Knowledge, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA)] published from 1 January 1980 to 31 December 2011; static models of clinical effectiveness and cost-effectiveness; and dynamic modelling studies to improve parameter estimation and examine effectiveness.\n General population and genitourinary medicine clinic attenders.\n Heterosexual women and men.\n Traditional partner notification by patient or provider referral, and new partner notification by expedited partner therapy (EPT) or its UK equivalent, accelerated partner therapy (APT).\n Population prevalence; index case reinfection; and partners treated per index case.\n Enhanced partner therapy reduced reinfection in index cases with curable STIs more than simple patient referral [risk ratio (RR) 0.71; 95% confidence interval (CI) 0.56 to 0.89]. There are no randomised trials of APT. The median number of partners treated for chlamydia per index case in UK clinics was 0.60. The number of partners needed to treat to interrupt transmission of chlamydia was lower for casual than for regular partners. In dynamic model simulations, >10% of partners are chlamydia positive with look-back periods of up to 18 months. In the presence of a chlamydia screening programme that reduces population prevalence, treatment of current partners achieves most of the additional reduction in prevalence attributable to partner notification. Dynamic model simulations show that cotesting and treatment for chlamydia and gonorrhoea reduce the prevalence of both STIs. APT has a limited additional effect on prevalence but reduces the rate of index case reinfection. Published quality-adjusted life-year (QALY) weights were of insufficient quality to be used in a cost-effectiveness study of partner notification in this project. Using an intermediate outcome of cost per infection diagnosed, doubling the efficacy of partner notification from 0.4 to 0.8 partners treated per index case was more cost-effective than increasing chlamydia screening coverage.\n There is evidence to support the improved clinical effectiveness of EPT in reducing index case reinfection. In a general heterosexual population, partner notification identifies new infected cases but the impact on chlamydia prevalence is limited. Partner notification to notify casual partners might have a greater impact than for regular partners in genitourinary clinic populations. Recommendations for future research are (1) to conduct randomised controlled trials using biological outcomes of the effectiveness of APT and of methods to increase testing for human immunodeficiency virus (HIV) and STIs after APT; (2) collection of HRQL data should be a priority to determine QALYs associated with the sequelae of curable STIs; and (3) standardised parameter sets for curable STIs should be developed for mathematical models of STI transmission that are used for policy-making.\n The National Institute for Health Research Health Technology Assessment programme.\n\nHerzog, Sereina Annik\n\n\n"
},
{
"text": "\n183396\nPrognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset.\n\nPETACC-8 study investigators\n\nThaler, J\n\nGreil, R\n\nGaenzer, J\n\nEisterer, W\n\nTschmelitsch, J\n\nSamonigg, H\n\nZabernigg, A\n\nSchmid, F\n\nSteger, G\n\nSteinacher, R\n\nAndel, J\n\nLang, A\n\nFügger, R\n\nHofbauer, F\n\nWoell, E\n\nGeissler, D\n\nLenauer, A\n\nPrager, M\n\nVan Laethem, JL\n\nVan Cutsem, E\n\nD'Haens, G\n\nDemolin, G\n\nKerger, J\n\nDeboever, G\n\nGhillebert, G\n\nPolus, M\n\nVan Cutsem, E\n\nRezaieKalantari, H\n\nDelaunoit, T\n\nGoeminne, JC\n\nPeeters, M\n\nVergauwe, P\n\nHoubiers, G\n\nHumblet, Y\n\nJanssens, J\n\nSchrijvers, D\n\nVanderstraeten, E\n\nVan Laethem, JL\n\nVermorken, J\n\nVan Daele, D\n\nFerrante, M\n\nForget, F\n\nHendlisz, A\n\nYilmaz, M\n\nNielsen, SE\n\nVestermark, L\n\nLarsen, J\n\nYchou, M\n\nZawadi, A\n\nZawadi, MA\n\nBouche, O\n\nMineur, L\n\nBennouna-Louridi, J\n\nDourthe, LM\n\nYchou, M\n\nBoucher, E\n\nTaieb, J\n\nPezet, D\n\nDesseigne, F\n\nDucreux, M\n\nTexereau, P\n\nMiglianico, L\n\nRougier, P\n\nFratte, S\n\nLevache, CB\n\nMerrouche, Y\n\nEllis, S\n\nLocher, C\n\nRamee, JF\n\nGarnier, C\n\nViret, F\n\nChauffert, B\n\nCojean-Zelek, I\n\nMichel, P\n\nLecaille, C\n\nBorel, C\n\nSeitz, JF\n\nSmith, D\n\nLombard-Bohas, C\n\nAndre, T\n\nGornet, JM\n\nFein, F\n\nCoulon-Sfairi, MA\n\nKaminsky, MC\n\nLagasse, JP\n\nLuet, D\n\nEtienne, PL\n\nGasmi, M\n\nVanoli, A\n\nNguyen, S\n\nAparicio, T\n\nPerrier, H\n\nStremsdoerfer, N\n\nLaplaige, P\n\nArsene, D\n\nAuby, D\n\nBedenne, L\n\nCoriat, R\n\nDenis, B\n\nGeoffroy, P\n\nPiot, G\n\nBecouarn, Y\n\nBordes, G\n\nDeplanque, G\n\nDupuis, O\n\nFruge, F\n\nGuimbaud, R\n\nLecomte, T\n\nLledo, G\n\nSobhani, I\n\nAsnacios, A\n\nAzzedine, A\n\nDesauw, C\n\nGalais, MP\n\nGargot, D\n\nLam, YH\n\nAbakar-Mahamat, A\n\nBerdah, JF\n\nCatteau, S\n\nClavero-Fabri, MC\n\nCodoul, JF\n\nLegoux, JL\n\nGoldfain, D\n\nGuichard, P\n\nVerge, DP\n\nProvencal, J\n\nVedrenne, B\n\nBrezault-Bonnet, C\n\nCleau, D\n\nDesir, JP\n\nFallik, D\n\nGarcia, B\n\nGaspard, MH\n\nGenet, D\n\nHartwig, J\n\nKrummel, Y\n\nMatysiakBudnik, T\n\nPalascak-Juif, V\n\nRandrianarivelo, H\n\nRinaldi, Y\n\nAleba, A\n\nDarut-Jouve, A\n\nde Gramont, A\n\nHamon, H\n\nWendehenne, F\n\nMatzdorff, A\n\nStahl, MK\n\nSchepp, W\n\nBurk, M\n\nMueller, L\n\nFolprecht, G\n\nGeissler, M\n\nMantovani-Loeffler, L\n\nHoehler, T\n\nAsperger, W\n\nKroening, H\n\nvon Weikersthal, LF\n\nFuxius, S\n\nGroschek, M\n\nMeiler, J\n\nTrarbach, T\n\nRauh, J\n\nZiegenhagen, N\n\nKretzschmar, A\n\nGraeven, U\n\nNusch, A\n\nvon Wichert, G\n\nHofheinz, RD\n\nKleber, G\n\nSchmidt, KH\n\nVehling-Kaiser, U\n\nBaum, C\n\nSchuette, J\n\nHaag, GM\n\nHoltkamp, W\n\nPotenberg, J\n\nReiber, T\n\nSchliesser, G\n\nSchmoll, HJ\n\nSchneider-Kappus, W\n\nAbenhardt, W\n\nDenzlinger, C\n\nHenning, J\n\nMarxsen, B\n\nGuenterDerigs, H\n\nLambertz, H\n\nBecker-Boost, I\n\nCaca, K\n\nConstantin, C\n\nDecker, T\n\nEschenburg, H\n\nGabius, S\n\nHebart, H\n\nHoffmeister, A\n\nHorst, HA\n\nKremers, S\n\nLeithaeuser, M\n\nMueller, S\n\nWagner, S\n\nDaum, S\n\nSchlegel, F\n\nStauch, M\n\nHeinemann, V\n\nLabianca, R\n\nColucci, G\n\nAmadori, D\n\nMini, E\n\nFalcone, A\n\nBoni, C\n\nMaiello, E\n\nLatini, L\n\nZaniboni, A\n\nAmadori, D\n\nAprile, G\n\nBarni, S\n\nMattioli, R\n\nMartoni, A\n\nPassalacqua, R\n\nNicolini, M\n\nPasquini, E\n\nRabbi, C\n\nAitini, E\n\nRavaioli, A\n\nBarone, C\n\nBiasco, G\n\nTamberi, S\n\nGambi, A\n\nVerusio, C\n\nMarzola, M\n\nLelli, G\n\nBoni, C\n\nCascinu, S\n\nBidoli, P\n\nVaghi, M\n\nCruciani, G\n\nDi Costanzo, F\n\nSobrero, A\n\nMini, E\n\nPetrioli, R\n\nAglietta, M\n\nAlabiso, O\n\nCapuzzo, F\n\nFalcone, A\n\nCorsi, DC\n\nLabianca, R\n\nSalvagni, S\n\nChiara, S\n\nFerraù, F\n\nGiuliani, F\n\nLonardi, S\n\nGebbia, N\n\nMantovani, G\n\nSanches, E\n\nSanches, E\n\nMellidez, JC\n\nSantos, P\n\nFreire, J\n\nSarmento, C\n\nCosta, L\n\nPinto, AM\n\nBarroso, S\n\nSanto, JE\n\nGuedes, F\n\nMonteiro, A\n\nSa, A\n\nFurtado, I\n\nTabernero, J\n\nSalazar, R\n\nAguilar, EA\n\nHerrero, FR\n\nTabernero, J\n\nValera, JS\n\nValladaresAyerbes, M\n\nFeliuBatlle, J\n\nGil, S\n\nGar ...\n\nBeiträge in Fachzeitschriften\nNone\n25814651.0\n10.1093/annonc/mdv070\nNone\nNone\n\nSamonigg, Hellmut\n\n\n"
},
{
"text": "\n169396\nPharyngeal electrical stimulation for early decannulation in tracheotomised patients with neurogenic dysphagia after stroke (PHAST-TRAC): a prospective, single-blinded, randomised trial.\n\nDziewas, R\n\nStellato, R\n\nvan der Tweel, I\n\nWalther, E\n\nWerner, CJ\n\nBraun, T\n\nCiterio, G\n\nJandl, M\n\nFriedrichs, M\n\nNötzel, K\n\nVosko, MR\n\nMistry, S\n\nHamdy, S\n\nMcGowan, S\n\nWarnecke, T\n\nZwittag, P\n\nBath, PM\n\nPHAST-TRAC investigators\n\nBeiträge in Fachzeitschriften\nISI:000444862200013\n30170898.0\n10.1016/S1474-4422(18)30255-2\nNone\nDysphagia after stroke is common, especially in severely affected patients who have had a tracheotomy. In a pilot trial, pharyngeal electrical stimulation (PES) improved swallowing function in this group of patients. We aimed to replicate and extend this single-centre experience.\n We did a prospective, single-blind, randomised controlled trial across nine sites (seven acute care hospitals, two rehabilitation facilities) in Germany, Austria, and Italy. Patients with recent stroke who required tracheotomy were randomly assigned to receive 3 days of either PES or sham treatment (1:1). All patients had the stimulation catheter inserted; sham treatment was applied by connecting the PES base station to a simulator box instead of the catheter. Randomisation was done via a computerised interactive system (stratified by site) in blocks of four patients per site. Patients and investigators applying PES were not masked. The primary endpoint was assessed by a separate investigator at each site who was masked to treatment assignment. The primary outcome was readiness for decannulation 24-72 h after treatment, assessed using fibreoptic endoscopic evaluation of swallowing and based on a standardised protocol, including absence of massive pooling of saliva, presence of one or more spontaneous swallows, and presence of at least minimum laryngeal sensation. We planned a sequential statistical analysis of superiority for the primary endpoint. Interim analyses were to be done after primary outcome data were available for 50 patients (futility), 70 patients, and every additional ten patients thereafter, up to 140 patients. Analysis was by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN18137204.\n From May 29, 2015, to July 5, 2017, of 81 patients assessed, 69 patients from nine sites were randomly assigned to receive PES (n=35) or sham (n=34) treatment. Median onset to randomisation time was 28 days (IQR 19-41; PES 28 [20-49]; sham 28 [18-40]). The Independent Data and Safety Monitoring Board recommended that the trial was stopped early for efficacy after 70 patients had been recruited and primary endpoint data for 69 patients were available. This decision was approved by the steering committee. More patients were ready for decannulation in the PES group (17 [49%] of 35 patients) than in the sham group (three [9%] of 34 patients; odds ratio [OR] 7·00 [95% CI 2·41-19·88]; p=0·0008). Adverse events were reported in 24 (69%) patients in the PES group and 24 (71%) patients in the sham group. The number of patients with at least one serious adverse event did not differ between the groups (ten [29%] patients in the PES group vs eight [23%] patients in the sham group; OR 1·30 [0·44-3·83]; p=0·7851). Seven (20%) patients in the PES group and three (9%) patients in the sham group died during the study period (OR 2·58 [0·61-10·97]; p=0·3059). None of the deaths or serious adverse events were judged to be related to PES.\n In patients with stroke and subsequent tracheotomy, PES increased the proportion of patients who were ready for decannulation in this study population, many of whom received PES within a month of their stroke. Future trials should confirm whether PES is beneficial in tracheotomised patients who receive stimulation similarly early after stroke and explore its effects in other cohorts.\n Phagenesis Ltd.\n Copyright © 2018 Elsevier Ltd. All rights reserved.\n\nKöstenberger, Markus\n\n\n"
},
{
"text": "\n153169\nSafety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial.\n\nBehr, J\n\nBendstrup, E\n\nCrestani, B\n\nGünther, A\n\nOlschewski, H\n\nSköld, CM\n\nWells, A\n\nWuyts, W\n\nKoschel, D\n\nKreuter, M\n\nWallaert, B\n\nLin, CY\n\nBeck, J\n\nAlbera, C\n\nBeiträge in Fachzeitschriften\nISI:000377059100020\n27161257.0\n10.1016/S2213-2600(16)30044-3\nNone\nOral acetylcysteine (also known as N-acetylcysteine) is used with pirfenidone to treat idiopathic pulmonary fibrosis (IPF) in Europe. However, no randomised studies have investigated the safety and tolerability of this combination. The PANORAMA study assessed the safety and tolerability of acetylcysteine combined with pirfenidone in patients with IPF. Exploratory efficacy endpoints were also assessed.\n We did a double-blind randomised trial at 48 sites in eight countries. Patients with IPF aged 40-80 years and established on pirfenidone (at least 1602 mg/day for 8 weeks or longer) were randomly assigned in a 1:1 ratio by interactive voice response system to receive concomitant oral acetylcysteine (600 mg, three times daily) or placebo for 24 weeks. A stratified blocked randomisation scheme was used with a block size of 4. Randomisation was stratified by dose of pirfenidone (2403 mg/day [the maximum dose] or <2403 mg/day). Patients, physicians, study staff and the sponsor were masked to treatment group allocation. The primary endpoint was assessment of adverse events, which were collected at each visit and for 28 days after the last dose of study drug. Exploratory efficacy measurements included forced vital capacity (FVC), carbon monoxide diffusing capacity, and 6 min walk distance. Analyses were done in the modified intention-to-treat population, which included all patients who were randomised and received at least one dose of study medication. This study is registered with the European Clinical Trials Database (EudraCT number 2012-000564-14) and has been completed.\n 123 patients participated in the study between June 28, 2013, and Feb 24, 2015. 61 were assigned to the acetylcysteine group (60 received study medication and included in analysis) and 62 were assigned to the placebo group (all included in analysis). The occurrence of at least one adverse event (46 [77%] patients receiving acetylcysteine vs 50 [81%] receiving placebo), adverse events related to study treatment (17 [28%] vs 16 [26%]), and the number of patients experiencing severe adverse events (three [5%] vs two [3%]), life-threatening adverse events (one [2%] vs one [2%]), or death (one [2%] vs three [5%]) was similar between treatment groups. One case of diarrhoea in the acetylcysteine group was considered severe and related to study treatment. Nine serious adverse events were reported by seven patients: dyspnoea, headache, hypertension, intervertebral disc protrusion, and malignant lung neoplasm in the acetylcysteine group, and aortic aneurysm, contusion, forearm fracture, and worsening IPF in the placebo group. The most common adverse events were cough, nasopharyngitis, and diarrhoea. Photosensitivity occurred more frequently with acetylcysteine (eight [13%] patients) than placebo (one [2%] patient; difference 11·7%; 95% CI 2·6-20·9; p=0·016]), and was not attributable to differences in location, season, or concomitant medication. Four (7%) patients receiving acetylcysteine and three (5%) receiving placebo discontinued study treatment due to adverse events. In the exploratory analysis, change in FVC indicated that clinical benefit from addition of acetylcysteine to pirfenidone is unlikely, with the possibility of a harmful effect in patients with IPF (adjusted rate of decline 125·6 mL/6 months for acetylcysteine vs 34·3 mL/6 months for placebo; difference -91·3 mL; 95% CI -174·4 to -8·3; p=0·031).\n Findings from the PANORAMA study suggest that addition of acetylcysteine to pirfenidone does not substantially alter the tolerability profile of pirfenidone, and is unlikely to be beneficial in IPF.\n InterMune International AG (Roche).\n Copyright © 2016 Elsevier Ltd. All rights reserved.\n\nOlschewski, Horst\n\n\n"
},
{
"text": "\n152295\nLong-term effects of weight-reducing drugs in people with hypertension.\n\nSiebenhofer, A\n\nJeitler, K\n\nHorvath, K\n\nBerghold, A\n\nPosch, N\n\nMeschik, J\n\nSemlitsch, T\n\nBeiträge in Fachzeitschriften\nISI:000373475200021\n26934640.0\n10.1002/14651858.CD007654.pub4\nNone\nAll major guidelines on antihypertensive therapy recommend weight loss; anti-obesity drugs may be able to help in this respect.\n \n To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).\n To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction.\n We obtained studies using computerised searches of the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, the clinical trials registry ClinicalTrials.gov, and from handsearches in reference lists and systematic reviews (status as of 13 April 2015).\n Randomised controlled trials in hypertensive adults of at least 24 weeks' duration that compared long-term pharmacologic interventions for weight loss with placebo. \n Two review authors independently selected studies, assessed risk of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of heterogeneity.\n After updating the literature search, which was extended to include four new weight-reducing drugs, we identified one additional study of phentermine/topiramate, bringing the total number of studies to nine that compare orlistat, sibutramine, or phentermine/topiramate to placebo and thus fulfil our inclusion criteria. We identified no relevant studies investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion. No study included mortality and cardiovascular morbidity as predefined outcomes. Incidence of gastrointestinal side effects was consistently higher in those participants treated with orlistat versus those treated with placebo. The most frequent side effects were dry mouth, constipation, and headache with sibutramine, and dry mouth and paresthaesia with phentermine/topiramate. In participants assigned to orlistat, sibutramine, or phentermine/topiramate body weight was reduced more effectively than in participants in the usual-care/placebo groups. Orlistat reduced systolic blood pressure as compared to placebo by -2.5 mm Hg (mean difference (MD); 95% confidence interval (CI): -4.0 to -0.9 mm Hg) and diastolic blood pressure by -1.9 mm Hg (MD; 95% CI: -3.0 to -0.9 mm Hg). Sibutramine increased diastolic blood pressure compared to placebo by +3.2 mm Hg (MD; 95% CI: +1.4 to +4.9 mm Hg). The one trial that investigated phentermine/topiramate suggested it lowered blood pressure.\n In people with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree, while phentermine/topiramate reduced body weight to a greater extent. In the same trials, orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We could include no trials investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. Long-term trials assessing the effect of orlistat, liraglutide, lorcaserin, phentermine/topiramate, or naltrexone/bupropion on mortality and morbidity are unavailable and needed. Rimonabant and sibutramine have been withdrawn from the market, after long-term trials on mortality and morbidity have confirmed concerns about the potential severe side effects of these two drugs. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while the application for European marketing authorisation for lorcaserin was withdrawn by the manufacturer after the Committee for Medicinal Products for Human Use judged the overall benefit/risk balance to be negative.\n\nBerghold, Andrea\n\nHorvath, Karl\n\nJeitler, Klaus\n\nPosch, Nicole\n\nSemlitsch, Thomas\n\nSiebenhofer-Kroitzsch, Andrea\n\n\n"
},
{
"text": "\n158205\nRole of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4(-/-) mouse model.\n\nReiter, FP\n\nWimmer, R\n\nWottke, L\n\nArtmann, R\n\nNagel, JM\n\nCarranza, MO\n\nMayr, D\n\nRust, C\n\nFickert, P\n\nTrauner, M\n\nGerbes, AL\n\nHohenester, S\n\nDenk, GU\n\nBeiträge in Fachzeitschriften\nISI:000439232100003\n27004088.0\n10.4254/wjh.v8.i8.401\nPMC4794530\nTo study the interleukin-1 (IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4(-/-) (Abcb4(-/-)) mouse model.\n Female and male Abcb4(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis (liver serum tests), extent of liver fibrosis (hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction (qPCR)]. For in vivo experiments, murine hepatic stellate cells (HSCs) were isolated via pronase-collagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/mL IL-1β with or without 2.5 μg/mL Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the BrdU assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis (FDH) assay. In vivo 8-wk-old Abcb4(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra (1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, qPCR, hydroxyproline content and Sirius red staining.\n Liver fibrosis was less pronounced in males than in female Abcb4(-/-) animals as defined by a lower hydroxyproline content (274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test) and lower mRNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1 (TIMP) (1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 mRNA expression (1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β mRNA expression levels (1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase (ALT); aspartate aminotransferase and alkaline phosphatase (AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units (A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/mL and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/mL in samples from n = 6 donor animals; P < 0.001; analyses of variance (ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/mL Anakinra (0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/mL, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/mL; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyproline content, liver serum tests (ALT and AP) and pro-fibrotic (collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2 (MMP2), MMP9 and MMP13] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 mRNA expression levels were unaffected by Anakinra treatment.\n IL-1β expression is associated with the degree of liver fibrosis in Abcb4(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4(-/-) mice.\n\nFickert, Peter\n\n\n"
},
{
"text": "\n168247\nInvestigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.\n\nKalman, JL\n\nPapiol, S\n\nForstner, AJ\n\nHeilbronner, U\n\nDegenhardt, F\n\nStrohmaier, J\n\nAdli, M\n\nAdorjan, K\n\nAkula, N\n\nAlda, M\n\nAnderson-Schmidt, H\n\nAndlauer, TF\n\nAnghelescu, IG\n\nArdau, R\n\nArias, B\n\nArolt, V\n\nAubry, JM\n\nBacklund, L\n\nBartholdi, K\n\nBauer, M\n\nBaune, BT\n\nBecker, T\n\nBellivier, F\n\nBenabarre, A\n\nBengesser, S\n\nBhattacharjee, AK\n\nBiernacka, JM\n\nBirner, A\n\nBrichant-Petitjean, C\n\nBudde, M\n\nCervantes, P\n\nChillotti, C\n\nCichon, S\n\nClark, SR\n\nColom, F\n\nComes, AL\n\nCruceanu, C\n\nCzerski, PM\n\nDannlowski, U\n\nDayer, A\n\nDel Zompo, M\n\nDePaulo, JR\n\nDietrich, DE\n\nÉtain, B\n\nEthofer, T\n\nFalkai, P\n\nFallgatter, A\n\nFigge, C\n\nFlatau, L\n\nFolkerts, H\n\nFrisen, L\n\nFrye, MA\n\nFullerton, JM\n\nGade, K\n\nGard, S\n\nGarnham, JS\n\nGoes, FS\n\nGrigoroiu-Serbanescu, M\n\nGryaznova, A\n\nHake, M\n\nHauser, J\n\nHerms, S\n\nHoffmann, P\n\nHou, L\n\nJäger, M\n\nJamain, S\n\nJiménez, E\n\nJuckel, G\n\nKahn, JP\n\nKassem, L\n\nKelsoe, J\n\nKittel-Schneider, S\n\nKliwicki, S\n\nKlohn-Sagatholislam, F\n\nKoller, M\n\nKönig, B\n\nKonrad, C\n\nLackner, N\n\nLaje, G\n\nLandén, M\n\nLang, FU\n\nLavebratt, C\n\nLeboyer, M\n\nLeckband, SG\n\nMaj, M\n\nManchia, M\n\nMartinsson, L\n\nMcCarthy, MJ\n\nMcElroy, SL\n\nMcMahon, FJ\n\nMitchell, PB\n\nMitjans, M\n\nMondimore, FM\n\nMonteleone, P\n\nNieratschker, V\n\nNievergelt, CM\n\nNovák, T\n\nÖsby, U\n\nPfennig, A\n\nPotash, JB\n\nReich-Erkelenz, D\n\nReif, A\n\nReimer, J\n\nReininghaus, E\n\nReitt, M\n\nRipke, S\n\nRouleau, GA\n\nRybakowski, JK\n\nSchalling, M\n\nScherk, H\n\nSchmauß, M\n\nSchofield, PR\n\nSchubert, KO\n\nSchulte, EC\n\nSchulz, S\n\nSenner, F\n\nSeverino, G\n\nShekhtman, T\n\nShilling, PD\n\nSimhandl, C\n\nSlaney, CM\n\nSpitzer, C\n\nSquassina, A\n\nStamm, T\n\nStegmaier, S\n\nStierl, S\n\nStopkova, P\n\nThiel, A\n\nTighe, SK\n\nTortorella, A\n\nTurecki, G\n\nVieta, E\n\nVeeh, J\n\nvon Hagen, M\n\nWigand, ME\n\nWiltfang, J\n\nWitt, S\n\nWright, A\n\nZandi, PP\n\nZimmermann, J\n\nNöthen, M\n\nRietschel, M\n\nSchulze, TG\n\nBeiträge in Fachzeitschriften\nISI:000459791000009\n29956436.0\n10.1111/bdi.12659\nPMC6585855\nBipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients.\n A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models.\n BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment.\n The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.\n © 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.\n\nBengesser, Susanne\n\nBirner, Armin\n\nDalkner, Nina\n\nReininghaus, Eva\n\n\n"
}
]
}