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Objective: Ataxia channelopathies share common features such as slow motor progression and variable degrees of cognitive dysfunction. Mutations in potassium voltage-gated channel subfamily D member 3 (KCND3), encoding the K+ channel, Kv4.3, are associated with spinocerebellar ataxia (SCA) 19, allelic with SCA22. Mutations in potassium voltage-gated channel subfamily C member 3 (KCNC3), encoding another K+ channel, Kv3.3, cause SCA13. First, a comprehensive phenotype assessment was carried out in a family with autosomal dominant ataxia harboring 2 genetic variants in KCNC3 and KCND3. To evaluate the physiological impact of these variants on channel currents, in vitro studies were performed. Methods: Clinical and psychometric evaluations, neuroimaging, and genotyping of a family (mother and son) affected by ataxia were carried out. Heterozygous and homozygous Kv3.3 A671V and Kv4.3 V374A variants were evaluated in Xenopus laevis oocytes using 2-electrode voltage-clamp. The influence of Kv4 conductance on neuronal activity was investigated computationally using a Purkinje neuron model. Results: The main clinical findings were consistent with adult-onset ataxia with cognitive dysfunction and acetazolamide-responsive paroxysmal motor exacerbations in the index case. Despite cognitive deficits, fluorodeoxyglucose (FDG)-PET displayed hypometabolism mainly in the severely atrophic cerebellum. Genetic analyses revealed the new variant c.1121T>C (V374A) in KCND3 and c.2012T>C (A671V) in KCNC3. In vitro electrophysiology experiments on Xenopus oocytes demonstrated that the V374A mutant was nonfunctional when expressed on its own. Upon equal co-expression of wild-type (WT) and V374A channel subunits, Kv4.3 currents were significantly reduced in a dominant negative manner, without alterations of the gating properties of the channel. By contrast, Kv3.3 A671V, when expressed alone, exhibited moderately reduced currents compared with WT, with no effects on channel activation or inactivation. Immunohistochemistry demonstrated adequate cell membrane translocation of the Kv4.3 V374A variant, thus suggesting an impairment of channel function, rather than of expression. Computational modeling predicted an increased Purkinje neuron firing frequency upon reduced Kv4.3 conductance. Conclusions: Our findings suggest that Kv4.3 V374A is likely pathogenic and associated with paroxysmal ataxia exacerbations, a new trait for SCA19/22. The present FDG PET findings contrast with a previous study demonstrating widespread brain hypometabolism in SCA19/22.

Purpose To determine if women with breast cancer that undergo fertility preservation (FP), with or without hormonal stimulation, present with an increased risk of breast cancer recurrence. Methods A matched cohort study on women with breast cancer attempting to ensure FP in Stockholm from 1999 to 2013 [exposed women (n = 188), age-matched unexposed controls (n = 378)] was designed using the Stockholm regional data from the Swedish National Breast Cancer Quality Register. Breast cancer relapse rates [incidence rate ratio (IRR)] and 95% confidence interval (CI) were estimated using Cox regression and adjusted for potential confounding factors. Completeness of the registry at the time of the study was close to 99%. Results Most women attempted FP by hormonal stimulation treatment (n = 148, 79%) with the objective of freezing their eggs or embryos. A smaller group elected FP methods without hormone stimulation (n = 40, 21%). Women who received hormone stimulation did not present with a higher relapse rate than unexposed control women in a model adjusted for age and calendar period of diagnosis (IRR 0.59, 95% CI 0.34–1.04). The results remained virtually unchanged after adjustment for tumor size, estrogen receptor status, affected lymph nodes, and chemotherapy treatment (IRR 0.66, 95% CI 0.37–1.17). Conclusion Evidence was not found that fertility preservation, with or without hormonal stimulation, was associated with an increased risk of breast cancer recurrence. The high coverage rate of this population-based study supports the safe practice of fertility preservation in young women with breast cancer.

Syfte Syftet med föreliggande uppsats var att med hjälp av intervjuer kartlägga hur HR-ansvariga och anställda upplevde att hälsoarbetet avseende förändring av hälsobeteenden utfördes på företag med kontorsanställda. Metod Studiegruppen bestod av kontorsanställda kvinnor (N=4) från två olika företag. Studien hade en kvalitativ ansats i form av semistrukturerade intervjuer. Två intervjuguider användes, en anpassad för HR-ansvariga och en för anställda. Intervjuerna spelades in med iPhones egna applikation för röstinspelning. Samtliga intervjuer transkriberades för att sedan analyseras. I analysen delades innehållet in i kategorier utifrån de teman som identifierades. Resultat Företagen som deltog i studien hade kommit olika långt med sitt hälsoarbete. Det ena hade ett framgångsrikt hälsoarbete medan det andra företaget inte bedrev ett alls i dagsläget. Det hälsoarbete som konstaterades var i form av gym och gruppträning på arbetsplatsen, friskvårdsbidrag, strategisk matsal, föreläsningar samt medarbetardrivna föreningar. Båda företag ansåg att det kunde göras mer i hälsofrågorna. Förutsättningarna såg olika ut på företagen vilket korrelerade med hur hälsoarbetet såg ut. HR-ansvarig och anställd gav lika svar men den anställde gav en mer verklig bild av verksamheten. Slutkommentar Det finns en skillnad i hur hälsoarbetet ser ut mellan olika företag. Skillnaderna handlar om bland annat förutsättningar och prioriteringar på arbetsplatsen. Att arbeta mer med hälsa skulle kunna gynna arbetsplatsen i form av minskat antal sjukskrivningar och ekonomisk vinning. Hälsoarbete av preventiv form är troligtvis mest effektivt. Purpose The purpose of the study was to examine how human resources managers and employees experienced health work, regarding health behaviors at office-based companies. Methods Four female office employees participated in the study. The study had a qualitative approach and semi structured interviews were used. Two interview guides were adapted, one towards HR-managers and one for employees. All interviews were recorded by the pre installed iPhone voice recording application. The interviews were transcribed and analysed. Results There was a big difference regarding the health work between the companies who participated in the study. One of the companies had developed a successful health work while the other company didn’t have one at all. Gym and fitness classes at the workplace, healthcare contribution, good food options, lectures and societies run by employees are advantages the companies had to offer. Still, both companies felt like more could be done. The companies had different prerequisites to pursue a health work and how good the prerequisites were correlated with the amount of health work being done. The HR-managers and the employees gave equal answers, but the employee showed a more genuine view of the workplace. Conclusion The workplace related health work looks different companies in between. The differences depend on prerequisites and priorities at the workplace, among others. A better health work could result in less people reporting sick and an economic gain for the company. A preventive health work is probably the most effective choice.

Purpose The number of women that perform fertility preservation (FP) before initiating chemotherapy for treatment of breast cancer is increasing. Our purpose was to investigate the safety of performance of fertility preservation with and without hormonal stimulation in the incidence rate of breast cancer relapse. Patients and methods The study was designed as a matched cohort study. Women who had undergone FP at the Reproductive Medicine clinic of Karolinska University Hospital (N=187), irrespective of whether hormonal stimulation was required or not, were considered exposed. For all exposed women, two age-matched women who had not undergone fertility preservation were identified in the Regional Breast Cancer Registry Stockholm-Gotland and the Swedish National Quality Registry for Breast Cancer (N=319). The proportional hazards assumption was evaluated by applying the Grambsch-Therneau test on the Schoenfeld residuals obtained from each model, respectively. When interpreting the test results, a significance level of 5% was used to determine statistical significance. Results In the exposed cohort, a higher proportion of women underwent FP with hormonal stimulation aiming at freezing eggs or embryos (81%, N=142), whereas only 19% underwent freezing of ovarian tissue or attempted egg retrieval without hormonal stimulation (N=35). The mean follow up time was 6.3 years (range: 1.5-17.8 years), and median follow-up: 5.7 years. There was no evidence of non-proportional hazards with respect to the effects of fertility preservation on the risk of relapse in the whole FP cohort, irrespective if the women underwent hormonal stimulation or not for FP, or of receptor status or tumour size at diagnosis. A stratified Cox regression model that allowed separate baseline hazard functions for each level for the investigation of the effect of number of involved lymph nodes was performed. In this model, the effect of fertility preservation on the risk of relapse was virtually unchanged (IRR: 1.02, 95% CI:0.56-1.84). Conclusion Fertility preservation either using hormone stimulation or not is unlikely to cause substantially increase recurrence risk of breast cancer, and irrespective of the receptor status, tumorur size of lymph node compromise. The incidence of breast cancer relapse after hormonal or non-hormonal fertility preservation was not different from that of matched controls from the Regional Breast Cancer Registry in this large cohort study. Citation Format: Rodriguez-Wallberg KA, Eloranta S, Krawiec K, Lissmats A, Liljegren A. Safety of fertility preservation indicated by a diagnosis of breast cancer: A Swedish registry-matched cohort study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-11-05.

En hög personalomsättning i ett företag kan leda till flera kostnader i och med nyrekrytering och minskad produktivitet. Detaljhandeln är en av de branscherna med högst personalomsättning i Sverige och i branschen kan säljares prestationer ha stor påverkan på företagets framgång. En motiverad säljare kan tillföra mer till ett företags resultat än en omotiverad säljare. För att kunna motverka den höga personalomsättningen bör företag veta hur de ska kunna behålla sina anställda vilket ligger till grund för studiens syfte, att undersöka vad som motiverar anställda inom detaljhandeln att stanna respektive lämna sina anställningar. Det teoretiska ramverket grundas på Fredrik Herzbergs tvåfaktorteori och studiens empiriska resultat bygger på en kvalitativ intervjustudie med ledning och anställda inom företaget Din elon butik. Studiens resultat visar att de faktorer som motiverade de anställda att stanna var arbetsuppgifter och prestation, trivsel samt trygghet. Främst var det trivsel samt arbetsuppgifter och prestation som var de motiverande faktorerna. De faktorer som motiverade de anställda att lämna sin anställning var lön, faktorer i privatlivet, avancemang samt anställningsförhållanden. De faktorer som ansågs främst påverka de anställdas beslut till att lämna sin tjänst var avancemang och sedan lön. Utifrån Herzbergs tvåfaktorteori vidareutvecklades en analysmodell som indikerar att en anställd kan vara motiverad i sitt arbete även fast alla kriterier (hygienfaktorer) enligt Herzberg tvåfaktorteori inte uppfyllts.

Oral mucositis, a severe complication during chemo- and/or radiotherapy, is prevented with palifermin treatment, a recombinant human keratinocyte growth factor (KGF/FGF-7). The FGF family belongs to the larger family of heparin-binding growth factors. Because it has been shown that heparin modulates binding of KGF to the KGF receptor and subsequently affects cellular proliferation induced by the KGF mitogenic signal, it is critical to understand the drug-drug interactions between palifermin and heparin, particularly because of heparin's narrow therapeutic margin. Two studies were performed in healthy subjects to characterize the effect of palifermin on the pharmacodynamics of heparin (activated partial thromboplastin time) and evaluate the impact of heparin on the pharmacokinetics and pharmacodynamics (Ki67 staining of buccal mucosal tissue) of palifermin. Results demonstrated a pronounced pharmacokinetic interaction; heparin coadministration increased the palifermin AUC 4- to 5-fold and decreased its half-life by 40%-45%, suggesting an approximate 70%-80% decrease in palifermin clearance and volume of distribution. These changes in the pharmacokinetics of palifermin during coadministration of heparin, however, did not affect the pharmacodynamic effect of palifermin, or the anticoagulant activity of heparin, and did not lead to increased safety findings. Therefore, these results suggest that dose adjustments for heparin and palifermin are not warranted when administered concurrently.

Människor tenderar att motiveras av olika saker och svarar på så vis olika på motivationsförsök. Det är därför viktigt för ledningen inom organisationer att ha kunskap kring dessa olikheter. Ekonomer och ingenjörer är två grupper av akademiker som ofta figurerar på samma typer av arbetsplatser, därför blir skillnaderna mellan ekonomer och ingenjörer och hur de tenderar att motiveras en viktig fråga. En individs prestation är i högsta grad beroende av hur motiverad individen är att utföra en arbetsuppgift. För att utföra ett bra arbete behöver därmed individer känna sig motiverade i sitt arbete. Studiens syfte är att undersöka vad ekonomer och ingenjörer motiveras av och vilka eventuella skillnader som finns mellan de två grupperna. Uppsatsen baseras på en enkätstudie. Enkätstudien är utförd på ekonomer och ingenjörer vid ett stort internationellt företag som kommer vara anonymt i studien, där många ekonomer och ingenjörer är anställda. Studiens syfte har besvarats genom en enkätstudie med grunder i Maslows behovshierarki, Herzbergs tvåfaktorteori och inre och yttre motivation. I undersökningen framkommer det att båda grupperna främst tenderar att motiveras av inre motivation och att det inre behovet är störst hos respondenterna. Faktorn som är viktigast för ekonomers motivation på arbetsplatsen är känslan av att prestera väl och den viktigaste faktorn för ingenjörernas motivation är ett intresse i arbetsuppgifterna. Den faktorn som gemensamt för de båda grupperna är den faktorn som är mest betydelselös för motivationen är status i min yrkesbefattning. Det har visats i studien att det främst är motivationsfaktorerna som är de mest betydelsefulla faktorerna för motivation hos båda grupper, även fast vissa hygienfaktorer visat sig mer betydelsefulla än vad Herzberg traditionellt förklarade de som. Studien har påvisat att det finns skillnader i hur de två grupperna motiveras. Skillnaderna är dock små men det finns tillfällen där det skiljer sig en del. Exempelvis motiveras ekonomer i en högre utsträckning av befordringsmöjligheter på arbetsplatsen än vad ingenjörer gör. Det är viktigt för ledningen i företag att lägga tyngd i ekonomer och ingenjörers inre motivation samt att försöka uppfylla det inre behovet hos individerna. Det finns även en betydelse för ledningen att behandla de två grupperna olika när det kommer till motivation för att uppnå bästa möjliga resultat för företaget.

Background: Data from clinical practice have only to a limited extent, been used routinely to monitor cancer patients initiated on new drugs. In this study of patients with cancer, focussing on prostate, breast, and skin cancer, two years of individual data from several registries was used to explore the possibilities to monitor patients with cancer. Methods: This study is based on a research database with more than 78 million records with person-linked diagnoses, drug treatment, and socioeconomic characteristics from eight national and regional registries, for patients with a recorded cancer diagnosis or treated with cancer drugs during 2001-2011. For this cross-sectional registry study 7,378 patients diagnosed with prostate, breast, or skin cancer during 2009-2010, were selected to assess patient characteristics, comorbidities and drug treatment. Results: Of the population selected from the Swedish Cancer Register with the three major diseases, 3,581 had prostate cancer, 2,760 had breast cancer, and 1,037 had skin cancer. The income was 70.1%, 62.9%, and 53.3% in the prostate, breast and skin cancer group, respectively. Urogenital- and cardiovascular diseases were common in both prostate (47.8% and 52.7%), and breast cancer (52.4% and 42.6%) patients. In skin cancer patients, other skin diagnoses were most common (50.7%) followed by cardiovascular disorders (48.3%). Cancer drugs, mainly mature, were received by 85.9% of patients with breast cancer, 32.4% of patients with prostate cancer, and 4.1% of patients with skin cancer. Additional tumour diagnoses for 5.2% of prostate cancer patients, 4.1% of breast cancer patients, and 17.3% of patients with skin cancer, were found in primary care data. Conclusion: Access to healthcare data, including primary care, and the opportunity to link records from multiple data sources by the Swedish personal identity number, allow the possibility to study treatment, disease pattern and characteristics in large cancer patient populations.

Two-stage designs offer substantial advantages for early phase II studies. The interim analysis following the first stage allows the study to be stopped for futility, or more positively, it might lead to early progression to the trials needed for late phase II and phase III. If the study is to continue to its second stage, then there is an opportunity for a revision of the total sample size. Two-stage designs have been implemented widely in oncology studies in which there is a single treatment arm and patient responses are binary. In this paper the case of two-arm comparative studies in which responses are quantitative is considered. This setting is common in therapeutic areas other than oncology. It will be assumed that observations are normally distributed, but that there is some doubt concerning their standard deviation, motivating the need for sample size review. The work reported has been motivated by a study in diabetic neuropathic pain, and the development of the design for that trial is described in detail.

Abstract 904 Palifermin administered pre and post radiochemotherapy conditioning has previously been shown to significantly reduce the incidence and duration of severe oral mucositis (OM) in patients undergoing autologous stem cell transplantation (ASCT). This randomized clinical trial (RCT) aimed to study the efficacy and safety of palifermin when administered in two different dosing regimens in a chemotherapy-only conditioning setting. The efficacy of palifermin relative to placebo was investigated with palifermin given either pre/post high-dose melphalan (HDM) or pre HDM only in patients with multiple myeloma (MM) undergoing ASCT. Assessment of oral mucositis was primarily based on WHO grades (0/1, 2, 3 or 4) and safety primarily on adverse event (AE) reporting. 281 patients (mean age 56 ± 8 years) were enrolled at 39 centers; 224 patients were randomized to receive palifermin and 57 patients to receive placebo. In the palifermin group, 109 patients were randomized to the pre-only arm, receiving palifermin (60 μg/kg/day) iv for 3 consecutive days before HDM and 115 subjects were randomized to the pre/post arm receiving palifermin on 3 consecutive days before HDM and again on 3 consecutive days after ASCT. The number of subjects actually receiving study drug in the these two arms was 109 and 111, respectively. Assessments of OM and safety were made daily until 32 days post transplant or hospital discharge. There was no difference in maximum severity of OM between placebo and palifermin administered pre/post HDM (odds ratio: 0.7 [CI: 0.4, 1.3]) or pre HDM (odds ratio: 1.2 [CI: 0.6, 2.4]). Severe OM (WHO grade 3 and 4) occurred in 37% (placebo), 38% (pre/post-HDM) and 24% (pre-HDM) of the patients. A total of 275 patients (99.3%) experienced at least 1 AE during the study. There were more serious AEs and AEs reported as treatment related by the investigators for patients in the pre/post HDM arm, and less in the pre-HDM arm but still more than in the placebo arm. Overall, no statistically significant differences were observed between placebo and either the palifermin pre-post HDM arm or pre-only HDM arm for maximum severity of OM in this clinical setting with a chemotherapy conditioning regimen of short duration and a comparably low incidence of severe oral mucositis. The pre-only group, however, showed a numerically better result than placebo for the primary and most of the secondary efficacy endpoints. Patients treated with palifermin in the pre HDM arm experienced a more favorable safety profile than the pre/post HDM arm. Possible explanations for the apparent discrepancy compared to previously published trials might be differences in high dose chemotherapy and/or the shorter time interval between the pre and post doses in this study. The impact of the timing of the palifermin post-dose in relation to the pre-dose and in relation to the onset of manifest OM and pathogenesis thus needs to be further explored. Disclosures: Blijlevens: Biovitrum: Consultancy. de Chateau:Biovitrum : Employment. Lissmats:Biovitrum: Employment. Niederwieser:Biovitrum: Consultancy.