Multi-ion radiotherapy has been suggested as a new way to treat cancer, combining the radiological advantages of lighter and heavier ions in a single treatment to improve plan robustness and increase LETd in the target. To succeed, multi-ion radiotherapy requires a treatment planning system capable of computing dose for and optimising multi-ion treatment plans. In this project, prototypical multi-ion radiotherapy treatment planning support has been implemented in the RayStation treatment planning system. The existing dose engine for helium and carbon ion beams has been extended to support protons, oxygen and neon ions, and support has been added for dose computation and plan optimisation for any combination of these ion species. The implemented functionality has been evaluated in two phantom cases and a patient case. Multi-ion treatment plans have been shown to outperform carbon ion treatment plans in terms of simultaneously providing plan robustness, uniform RBE-weighted dose and high LETd. In the patient case, the multi-ion plan displayed significant improvements in the ability to "paint" high LETd in the target. Clinical studies are required to determine to what extent this new modality increases treatment quality in practice.

Bakgrund: Årligen diagnostiseras 350 000 nya patienter med oral cancer i världen. Denna cancer klassas som en av de vanligaste cancerformerna. Oral cancer påverkar munhälsan och cancerbehandlingarna medför ofta svåra biverkningar där fysiska symptom riskerar att bli ihållande vilket kan leda till psykiska och sociala svårigheter. Det primära omvårdnadproblemet är att sjuksköterskor saknar tillräcklig kunskap för att utföra evidensbaserad omvårdnad för denna patientgrupp. Syfte: Syftet var att beskriva patienters upplevelser av att ha oral cancer. Metod: En litteraturstudie där tio vetenskapliga artiklar granskats på ett strukturerat vis. Resultat: I resultatet framkom fyra huvudkategorier: Upplevelser av fysiska utmaningar, Upplevelser av psykiska utmaningar, Upplevelser av sociala utmaningar samt Upplevelser av hanterbarhet och acceptans. Upplevelser av fysiska utmaningar var grundat i smärta, tal, ät och sväljsvårigheter. Psykiska utmaningar bestod huvudsakligen av oro och rädsla. I sociala utmaningar upplevde patienterna svårigheter att interagera med andra människor. Upplevelser av hanterbarhet och acceptans innefattar patienternas strategier att hantera och acceptera den nya livssituationen. Konklusion: Patienters upplevelser av oral cancer är viktiga att uppmärksamma då forskning visar att tidigt insättande av omvårdnadsåtgärder är relevanta utifrån fysiska, psykiska och sociala perspektiv. Sjuksköterskor avsaknad av relevant grundkunskap om oral hälsa kräver därför kontinuerlig utbildning om munhälsa och förebyggande omvårdnadsåtgärder. / Background: Annually, 350,000 new patients are diagnosed with oral cancer in the world. This cancer is classified as one of the most common forms of cancer. Oral cancer affects oral health and cancer treatments often cause severe side effects where physical symptoms risk becoming persistent, which can lead to psychological and social difficulties. The primary nursing problem is that nurses lack sufficient knowledge to perform evidence-based nursing for this patient group. Aim: The purpose was to describe patients' experiences of having oral cancer. Method: A literature study where ten scientific articles were reviewed in a structured manner. Results: The results revealed four main categories: Experiences of physical challenges, Experiences of psychological challenges, Experiences of social challenges and Experiences of manageability and acceptance. Experiences of physical challenges were based on pain, speech, eating and swallowing difficulties. Mental challenges mainly consisted of worry and fear. In social challenges, patients experienced difficulty interacting with other people. Experiences of manageability and acceptance include the patients' strategies to manage and accept the new life situation. Conclusion: Patients' experiences of oral cancer are important to pay attention to as research shows that early initiation of nursing measures is relevant based on physical, psychological and social perspectives. Nurses lacking relevant basic knowledge about oral health therefore require continuous education about oral health and preventive nursing measures.

Bakgrund: När en person drabbas av bröstcancer påverkas även deras anhöriga, särskilt partnern till den som är sjuk. Med ett stigande antal cancerfall har antal anhörigvårdare ökat, vilket har lett till en ökning av sjukskrivningar bland partners till den bröstcancersjuka. För att kunna bemöta anhörigas omvårdnadsbehov på ett adekvat sätt krävs utökad kunskap kring deras upplevelser av livet med en bröstcancersjuk kvinna. Syfte: Syftet var att beskriva anhörigas upplevelse av att leva med en kvinnlig partner som genomgår en bröstcancerbehandling.  Metod: En litteraturöversikt med kvalitativ metod genomfördes. Totalt 12 artiklar inkluderades via sökningar i databaserna CINAHL, MEDLINE och Pubmed. Artiklarna har analyserats enligt Fribergs femstegsmodell.  Resultat: Litteraturöversiktens resultat bestod av två teman och fem subteman. Teman var att uppleva barriärer till följd av partnerns sjukdom och att axla rollen som anhörigvårdare. Resultatet visade att anhöriga till personer med bröstcancer upplevde en förändrad vardag med förändrade roller, vilket försämrade deras psykiska och fysiska välbefinnande. Familjesammanhållningen sågs som betydande för att kunna hantera vardagen med närvaro av sjukdom.  Slutsats: För att främja anhörigas välbefinnande är det viktigt att hantera både de känslomässiga och praktiska aspekterna av deras upplevelse. Genom att arbeta familjefokuserat kan sjuksköterskan främja till anhörigas delaktighet i sin partners vård, vilket kan svara på deras behov av information, kunskap och strategier. Detta kan hjälpa anhöriga att tydliggöra deras roll som anhörigvårdare.  Nyckelord: cancer, partner, anhörig, upplevelse, familjefokuserad omvårdnad. / Background: When a person is affected by breast cancer, their relatives are also affected, especially the partner of the person who is ill. With an increasing number of cancer cases, the number of family caregivers has also increased, according to research this has led to an increase in sick leave among partners of the breast cancer patient. In order to be able to respond to the nursing needs of relatives in an adequate way, increased knowledge is required regarding their experiences of life with a woman with breast cancer. Aim: The aim was to describe relatives' experience of living with a female partner undergoing breast cancer treatment. Method: A literature review with a qualitative method was conducted. A total of 12 articles were included via searches in the databases Cinahl, MEDLINE and Pubmed. The articles have been analyzed according to Friberg's five-step model. Result: The results of the literature review consisted of two themes and five subthemes. The themes were experiencing barriers as a result of the partner's illness and assuming the role of family carer. The results showed that relatives of people with breast cancer experienced a changed everyday life with changed roles, which affected their psychological and physical well-being. Family cohesion was seen as important in being able to manage everyday life with the presence of illness. Conclusion: In order to promote the well-being of relatives, it is important to manage both the emotional and practical aspects of their experience. By working family-focused, the nurse can promote relatives' participation in their partner's care, which can respond to their need for information, knowledge and strategies. This can help relatives clarify their role as relative carers. Keywords: cancer, partner, relative, experience, family-focused nursing.

Titel: Patienters upplevelser av diagnos och behandling vid akut myeloisk leukemi    Bakgrund: Akut myeloisk leukemi (AML) är den vanligaste formen av akut leukemi. Behandlingen och symtomen är påfrestande och långvariga, vilket inverkar på patienters livskvalitet. Genom god personcentrerad vård kan sjuksköterskan försöka tillgodose många av behoven som patienten kan få under vårdtiden.  Syfte: Att beskriva patienters upplevelser av att diagnostiseras med och genomgå behandling mot akut myeloisk leukemi. Metod: En litteraturöversikt med kvalitativ metod och induktiv ansats. Efter sökning i databaserna Cinahl, PubMed och PsyINFO samt artikelgranskning inkluderades tolv artiklar. Artiklarna analyserades genom Fribergs fem steg.  Resultat: Genom en sammanställning av artiklarna framkom det två olika teman (känslomässiga reaktioner och förändrad kroppsuppfattning) och sex olika subteman (att få ett obegripligt besked, känsla av att få svår och komplex information, känsla av isolering, förändrat utseende relaterat till symtom, fysiska symtom relaterat till behandling och känsla av att vara en börda). Slutsatser: I litteraturöversikten framkom det att beskedet om diagnosen var obegripligt. Patienterna upplevde att sjuksköterskan hade svårt att förmedla den komplexa informationen personcentrerat. Behandlingstiden orsakade att patienterna upplevde sig isolerade och att symtomen (illamående, trötthet och håravfall) påverkade patienternas vardagliga liv negativt. Sjuksköterskans stöd och undervisning relaterat till symtomhantering och omvårdnadsåtgärder till såväl patient och anhöriga är avgörande för att minska de negativa känslorna som framkom i resultatet.  Nyckelord: Cancer, cytostatikabehandling, personcentrerad vård, stamcellstransplantation

Background: Cancer is a leading cause of death. For this reason, cancer is commonly perceived as a potentially fatal disease that causes both current and future existential suffering. In recent years, research has revealed that patients' implementation of coping strategies has increased the manageability and control of cancer. Aim: The purpose of this study was to examine which coping strategies adult patients with malignant diseases/cancer use, and how their coping strategies affect their health. Method: A literature review was conducted. The articles were analyzed through a four-step model and based on four qualitative and four quantitative scientific articles in order to contribute to evidence-based knowledge. Two themes and seven subthemes were analysed in the result. Results: What emerged in the results showed that the patient's external resources as the environment was an important support, followed by internal resources as personal abilities where faith and hope were central components. Seven subthemes were identified consisted of seeking professional support, find support from social networks, self-destruction, maintain a positive attitude, self-efficacy, acceptance and turn to their faith. Patients experienced improved health during the disease progression when using coping strategies. Conclusion: Coping strategies improve the patient's health by managing the disease and suffering, which may be accomplished using the patient's internal and external resources for management. By assisting the patient in employing appropriate coping mechanisms, the nurse can promote a higher quality of life, reduce suffering, and promote health.

Bakgrund: Runt 429 000 barn drabbas årligen av cancer världen över. Att leva med cancer och genomgå behandlingar är en svår utmaning för barn och närstående. Coping är ett verktyg som hjälper individer möta påfrestande situationer. Många studier belyser copingstrategier använda av föräldrar och andra personer nära cancerdrabbade barn, men underlaget är inte lika stort gällande barns egna beskrivningar av sin coping. Av denna anledning är det väsentligt att identifiera använda copingstrategier ur barns perspektiv. Syfte: Syftet med litteraturstudien var att beskriva vilka copingstrategier barn med cancer använder sig av för att hantera sjukdomen och dess behandling. Metod: Studien är en beskrivande litteraturstudie. Databassökningen genomfördes i PubMed. Sökningen resulterade i tio artiklar där åtta var kvalitativa, en var kvalitativ med mixad metod och en var kvantitativ. Framkomna data analyserades genom tematisk dataanalys. Huvudresultat: Barn med cancer använde olika copingstrategier som kategoriseras som problemfokuserade, emotionsfokuserade och meningsskapande copingstrategier. Till problemfokuserade copingstrategier hörde ”Symtomlindring och underlättande av behandling”, ”Information, kunskap och insikt” samt ”Anpassning och bibehållande av en normal vardag”. I emotionsfokuserade copingstrategier återfanns ”Stöd och känslohantering”, ”Distrahering och undvikande” samt ”Acceptans, motivation och framtidshopp”. Meningsskapande copingstrategier var ”Positiv omvärdering” och ”Personlig utveckling och att se sjukdomen som en utmaning”. Slutsats: Barn med cancer använder olika copingstrategier för att hantera sin sjukdom och dess behandling. Strategierna tillämpas växelvis beroende på situation och syftet med användningen av vald copingstrategi är individuell. Genom ökad kännedom kring ämnet kan cancerdrabbade barn erbjudas personcentrerad vård och lämpligt stöd. / Background: About 429 000 children are annually affected by cancer worldwide. Living with cancer and undergoing treatment is a difficult challenge for children and close relatives. Coping is a tool that helps individuals face stressful situations. Many studies shed light on coping strategies used by parents and other people close to children affected by cancer, but the basis is not as extensive regarding children's own descriptions of their coping. For this reason, it is essential to identify used coping strategies from children's perspective. Aim: The purpose of the literature study was to describe which coping strategies children with cancer use to manage the disease and its treatment. Method: The study is a descriptive literature study. The database search was conducted in PubMed. The search resulted in ten articles, eight of which were qualitative, one was qualitative with a mixed method and one was quantitative. The data were analyzed through thematic data analysis. Main results: Children with cancer used different coping strategies categorized as problem-focused, emotion-focused and meaning-making coping strategies. Problem-focused coping strategies included “Symptom relief and facilitation of treatment”, “Information, knowledge and insight” and “Adaptation and maintaining a normal everyday life”. In emotion-focused coping the strategies found were “Support and emotion management”, “Distraction and avoidance” and “Acceptance, motivation and hope for the future”. Meaning-focused coping strategies were “Positive reappraisal” and “Personal development and seeing the disease as a challenge”. Conclusion: Children with cancer use different coping strategies to deal with their illness and its treatment. The strategies are applied alternately depending on the situation and the purpose of using the chosen coping strategy is individual. Through increased awareness of the subject, children affected by cancer can be offered person-centred care and appropriate support.

Background: Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women worldwide. Adenomas can be precursors to CRC, and inflammatory bowel disease (IBD) can present with the same symptoms as CRC. The majority of patients with CRC initially consult primary care. Symptoms associated with CRC are also common among primary care patients, but seldom caused by any significant disease. Reliable diagnostic aids would be helpful in deciding which patients to refer. Faecal immunochemical tests (FITs) are commonly used for this purpose in primary care in Sweden, but there is little evidence to support this use. Faecal calprotectin (FC) has been suggested as an additional test. Aim: To explore how doctors in primary care investigate patients with suspected CRC, the value of FITs, symptoms and presence of anaemia in diagnosing CRC and adenomas in primary care, and whether FC tests could contribute to diagnosis. Methods: Three studies (1-3) were carried out in Region Jämtland Härjedalen, Sweden. There was no screening programme for CRC. We used a point of care qualitative dip-stick 3-sample FIT with a cut-off of 25-50μg haemoglobin/g faeces, and a calprotectin enzyme-linked immunosorbent assay (ELISA) test with a cut-off of 100 μg/g faeces. 1: A retrospective, population-based study including all patients diagnosed with CRC or adenomas with high-grade dysplasia (HGD) during the period 2005-2009 that initially consulted primary care. Symptoms, FIT results, anaemia and time to diagnosis were retrieved from medical records. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated from FIT results at the region’s health centres 2008- 2009. (Paper I.) 2: A prospective cohort study including consecutive patients where primary care doctors requested FITs and/or FC tests, at four health centres, from 30 Jan 2013 to 31 May 2014. FITs, FC tests, haemoglobin and iron deficiency tests were analysed; patients and doctors answered questionnaires about symptoms. Patients were examined with bowel imaging or followed for two years. Findings of CRC, adenomas with HGD, adenomas with low grade dysplasia (LGD) ≥1 cm and IBD were registered. (Papers II and III.) 3: A qualitative study of interviews with eleven primary care doctors. We explored what made them suspect CRC, and their practices regarding investigation and referral with particular attention to their use of FITs. Qualitative content analysis with an inductive approach was used for the analysis. (Paper IV.) Results: 1: Paper I: Of 495 patients 323 (65.3%) started the investigation in primary care. FITs were analysed in 215. In 23 cases with CRC, FITs were negative; 15 (65.2%) had anaemia. In 33 cases with CRC, FITs were performed due to asymptomatic anaemia; 10 (30.3%) had negative FITs. The time from start of investigation, to the diagnosis of CRC or adenomas with HGD, was significantly longer for patients with negative FITs. 2: 377 patients (9 diagnosed with CRC, 10 with IBD) were included. Paper II: Concordance of positive answers about symptoms from patients and doctors was generally low. Rectal bleeding (recorded by 43.5% of patients and 25.6% of doctors) was the only symptom related to CRC and IBD. The FIT showed a better PPV than rectal bleeding for CRC and IBD. When patients recorded rectal bleeding, the FIT had a PPV of 22.6% and a NPV of 98.9% for CRC and IBD. Paper III: The best test for detecting CRC and IBD was the combination of a positive FIT and/or anaemia with a sensitivity, specificity, PPV and NPV of 100%, 61.7%, 11.7% and 100% respectively. The FC test had no additional value to the FIT alone. The sensitivity, specificity, PPV and NPV of the FIT for CRC in study 1 was estimated at 88.4%, 73.3%, 6.2% and 99.7% respectively. In study 2, corresponding figures were 88.9%, 67.4%, 6.3% and 99.6% respectively. 3: Paper IV: We identified four categories: “Careful listening – with awareness of the pit-falls”, “tests can help – the FIT can also complicate the diagnosis”, “to refer or not to refer – safety margins are necessary”, and “growing more confident – but also more humble”. All doctors had found their own way to handle FIT results in the absence of guidelines. Conclusion: The diagnostic process when suspecting CRC can be described as navigating uncertain waters with safety margins. FITs were often used by primary care doctors but with considerable variations in interpretation and handling of results. Rectal bleeding was the only symptom related to CRC and IBD, but the FIT showed a better PPV than rectal bleeding. The combination of a negative FIT and no anaemia may be useful as a rule-out test when CRC is suspected in primary care, and this potentially also applies when patients present with rectal bleeding. Further studies are needed to confirm this and to determine the optimal FIT cut-off value for this use.

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy in both men and women, and one of the leading causes of cancer-related deaths worldwide. One frequently mutated pathway involved in oncogenesis in CRC is the RAS/RAF/MAP kinase pathway. Oncogenic activation of KRAS and BRAF occur in 30‒40% and 5‒15% of all CRCs, respectively, and the mutations are mutually exclusive. Even though KRAS and BRAF are known to act in the same pathway, KRAS- and BRAF-mutated CRCs have different clinical and histopathological features. For example, BRAF mutation in CRC is tightly linked to microsatellite instability (MSI) and a CpG island methylator phenotype (CIMP), which is not seen in KRAS-mutated tumours. BRAF-mutated CRCs are also more often found in right-sided tumours. However, the underlying molecular reasons for these differences have not yet been defined. The overall aim of this thesis was to investigate molecular differences between KRAS- and BRAF-mutated CRCs to understand how KRAS and BRAF mutations differentially affect tumour progression. We used an in vitro cell culture system to explore molecular differences between KRAS- and BRAF-mutated CRCs and verified our findings using CRC tissue specimens from the Colorectal Cancer in Umeå Study (CRUMS). We found that BRAF mutation, but not KRAS mutation, was associated with expression of the stem cell factor SOX2. Furthermore, SOX2 was found to be correlated to a poor patient prognosis, especially in BRAF-mutated cancers. We further investigated the role of BRAF in regulation of SOX2 expression and found that SOX2 is at least partly regulated by BRAF in vitro. We continued by investigating the functional role of SOX2 in CRC and found that SOX2-expressing cells shared several characteristics with cancer stem cells, and also had down-regulated expression of the intestinal epithelial marker CDX2. There was a strong correlation between loss of CDX2 expression and poor patient prognosis, and patients with SOX2 expression were found to have a particularly poor prognosis when CDX2 levels were down-regulated. In conclusion, in these studies we identified a subgroup of BRAF-mutated CRCs with a particularly poor prognosis, and having a cancer stem cell-like appearance with increased expression of SOX2 and decreased expression of CDX2. Tumour progression is regulated by interactions with cells of the immune system. We found that BRAF-mutated CRCs were more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours, while the opposite was true for KRAS-mutated CRCs. Interestingly, we found that part of this difference is probably caused by differences in secreted chemokines and cytokines between KRAS- and BRAF-mutated CRCs, stimulating different arms of the immune response. Altered levels of expression of miRNAs have been seen in several malignancies, including CRC. We found that BRAF- and KRAS-mutated CRCs showed miRNA signatures different from those of wild-type CRCs, but the expression of miRNAs did not distinguish KRAS-mutated tumours from BRAF-mutated tumours. In summary, our findings have revealed possible molecular differences between KRAS- and BRAF-mutated CRCs that may explain some of the differences in their clinical and histopathological behaviour.

<p>Varje år diagnostiseras över 50 000 individer med cancer i Sverige. Ett cancerbesked väcker blandade känslor och associeras ofta med lidande och död. Ett svårt besked kan leda till en förändrad livssituation och kan även ses som början på en lång och mödosam resa. En vetenskaplig litteraturstudie baserad på 15 originalartiklar genomfördes med syftet att belysa patientens upplevelse av ett cancerbesked och därmed öka sjuksköterskans förståelse för patientens situation samt fördjupa kunskaperna inom ämnet. Genom litteraturgranskningen identifierades tre teman: information, emotionella reaktioner samt psykosocialt stöd. Patienten upplever att det är viktigt att informationen ges på ett öppet och ärligt sätt. Vidare framkom det betydelsefullt att uppmärksamma patientens emotionella reaktioner i samband med beskedet. Eftersom upplevelsen av ett cancerbesked påverkar patientens fortsatta upplevelse av sin sjukdom, har sjuksköterskan en viktig roll att fylla genom att erbjuda psykosocialt stöd i de olika tänkbara situationer som kan uppkomma i samband med ett livsavgörande besked. Fortsatt forskning behövs för att jämföra hur de rekommendationer som finns angående delgivandet av ett svårt besked överensstämmer med patienternas egna upplevelser och önskemål.</p> / <p>Every year, over 50 000 individuals in Sweden are diagnosed with cancer. The disclosure of the cancer diagnosis arouses emotions and is often associated with suffering and death. Receiving bad news may lead to changes in life and can also be seen as the beginning of a long and difficult journey. A scientific study based on 15 original articles was carried out with the purpose to identify the patient’s experience of receiving a cancer diagnosis and therefore increase the nurse’s understanding for the patient’s situation and deepen the knowledge of the subject. When examining the articles three themes were identified: information, emotional reactions and psychosocial support. The patient experience that it is important that the information is given in an open and honest manner. Patients also find it important that their emotional reaction is being observed as receiving the diagnosis. As the disclosure of the cancer diagnosis affects the patient’s further perception of the disease the nurse has an important role providing psychosocial support in various situations that may arise in connection with the disclosure. Continued research is needed to compare how guidelines for giving bad news to a patient correspond with the patient’s own experiences and preferences.</p>

<p>Syftet är att beskriva symtom och biverkningar som kvinnor med avancerad bröstcancer och cytostatikabehandling rapporterat i ett datoriserat rapporteringssystem före läkarbesök. Undersöka tillfredsställelsen med detta system; se om det finns en skillnad mellan äldre och yngre; undersöka kvinnornas uppfattning om vad som kan förbättras i uppföljningen av symtom/biverkningar samt stödet från läkare. Detta är en kvantitativ, deskriptiv tvärsnittsstudie baserat på rapporteringssystemets databas samt enkätundersökning.</p><p> </p><p>Biverkningarna trötthet, smärta och nervpåverkan rapporterades mest frekvent. Tidsåtgången för rapportering ansågs utav de flesta vara kort eller mycket kort och formuläret upplevdes av majoriteten vara ganska lätt till mycket lätt att använda oberoende av datorvana. Läkaren ansågs från hög grad till mycket hög grad vara ett stöd i att hantera symtom och biverkningar av två tredjedelar av respondenterna. Hälften ansåg att rapporterade biverkningar och symtom uppmärksammades av läkaren i hög grad till mycket hög grad.</p><p> </p><p>Undersökningen bekräftar det tidigare forskning visat om datoriserade rapporteringssystem i vården, att de är funktionella oavsett ålder samt att intresse finns för att använda dessa i större utsträckning. På grund av litet urval och relativt stort bortfall i enkätstudien kan dock inga direkta slutsatser dras men undersökningen antyder att behov finns att vidareutveckla rapporteringssystemet.</p> / <p>The aim of the study is to describe symptoms and side effects that women with advanced breast cancer and chemotherapy reported in an adverse drug reporting system before seeing their oncologist; examine the satisfaction with this system; if there are any differences between older and younger women; the women’s opinion of what improvements could be done in the follow-up of the symptoms/side effects and the support from the oncologist. This is a quantitative, descriptive cross-sectional study based on the database of the adverse drug reporting system and the questionnaire survey.</p><p> </p><p>The side effects fatigue, pain and peripheral neuropathy were most frequently reported. The time consumption for reporting was considered short or very short and the majority thought that the questionnaire was fairly easy to very easy to use independent of computer habits. The oncologists where considered from a high extent to a very high extent being a support in handling the symptoms/side effects by two thirds of the respondents. Two fourths felt that the oncologists attended reported symptoms/side effects from a high extent to a very high extent.</p><p>Because of a small sample and a relatively large drop-out no real conclusions can be drawn except the need for further development of the system.</p>