Cutaneous squamous cell carcinoma (SCC) is a common cancer yet its treatment is under-researched. The objective of this thesis was to develop a proposal for a randomised controlled trial (RCT) to address uncertainties relating to the management of the condition, and to ultimately improve the management of affected patients. Two systematic reviews were initially conducted to appraise the current evidence base for SCC treatments. Only one RCT was eligible for inclusion in the Cochrane systematic review; a small study which found no significant difference in time to recurrence between patients treated with post-operative 13-cis retinoic acid and interferon, and those not receiving adjuvant treatment. Systematic review and meta-analysis of observational studies included 118 studies. Pooled estimates of recurrence were lowest after cryotherapy and curettage and electrodesiccation, although lesions treated by these modalities were mostly small and low-risk. Although pooled recurrence after Mohs surgery appeared lower than after conventional excision or radiotherapy, the differences were not significant with overlapping 95% confidence intervals. For photodynamic therapy, pooled recurrence after apparently successful initial treatment was particularly high (26%). Evidence relating to the effectiveness of topical and systemic treatments was very limited. Estimates of recurrence were used to inform the sample size calculation for the proposed RCT. A survey of healthcare professionals was conducted to establish research priorities and identify clinically important management uncertainties from which initial trial scenarios were formulated. High-risk SCCs were identified as a research priority, with optimal surgical management and the role of adjuvant radiotherapy being key areas of uncertainty. Through multi-disciplinary collaboration, a proposal for a two-stage RCT has been developed; in the first stage, locoregional recurrence after conventional surgery with a controlled excision margin will be compared with Mohs surgery, and in the second stage locoregional recurrence will be compared between patients treated with adjuvant radiotherapy versus those receiving no adjuvant treatment. Feasibility work conducted during the development of the trial has involved: a) A retrospective analysis of SCCs treated over twelve-months to determine the number of patients and types of SCCs potentially eligible for recruitment into the proposed trial and to further inform the sample size calculation. Within five years of treatment 6% of 357 patients experienced local recurrence, 3% had regional recurrence and 1.5% died of their SCC. Comparison of the most recent American Joint Cancer Council (AJCC7) and an alternative Brigham and Women’s Hospital (BWH) classification showed that approximately 50% of SCCs were T2 in both schemes and eligible for entry into the first stage of the proposed trial. However, an additional BHW T2b substage better stratified outcomes dependent on the number of risk features, and indicated that 19% of all SCCs would potentially be also eligible for the second stage of the trial. b) A questionnaire and focus group study to assess the acceptability of the RCT and to identify possible barriers to recruitment. Participants had a desire to be better informed about SCC, wanting information relating to the trial to be provided in a variety of formats. 71% of participants were hypothetically willing to be randomised into the surgical stage of the proposed trial but had more concerns about the second stage involving adjuvant radiotherapy. Lack of equipoise and confusion about the concept of randomisation will need to be carefully addressed when presenting the trial to participants. The proposed trial will be the first to directly compare treatments for the types of SCC seen commonly in clinical practice. For the trial to be adequately powered, an estimated 5400 participants will need to be recruited, so a multi-centre, multi-disciplinary approach will be necessary.

Background: Eczema is an important condition as it affects 20% of children in the UK and is associated with significant morbidity for children and their families. Although some progress in understanding factors associated with the occurrence of eczema has been made, very little is known about factors associated with disease worsening. Most textbooks and review articles quote long lists of exacerbating factors but with very little scientific data to support them. Before I could begin to study this topic, I first had to define a disease flare in eczema, systematically review the literature on flare factors in eczema and review available outcome measures for eczema. Objectives: The objectives of the main study described in this thesis were to assess the role of various environmental factors on the severity of eczema in a cohort of children with eczema. Hypotheses: 1. In hot weather, the combination of heat, sweating and grass pollen precipitates increased severity in children with eczema in the UK. 2. In cold weather, the combination of cold weather, indoor aeroallergen exposure and reduced relative humidity from central heating lead to increased severity in children with eczema in the UK. These first two hypotheses were informed by previous research which proposed "summer" and "winter" types of eczema. 3. Detergents (soap, shampoo) increase the propensity to disease flares triggered by other factors at all temperatures, but more in cold weather due to impaired skin barrier function. 4. UK children with filaggrin mutations are more prone to the effects of climatic factors such as cold and heat than individuals who are wild type for filaggrin. 5. Any combination of greater than or equal to three exposures at any time is associated with worsening of eczema. The exposures assessed included: dust, exposure to pets, shampoo, sweating, swimming, nylon clothing next to the skin and a change in mean temperature of more than 3°C from the previous weekly average. Methods: Pilot study: 30 children with moderate to severe eczema aged 0 to 15 years participated in a panel study over a one month period in June 2003 in Cork, Ireland. This study involved daily completion of a paper diary recording eczema severity and exposures. Feasibility of a panel study design was assessed and associations between exposures and disease severity were analysed. Main study: A prospective cohort study (n=60) of children aged up to 15 years with moderate to severe eczema was studied for between six and nine months with overlapping start dates to allow study of seasonal factors. Exposures studied included: temperature, relative humidity, sun exposure, sweating, clothing, cleansing products/ washing, outdoor pollen level, extent and nature of exposure to household pets, dusty environments and swimming. Children or their parents completed daily novel electronic diaries recording eczema severity and exposures. Portable dataloggers were used to record indoor temperature and relative humidity. External meteorological data was obtained from a local monitoring centre. The primary outcome was a daily "bother" score and the secondary outcomes were daily "scratch" scores and flares of eczema. Autoregressive moving average models (ARMA) were used to model the impact of each exposure on eczema severity for each individual. Standard random effects meta-analysis techniques were used to pool estimated coefficients across participants. Heterogeneity of responses as detected using Chi-squared tests represented inter-individual variation. The body site-specificity of reactions was also examined as was the interaction between filaggrin mutations and disease worsening with exposures. Findings. Pilot study: The pilot study highlighted the issue of drop outs and missing data during the study. 83% (n=25) returned the diaries at the end of the study period, and within these, recording of disease severity was good (97% complete). However, there was variability in recording of exposures (65% to 83% complete). Preliminary findings suggested a temporal association between eczema severity and heat (lag 0, i.e. the day of exposure, p=0.04), damp (lag day 2, p=0.03), sweating and stress (lag day 3, p=0.03 and p=0.02 respectively) and damp (lag day 4, p=0.001). Main study: Primary outcome: "bother scores": Increased disease severity was associated with direct contact with nylon clothing (pooled regression coefficient 0.23, 95% CI 0.03 to 0.43), increasing exposure to dust (pooled regression coefficient 0.53, 0.23 to 0.83), exposure to unfamiliar pets (pooled regression coefficient 0.22, 0.10 to 0.34), sweating (pooled regression coefficient 0.24, 0.09 to 0.39) and shampoo exposure (pooled regression coefficient 0.07, 0.01 to 0.13). The association between shampoo use and worsening of eczema was enhanced in cold weather (pooled regression coefficient 0.30, 0.04 to 0.57). Body site specificity was observed for the reactions to nylon clothing, which was greater on covered sites (trunk p=0.02, limbs p=0.03), reactions to wool clothing on truncal covered sites (p=0.03) but not limbs (p=0.62), while worsening of hand eczema was associated with exposure to pets (p<0.001). The only interaction with filaggrin mutations was observed for the 2282del4 mutation and worsening of eczema in summer. Significant heterogeneity of responses between individuals was observed for exposure to grass pollen and outdoor temperature. In regard to the final hypothesis, a combination of any three of seven likely variables was associated with worsening of eczema (pooled regression coefficient 0.41, 0.20 to 0.63). Secondary outcome: "scratch" scores: Increased disease severity was seen associated with swimming (pooled regression coefficient 0.14,0.00 to 0.28), exposure to wool clothing (pooled regression coefficient 0.28, 0.11 to 0.45), sweating (pooled regression coefficient 0.15, 0.04 to 0.26), shampoo (pooled regression coefficient 0.07, 0.01 to 0.13), dust (pooled regression coefficient 0.36, 0.12 to 0.59) and high grass pollen levels (pooled regression coefficient 0.10, 0.01 to 0.73). Secondary outcome: flares of eczema: Only swimming was clearly associated with worsening of eczema using this outcome measure (pooled regression coefficient 0.42, 0.05 to 0.80). Conclusions: The following factors were shown to be associated with disease worsening in children with eczema in this UK study: clothing (wool and nylon), sweating, shampoo, swimming, dust, contact with unfamiliar pets and high grass pollen levels. Relative to the study hypotheses, the association between shampoo exposure and eczema worsening was shown to be increased in cold weather. There was also evidence showing an association between various combinations of exposures and disease worsening. There was insufficient evidence to support the other hypotheses tested in this study but this may be explained by low prevalence of these exposures. The implications of the findings of this study for clinical practice are that for the first time, it has been shown that shampoo exposure may be associated with eczema worsening and that this is more pronounced in cold weather. This study also suggests that worsening of eczema may be more complicated in that multiple exposures acting in concert may be associated with worsening of disease. Future research with increased participant numbers is required to specifically study possible gene-environment interactions with filaggrin mutations and their relevance in relation to disease flares and to look at shampoo formulations in relation to worsening of eczema.

Vitiligo is the most common skin disorder resulting in depigmentation, but high-quality research is lacking. A Cochrane review of interventions for vitiligo published in 2010 highlighted methodological limitations with existing trials; which have generally been too small and heterogeneous to inform clinical recommendations. The objective of this thesis was to improve the evidence base for the treatment of vitiligo. This PhD was funded by the National Institute for Health Research, as part of the research programme called “Setting Priorities and Reducing Uncertainties for people with Skin Diseases”. It includes the following: 1) identifying the most important research priorities for patients and clinicians, thereby informing the research agenda; 2) conducting a systematic review of outcome measures used in vitiligo trials and a survey of the most desirable outcomes for patients and clinicians; and 3) conducting a pilot double blind, randomised controlled trial (RCT) on home hand-held phototherapy in preparation of the first national multi-centre RCT for the treatment of vitiligo. For the prioritisation exercise, a total of 660 treatment uncertainties were submitted by 460 patients and clinicians. The identified priority areas included interventions such as combination of topical agents and phototherapy. The systematic review on outcome measures identified 25 different domains that had been used in previous trials. Although percentage repigmentation was measured in 96%; 48 different scales had been used. In contrast, patients and clinicians favoured the use of “cosmetically acceptable” repigmentation. Finally, a 4-month pilot trial recruited 29 participants and tested the logistics of running a future RCT. This work resulted in a commissioned call and funding of a national RCT on vitiligo (topical corticosteroids in combination with home hand-held phototherapy); the initiation of an international consensus exercise on core outcome measures for use in vitiligo trials; and informed the design and conduct of a future national RCT.

Erosive lichen planus affecting the vulvovaginal region (ELPV) is a rare chronic inflammatory condition causing painful raw areas that can lead to scarring, at the vaginal entrance. Symptoms considerably impact upon daily function and quality of life. There is risk of cancerous change in affected skin of 1-3%. A Cochrane Systematic Review, published in 2012, found no randomised controlled trials (RCT) on which to base treatment for ELPV. Retrospective case series suggest that super-potent topical corticosteroids are frequently used as first-line therapy, although one third of patients fail to respond adequately and require escalation of therapy. There is clinical uncertainty regarding which second-line therapies should be used. The following steps were taken to inform the design of an RCT to determine optimal second-line therapy for EVLP resistant to topical steroids: • A multi-centre retrospective review and audit of case notes to assess current clinical management in the UK. • A qualitative investigation with UK clinicians to establish their views and principles of management of ELPV. • An international multi-disciplinary electronic-delphi consensus exercise to agree a set of diagnostic criteria for ELPV. • A systematic review to assess existing outcome measure tools that have been used in randomised controlled trials of vulval skin disorders. • Assessment of patients views through a survey of a national patient group and subsequent focus groups with patients. The resulting multi-centre, four-armed, open-label, pragmatic randomised controlled trial will compare hydroxychloroquine, methotrexate and mycophenolate mofetil against a standard care group of clobetasol propionate 0.05% plus a short course of oral prednisolone. This will be the first RCT to test systemic agents for patients with ELPV and will add to the existing evidence base. The methodologies employed to develop the RCT protocol, and the trial design itself, may act as a template for clinical research into the therapeutic management of other rare inflammatory conditions.

This thesis report describes an attempt to build a recommender system for recommending sporting goods in an e-commerce setting, using the customer purchase history as the input dataset. Two input datasets were considered, the item purchases dataset and the item-category dataset. Both the datasets are implicit, that is not explicitly rated by the customer. The data is also very sparse that very few users have purchased more than a handful of the items featured in the dataset. The report describes a method for dealing with both the implicit datasets as well as addressing the problem of sparsity. The report introduces SVD (Single Value Decomposition) with matrix factorization as a implementation for recommendation systems. Specifically implementations in the Apache Mahout machine learning framework. / Denna rapport beskriver ett tillvägagångssätt för att med kundernas köphistorik bygga ett rekommendationssystem för rekommendation av sportprodukter på en e-handelsplats. Två olika datamängder behandlas, köphistorik per produkt och kund, samt köpfrekvensen per produktkategori per kund i köphistoriken. Båda är implicita datamängder, vilket betyder att kunderna inte har explicit uttryckt en åsikt för eller emot produkten, utan implicit uttrycker preferens genom sitt köp. Datan är även mycket gles, vilket betyder att den enskilda kunden generellt bara köpt en liten del av den totala mängden av sålda varor. Rapporten behandlar en metod som behandlar både den implicita karaktären av data och gleshets problemet. Rapporten introducerar SVD (Single Value Decomposition) med matrisfaktorisering som en metod för att implementera rekommendationssystem. Specifikt implementerat med hjälp av maskininlärningsbiblioteket Apache Mahout.

WR 25 is a colliding-wind binary star system comprising a very massive O2.5If∗/WN6 primary and an O-star secondary in an eccentric orbit with a 208 day period. These hot stars have strong, highly supersonic winds that interact to form a bright X-ray source from wind-collision shocks whose conditions change with stellar separation. Different views through the winds of Wolf-Rayet and O stars are afforded with orbital phase as the stars move about their orbits, allowing for exploration of wind structure in ways not easy or even possible for single stars. We have analyzed an on-axis Chandra/HETGS spectrum of WR 25 obtained shortly before periastron when the X-rays emanating from the system are the brightest. From the on-axis observations, we constrain the line fluxes, centroids, and widths of various emission lines, including He triplets of Si xiii and Mg xi. We have also been able to include several serendipitous off-axis HETG spectra from the archive and study their flux variation with phase. This is the first report on high-resolution spectral studies of WR 25 in X-rays.

L’étoile Wolf-Rayet WR 46 est connue pour sa variabilité complexe sur des échelles de temps relativement courtes de quelques heures et sur des échelles de temps plus longues de plusieurs mois. Des décalages périodiques mais intermittents en vitesse radiale ont déjà été observés dans ses raies d’émission optiques. Plusieurs périodes photométriques ont aussi été mesurées dans le passé. Des pulsations non-radiales, une modulation liée à la rotation rapide, ou encore la présence d’un compagnon de faible masse dont la présence reste à confirmer ont été proposées pour expliquer le comportement de l’étoile sur des échelles de temps de quelques heures. Dans un effort pour dévoiler sa vraie nature, nous avons observé WR 46 avec le satellite FUSE sur plusieurs cycles de variabilité à court terme. Nous avons trouvé des variations sur une échelle de temps d’environ 7,5 heures dans le continu ultraviolet lointain, dans l’aile bleue de la composante d’absorption du profil P Cygni du doublet de O vi 1032, 1038, ainsi que dans la composante d’absorption du profil P Cygni de S vi 933, 944. Nous avons également récupéré des données archivées de cette étoile obtenues avec le satellite XMM-Newton. La courbe de lumière en rayons X montre des variations sur une échelle de temps similaire aux courbes de lumière du continu ultraviolet et ultraviolet lointain, et le spectre rayons X de WR 46 est très mou avec un pic d’émission à des énergies plus faibles que 1 keV. Nous discutons des différentes contraintes sur la nature de la variabilité de cette étoile que ces nouvelles observations aident à poser. Parmi les scénarios suggérés, nous concluons que celui des pulsations non-radiales est le plus probable, bien que nous soyons encore loin d’une compréhension détaillée de WR 46. / The Wolf-Rayet star WR 46 is known to exhibit a very complex variability pattern on relatively short timescales of a few hours and also on longer timescales of months. Periodic but intermittent radial velocity shifts of optical lines as well as multiple photometric periods have been found in the past. Nonradial pulsations, rapid rotational modulation or the presence of a yet-to-be-confirmed low-mass companion have been proposed to explain the short-term behaviour. In an effort to unveil its true nature, we observed WR 46 with FUSE over several short-term variability cycles. We found significant variations on a timescale of about 7.5 hours in the FUV continuum, in the blue edge of the absorption trough of the O vi 1032, 1038 doublet P Cygni profile, and in the S vi 933, 944 P Cygni absorption profile. We also retrieved archival XMM-Newton data of this star. We found the X-ray light-curve to show variations on a timescale similar to the UV and FUV continuum light-curves, and the X-ray spectrum of WR 46 to be very soft with a peak below 1 keV. We discuss the different constraints on the nature of the variability that these new observations help to establish. Among the suggested scenarios, we conclude that non-radial pulsations is the most likely, although we are far from a complete picture.

Nous savons que la grande majorité des étoiles WC9 produit de la poussière à base de carbone. Cette dernière doit se former dans des zones de très haute densité afin de survivre à l’environnement hostile qu’est celui du vent d’une étoile WR. Les étoiles WC appartenant à un système binaire WR + O produisent de la poussière quand les vents des deux étoiles entrent en collision et forment une zone de choc pouvant augmenter la densité du gaz d’un facteur 1000. Par contre, plusieurs étoiles WC9 n’ont, à ce jour, montré aucun signe de la présence d’un compagnon. Le but du projet est de tenter d’identifier un mécanisme alternatif responsable de la formation de poussière dans les étoiles WC9 n’appartenant pas à un système binaire. Nous présentons les résultats d’une campagne d’observation visant à caractériser la variabilité spectroscopique d’un échantillon de huit étoiles WC9 et une étoile WC8d. Nos résultats indiquent que la majorité des étoiles montrent des variations à grande échelle dans la raie d’émission C III 5696, soit à un niveau d’au moins 5% du flux de la raie et que les structures dans le vent ont une dispersion de vitesses de l’ordre de 150-300 km/s. De manière générale, les variations de vitesse radiales sont anti-corrélées avec le coefficient d’asymétrie de la raie, ce qui semble infirmer la présence d’un compagnon. Des observations en photométrie de l’étoile WR103 montrent une période de 9.1 ± 0.6 jours qui s’accorde avec les variations spectroscopiques et qui ne semble pas, de manière évidente, d’origine binaire. / We know that the majority of WC9 stars produces carbon-based dust. To survive in the hot and harsh environement that is the wind of a WR star, the dust grains must be formed in regions of very high density. We know that WC stars that are part of a WR + O system can produce dust at periastron passage where the collision of the two stellar winds is strong enough to produce shocks that compress the gas to densities up to a factor 103 higher than that of the WR star. However, so far, many WC9 stars have shown no signs of a companion. The goal of the current project is to identify a mechanism that could be responsible for the formation of dust in single WC9 stars. We present the results of an observing campaign which aimed to characterize the spectroscopic variability of eight WC9 stars and one WC8d star. Our results indicate that most stars show large scale variations of their C III 5696 emission line that reach at least 5% of the total line flux, and that the structures in the wind have a mean velocity dispersion of 150-300 km/s. In general, the radial velocity variations are anti-correlated with the skewness variations. This seems to indicate that the variations are not due to the presence of a companion. Photometric observations of WR 103 show a period of 9.1 ± 0.6 days that agrees with the spectroscopic variations and does not seem from binary origin.

Nous savons que la grande majorité des étoiles WC9 produit de la poussière à base de carbone. Cette dernière doit se former dans des zones de très haute densité afin de survivre à l’environnement hostile qu’est celui du vent d’une étoile WR. Les étoiles WC appartenant à un système binaire WR + O produisent de la poussière quand les vents des deux étoiles entrent en collision et forment une zone de choc pouvant augmenter la densité du gaz d’un facteur 1000. Par contre, plusieurs étoiles WC9 n’ont, à ce jour, montré aucun signe de la présence d’un compagnon. Le but du projet est de tenter d’identifier un mécanisme alternatif responsable de la formation de poussière dans les étoiles WC9 n’appartenant pas à un système binaire. Nous présentons les résultats d’une campagne d’observation visant à caractériser la variabilité spectroscopique d’un échantillon de huit étoiles WC9 et une étoile WC8d. Nos résultats indiquent que la majorité des étoiles montrent des variations à grande échelle dans la raie d’émission C III 5696, soit à un niveau d’au moins 5% du flux de la raie et que les structures dans le vent ont une dispersion de vitesses de l’ordre de 150-300 km/s. De manière générale, les variations de vitesse radiales sont anti-corrélées avec le coefficient d’asymétrie de la raie, ce qui semble infirmer la présence d’un compagnon. Des observations en photométrie de l’étoile WR103 montrent une période de 9.1 ± 0.6 jours qui s’accorde avec les variations spectroscopiques et qui ne semble pas, de manière évidente, d’origine binaire. / We know that the majority of WC9 stars produces carbon-based dust. To survive in the hot and harsh environement that is the wind of a WR star, the dust grains must be formed in regions of very high density. We know that WC stars that are part of a WR + O system can produce dust at periastron passage where the collision of the two stellar winds is strong enough to produce shocks that compress the gas to densities up to a factor 103 higher than that of the WR star. However, so far, many WC9 stars have shown no signs of a companion. The goal of the current project is to identify a mechanism that could be responsible for the formation of dust in single WC9 stars. We present the results of an observing campaign which aimed to characterize the spectroscopic variability of eight WC9 stars and one WC8d star. Our results indicate that most stars show large scale variations of their C III 5696 emission line that reach at least 5% of the total line flux, and that the structures in the wind have a mean velocity dispersion of 150-300 km/s. In general, the radial velocity variations are anti-correlated with the skewness variations. This seems to indicate that the variations are not due to the presence of a companion. Photometric observations of WR 103 show a period of 9.1 ± 0.6 days that agrees with the spectroscopic variations and does not seem from binary origin.

L’étoile Wolf-Rayet WR 46 est connue pour sa variabilité complexe sur des échelles de temps relativement courtes de quelques heures et sur des échelles de temps plus longues de plusieurs mois. Des décalages périodiques mais intermittents en vitesse radiale ont déjà été observés dans ses raies d’émission optiques. Plusieurs périodes photométriques ont aussi été mesurées dans le passé. Des pulsations non-radiales, une modulation liée à la rotation rapide, ou encore la présence d’un compagnon de faible masse dont la présence reste à confirmer ont été proposées pour expliquer le comportement de l’étoile sur des échelles de temps de quelques heures. Dans un effort pour dévoiler sa vraie nature, nous avons observé WR 46 avec le satellite FUSE sur plusieurs cycles de variabilité à court terme. Nous avons trouvé des variations sur une échelle de temps d’environ 7,5 heures dans le continu ultraviolet lointain, dans l’aile bleue de la composante d’absorption du profil P Cygni du doublet de O vi 1032, 1038, ainsi que dans la composante d’absorption du profil P Cygni de S vi 933, 944. Nous avons également récupéré des données archivées de cette étoile obtenues avec le satellite XMM-Newton. La courbe de lumière en rayons X montre des variations sur une échelle de temps similaire aux courbes de lumière du continu ultraviolet et ultraviolet lointain, et le spectre rayons X de WR 46 est très mou avec un pic d’émission à des énergies plus faibles que 1 keV. Nous discutons des différentes contraintes sur la nature de la variabilité de cette étoile que ces nouvelles observations aident à poser. Parmi les scénarios suggérés, nous concluons que celui des pulsations non-radiales est le plus probable, bien que nous soyons encore loin d’une compréhension détaillée de WR 46. / The Wolf-Rayet star WR 46 is known to exhibit a very complex variability pattern on relatively short timescales of a few hours and also on longer timescales of months. Periodic but intermittent radial velocity shifts of optical lines as well as multiple photometric periods have been found in the past. Nonradial pulsations, rapid rotational modulation or the presence of a yet-to-be-confirmed low-mass companion have been proposed to explain the short-term behaviour. In an effort to unveil its true nature, we observed WR 46 with FUSE over several short-term variability cycles. We found significant variations on a timescale of about 7.5 hours in the FUV continuum, in the blue edge of the absorption trough of the O vi 1032, 1038 doublet P Cygni profile, and in the S vi 933, 944 P Cygni absorption profile. We also retrieved archival XMM-Newton data of this star. We found the X-ray light-curve to show variations on a timescale similar to the UV and FUV continuum light-curves, and the X-ray spectrum of WR 46 to be very soft with a peak below 1 keV. We discuss the different constraints on the nature of the variability that these new observations help to establish. Among the suggested scenarios, we conclude that non-radial pulsations is the most likely, although we are far from a complete picture.