Budget impact of sequential treatment with first-line afatinib versus first-line osimertinib in non-small-cell lung cancer patients with common EGFR mutations

Background The therapeutic landscape for non-small-cell lung cancer (NSCLC) patients that have common epidermal growth factor receptor (EGFR) mutations has changed radically in the last decade. The availability of these treatment options has an economic impact, therefore a budget impact analysis was performed. Methods A budget impact analysis was conducted from a Dutch healthcare perspective over a 5-year time horizon in EGFR-mutant NSCLC patients receiving first-line afatinib (Gilotrif(R)) versus first-line osimertinib (Tagrisso(R)), followed by subsequent treatments. A decision analysis model was constructed in Excel. Scenario analyses and one-way sensitivity analysis were used to test the models' robustness. Results Sequential treatment with afatinib versus first-line treatment with osimertinib showed mean total time on treatment (ToT) of 29.1 months versus 24.7 months, quality-adjusted life months (QALMs) of 20.2 versus 17.4 with mean cost of euro108,166 per patient versus euro143,251 per patient, respectively. The 5-year total budget impact was euro110.4 million for the afatinib sequence versus euro158.6 million for the osimertinib sequence, leading to total incremental cost savings of euro48.15 million. Conclusions First-line afatinib treatment in patients with EGFR-mutant NSCLC had a lower financial impact on the Dutch healthcare budget with a higher mean ToT and QALM compared to osimertinib sequential treatment

How do people with experience of infertility value different aspects of assistive reproductive therapy? Results from a multi-country discrete choice experiment

Objectives: Assistive reproductive therapies can help those who have difficulty conceiving but different forms of assistive reproductive therapies are associated with different treatment characteristics. We undertook a large, multinational discrete choice experiment to understand patient preferences for assistive reproductive therapies. Methods: We administered an online discrete choice experiment with persons who had experience with subfertility or assistive reproductive therapies in the USA, UK, the Nordic region (Denmark, Norway, Sweden, Finland), Spain, and China. Attributes encouraged trade-offs between effectiveness, risk of adverse effects, treatment (dis)comfort, (in)convenience, cost per cycle and shared decision making. We used multinomial logit and mixed-logit models to estimate preferences and attribute importance by country/region, and estimated willingness to pay for changes in attribute levels. Results: A total of 7565 respondents participated. Mixed logit had a better fit than multinomial logit across all samples. Preferences moved in expected directions across all samples, but the relative importance of attributes differed between countries. Willingness to pay was greatest for improvements in effectiveness and a greater degree of shared decision making, and we observe a substantial ‘option value’ independent of treatment characteristics. Unexpectedly, preferences over cost were insignificant in the Chinese sample, limiting the use of willingness to pay in this sample. Conclusions: Respondents balanced concerns for effectiveness with other considerations, including the cost and (dis)comfort of treatment, and the degree of shared decision making, but there is also substantial option value independent of treatment characteristics, demonstrating value of assistive reproductive therapies to individuals with experience of subfertility. We hypothesise that price insensitivity in the Chinese sample may reflect a degree of social desirability bias

Tailored support may be required to reduce the impact of the infertility journey on mental health, relationships and daily lives of infertile patients and partners to infertile patients

Research question What is the psychological impact of infertility on infertile patients and partners of infertile patients? Design This online, international, quantitative survey assessed the impact of infertility on mental health, relationships and daily activities for 1944 respondents. Respondents were male or female infertile patients (n = 1037) or partners to infertile patients (n = 907; not necessarily partners of the patient sample) and were recruited at different stages of the treatment journey. Results The most common emotions were ‘sadness’ at infertility diagnosis and ‘anxiety’ during treatment. Emotions differed in nature and intensity throughout the journey. Envy of others who achieved pregnancy was frequently reported by women. More than half of respondents (60.4%; n = 1174) perceived the infertility journey to have impacted their mental health, and 44.1% (n = 857) of respondents sought mental health support. More patients reported mental health impacts (70.1%, n = 727) than partners (49.3%, n = 447). One in three respondents indicated that their relationship had suffered due to the infertility diagnosis. Of these respondents, 55.0% (n = 409) strongly agreed that infertility caused an emotional strain. Patients more often than partners reported a detrimental impact on daily activities. Respondents most commonly agreed with statements regarding an ‘effect on work–life balance’. Conclusion Treatment journey stages are defined by their impact profile, which differs between infertile patients and partners of infertile patients. Negative impacts are diverse (mental health, relational, daily activities). There was disparity between the number of respondents reporting mental health issues and the number seeking mental health support. This indicates the need for support services tailored to different treatment stages

Anchoring in the Lead-Time Time Trade-Off : does the “Starting-point” influence preference elicitation?

Background: The standard TTO’s different treatment of states worse than death (SWD) and states better than death (SBD) is by many viewed as a prima-facie cause for concern related to potential bias caused by using two different elicitation regimens. In response to this concern, Robinson and Spencer (2006) described an approach that made it possible to value SWD and SBD in the same exercise by adding a “lead-time” to the valuation tasks. There is a considerable literature suggesting that theoretically irrelevant fac- tors influence preference elicitation trough heuristic processes, and that these processes may bias the resulting TTO values. If the lead-time extension serve as a heuristic anchor, the a priori choice of the lead-times initial position might have consequences on the respondents elicitation process, and if pro- nounced, cause of bias and error. Assessing the existence, the magnitude or the direction of the potential influence might provide researchers with valu- able information for future LT-TTO studies. Purpose: To explore potential influence caused by the added “lead-time” component in the elicited LT-TTO values. Methods: A LT-TTO survey with manipulated “lead-time” starting points were run on a sample of the Norwegian population. The manipula- tions added starting points ranging from 0 to 10 years above the starting point of the comparator health state. The respondents received eight EQ-5D descriptions of hypothetical health states and valued them using the manip- ulated LT-TTO survey. The Kruskal-Wallis one-way analysis of variance by ranks was applied, and a robust regression with Huber and Tukey bi weights was fitted to detect potential influence attributable to the starting points. Results: A significant between group variation in the elicited results were detected by the statistical testing, and the robust regression revealed a pos- itive linear relationship between the TTO-values and the lead-time starting points with a coefficient of 0.039. Conclusion: The findings suggest that the LT-TTO values are influenced by the starting point of the “lead-time” and that the method is sensitive to heuristic processes mediated by the “lead- times” initial positioning. The observed variation raises doubts w ether the LT-TTO leads us closer to an unbiased preference elicitation tool, or if it only trades one type of heuristic effect off for another. Since it is difficult to perceive that the dependency is a result of an a priori property of peo- ples’ perceptions of health and time, anchoring should be considered when designing and interpreting LT-TTO studies

Yrkesfagelevers og læreres oppfatninger av didaktiske verktøy brukt i SpaStudy, et internasjonalt samarbeidsprosjekt på Facebook.

Yrkesfagene står overfor store utfordringer med høyt frafall. Denne oppgaven undersøker pedagogiske og didaktiske grep som ble brukt i delprosjektet SpaStudy i prosjektet «Learning With Companies». Formålet med SpaStudy var å bruke Facebook til å se på digital markedsføring av spa i et samarbeidsprosjekt med yrkesfagelever og lærere i Estland, Finland og Norge. Problemstillingen var: Hvilke oppfatninger hadde yrkesfagelever og lærere av bruken av Facebook og FYR i SpaStudy, et internasjonalt samarbeidsprosjekt? Forskningsspørsmålen var: Hvordan opplevde yrkesfagelever og lærere deltakelse i SpaStudy prosjektet? Hvilke positive og negative sider hadde bruken av Facebook som et læringsverktøy for yrkesfagelever og lærere? Hva sier yrkesfagelever og lærere om FYR samarbeidet i SpaStudy prosjektet? Oppgaven benyttet kvalitativ metode. Det ble i 2016 gjort semistrukturerte intervjuer med 2 elever, 2 studenter og 3 lærere som hadde deltatt i SpaStudy. Gjennom intervjuene kom det frem at både elever og lærere opplevde at SpaStudy hadde mange gode sider. Elevene sa at spesielt samarbeidet med elever fra flere land og bruken av Facebook var positivt. Lærerne syntes at samarbeidet gav økt motivasjon hos elevene. Men både elevene og lærerne reflekterte at det var negativt att ikke alle elever i klassen fikk være med hele veien. Elevene var positive til bruken av Facebook som læringsverktøy men tok opp at den store mengden kommentarer kan være negativt. I SpaStudy jobbet programfaglærere sammen med engelsklærere i all tre landene. I Norge var det en del av FYR samarbeidet og den norske læreren uttrykte at dette var bedre som følge av deltakelsen i SpaStudy. De norske elevene syntes FYR samarbeidet var nyttig fordi de måtte bruke engelsk som fellesspråk i SpaStudy. Denne studien viser at et yrkesorientert internasjonalt samarbeid og bruken av Facebook som didaktisk verktøy oppfattes som positivt og at slike prosjekt kan bidra til å gjøre yrkesfaglig undervisning mer interessant og relevant

Budget impact of sequential treatment with first-line afatinib versus first-line osimertinib in non-small-cell lung cancer patients with common EGFR mutations

BACKGROUND: The therapeutic landscape for non-small-cell lung cancer (NSCLC) patients that have common epidermal growth factor receptor (EGFR) mutations has changed radically in the last decade. The availability of these treatment options has an economic impact, therefore a budget impact analysis was performed.METHODS: A budget impact analysis was conducted from a Dutch healthcare perspective over a 5-year time horizon in EGFR-mutant NSCLC patients receiving first-line afatinib (Gilotrif®) versus first-line osimertinib (Tagrisso®), followed by subsequent treatments. A decision analysis model was constructed in Excel. Scenario analyses and one-way sensitivity analysis were used to test the models' robustness.RESULTS: Sequential treatment with afatinib versus first-line treatment with osimertinib showed mean total time on treatment (ToT) of 29.1 months versus 24.7 months, quality-adjusted life months (QALMs) of 20.2 versus 17.4 with mean cost of €108,166 per patient versus €143,251 per patient, respectively. The 5-year total budget impact was €110.4 million for the afatinib sequence versus €158.6 million for the osimertinib sequence, leading to total incremental cost savings of €48.15 million.CONCLUSIONS: First-line afatinib treatment in patients with EGFR-mutant NSCLC had a lower financial impact on the Dutch healthcare budget with a higher mean ToT and QALM compared to osimertinib sequential treatment.</p

Structural insights into the enhanced carbapenemase efficiency of OXA-655 compared to OXA-10

Carbapenemases are the main cause of carbapenem resistance in Gram‐negative bacteria. How β‐lactamases with weak carbapenemase activity, such as the OXA‐10‐type class D β‐lactamases, contribute to anti‐bacterial drug resistance is unclear. OXA‐655 is a T26M and V117L OXA‐10 variant, recently identified from hospital wastewater. Despite exhibiting stronger carbapenemase activity towards ertapenem (ETP) and meropenem (MEM) in Escherichia coli, OXA‐655 exhibits reduced activity towards oxyimino‐substituted β‐lactams like ceftazidime. Here, we have solved crystal structures of OXA‐10 in complex with imipenem (IPM) and ETP, and OXA‐655 in complex with MEM in order to unravel the structure–function relationship and the impact of residue 117 in enzyme catalysis. The new crystal structures show that L117 is situated at a critical position with enhanced Van der Waals interactions to L155 in the omega loop. This restricts the movements of L155 and could explain the reduced ability for OXA‐655 to bind a bulky oxyimino group. The V117L replacement in OXA‐655 makes the active site S67 and the carboxylated K70 more water exposed. This could affect the supply of new deacylation water molecules required for hydrolysis and possibly the carboxylation rate of K70. But most importantly, L117 leaves more space for binding of the hydroxyethyl group in carbapenems. In summary, the crystal structures highlight the importance of residue 117 in OXA‐10 variants for carbapenemase activity. This study also illustrates the impact of a single amino acid substitution on the substrate profile of OXA‐10 and the evolutionary potential of new OXA‐10 variants

Emotional reactions to infertility diagnosis in patients and partners: Thematic and natural language processing analyses of textual data from the 1000 Dreams infertility survey

Research question : What are the emotional impacts of infertility on patients and/or partners, and how can qualitative thematic analyses (TA) and natural language processing (NLP) help evaluate textual data? Design : This was a cross-sectional, multi-country survey conducted from March to May 2019. A total of 1,944 patients and/or partners from nine countries responded to the open-ended question asking about their initial feelings related to an infertility diagnosis. A mixed-method approach that integrated NLP topic modelling and TA was used to analyse responses. Sentiment polarity, which expresses the valence of respondent sentiments in NLP, was quantified for each response. Linear regression was used to evaluate the association between patient characteristics and sentiment negativity. Results : NLP and TA showed that the most common emotional reactions to infertility diagnoses were sadness, depression, stress, disappointment, anxiety, frustration, confusion, and loss of self-confidence. NLP topic modelling found additional reactions such as shared feelings with partners, recollections about causes of infertility, and treatment experience. Responses to the open-ended question were brief (median: three words) with 71.8% conveying negative sentiments. Some respondent characteristics showed small but significant associations with sentiment negativity, such as country (Spain, China, and France were more negative than the United States), treatment engagement (no treatment was more negative than one or more treatment), and marital status (missing/other was more negative than divorced). Conclusion : Infertility diagnoses create an emotional burden for patients and partners. The mixed-method approach provides a compelling synergy in support of the validity of these findings and shows potential for these techniques in future research

Structural insights into the enhanced carbapenemase efficiency of OXA‐655 compared to OXA‐10

Carbapenemases are the main cause of carbapenem resistance in Gram‐negative bacteria. How β‐lactamases with weak carbapenemase activity, such as the OXA‐10‐type class D β‐lactamases, contribute to anti‐bacterial drug resistance is unclear. OXA‐655 is a T26M and V117L OXA‐10 variant, recently identified from hospital wastewater. Despite exhibiting stronger carbapenemase activity towards ertapenem (ETP) and meropenem (MEM) in Escherichia coli, OXA‐655 exhibits reduced activity towards oxyimino‐substituted β‐lactams like ceftazidime. Here, we have solved crystal structures of OXA‐10 in complex with imipenem (IPM) and ETP, and OXA‐655 in complex with MEM in order to unravel the structure–function relationship and the impact of residue 117 in enzyme catalysis. The new crystal structures show that L117 is situated at a critical position with enhanced Van der Waals interactions to L155 in the omega loop. This restricts the movements of L155 and could explain the reduced ability for OXA‐655 to bind a bulky oxyimino group. The V117L replacement in OXA‐655 makes the active site S67 and the carboxylated K70 more water exposed. This could affect the supply of new deacylation water molecules required for hydrolysis and possibly the carboxylation rate of K70. But most importantly, L117 leaves more space for binding of the hydroxyethyl group in carbapenems. In summary, the crystal structures highlight the importance of residue 117 in OXA‐10 variants for carbapenemase activity. This study also illustrates the impact of a single amino acid substitution on the substrate profile of OXA‐10 and the evolutionary potential of new OXA‐10 variants