Validating Health Economic Models With the Probabilistic Analysis Check dashBOARD.

OBJECTIVES: Health economic (HE) models are often considered as "black boxes" because they are not publicly available and lack transparency, which prevents independent scrutiny of HE models. Additionally, validation efforts and validation status of HE models are not systematically reported. Methods to validate HE models in absence of their full underlying code are therefore urgently needed to improve health policy making. This study aimed to develop and test a generic dashboard to systematically explore the workings of HE models and validate their model parameters and outcomes. METHODS: The Probabilistic Analysis Check dashBOARD (PACBOARD) was developed using insights from literature, health economists, and a data scientist. Functionalities of PACBOARD are (1) exploring and validating model parameters and outcomes using standardized validation tests and interactive plots, (2) visualizing and investigating the relationship between model parameters and outcomes using metamodeling, and (3) predicting HE outcomes using the fitted metamodel. To test PACBOARD, 2 mock HE models were developed, and errors were introduced in these models, eg, negative costs inputs, utility values exceeding 1. PACBOARD metamodeling predictions of incremental net monetary benefit were validated against the original model's outcomes. RESULTS: PACBOARD automatically identified all errors introduced in the erroneous HE models. Metamodel predictions were accurate compared with the original model outcomes. CONCLUSIONS: PACBOARD is a unique dashboard aiming at improving the feasibility and transparency of validation efforts of HE models. PACBOARD allows users to explore the working of HE models using metamodeling based on HE models' parameters and outcomes.

Cost-effectiveness of home-based screening of the general population for albuminuria to prevent progression of cardiovascular and kidney disease.

Background: Chronic kidney disease (CKD) is often detected late, leading to substantial health loss and high treatment costs. Screening the general population for albuminuria identifies individuals at high risk of kidney events and cardiovascular disease (CVD) who may benefit from early start of preventive interventions. Previous studies on the cost-effectiveness of albuminuria population screening were inconclusive, but were based on survey or cohort data rather than an implementation study, modelled screening as performed by general practitioners rather than home-based screening, and often included only benefits with respect to kidney events. We evaluated the cost-effectiveness of home-based general population screening for increased albuminuria based on real-world data obtained from a prospective implementation study taking into account prevention of CKD as well as CVD events. Methods: We developed an individual-level simulation model to compare home-based screening using a urine collection device with usual care (no home-based screening) in individuals of the general population aged 45-80, based on the THOMAS study (Towards HOMe-based Albuminuria Screening). Cost-effectiveness was assessed from the Dutch healthcare perspective with a lifetime horizon. The costs of the screening process and benefits of preventing CKD progression (dialysis and kidney transplantation) and CVD events (non-fatal myocardial infarction, non-fatal stroke, fatal CVD event) were reflected. Albuminuria detection led to treatment of identified risk factors. The model subsequently simulated CKD progression, the occurrence of CVD events, and death. The risks of experiencing CVD events were calculated using the SCORE2 CKD risk prediction model and individual-level data from the THOMAS study. Relative treatment effectiveness, quality of life scores, resource use, and cost inputs were obtained from literature. Model outcomes were the number of CKD and CVD-related events, total costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) per QALY gained by screening versus usual care. All results were obtained through probabilistic analysis. Findings: The absolute difference between screening versus usual care in lifetime probability of dialysis, kidney transplantation, non-fatal myocardial infarction, non-fatal stroke, and fatal CVD events were 0.2%, 0.05%, 0.6%, 0.6%, and 0.2%, respectively. This led to relative decreases compared to usual care in lifetime incidence of these events of 10.7%, 11.1%, 5.1%, 4.1%, and 1.6%, respectively. The incremental costs and QALYs of screening were €1607 and 0.17 QALY, respectively, which led to a corresponding ICER of €9225/QALY. The probability of screening being cost-effective for the Dutch willingness-to-pay threshold for preventive population screening of €20,000/QALY was 95.0%. Implementing the screening in the subgroup of 45-64 years old reduced the ICER (€7946/QALY), whereas implementing screening in the subgroup of 65-80 years old increased the ICER (€10,310/QALY). A scenario analysis assuming treatment optimization in all individuals with newly diagnosed risk factors or known risk factors not within target range reduced the ICER to €7083/QALY, resulting from the incremental costs and QALY gain of €2145 and 0.30, respectively. Interpretation: Home-based screening for increased albuminuria to prevent CVD and CKD events is likely cost-effective. More health benefits can be obtained by screening younger individuals and better optimization of care in individuals identified with newly diagnosed or known risk factors outside target range. Funding: Dutch Kidney Foundation, Top Sector Life Sciences & Health of the Dutch Ministry of Economic Affairs.

Cost-effectiveness of screening for chronic kidney disease: existing evidence and knowledge gaps.

It is well known that the worldwide prevalence of chronic kidney disease (CKD) has risen to over 10% of the general population during the past decades. Patients with CKD are at increased risk of both kidney failure and cardiovascular disease (CVD), posing a substantial health challenge. Therefore, screening for CKD is warranted to identify and treat patients early to prevent progression and complications. In this issue of the Journal, Yeo and colleagues provide an updated systematic review of the cost-effectiveness of screening for CKD in the general adult population. They show that screening for CKD in high-risk populations is cost-effective and that there is limited evidence for screening the general population. It should be noted that most studies they discuss do not consider the benefit of screening to prevent CVD in addition to preventing kidney failure, the treatment effect of novel therapeutic agents such as SGLT2 inhibitors, and the possibility of screening in a home-based setting. These three aspects will likely improve the cost-effectiveness of CKD screening, making it feasible to move towards general population screening for CKD.

Introducing Open Science in Teaching Health Economic Modelling.

Open Science is gaining ground in all research fields, including health economics and outcomes research (HEOR). However, teaching Open Science is still in its infancy. This paper describes the design, implementation and evaluation of a teaching activity focusing on introducing Open Science during a Master's course during which participants have to develop a discrete event simulation. The teaching activity was organised as a series of lectures introducing different aspects of the Open Science philosophy and practices, such as good software coding practices, version control systems and reproducible research. The participants' increase in Open Science knowledge was elicited through a survey before and after the teaching innovation. After the teaching innovation, participants' knowledge of Open Science increased and they reported an improvement in Open Science-related skills, such as using a script-based statistical software, identifying and re-using open data, and collaborative script development. During the evaluation at the end of the course, the course participants mentioned that the Open Science-related content was interesting but would fit better within a course in which broader research-related content is taught. Based on this feedback, we will most likely narrow the scope of the Open-Science-related content in this course to Open Source Modelling which may better fit the scope of the course. This paper contains links to the teaching activities we developed and other resources which may be used to design teaching activities on Open Science. Herewith, we hope to inspire other teachers in including Open Science into their teaching.

Loop Ileostomy Closure as a 23-Hour Stay Procedure With Preoperative Efferent Limb Enteral Stimulation: A Randomized Controlled Trial.

BACKGROUND: Loop ileostomy closure is a common procedure in colorectal surgery. Often seen as a simple operation associated with a low complication rate, it still leads to lengthy hospitalizations. Reducing postoperative complications and ileus rates could lead to a shorter length of stay and even ambulatory surgery. OBJECTIVES: This study aimed to assess the safety and feasibility of ileostomy closure performed in a 23-hour hospitalization setting using a standardized enhanced recovery pathway. DESIGN: Randomized controlled trial. SETTINGS: Two high-volume colorectal surgery centers. PATIENTS: Healthy adults undergoing elective ileostomy closure from July 2019 to January 2022. INTERVENTION: All patients were enrolled in a standardized enhanced recovery pathway specific to ileostomy closure, including daily irrigation of efferent limb with a nutritional formula for 7 days before surgery. Patients were randomly allocated to either conventional hospitalization (n = 23) or a 23-hour stay (n = 24). MAIN OUTCOME MEASURES: Primary outcome was total length of stay and secondary outcomes were 30-day rates of readmission, postoperative ileus, surgical site infections, and postoperative morbidity and mortality. RESULTS: A total of 47 patients were ultimately randomly allocated. Patients in the 23-hour hospitalization arm had a shorter median length of stay (1 vs 2 days, p = 0.02) and similar rates of readmission (4% vs 13%, p = 0.35), postoperative ileus (none in both arms), surgical site infection (0% vs 4%, p = 0.49), postoperative morbidity (21% vs 22%, p = 1.00), and mortality (none in both arms). LIMITATIONS: Due to coronavirus disease 2019, access to surgical beds was greatly limited, leading to a shift toward ambulatory surgery for ileostomy closure. The study was terminated early, which affected its statistical power. CONCLUSION: Loop ileostomy closures as 23-hour stay procedures are feasible and safe. Ileus rate might be reduced by preoperative intestinal stimulation with nutritional formula through the stoma's efferent limb, although specific randomized controlled trials are needed to confirm this association. See Video Abstract . CIERRE DE ILEOSTOMA EN ASA COMO PROCEDIMIENTO AMBULATORIO DE HORAS CON ESTMULO PREOPERATORIO ENTERAL EFERENTE ESTUDIO ALEATORIO CONTROLADO: ANTECEDENTES:El cierre de la ileostomía en asa es un procedimiento común en la cirugía colorrectal. A menudo vista como una operación simple asociada con bajas tasas de complicaciones, aún conduce a largas hospitalizaciones. La reducción de las complicaciones postoperatorias y las tasas de íleo podría conducir a una estadía hospitalaria más corta o incluso a una cirugía ambulatoria.OBJETIVOS:El presente estudio pretende evaluar la seguridad y la viabilidad del cierre de ileostomía realizadas en un entorno de hospitalización de 23 horas utilizando una vía de recuperación mejorada y estandarizada.DISEÑO:Estudio aleatorio controladoAJUSTES:Dos centros de cirugía colorrectal de gran volúmenPACIENTES:Adultos sanos sometidos a cierre electivo de ileostomía, desde Julio de 2019 hasta Enero de 2022.INTERVENCIÓN:Todos los pacientes fueron inscritos en una vía de recuperación mejorada y estandarizada específica para el cierre de la ileostomía, incluyendo la irrigación diaria de la extremidad eferente del intestino asociada a una fórmula nutricional durante 7 días previos a la cirugía. Los pacientes fueron asignados aleatoriamente en hospitalización convencional (n = 23) o a una estadía de 23 horas (n = 24).PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la duración total de la estadía hospitalaria y los resultados secundarios fueron las tasas de reingreso a los 30 días, el íleo postoperatorio, las infecciones de la herida quirúrgica, la morbilidad y mortalidad postoperatorias.RESULTADOS:Finalmente fueron randomizados un total de 47 pacientes. Aquellos que se encontraban en el grupo de hospitalización de 23 horas tuvieron una estadía media más corta (1 día versus 2 días, p = 0,02) y tasas similares de reingreso (4% vs 13%, p = 0,35), de íleo postoperatorio (ninguno en ambos brazos), de infección del sitio quirúrgico (0 vs 4%, p = 0,49), de morbilidad postoperatoria (21% vs 22%, p > 0,99) y de mortalidad (ninguna en ambos brazos).LIMITACIONES:Debido a la pandemia SARS CoV-2, el acceso a las camas quirúrgicas fue muy limitado, lo que llevó a un cambio hacia la cirugía ambulatoria para el cierre de ileostomías. El estudio finalizó anticipadamente, lo que afectó su poder estadístico.CONCLUSIÓN:Los cierres de ileostomía en asa como procedimientos de estadía de 23 horas son factibles y seguros. La tasa de íleo podría reducirse mediante la estimulación intestinal preoperatoria a través de la rama eferente del estoma asociada a fórmulas nutricionales, por lo que se necesitan estudios randomizados específicos para confirmar esta asociación. (Traducción-Dr. Xavier Delgadillo ).

Verbal memory and executive components of recall in adolescent binge drinkers.

Introduction: Binge drinking (BD) is a common health-risk behavior among young people. Due to the incomplete maturation of the adolescent brain, BD can lead to structural and functional changes that impact neurocognitive processes, particularly executive functioning and verbal memory. This study aimed to investigate the influence of executive components, such as mnemonic strategies and error avoidance, on performance in a verbal memory test and the potential effects of BD on this performance. Methods: A sample of 160 college students (51.55% female) with a mean age of 18.12 ± 0.32 years completed assessments for alcohol use disorders using the Alcohol Use Disorder Identification Test (AUDIT), as well as psychopathological (Symptom Checklist-90-R) and neuropsychological evaluations (Verbal Learning Test Spain-Complutense and WMS-III Logical Memory). The Intensive Drinking Evaluation Instrument (IECI) was utilized to gather detailed information about binge drinking habits, including the calculation of the highest blood alcohol concentration (BAC) during an episode of intake. Results: Correlation and clustering analyses revealed a negative association between BAC values and verbal memory performance, as well as the use of memory strategies. The high BAC group (BD) exhibited negative values in verbal memory variables, higher accuracy errors, and less efficient strategy usage, while the low BAC group (No BD) demonstrated better memory test performance, fewer precision errors, and superior use of memory strategies. Discussion: These findings support the hypothesis that, when solving tests requiring verbal memory, adolescents reporting a BD consumption pattern show fewer executive skills in their resolution and, therefore, achieved poorer performance than non-binge drinkers. Addressing excessive alcohol consumption in young individuals is crucial for safeguarding their cognitive development and overall well-being.

Health Economic Research Assessing the Value of Early Detection of Cardiovascular Disease: A Systematic Review.

INTRODUCTION: Cardiovascular disease (CVD) is the most prominent cause of death worldwide and has a major impact on healthcare budgets. While early detection strategies may reduce the overall CVD burden through earlier treatment, it is unclear which strategies are (most) efficient. AIM: This systematic review reports on the cost effectiveness of recent early detection strategies for CVD in adult populations at risk. METHODS: PubMed and Scopus were searched to identify scientific articles published between January 2016 and May 2022. The first reviewer screened all articles, a second reviewer independently assessed a random 10% sample of the articles for validation. Discrepancies were solved through discussion, involving a third reviewer if necessary. All costs were converted to 2021 euros. Reporting quality of all studies was assessed using the CHEERS 2022 checklist. RESULTS: In total, 49 out of 5552 articles were included for data extraction and assessment of reporting quality, reporting on 48 unique early detection strategies. Early detection of atrial fibrillation in asymptomatic patients was most frequently studied (n = 15) followed by abdominal aortic aneurysm (n = 8), hypertension (n = 7) and predicted 10-year CVD risk (n = 5). Overall, 43 strategies (87.8%) were reported as cost effective and 11 (22.5%) CVD-related strategies reported cost reductions. Reporting quality ranged between 25 and 86%. CONCLUSIONS: Current evidence suggests that early CVD detection strategies are predominantly cost effective and may reduce CVD-related costs compared with no early detection. However, the lack of standardisation complicates the comparison of cost-effectiveness outcomes between studies. Real-world cost effectiveness of early CVD detection strategies will depend on the target country and local context. REGISTRATION OF SYSTEMATIC REVIEW: CRD42022321585 in International Prospective Registry of Ongoing Systematic Reviews (PROSPERO) submitted at 10 May 2022.

Dynamic generation of photonic spatial quantum states with an all-fiber platform.

Photonic spatial quantum states are a subject of great interest for applications in quantum communication. One important challenge has been how to dynamically generate these states using only fiber-optical components. Here we propose and experimentally demonstrate an all-fiber system that can dynamically switch between any general transverse spatial qubit state based on linearly polarized modes. Our platform is based on a fast optical switch based on a Sagnac interferometer combined with a photonic lantern and few-mode optical fibers. We show switching times between spatial modes on the order of 5 ns and demonstrate the applicability of our scheme for quantum technologies by demonstrating a measurement-device-independent (MDI) quantum random number generator based on our platform. We run the generator continuously over 15 hours, acquiring over 13.46 Gbits of random numbers, of which we ensure that at least 60.52% are private, following the MDI protocol. Our results show the use of photonic lanterns to dynamically create spatial modes using only fiber components, which due to their robustness and integration capabilities, have important consequences for photonic classical and quantum information processing.

Ultralow-Dose Intraoperative Computed Tomography During Endoscopic Stone Surgery: A Quality Improvement Project.

Objectives: To improve care in patients with large kidney stones using advanced intraoperative imaging techniques to reduce perioperative radiation exposure, improve stone-free rates (SFRs), and reduce the number of surgical interventions in a quality improvement project. Patients and Methods: Patients with kidney stones appropriate for percutaneous nephrolithotomy (PCNL) treatment were scheduled into a hybrid operating room for endoscopic surgery (PCNL and/or ureteroscopy) with intent to perform intraoperative CT (ICT). Imaging was performed using an Artis Zeego Care+Clear™ (Siemens) robotic-armed multiplanar fluoroscopy system with collimation to the level of the affected kidney(s). After the initial case, the proprietary CARE™ (combined applications to reduce exposure) protocol was used. When the hybrid room was unavailable, a mobile CT scanner (O-Arm; Medtronics) was used in the traditional room (n = 2). Results: Thirty-one ICTs were performed in 23 consecutive patients during endoscopic stone procedures with a median effective radiation dose of 1.39 mSv per scan, significantly less than the preoperative noncontrast CT (12.02 mSv) in the same patients (p < 0.001). Longitudinal radiation exposure associated with stone treatment significantly decreased by 83% (15.80 to 2.68 mSv, p < 0.001) compared with a similar historical PCNL cohort. Clinically significant residual stones (≥3 mm) were identified at initial ICT in eight patients (35%) and further treated in six patients. One patient had missed residual stone diagnosed 34 days after surgery, which was apparent on re-review of the ICT. Thus, final verified SFR was 87% for all stages. Mean number of procedures improved from 1.77 to 1.30 (p = 0.05) and rate of postoperative CT scans improved from 82% to 26% (p < 0.001). Conclusion: Ultralow-dose ICT was demonstrated to simultaneously improve SFR and number of staged treatments, and greatly reduce the perioperative radiation dose for our patients. The findings support the continued use of this modality to benefit all patients with large stones.

Opportunities and Barriers to the Development and Use of Open Source Health Economic Models: A Survey.

OBJECTIVES: Health economic (HE) models are routinely used to support health policy and resource allocation decisions but are often considered "black boxes" that may be prone to error and bias. Open source models (OSMs) have been advocated to increase the transparency, credibility, and reuse of HE models. Previous studies have demonstrated interest in OSMs among the health economics and outcomes research community, but the number of OSMs remains low. METHODS: We conducted an online survey of ISPOR (the leading professional society for health economics and outcomes research) members' perspectives on the usefulness of OSMs and barriers to their development and implementation. RESULTS: Respondents (N = 230) included academics (27%), pharmaceutical (or related) industry representatives (23%), health research or consulting representatives (21%), governmental or nonprofit agency representatives (10%), and others (19%). Respondents were generally not familiar with barriers to the development and adoption of OSMs. Most agreed that OSMs would improve transparency (92%), efficiency (76%), and HE model reuse (86%) and promote confidence in using HE models (75%). The use of OSMs by health technology assessment authorities was considered a very important indicator of the usefulness of OSMs by 49% of respondents. Three-quarters of respondents perceived legal concerns and the ability to transfer data as important barriers to the development and use of OSMs. CONCLUSIONS: Respondents believe that OSMs could increase the transparency, efficiency, and credibility of HE models, but that several barriers hamper their widespread adoption. Our results suggest that fundamental changes may be needed across the health economics and outcomes research community if OSMs are to become widely adopted.

Efficacy, cost-minimization, and budget impact of a personalized discharge letter for basal cell carcinoma patients to reduce low-value follow-up care.

BACKGROUND: The incidence of keratinocyte carcinomas is high and rapidly growing. Approximately 80% of keratinocyte carcinomas consist of basal cell carcinomas (BCC) with 50% of these being considered as low-risk tumors. Nevertheless, 83% of the low-risk BCC patients were found to receive more follow-up care than recommended according to the Dutch BCC guideline, which is one visit post-treatment for this group. More efficient management could reduce unnecessary follow-up care and related costs. OBJECTIVES: To study the efficacy, cost-utility, and budget impact of a personalized discharge letter for low-risk BCC patients compared with usual care (no personalized letter). METHODS: In a multi-center intervention study, a personalized discharge letter in addition to usual care was compared to usual care in first-time BCC patients. Model-based cost-utility and budget impact analyses were conducted, using individual patient data gathered via surveys. The outcome measures were number of follow-up visits, costs and quality adjusted life years (QALY) per patient. RESULTS: A total of 473 first-time BCC patients were recruited. The personalized discharge letter decreased the number of follow-up visits by 14.8% in the first year. The incremental costs after five years were -€24.45 per patient. The QALYs were 4.12 after five years and very similar in both groups. The national budget impact was -€2,7 million after five years. CONCLUSIONS: The distribution of a personalized discharge letter decreases the number of unnecessary follow-up visits and implementing the intervention in a large eligible population would results in substantial cost savings, contributing to restraining the growing BCC costs.

Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog.

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS).

BACKGROUND: Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML. METHODS: This randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109 /L and ≥10 × 109 /L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1-year survival. The trial is registered at ClinicalTrials.gov (NCT01303796). RESULTS: Between October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109 /L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017). CONCLUSIONS: The regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109 /L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.

Effect of a comprehensive deep-learning model on the accuracy of chest x-ray interpretation by radiologists: a retrospective, multireader multicase study.

BACKGROUND: Chest x-rays are widely used in clinical practice; however, interpretation can be hindered by human error and a lack of experienced thoracic radiologists. Deep learning has the potential to improve the accuracy of chest x-ray interpretation. We therefore aimed to assess the accuracy of radiologists with and without the assistance of a deep-learning model. METHODS: In this retrospective study, a deep-learning model was trained on 821 681 images (284 649 patients) from five data sets from Australia, Europe, and the USA. 2568 enriched chest x-ray cases from adult patients (≥16 years) who had at least one frontal chest x-ray were included in the test dataset; cases were representative of inpatient, outpatient, and emergency settings. 20 radiologists reviewed cases with and without the assistance of the deep-learning model with a 3-month washout period. We assessed the change in accuracy of chest x-ray interpretation across 127 clinical findings when the deep-learning model was used as a decision support by calculating area under the receiver operating characteristic curve (AUC) for each radiologist with and without the deep-learning model. We also compared AUCs for the model alone with those of unassisted radiologists. If the lower bound of the adjusted 95% CI of the difference in AUC between the model and the unassisted radiologists was more than -0·05, the model was considered to be non-inferior for that finding. If the lower bound exceeded 0, the model was considered to be superior. FINDINGS: Unassisted radiologists had a macroaveraged AUC of 0·713 (95% CI 0·645-0·785) across the 127 clinical findings, compared with 0·808 (0·763-0·839) when assisted by the model. The deep-learning model statistically significantly improved the classification accuracy of radiologists for 102 (80%) of 127 clinical findings, was statistically non-inferior for 19 (15%) findings, and no findings showed a decrease in accuracy when radiologists used the deep-learning model. Unassisted radiologists had a macroaveraged mean AUC of 0·713 (0·645-0·785) across all findings, compared with 0·957 (0·954-0·959) for the model alone. Model classification alone was significantly more accurate than unassisted radiologists for 117 (94%) of 124 clinical findings predicted by the model and was non-inferior to unassisted radiologists for all other clinical findings. INTERPRETATION: This study shows the potential of a comprehensive deep-learning model to improve chest x-ray interpretation across a large breadth of clinical practice. FUNDING: Annalise.ai.

Lenalidomide with Rituximab for Previously Treated Follicular Lymphoma and Marginal Zone Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of lenalidomide (Revlimid®), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of lenalidomide in combination with rituximab (MabThera®), together referred to as R2, for the treatment of adults with treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The CS included one relevant study, for the comparison of R2 versus rituximab monotherapy (R-mono): the AUGMENT trial. In addition, the company performed an unanchored indirect comparison of R2 versus rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) and rituximab combined with cyclophosphamide, vincristine, and prednisolone (R-CVP), using data for R2 from the AUGMENT trial and pooled data for R-CHOP/R-CVP from the Haematological Malignancy Research Network (HMRN) database. During the STA process, the company provided an addendum containing evidence on only the FL population, in line with the marketing authorisation obtained at that time, which did not include MZL. The probabilistic incremental cost-effectiveness ratios (ICERs) presented by the company were £27,768 per quality-adjusted life year (QALY) gained for R2 versus R-CHOP, £41,602 per QALY gained for R2 versus R-CVP, and £23,412 per QALY gained for R2 versus R-mono. The ERG's concerns included the validity of the unanchored comparison, the unavailability of a state transition model to verify the outcomes of the partitioned survival model, substantial uncertainty in survival curves, and potential over-estimation of utility values. The revised ERG base case resulted in ICERs ranging from £16,874 to £44,888 per QALY gained for R2 versus R-CHOP, from £23,135 to £59,810 per QALY gained for R2 versus R-CVP, and from £18,779 to £27,156 per QALY gained for R2 versus R-mono. Substantial uncertainty remained around these ranges. NICE recommended R2 within its marketing authorisation, as an option for previously treated FL (grade 1-3A) in adults, contingent on the company providing lenalidomide according to the commercial arrangement.

Exploring the Cost Effectiveness of Shared Decision Making for Choosing between Disease-Modifying Drugs for Relapsing-Remitting Multiple Sclerosis in the Netherlands: A State Transition Model.

BACKGROUND: Up to 31% of patients with relapsing-remitting multiple sclerosis (RRMS) discontinue treatment with disease-modifying drug (DMD) within the first year, and of the patients who do continue, about 40% are nonadherent. Shared decision making may decrease nonadherence and discontinuation rates, but evidence in the context of RRMS is limited. Shared decision making may, however, come at additional costs. This study aimed to explore the potential cost-effectiveness of shared decision making for RRMS in comparison with usual care, from a (limited) societal perspective over a lifetime. METHODS: An exploratory economic evaluation was conducted by adapting a previously developed state transition model that evaluates the cost-effectiveness of a range of DMDs for RRMS in comparison with the best supportive care. Three potential effects of shared decision making were explored: 1) a change in the initial DMD chosen, 2) a decrease in the patient's discontinuation in using the DMD, and 3) an increase in adherence to the DMD. One-way and probabilistic sensitivity analyses of a scenario that combined the 3 effects were conducted. RESULTS: Each effect separately and the 3 effects combined resulted in higher quality-adjusted life years (QALYs) and costs due to the increased utilization of DMD. A decrease in discontinuation of DMDs influenced the incremental cost-effectiveness ratio (ICER) most. The combined scenario resulted in an ICER of €17,875 per QALY gained. The ICER was sensitive to changes in several parameters. CONCLUSION: This study suggests that shared decision making for DMDs could potentially be cost-effective, especially if shared decision making would help to decrease treatment discontinuation. Our results, however, may depend on the assumed effects on treatment choice, persistence, and adherence, which are actually largely unknown.

Polarization-independent single-photon switch based on a fiber-optical Sagnac interferometer for quantum communication networks.

An essential component of future quantum networks is an optical switch capable of dynamically routing single photons. Here we implement such a switch, based on a fiber-optical Sagnac interferometer design. The routing is implemented with a pair of fast electro-optical telecom phase modulators placed inside the Sagnac loop, such that each modulator acts on an orthogonal polarization component of the single photons, in order to yield polarization-independent capability that is crucial for several applications. We obtain an average extinction ratio of more than 19 dB between both outputs of the switch. Our experiment is built exclusively with commercial off-the-shelf components, thus allowing direct compatibility with current optical communication systems.

An economic evaluation of eribulin for advanced breast cancer treatment based on the Southeast Netherlands advanced breast cancer registry.

Background: In 2013, eribulin was reimbursed under a coverage with evidence development (CED) as third or later chemotherapy line for advanced breast cancer (ABC) patients in the Netherlands because of uncertain cost effectiveness. In 2016, the final decision of reimbursing eribulin was taken without considering the evidence collected during CED research. We analysed the cost effectiveness of eribulin versus non-eribulin chemotherapy, using real-world data.Methods: A three health states (progression-free, progressed disease, dead) partitioned survival model was developed. The SOuth East Netherlands Advanced BREast Cancer (SONABRE) registry informed the effectiveness and costs inputs. Health state utility values were obtained from the literature. Incremental cost-effectiveness ratio (ICER) between the eribulin and matched non-eribulin chemotherapy was estimated. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. The financial risk (i.e., the expected value of perfect information (EVPI) plus the expected monetary loss (eML) associated with reimbursing eribulin) and budget impact associated with reimbursing eribulin were calculated.Results: Eribulin led to higher health benefits (0.07 quality-adjusted life year (QALY)) and costs (€15,321) compared with non-eribulin chemotherapy. This resulted in an ICER of €220,608. At a €80,000 per QALY threshold, the risk of reimbursing eribulin was €9,791 per patient (EVPI €13, eML €9,778). Scaled up to the Dutch population, the estimated annual budget impact was €1.9 million and the annual risk of reimbursing eribulin was €2.7 million.Conclusion: From a Dutch societal perspective, eribulin is not cost effective when considering its list price as third and later chemotherapy line for ABC patients.

Variability of cost trajectories over the last year of life in patients with advanced breast cancer in the Netherlands.

OBJECTIVE: In breast cancer patients, treatment at the end of life accounts for a major share of medical spending. However, little is known about the variability of cost trajectories between patients. This study aims to identify underlying latent groups of advanced breast cancer patients with similar cost trajectories over the last year before death. METHODS: Data from deceased advanced breast cancer patients, diagnosed between 2010 and 2017, were retrieved from the Southeast Netherlands Advanced Breast Cancer (SONABRE) Registry. Costs of hospital care over the last twelve months before death were analyzed, and the variability of longitudinal patterns between patients were explored using group-based trajectory modeling. Descriptive statistics and multinomial logistic regression were applied to investigate differences between the identified latent groups. RESULTS: We included 558 patients. Over the last twelve months before death, mean hospital costs were €2,255 (SD = €492) per month. Costs increased over the last five months and reached a maximum of €3,614 in the last month of life, driven by hospital admissions, while spending for medication declined over the last three months of life. Based on patients' individual cost trajectories, we identified six latent groups with distinct longitudinal patterns, of which only two showed a marked increase in costs over the last twelve months before death. Latent groups were constituted of heterogeneous patients, and clinical characteristics explained membership only to a limited extent. CONCLUSIONS: The average costs of advanced breast cancer patients increased towards the end of life. However, we uncovered several latent groups of patients with divergent cost trajectories, which did not reflect the overall increasing trend. The mechanisms underlying the variability in cost trajectories warrants further research.