Noninvasive minimal residual disease assessment in relapsed/refractory large B-cell lymphoma using digital droplet PCR.

Although several promising approaches for the treatment of relapsed/refractory diffuse large B-cell lymphoma (rrDLBCL) have been approved recently, it remains unclear which patients will ultimately achieve long-term responses. Circulating tumor (ct)DNA sequencing has emerged as a valuable tool to assess minimal residual disease (MRD). Correlations between MRD and outcomes have been shown in previously untreated DLBCL, but data on the repeated assessment of MRD in the dynamic course of rrDLBCL is limited. Here, we present an approach leveraging cost- and time-sensitivity of digital droplet (dd)PCR to repeatedly assess MRD in rrDLBCL and present proof-of-principle for its ability to predict outcomes.

Prevalence, diagnostic delay and economic burden of endometriosis and its impact on quality of life: results from an Eastern Mediterranean population.

BACKGROUND: There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an under-represented region in Europe. METHODS: Cyprus Women's Health Research Initiative, a cross-sectional study recruited 7646 women aged 18-55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n = 2922) and without (n = 4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. RESULTS: Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9-5.9%, n = 410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P < 0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P = 0.027) and asymptomatic (0.3%, P < 0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03-2.38) higher than the symptomatic and 1.95 (95% CI: 1.30-2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P = 0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811-$10 917) including healthcare, costs relating to absence and loss of productivity at work. CONCLUSION: Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain.

Simulation study on LDL cholesterol target attainment, treatment costs, and ASCVD events with bempedoic acid in patients at high and very-high cardiovascular risk.

BACKGROUND AND AIMS: The LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. The study objective was to estimate the impact of bempedoic acid treatment on LDL-C target attainment, drug costs, and atherosclerotic cardiovascular disease (ASCVD) events. The simulation used a Monte Carlo approach in a representative cohort of German outpatients at high or very-high cardiovascular risk. Additionally to statins, consecutive treatment with ezetimibe, bempedoic acid, and a PCSK9 inhibitor was simulated in patients not achieving their LDL-C goal. Considered were scenarios without and with bempedoic acid (where bempedoic acid was replaced by a PCSK9 inhibitor when LDL-C was not controlled). RESULTS: The simulation cohort consisted of 105,577 patients, of whom 76,900 had very-high and 28,677 high cardiovascular risk. At baseline, 11.2% of patients achieved their risk-based LDL-C target. Sequential addition of ezetimibe and bempedoic acid resulted in target LDL-C in 33.1% and 61.9%, respectively. Treatment with bempedoic acid reduced the need for a PCSK9 inhibitor from 66.6% to 37.8% and reduced drug costs by 35.9% per year on stable lipid-lowering medication. Compared to using only statins and ezetimibe, this approach is projected to prevent additional 6,148 ASCVD events annually per 1 million patients, whereas PCSK9 inhibition alone would prevent 7,939 additional ASCVD events annually. CONCLUSIONS: A considerably larger proportion of cardiovascular high- and very-high-risk patients can achieve guideline-recommended LDL-C goals with escalated lipid-lowering medication. Bempedoic acid is projected to substantially decrease the need for PCSK9 inhibitor treatment to achieve LDL-C targets, associated with reduced drug costs albeit with fewer prevented events.

Prevalence of Common Gynecological Conditions in the Middle East: Systematic Review and Meta-Analysis.

Introduction: High prevalence of gynecological conditions in women of Middle Eastern origin is reported, likely due to regional risk factors and mediators. The objective of this systematic review and meta-analysis is to investigate the prevalence of polycystic ovary syndrome (PCOS), endometriosis, uterine fibroids, and adenomyosis in women of Middle Eastern origin. Methods: MEDLINE, EMBASE, PsycINFO, Global Health, and Google Scholar databases were searched from database inception until 14 February 2021 to identify relevant studies. Peer-reviewed research articles that reported the prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern population were written in English or Arabic. The primary outcome was the estimated pooled prevalence of PCOS, endometriosis, uterine fibroids, and adenomyosis in the Middle Eastern populations. The secondary outcome was to assess the evidence in the data for the presence of heterogeneity, by conducting subtype-pooled analysis of prevalence estimates of the conditions. Total weighted prevalence was calculated via Freeman-Tukey arcsine transformation and heterogeneity through the I 2 statistic. Quality control was performed using GRADE criteria. Results: A total of 47 studies, 26 on PCOS, 12 on endometriosis, eight on uterine fibroids, and seven on adenomyosis, were included. The pooled prevalence of PCOS diagnosed according to the NIH criteria was 8.9% (95% CI: 6.5-11.7; prevalence range: 4.0-27.6%), with a higher prevalence from the Gulf Arab states (18.8%, 95% CI: 9.5-30.3; range: 12.1-27.6%). According to the Rotterdam criteria, the pooled prevalence of PCOS was 11.9% (95% CI: 7.1-17.7; range: 3.4-19.9%) with studies limited to the Persian and Levant regions. Endometriosis was diagnosed in 12.9% (95% CI: 4.2-25.4; range: 4.2-21.0%) of women undergoing laparoscopy, for any indication. Uterine fibroid and adenomyosis prevalence of women was 30.6% (95% CI: 24.9-36.7; range: 18.5-42.6%) and 30.8% (95% CI: 27.1-34.6, range: 25.6-37.7%), respectively. Heterogeneity was present between studies due to statistical and methodological inconsistencies between studies, and quality of evidence was low due to sample size and unrepresentative participant selection. Conclusion: This is the first review that has reported the prevalence of gynecological diseases in the Middle Eastern population, suggesting that gynecological morbidity is a public health concern. Due to the health disparities in women, further research is required to understand the relative roles of environmental and genetic factors in the region to serve as a benchmark for evaluation and comparative purposes with other populations.

Effects of adherence to pharmacological secondary prevention after acute myocardial infarction on health care costs - an analysis of real-world data.

BACKGROUND: Acute myocardial infarction (AMI), a major source of morbidity and mortality, is also associated with excess costs. Findings from previous studies were divergent regarding the effect on health care expenditure of adherence to guideline-recommended medication. However, gender-specific medication effectiveness, correlating the effectiveness of concomitant medication and variation in adherence over time, has not yet been considered. METHODS: We aim to measure the effect of adherence on health care expenditures stratified by gender from a third-party payer's perspective in a sample of statutory insured Disease Management Program participants over a follow-up period of 3-years. In 3627 AMI patients, the proportion of days covered (PDC) for four guideline-recommended medications was calculated. A generalized additive mixed model was used, taking into account inter-individual effects (mean PDC rate) and intra-individual effects (deviation from the mean PDC rate). RESULTS: Regarding inter-individual effects, for both sexes only anti-platelet agents had a significant negative influence indicating that higher mean PDC rates lead to higher costs. With respect to intra-individual effects, for females higher deviations from the mean PDC rate for angiotensin-converting enzyme (ACE) inhibitors, anti-platelet agents, and statins were associated with higher costs. Furthermore, for males, an increasing positive deviation from the PDC mean increases costs for ß-blockers and a negative deviation decreases costs. For anti-platelet agents, an increasing deviation from the PDC-mean slightly increases costs. CONCLUSION: Positive and negative deviation from the mean PDC rate, independent of how high the mean was, usually negatively affect health care expenditures. Therefore, continuity in intake of guideline-recommended medication is important to save costs.

Patients with coronary artery disease after acute myocardial infarction: effects of continuous enrollment in a structured Disease Management Program on adherence to guideline-recommended medication, health care expenditures, and survival.

OBJECTIVE: Acute myocardial infarction (AMI) carries increased risk of mortality and excess costs. Disease Management Programs (DMPs) providing guideline-recommended care for chronic diseases seem an intuitively appealing way to enhance health outcomes for patients with chronic conditions such as AMI. The aim of the study is to compare adherence to guideline-recommended medication, health care expenditures and survival of patients enrolled and not enrolled in the German DMP for coronary artery disease (CAD) after an AMI from the perspective of a third-party payer over a follow-up period of 3 years. METHODS: The study is based on routinely collected data from a regional statutory health insurance fund (n = 15,360). A propensity score matching with caliper method was conducted. Afterwards guideline-recommended medication, health care expenditures, and survival between patients enrolled and not enrolled in the DMP were compared with generalized linear and Cox proportional hazard models. RESULTS: The propensity score matching resulted in 3870 pairs of AMI patients previously and continuously enrolled and not enrolled in the DMP. In the 3-year follow-up period the proportion of days covered rates for ACE-inhibitors (60.95% vs. 58.92%), anti-platelet agents (74.20% vs. 70.66%), statins (54.18% vs. 52.13%), and ß-blockers (61.95% vs. 52.64%) were higher in the DMP group. Besides that, DMP participants induced lower health care expenditures per day (€58.24 vs. €72.72) and had a significantly lower risk of death (HR: 0.757). CONCLUSION: Previous and continuous enrollment in the DMP CAD for patients after AMI is a promising strategy as it enhances guideline-recommended medication, reduces health care expenditures and the risk of death.

Telemedicine in the ICU: clinical outcomes, economic aspects, and trainee education.

PURPOSE OF REVIEW: The evidence base for telemedicine in the ICU (tele-ICU) is rapidly expanding. The last 2 years have seen important additions to our understanding of when, where, and how telemedicine in the ICU adds value. RECENT FINDINGS: Recent publications and a recent meta-analysis confirm that tele-ICU improves core clinical outcomes for ICU patients. Recent evidence further demonstrates that comprehensive tele-ICU programs have the potential to quickly recuperate their implementation and operational costs and significantly increase case volumes and direct contribution margins particularly if additional logistics and care standardization functions are embedded to optimize ICU bed utilization and reduce complications. Even though the adoption of tele-ICU is increasing and the vast majority of today's medical graduates will regularly use some form of telemedicine and/or tele-ICU, telemedicine modules have not consistently found their way into educational curricula yet. Tele-ICU can be used very effectively to standardize supervision of medical trainees in bedside procedures or point-of-care ultrasound exams, especially during off-hours. Lastly, tele-ICUs routinely generate rich operational data, as well as risk-adjusted acuity and outcome data across the spectrum of critically ill patients, which can be utilized to support important clinical research and quality improvement projects. SUMMARY: The value of tele-ICU to improve patient outcomes, optimize ICU bed utilization, increase financial performance and enhance educational opportunities for the next generation of providers has become more evident and differentiated in the last 2 years.

A pilot study on patient-related costs and factors associated with the cost of specialist palliative care in the hospital: first steps towards a patient classification system in Germany.

BACKGROUND: Specialist palliative care in the hospital addresses a heterogeneous patient population with complex care needs. In Germany, palliative care patients are classified based on their primary diagnosis to determine reimbursement despite findings that other factors describe patient needs better. To facilitate adequate resource allocation in this setting, in Australia and in the UK important steps have been undertaken towards identifying drivers of palliative care resource use and classifying patients accordingly. We aimed to pioneer patient classification based on determinants of resource use relevant to specialist palliative care in Germany first, by calculating the patient-level cost of specialist palliative care from the hospital's perspective, based on the recorded resource use and, subsequently, by analysing influencing factors. METHODS: Cross-sectional study of consecutive patients who had an episode of specialist palliative care in Munich University Hospital between 20 June and 4 August, 2016. To accurately reflect personnel intensity of specialist palliative care, aside from administrative data, we recorded actual use of all involved health professionals' labour time at patient level. Factors influencing episode costs were assessed using generalized linear regression and LASSO variable selection. RESULTS: The study included 144 patients. Mean costs of specialist palliative care per palliative care unit episode were 6542€ (median: 5789€, SE: 715€) and 823€ (median: 702€, SE: 31€) per consultation episode. Based on multivariate models that considered both variables recorded at beginning and at the end of episode, we identified factors explaining episode cost including phase of illness, Karnofsky performance score, and type of discharge. CONCLUSIONS: This study is an important step towards patient classification in specialist palliative care in Germany as it provides a feasible patient-level costing method and identifies possible starting points for classification. Application to a larger sample will allow for meaningful classification of palliative patients.

Expert opinions on good practice in evaluation of health promotion and primary prevention measures related to children and adolescents in Germany.

BACKGROUND: Determining what constitutes "good practice" in the measurement of the costs and effects of health promotion and disease prevention measures is of particular importance. The aim of this paper was to gather expert knowledge on (economic) evaluations of health promotion and prevention measures for children and adolescents, especially on the practical importance, the determinants of project success, meaningful parameters for evaluations, and supporting factors, but also on problems in their implementation. This information is targeted at people responsible for the development of primary prevention or health promotion programs. METHODS: Partially structured open interviews were conducted by two interviewers and transcribed, paraphrased, and summarized for further use. Eight experts took part in the interviews. RESULTS: The interviewed experts saw evaluation as a useful tool to establish the effects of prevention programs, to inform program improvement and further development, and to provide arguments to decision making. The respondents' thought that determinants of a program's success were effectiveness with evidence of causality, cost benefit relation, target-group reach and sustainability. It was considered important that hard and soft factors were included in an evaluation; costs were mentioned only by one expert. According to the experts, obstacles to evaluation were lacking resources, additional labor requirements, and the evaluators' unfamiliarity with a program's contents. It was recommended to consider evaluation design before a program is launched, to co-operate with people involved in a program and to make use of existing structures. CONCLUSION: While in in this study only a partial view of expert knowledge is represented, it could show important points to consider when developing evaluations of prevention programs. By considering these points, researchers could further advance towards a more comprehensive approach of evaluation targeting measures in children and adolescents.

Manual Compression versus Vascular Closing Device for Closing Access Puncture Site in Femoral Left-Heart Catheterization and Percutaneous Coronary Interventions: A Retrospective Cross-Sectional Comparison of Costs and Effects in Inpatient Care.

OBJECTIVES: To compare complication rates, length of hospital stay, and resulting costs between the use of manual compression and a vascular closing device (VCD) in both diagnostic and interventional catheterization in a German university hospital setting. METHODS: A stratified analysis according to risk profiles was used to compare the risk of complications in a retrospective cross-sectional single-center study. Differences in costs and length of hospital stay were calculated using the recycled predictions method, based on regression coefficients from generalized linear models with gamma distribution. All models were adjusted for propensity score and possible confounders, such as age, sex, and comorbidities. The analysis was performed separately for diagnostic and interventional catheterization. RESULTS: The unadjusted relative risk (RR) of complications was not significantly different in diagnostic catheterization when a VCD was used (RR = 0.70; 95% confidence interval [CI] 0.22-2.16) but significantly lower in interventional catheterization (RR = 0.44; 95% CI 0.21-0.93). Costs were on average €275 lower in the diagnostic group (95% CI -€478.0 to -€64.9; P = 0.006) and around €373 lower in the interventional group (95% CI -€630.0 to -€104.2; P = 0.014) when a VCD was used. The adjusted estimated average length of stay did not differ significantly between the use of a VCD and manual compression in both types of catheterization. CONCLUSIONS: In interventional catheterization, VCDs significantly reduced unadjusted complication rates, as well as costs. A significant reduction in costs also supports their usage in diagnostic catheterization on a larger scale.

Atomic-Level Quality Assessment of Enzymes Encapsulated in Bioinspired Silica.

Among protein immobilization strategies, encapsulation in bioinspired silica is increasingly popular. Encapsulation offers high yields and the solid support is created through a protein-catalyzed polycondensation reaction that occurs under mild conditions. An integrated strategy is reported for the characterization of both the protein and bioinspired silica scaffold generated by the encapsulation of enzymes with an external silica-forming promoter or with the promoter expressed as a fusion to the enzyme. This strategy is applied to the catalytic domain of matrix metalloproteinase 12. Analysis reveals that the structure of the protein encapsulated by either method is not significantly altered with respect to the native form. The structural features of silica obtained by either strategy are also similar, but differ from those obtained by other approaches. In case of the covalently linked R5-enzyme construct, immobilization yields are higher. Encapsulation through a fusion protein, therefore, appears to be the method of choice.

The excess health care costs of KardioPro, an integrated care program for coronary heart disease prevention.

Coronary heart disease (CHD) is a major cause of death and important driver of health care costs. Recent German health care reforms have promoted integrated care contracts allowing statutory health insurance providers more room to organize health care provision. One provider offers KardioPro, an integrated primary care-based CHD prevention program. As insurance providers should be aware of the financial consequences when developing optional programs, this study aims to analyze the costs associated with KardioPro participation. 13,264 KardioPro participants were compared with a propensity score-matched control group. Post-enrollment health care costs were calculated based on routine data over a follow-up period of up to 4 years. For those people who incurred costs, KardioPro participation was significantly associated with increased physician costs (by 33%), reduced hospital costs (by 19%), and reduced pharmaceutical costs (by 16%). Overall costs were increased by 4%, but this was not significant. Total excess costs per observation year were €131 per person (95% confidence interval: [€-36.5; €296]). Overall, KardioPro likely affected treatment as the program increased costs of physician services and reduced costs of hospital services. Further effects of substituting potential inpatient care with increased outpatient care might become fully apparent only over a longer time horizon.

The effectiveness of the cardiovascular disease prevention programme 'KardioPro' initiated by a German sickness fund: a time-to-event analysis of routine data.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in the developed world. To reduce this burden of disease, a German sickness fund ('Siemens-Betriebskrankenkasse', SBK) initiated the prevention programme 'KardioPro' including primary (risk factor reduction) and secondary (screening) prevention and guideline-based treatment. The aim of this study was to assess the effectiveness of 'KardioPro' as it is implemented in the real world. METHODS: The study is based on sickness fund routine data. The control group was selected from non-participants via propensity score matching. Study analysis was based on time-to-event analysis via Cox proportional hazards regression with the endpoint 'all-cause mortality, acute myocardial infarction (MI) and ischemic stroke (1)', 'all-cause mortality (2)' and 'non-fatal acute MI and ischemic stroke (3)'. RESULTS: A total of 26,202 insurants were included, 13,101 participants and 13,101 control subjects. 'KardioPro' enrollment was associated with risk reductions of 23.5% (95% confidence interval (CI) 13.0-32.7%) (1), 41.7% (95% CI 30.2-51.2%) (2) and 3.5% (hazard ratio 0.965, 95% CI 0.811-1.148) (3). This corresponds to an absolute risk reduction of 0.29% (1), 0.31% (2) and 0.03% (3) per year. CONCLUSION: The prevention programme initiated by a German statutory sickness fund appears to be effective with regard to all-cause mortality. The non-significant reduction in non-fatal events might result from a shift from fatal to non-fatal events.

Cost-of-illness studies of atrial fibrillation: methodological considerations.

Atrial fibrillation (AF) is the most common heart rhythm arrhythmia, which has considerable economic consequences. This study aims to identify the current cost-of-illness estimates of AF; a focus was put on describing the studies' methodology. A literature review was conducted. Twenty-eight cost-of-illness studies were identified. Cost-of-illness estimates exist for health insurance members, hospital and primary care populations. In addition, the cost of stroke in AF patients and the costs of post-operative AF were calculated. The methods used were heterogeneous, mostly studies calculated excess costs. The identified annual excess costs varied, even among studies from the USA (∼US$1900 to ∼US$19,000). While pointing toward considerable costs, the cost-of-illness studies' relevance could be improved by focusing on subpopulations and treatment mixes. As possible starting points for subsequent economic studies, the methodology of cost-of-illness studies should be taken into account using methods, allowing stakeholders to find suitable studies and validate estimates.

Should health insurers target prevention of cardiovascular disease? A cost-effectiveness analysis of an individualised programme in Germany based on routine data.

BACKGROUND: Cardiovascular diseases are the main cause of death worldwide, making their prevention a major health care challenge. In 2006, a German statutory health insurance company presented a novel individualised prevention programme (KardioPro), which focused on coronary heart disease (CHD) screening, risk factor assessment, early detection and secondary prevention. This study evaluates KardioPro in CHD risk subgroups, and analyses the cost-effectiveness of different individualised prevention strategies. METHODS: The CHD risk subgroups were assembled based on routine data from the statutory health insurance company, making use of a quasi-beta regression model for risk prediction. The control group was selected via propensity score matching based on logistic regression and an approximate nearest neighbour approach. The main outcome was cost-effectiveness. Effectiveness was measured as event-free time, and events were defined as myocardial infarction, stroke and death. Incremental cost-effectiveness ratios comparing participants with non-participants were calculated for each subgroup. To assess the uncertainty of results, a bootstrapping approach was applied. RESULTS: The cost-effectiveness of KardioPro in the group at high risk of CHD was € 20,901 per event-free year; in the medium-risk group, € 52,323 per event-free year; in the low-risk group, € 186,074 per event-free year; and in the group with known CHD, € 26,456 per event-free year. KardioPro was associated with a significant health gain but also a significant cost increase. However, statistical significance could not be shown for all subgroups. CONCLUSION: The cost-effectiveness of KardioPro differs substantially according to the group being targeted. Depending on the willingness-to-pay, it may be reasonable to only offer KardioPro to patients at high risk of further cardiovascular events. This high-risk group could be identified from routine statutory health insurance data. However, the long-term consequences of KardioPro still need to be evaluated.

The quality of three decision-analytic diabetes models: a systematic health economic assessment.

AIMS: Diabetes mellitus has important economic impacts worldwide. Interventions to prevent diabetes-related complications are often analyzed using model-based cost-effectiveness analyses. As model results are usually influenced by structural assumptions and by the data used, decision-makers should be able to assess the quality of diabetes models. The aim of this study was to assess the quality of selected diabetes models and to determine if modeling recommendations by the American Diabetes Association are considered. METHODS: The quality of three selected diabetes models (Archimedes Model, CDC Model and Center for Outcomes Research [CORE] Diabetes Model) was assessed using systematic methods. RESULTS: This systematic approach to assess model quality proved to be feasible and highlighted two areas for improvement: the rationale for model structure and methods to identify parameter values, which should be presented more transparently. CONCLUSIONS: Overall, the need for a quality assessment of diabetes models is emphasized.