Long-term benefits and harms of early colorectal cancer screening in German individuals with familial cancer risk.

Individuals with a family history of colorectal cancer (CRC) may benefit from early screening with colonoscopy or immunologic fecal occult blood testing (iFOBT). We systematically evaluated the benefit-harm trade-offs of various screening strategies differing by screening test (colonoscopy or iFOBT), interval (iFOBT: annual/biennial; colonoscopy: 10-yearly) and age at start (30, 35, 40, 45, 50 and 55 years) and end of screening (65, 70 and 75 years) offered to individuals identified with familial CRC risk in Germany. A Markov-state-transition model was developed and used to estimate health benefits (CRC-related deaths avoided, life-years gained [LYG]), potential harms (eg, associated with additional colonoscopies) and incremental harm-benefit ratios (IHBR) for each strategy. Both benefits and harms increased with earlier start and shorter intervals of screening. When screening started before age 50, 32-36 CRC-related deaths per 1000 persons were avoided with colonoscopy and 29-34 with iFOBT screening, compared to 29-31 (colonoscopy) and 28-30 (iFOBT) CRC-related deaths per 1000 persons when starting age 50 or older, respectively. For iFOBT screening, the IHBRs expressed as additional colonoscopies per LYG were one (biennial, age 45-65 vs no screening), four (biennial, age 35-65), six (biennial, age 30-70) and 34 (annual, age 30-54; biennial, age 55-75). Corresponding IHBRs for 10-yearly colonoscopy were four (age 55-65), 10 (age 45-65), 15 (age 35-65) and 29 (age 30-70). Offering screening with colonoscopy or iFOBT to individuals with familial CRC risk before age 50 is expected to be beneficial. Depending on the accepted IHBR threshold, 10-yearly colonoscopy or alternatively biennial iFOBT from age 30 to 70 should be recommended for this target group.

Comparative Analysis of Instrumental Variables on the Assignment of Buprenorphine/Naloxone or Methadone for the Treatment of Opioid Use Disorder.

BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.

Acceptability of Using Real-World Data to Estimate Relative Treatment Effects in Health Technology Assessments: Barriers and Future Steps.

OBJECTIVES: Evidence about the comparative effects of new treatments is typically collected in randomized controlled trials (RCTs). In some instances, RCTs are not possible, or their value is limited by an inability to capture treatment effects over the longer term or in all relevant population subgroups. In these cases, nonrandomized studies (NRS) using real-world data (RWD) are increasingly used to complement trial evidence on treatment effects for health technology assessment (HTA). However, there have been concerns over a lack of acceptability of this evidence by HTA agencies. This article aims to identify the barriers to the acceptance of NRS and steps that may facilitate increases in the acceptability of NRS in the future. METHODS: Opinions of the authorship team based on their experience in real-world evidence research in academic, HTA, and industry settings, supported by a critical assessment of existing studies. RESULTS: Barriers were identified that are applicable to key stakeholder groups, including HTA agencies (eg, the lack of comprehensive methodological guidelines for using RWD), evidence generators (eg, avoidable deviations from best practices), and external stakeholders (eg, data controllers providing timely access to high-quality RWD). Future steps that may facilitate future acceptability of NRS include improvements in the quality, integration, and accessibility of RWD, wider use of demonstration projects to highlight the value and applicability of nonrandomized designs, living, and more detailed HTA guidelines, and improvements in HTA infrastructure relating to RWD. CONCLUSION: NRS can represent a crucial source of evidence on treatment effects for use in HTA when RCT evidence is limited.

Nature-based social interventions to address loneliness among vulnerable populations: a common study protocol for three related randomized controlled trials in Barcelona, Helsinki, and Prague within the RECETAS European project.

BACKGROUND: The negative effects of loneliness on population health and wellbeing requires interventions that transcend the medical system and leverage social, cultural, and public health system resources. Group-based social interventions are a potential method to alleviate loneliness. Moreover, nature, as part of our social and health infrastructure, may be an important part of the solutions that are needed to address loneliness. The RECETAS European project H2020 (Re-imagining Environments for Connection and Engagement: Testing Actions for Social Prescribing in Natural Spaces) is an international research project aiming to develop and test the effectiveness of nature-based social interventions to reduce loneliness and increase health-related quality of life. METHODS: This article describes the three related randomized controlled trials (RCTs) that will be implemented: the RECETAS-BCN Trial in Barcelona (Spain) is targeting people 18+ from low socio-economic urban areas; the RECETAS-PRG Trial in Prague (Czech Republic) is addressing community-dwelling older adults over 60 years of age, and the RECETAS-HLSNK trial is reaching older people in assisted living facilities. Each trial will recruit 316 adults suffering from loneliness at least sometimes and randomize them to nature-based social interventions called "Friends in Nature" or to the control group. "Friends in Nature" uses modifications of the "Circle of Friends" methodology based on group processes of peer support and empowerment but including activities in nature. Participants will be assessed at baseline, at post-intervention (3 months), and at 6- and 12-month follow-up after baseline. Primary outcomes are the health-related quality-of-life according to 15D measure and The De Jong Gierveld 11-item loneliness scale. Secondary outcomes are health and psychosocial variables tailored to the specific target population. Nature exposure will be collected throughout the intervention period. Process evaluation will explore context, implementation, and mechanism of impact. Additionally, health economic evaluations will be performed. DISCUSSION: The three RECETAS trials will explore the effectiveness of nature-based social interventions among lonely people from various ages, social, economic, and cultural backgrounds. RECETAS meets the growing need of solid evidence for programs addressing loneliness by harnessing the beneficial impact of nature on enhancing wellbeing and social connections. TRIAL REGISTRATION: Barcelona (Spain) trial: ClinicalTrials.gov, ID: NCT05488496. Registered 29 July 2022. Prague (Czech Republic) trial: ClinicalTrials.gov, ID: NCT05522140. Registered August 25, 2022. Helsinki (Finland) trial: ClinicalTrials.gov, ID: NCT05507684. Registered August 12, 2022.

Intracranial arteriosclerosis and the risk of dementia: A population-based cohort study.

BACKGROUND: The impact of intracranial arteriosclerosis on dementia remains largely unclear. METHODS: In 2339 stroke-free and dementia-free participants (52.2% women, mean age 69.5 years) from the general population, we assessed intracranial carotid artery calcification (ICAC) and vertebrobasilar artery calcification (VBAC) as proxy for arteriosclerosis. Associations with dementia were assessed using Cox models. In addition, indirect effects through cerebral small vessel disease (cSVD) and subcortical brain structure volumes were assessed using causal mediation analyses. RESULTS: During a median of 13.4 years (25th-75th percentiles 9.9-14.5) of follow-up, 282 participants developed dementia. Both ICAC presence (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: 1.00-2.32]) and volume (HR per standard deviation: 1.19, 95% CI: 1.01-1.40) increased dementia risk. For VBAC, severe calcifications increased dementia risk (HR for third vs first volume tertile: 1.89, 95% CI: 1.00-3.59). These effects were mediated partly through increased cSVD (percentage mediated for ICAC: 13% and VBAC: 24%). DISCUSSION: Intracranial arteriosclerosis increases the risk of dementia.

Prevalence of Mycoplasma genitalium infection among HIV PrEP users: a systematic review and meta-analysis.

OBJECTIVES: To summarise the prevalence of Mycoplasma genitalium (MG) and antibiotic-resistant MG infection among HIV pre-exposure prophylaxis (PrEP) users. METHODS: We searched MEDLINE, Embase, Web of Science and Global Index Medicus up to 30 September 2022. We included studies reporting the prevalence of MG and/or antibiotic-resistant MG infection among PrEP users. Two reviewers independently searched for studies and extracted data. A systematic review with random-effects meta-analysis was performed to quantitatively summarise the results of included studies. The critical appraisal of included studies was conducted with the Joanna Briggs Institute checklist for prevalence studies and the quality of evidence was assessed with Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: A total of 15 studies were included in the systematic review, with 2341 individuals taking PrEP. Studies were conducted in high-income level countries between 2014 and 2019. Median age of participants varied from 23.5 to 40 years. The majority were men (85%) and among them, 93% were men who have sex with men. To identify MG, urine samples were analysed in 14 studies, rectal or anal swabs in 12 studies, oral or pharyngeal swabs in 9 studies, and urethral or vaginal in 3 studies. The pooled point prevalence of MG among PrEP users was 16.7% (95% CI 13.6% to 20.3%; 95% prediction interval (95% PI) 8.2% to 31.1%). The pooled point prevalence of macrolide-resistant infections was 82.6% (95% CI 70.1% to 90.6%; 95% PI 4.7% to 99.8%) and the prevalence of fluoroquinolone-resistant infections was 14.3% (95% CI 1.8% to 42.8%). Individuals taking PrEP have a higher chance of being infected with MG compared with those not taking PrEP (OR 2.30; 95% CI 1.6 to 3.4). The quality of evidence was very low to moderate. CONCLUSION: We observed a high prevalence of MG and its macrolide resistance among PrEP users, highlighting the need to reinforce prevention strategies against sexually transmitted infections in this population. PROSPERO REGISTRATION NUMBER: CRD42022310597.

Decision-analytic evaluation of the comparative effectiveness and cost-effectiveness of strategies to prevent breast and ovarian cancer in German women with BRCA-1/2 mutations.

BACKGROUND: Women with inherited mutations in the BRCA1 or BRCA2 genes have increased lifetime risks for developing breast and/or ovarian cancer and may develop these cancers around the age of 30 years. Therefore, prevention of breast and ovarian cancer in these women may need to start relatively early in life. In this study we systematically evaluate the long-term effectiveness and cost effectiveness of different prevention strategies for breast and ovarian cancer in women with BRCA-1/2 mutation in Germany. METHODS: A decision-analytic Markov model simulating lifetime breast and ovarian cancer development in BRCA-1/2 carriers was developed. Different strategies including intensified surveillance (IS), prophylactic bilateral mastectomy (PBM), and prophylactic bilateral salpingo-oophorectomy (PBSO) alone or in combination at different ages were evaluated. German clinical, epidemiological, and economic (in 2022 Euro) data were used. Outcomes included cancer incidences, mortality, life years (LYs), quality-adjusted life years (QALYs), and discounted incremental cost-effectiveness ratios (ICER). We adopted the German health-care system perspective and discounted costs and health effects with 3% annually. RESULTS: All intervention strategies are more effective and less costly than IS alone. Prevention with PBM plus PBSO at age 30 maximizes life expectancy with 6.3 LYs gained, whereas PBM at age 30 with delayed PBSO at age 35 improves quality of life with 11.1 QALYs gained, when compared to IS alone. A further delay of PBSO was associated with lower effectiveness. Both strategies are cost effective with ICERs significantly below 10,000 EUR/LYG or QALY. CONCLUSION: Based on our results, PBM at age 30 plus PBSO between age 30 and 40 prolongs life and is cost effective in women with BRCA-1/2 mutations in Germany. Serial preventive surgeries with delayed PBSO potentially improve quality of life for women. However, delaying PBM and/or PBSO further may lead to increased mortality and reduced QALYs.

Guidance on the use of complex systems models for economic evaluations of public health interventions.

To help health economic modelers respond to demands for greater use of complex systems models in public health. To propose identifiable features of such models and support researchers to plan public health modeling projects using these models. A working group of experts in complex systems modeling and economic evaluation was brought together to develop and jointly write guidance for the use of complex systems models for health economic analysis. The content of workshops was informed by a scoping review. A public health complex systems model for economic evaluation is defined as a quantitative, dynamic, non-linear model that incorporates feedback and interactions among model elements, in order to capture emergent outcomes and estimate health, economic and potentially other consequences to inform public policies. The guidance covers: when complex systems modeling is needed; principles for designing a complex systems model; and how to choose an appropriate modeling technique. This paper provides a definition to identify and characterize complex systems models for economic evaluations and proposes guidance on key aspects of the process for health economics analysis. This document will support the development of complex systems models, with impact on public health systems policy and decision making.

[Testicular Cancer Screening in Men Aged 16 Years and Older: IQWiG ThemenCheck Health Technology Assessment Report on Medical, Economic, Social, Ethical, Legal and Organisational Aspects]. / Hodenkrebsscreening bei Männern ab 16 Jahren: IQWiG ThemenCheck Health Technology Assessment-Bericht zu medizinischen, ökonomischen, sozialen, ethischen, rechtlichen und organisatorischen Aspekten.

BACKGROUND: Testicular cancer occurs mainly in young men between 25 and 45 years and is the most common cancer at this age. Possible testicular cancer early detection measures, clinical palpation and scrotal ultrasound (CUS) or testicular self-examination (TSE) in asymptomatic men aged 16 years and older, could perhaps avoid deaths and aggressive late therapies. Therefore, we investigated whether these measures have an additional benefit compared to the current situation. Ethical, legal, social and organisational aspects were considered as well. METHODS: The methodology of this review follows IQWiG's "Allgemeine[n] Methoden Version 5.0". In addition, to estimate the theoretically possible benefits and potential harms of screening, a supplementary presentation was used for the benefit assessment based on published data from tumour registries and data on predictive values from diagnostic studies. RESULTS: No intervention studies were identified, therefore evidence-based statements on additional benefit or harm of the studied interventions could not be made. The epidemiological data showed that per 100,000 men participating in screening annually, a maximum of 1.2 advanced tumours and 0.4 deaths would have been preventable. Harm calculations suggest that with CUS of 100,000 men, 1 to 22 unnecessary testicular exposures or removals might be expected, with TSE it would be 2 cases. However, these data on the possible harm of screening are subject to great uncertainty. CONCLUSIONS: There are no intervention studies demonstrating that the benefit of testicular cancer screening in men aged 16 years and older outweighs the harm. The maximum possible additional benefit is low and chances of detection and cure are good even without screening. At present, testicular cancer screening cannot be recommended.

Cost-effectiveness analysis of superabsorbent wound dressings in patients with moderate-to-highly exuding leg ulcers in Germany.

The study aims to estimate the cost-effectiveness of superabsorbent wound dressings compared to the standard-of-care (SoC) dressings mix for treatment of patients with moderate-to-highly exuding leg ulcers in the German healthcare settings. A model-based cost-effectiveness analysis was conducted from the German statutory health insurance perspective, following German specific and international recommendations of good research practice. An individual-level (microsimulation) state-transition model has been used with a cycle length of 1 week and time horizon of 6 months. Several comprehensive systematic reviews were conducted to inform all model inputs, including clinical parameters, efficacy, quality of life, resources utilisation, and cost inputs. In addition, primary data from two clinical trials were used. Based on this cost-effectiveness analysis, using superabsorbent wound dressings instead of the SoC dressings of patients with moderate-to-highly exuding leg ulcers in Germany can lead to an improved healing rate of 2.57% (benefit ratio 1.08), improved health-related quality of life of 0.152 quality-adjusted life weeks, and total direct cost savings of €771 per patient in 6 months. Robustness of results was confirmed in sensitivity and scenario analyses.

International Validation of Reduced Major Morbidity After Minimally Invasive Distal Pancreatectomy Compared With Open Pancreatectomy.

OBJECTIVE: To quantify the nationwide impact of minimally invasive distal pancreatectomy (MIDP) on major morbidity as compared with open distal pancreatectomy (ODP). BACKGROUND: A recent randomized controlled trial (RCT) demonstrated significant reduction in time to functional recovery after MIDP compared with ODP, but was not powered to assess potential risk reductions in major morbidity. METHODS: International cohort study using the American College of Surgeons' National Quality Improvement Program (ACS-NSQIP) (88 centers; 2014-2016) to evaluate the association between surgical approach (MIDP vs ODP) and 30-day composite major morbidity (CMM; death or severe complications) with external model validation using Dutch Pancreatic Cancer Group data (17 centers; 2005-2016). Multivariable logistic regression assessed the impact of nationwide MIDP rates between 0% and 100% on postoperative CMM at conversion rates between 0% and 25%, using estimated marginal effects. A sensitivity analysis tested the impact at various scenarios and patient populations. RESULTS: Of 2921 ACS-NSQIP patients, 1562 (53%) underwent MIDP with 18% conversion, and 1359 (47%) underwent ODP. MIDP was independently associated with reduced CMM [odds ratio (OR) 0.50, 95% confidence interval (CI) 0.42-0.60, P < 0.001], confirmed by external model validation (n = 637, P < 0.003). The association between rising MIDP implementation rates and falling postoperative morbidity was linear between 0% (all ODP) and 100% (all MIDP). The absolute risk reduction for CMM was 11% (95% CI 7.3%-15%) at observed conversion rates and improved to 14% (95% CI 11%-18%) as conversion approached 0%. Similar effects were seen across subgroups. CONCLUSION: This international study predicted a nationwide 11% risk reduction for CMM after MIDP versus ODP, which is likely to improve as conversion rates decrease. These findings confirm secondary outcomes of the recent LEOPARD RCT.

The anemia-independent impact of myelodysplastic syndromes on health-related quality of life.

Myelodysplastic syndromes (MDS) are in the majority of cases characterized by anemia. Both anemia and MDS per se may directly contribute to impairments in health-related quality of life (HRQoL). In this study, we aimed to investigate the anemia-independent impact of MDS on HRQoL. We evaluated participants (≥ 50 years) from the large population-based Lifelines cohort (N = 44,694, mean age 59.0 ± 7.4 years, 43.6% male) and the European MDS Registry (EUMDS) (N = 1538, mean age 73.4 ± 9.0 years, 63.0% male), which comprises a cohort of lower-risk MDS patients. To enable comparison concerning HRQoL, SF-36 scores measured in Lifelines were converted to EQ-5D-3L index (range 0-1) and dimension scores. Lower-risk MDS patients had significantly lower HRQoL than those from the Lifelines cohort, as illustrated in both the index score and in the five different dimensions. Multivariable linear regression analysis demonstrated that MDS had an adjusted total impact on the EQ-5D index score (B = - 0.12, p < 0.001) and an anemia-independent "direct" impact (B = - 0.10, p < 0.001). Multivariable logistic regression analysis revealed an anemia-independent impact of MDS in the dimension mobility, self-care, usual activities, and anxiety/depression (all except pain/discomfort). This study demonstrates that the major part of the negative impact of lower-risk MDS on HRQoL is not mediated via anemia. Thus, the therapeutic focus should include treatment strategies directed at underlying pathogenic mechanisms to improve HRQoL, rather than aiming predominantly at increasing hemoglobin levels.

Adult patient access to electronic health records.

BACKGROUND: To support patient-centred care, healthcare organisations increasingly offer patients access to data stored in the institutional electronic health record (EHR). OBJECTIVES: Primary objective 1. To assess the effects of providing adult patients with access to electronic health records (EHRs) alone or with additional functionalities on a range of patient, patient-provider, and health resource consumption outcomes, including patient knowledge and understanding, patient empowerment, patient adherence, patient satisfaction with care, adverse events, health-related quality of life, health-related outcomes, psychosocial health outcomes, health resource consumption, and patient-provider communication. Secondary objective 1. To assess whether effects of providing adult patients with EHR access alone versus EHR access with additional functionalities differ among patient groups according to age, educational level, or different status of disease (chronic or acute). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and Scopus in June 2017 and in April 2020. SELECTION CRITERIA: Randomised controlled trials and cluster-randomised trials of EHR access with or without additional functionalities for adults with any medical condition. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. MAIN RESULTS: We included 10 studies with 78 to 4500 participants and follow-up from 3 to 24 months. Nine studies assessed the effects of EHR with additional functionalities, each addressing a subset of outcomes sought by this review. Five studies focused on patients with diabetes mellitus, four on patients with specific diseases, and one on all patients. All studies compared EHR access alone or with additional functionalities plus usual care versus usual care only. No studies assessing the effects of EHR access alone versus EHR access with additional functionalities were identified. Interventions required a variety of data within the EHR, such as patient history, problem list, medication, allergies, and lab results. In addition to EHR access, eight studies allowed patients to share self-documented data, seven offered individualised disease management functions, seven offered educational disease-related information, six supported secure communication, and one offered preventive reminders. Only two studies were at low or unclear risk of bias across domains. Meta-analysis could not be performed, as participants, interventions, and outcomes were too heterogeneous, and most studies presented results based on different adjustment methods or variables. The quality of evidence was rated as low or very low across outcomes. Overall differences between intervention and control groups, if any, were small. The relevance of any small effects remains unclear for most outcomes because in most cases, trial authors did not define a minimal clinically important difference. Overall, results suggest that the effects of EHR access alone and with additional functionalities are mostly uncertain when compared with usual care. Patient knowledge and understanding: very low-quality evidence is available from one study, so we are uncertain about effects of the intervention on patient knowledge about diabetes and blood glucose testing. Patient empowerment: low-quality evidence from three studies suggests that the intervention may have little or no effect on patient empowerment measures. Patient adherence: low-quality evidence from two studies suggests that the intervention may slightly improve adherence to the process of monitoring risk factors and preventive services. Effects on medication adherence are conflicting in two studies; this may or may not improve to a clinically relevant degree. Patient satisfaction with care: low-quality evidence from three studies suggests that the intervention may have little or no effect on patient satisfaction, with conflicting results. Adverse events: two small studies reported on mortality; one of these also reported on serious and other adverse events, but sample sizes were too small for small differences to be detected. Therefore, low-quality evidence suggests that the intervention may have little to no effect on mortality and other adverse events. Health-related quality of life: only very low-quality evidence from one study is available. We are uncertain whether the intervention improves disease-specific quality of life of patients with asthma. Health-related outcomes: low-quality evidence from eight studies suggests that the intervention may have little to no effect on asthma control, glycosylated haemoglobin (HbA1c) levels, blood pressure, low-density lipoprotein or total cholesterol levels, body mass index or weight, or 10-year Framingham risk scores. Low-quality evidence from one study suggests that the composite scores of risk factors for diabetes mellitus may improve slightly with the intervention, but there is uncertainty about effects on ophthalmic medications or intraocular pressure. Psychosocial health outcomes: no study investigated psychosocial health outcomes in a more than anecdotal way. Health resource consumption: low-quality evidence for adult patients in three studies suggests that there may be little to no effect of the intervention on different measures of healthcare use. Patient-provider communication: very low-quality evidence is available from a single small study, and we are uncertain whether the intervention improves communication measures, such as the number of messages sent. AUTHORS' CONCLUSIONS: The effects of EHR access with additional functionalities in comparison with usual care for the most part are uncertain. Only adherence to the process of monitoring risk factors and providing preventive services as well as a composite score of risk factors for diabetes mellitus may improve slightly with EHR access with additional functionalities. Due to inconsistent terminology in this area, our search may have missed relevant studies. As the overall quality of evidence is very low to low, future research is likely to change these results. Further trials should investigate the impact of EHR access in a broader range of countries and clinical settings, including more patients over a longer period of follow-up, as this may increase the likelihood of detecting effects of the intervention, should these exist. More studies should focus on assessing outcomes such as patient empowerment and behavioural outcomes, rather than concentrating on health-related outcomes alone. Future studies should distinguish between effects of EHR access only and effects of additional functionalities, and investigate the impact of mobile EHR tools. Future studies should include information on usage patterns, and consider the potential for widening health inequalities with implementation of EHR access. A taxonomy for EHR access and additional functionalities should be developed to promote consistency and comparability of outcome measures, and facilitate future reviews by better enabling cross-study comparisons.

A systematic review of ethical and legal issues in elder care.

BACKGROUND: Ethical and legal issues are increasingly being reported by health caregivers; however, little is known about the nature of these issues in geriatric care. These issues can improve work and care conditions in healthcare, and consequently, the health and welfare of older people. AIM: This literature review aims to identify research focusing on ethical and legal issues in geriatric care, in order to give nurses and other health care workers an overview of existing grievances and possible solutions to take care of old patients in a both ethical and legally correct way. METHODS: Using a systematic approach based on Aveyard, a search of the PubMed, CINAHL, and Ethicshare databases was conducted to find out the articles published on ethical and legal issues in geriatric care. ETHICAL CONSIDERATIONS: The approval for the study was obtained from UMIT-The Health and Life Sciences University, Austria. RESULTS: Only 50 articles were included for systematic analysis reporting ethical and legal issues in the geriatric care. The results presented in this article showed that the main ethical issues were related to the older people's autonomy, respect for their needs, wishes and values, and respect for their decision-making. The main legal issues were related to patients' rights, advance directives, elderly rights, treatment nutrition dilemma, and autonomy. CONCLUSION: Further education for professional caregivers, elderly people, and their families is needed on following topics: care planning, directive and living wills, and caregiver-family member relationships to guide and support the elderly people within their decision-making processes and during the end-of-life care.

Reducing overtreatment associated with overdiagnosis in cervical cancer screening-A model-based benefit-harm analysis for Austria.

A general concern exists that cervical cancer screening using human papillomavirus (HPV) testing may lead to considerable overtreatment. We evaluated the trade-off between benefits and overtreatment among different screening strategies differing by primary tests (cytology, p16/Ki-67, HPV alone or in combinations), interval, age and diagnostic follow-up algorithms. A Markov state-transition model calibrated to the Austrian epidemiological context was used to predict cervical cancer cases, deaths, overtreatments and incremental harm-benefit ratios (IHBR) for each strategy. When considering the same screening interval, HPV-based screening strategies were more effective compared to cytology or p16/Ki-67 testing (e.g., relative reduction in cervical cancer with biennial screening: 67.7% for HPV + Pap cotesting, 57.3% for cytology and 65.5% for p16/Ki-67), but were associated with increased overtreatment (e.g., 19.8% more conizations with biennial HPV + Papcotesting vs. biennial cytology). The IHBRs measured in unnecessary conizations per additional prevented cancer-related death were 31 (quinquennial Pap + p16/Ki-67-triage), 49 (triennial Pap + p16/Ki-67-triage), 58 (triennial HPV + Pap cotesting), 66 (biennial HPV + Pap cotesting), 189 (annual Pap + p16/Ki-67-triage) and 401 (annual p16/Ki-67 testing alone). The IHBRs increased significantly with increasing screening adherence rates and slightly with lower age at screening initiation, with a reduction in HPV incidence or with lower Pap-test sensitivity. Depending on the accepted IHBR threshold, biennial or triennial HPV-based screening in women as of age 30 and biennial cytology in younger women may be considered in opportunistic screening settings with low or moderate adherence such as in Austria. In organized settings with high screening adherence and in postvaccination settings with lower HPV prevalence, the interval may be prolonged.

Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma.

BACKGROUND: In the Phase 3 REFLECT trial in patients with unresectable hepatocellular carcinoma (uHCC), the multitargeted tyrosine kinase inhibitor, lenvatinib, was noninferior to sorafenib in the primary outcome of overall survival. Post-hoc review revealed imbalances in prognostic variables between treatment arms. Here, we re-analyse overall survival data from REFLECT to adjust for the imbalance in covariates. METHODS: Univariable and multivariable adjustments were undertaken for a candidate set of covariate values that a physician panel indicated could be prognostically associated with overall survival in uHCC. The values included baseline variables observed pre- and post-randomisation. Univariable analyses were based on a stratified Cox model. The multivariable analysis used a "forwards stepwise" Cox model. RESULTS: Univariable analysis identified alpha-fetoprotein (AFP) as the most influential variable. The chosen multivariable Cox model analysis resulted in an estimated adjusted hazard ratio for lenvatinib of 0.814 (95% CI: 0.699-0.948) when only baseline variables were included. Adjusting for post-randomisation treatment variables further increased the estimated superiority of lenvatinib. CONCLUSIONS: Covariate adjustment of REFLECT suggests that the original noninferiority trial likely underestimated the true effect of lenvatinib on overall survival due to an imbalance in baseline prognostic covariates and the greater use of post-treatment therapies in the sorafenib arm. TRIAL REGISTRATION: Trial number: NCT01761266 (Submitted January 2, 2013).

Development of a core outcome set for myelodysplastic syndromes - a Delphi study from the EUMDS Registry Group.

Treatment options for myelodysplastic syndromes (MDS) vary widely, depending on the natural disease course and patient-related factors. Comparison of treatment effectiveness is challenging as different endpoints have been included in clinical trials and outcome reporting. Our goal was to develop the first MDS core outcome set (MDS-COS) defining a minimum set of outcomes that should be reported in future clinical studies. We performed a comprehensive systematic literature review among MDS studies to extract patient- and/or clinically relevant outcomes. Clinical experts from the European LeukemiaNet MDS (EUMDS) identified 26 potential MDS core outcomes and participated in a three-round Delphi survey. After the first survey (56 experts), 15 outcomes met the inclusion criteria and one additional outcome was included. The second round (38 experts) resulted in six included outcomes. In the third round, a final check on plausibility and practicality of the six included outcomes and their definitions was performed. The final MDS-COS includes: health-related quality of life, treatment-related mortality, overall survival, performance status, safety, and haematological improvement. This newly developed MDS-COS represents the first minimum set of outcomes aiming to enhance comparability across future MDS studies and facilitate a better understanding of treatment effectiveness.

Status epilepticus admissions during the COVID-19 pandemic in Salzburg-A population-based study.

Several emergencies were admitted less frequently to the hospital during the coronavirus disease 2019 (COVID-19) pandemic. To investigate whether this also occurred with status epilepticus (SE) we compared admissions due to first SE from March to April 2020 ("Time of COVID," TOC) with January to February 2020 ("pre-COVID," preCOV). We also compared admission numbers in TOC and preCOV with the respective 2-month periods in 2018 and 2019 in a retrospective cohort analysis. Two investigators independently searched the hospital patient database for various forms of SE. There was no significant change in the 2-month incidences of first SE in the city of Salzburg from preCOV of 6.1 (95% confidence interval [CI] 2.9-12.3) to TOC of 6.9/100 000 adults (95% CI 3.4-13.3). Admission numbers did not differ significantly from previous years. Estimated adjusted incidence was in line with a recent 5-year epidemiological study in Salzburg. However, a trend toward less-frequent nonconvulsive SE (NCSE) and loss of female predominance were indirect hints of underdiagnosing SE. In contrast to other medical conditions, SE most often presents clinically with impaired consciousness, which may promote admission to emergency departments even in times of lock-down. Further research of medical support of women and patients with NCSE during pandemic-related restrictions is warranted.

Patient-reported outcome measures in studies of myelodysplastic syndromes and acute myeloid leukemia: Literature review and landscape analysis.

OBJECTIVES: This study aims to describe the use of patient-reported outcome measures (PROMs) in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) studies and the PROMs landscape. METHODS: A comprehensive literature review was performed in Medline/Embase (since 2000) and ClinicalTrials.gov (since 2013) to identify PROMs used in MDS and AML clinical studies. Additionally, PROMs included in approved drug labels since 2000 were reviewed. RESULTS: Overall, 112 different PROMs were used in 168 published MDS studies and 152 PROMs were used in 172 AML studies. From ClinicalTrials.gov, 16 different PROMs were used in 22 ongoing registered studies in MDS, and 24 were reported in 41 AML studies. The most frequently used PROMs were cancer-specific (eg, EORTC QLQ-C30, FACT-An) or generic (SF-36, EQ-5D) instruments, whereas MDS- and AML-specific instruments (eg, QUALMS and QOL-E in MDS; FACT-Leu and EORTC QLQ-Leu in AML) were used in a minority of studies. Two EMA-approved drugs for MDS included PROMs in their label. EORTC QLQ-C30 is by far the most frequently used cancer-specific PROM in both MDS and AML studies. CONCLUSIONS: This research indicated an underuse of AML/MDS-specific PROMs for these two indications in clinical studies and labeling claims. However, AML/MDS-specific instruments in development might be considered in future studies.

Being Precise About Precision Medicine: What Should Value Frameworks Incorporate to Address Precision Medicine? A Report of the Personalized Precision Medicine Special Interest Group.

Precision medicine is a dynamic area embracing a diverse and increasing type of approaches that allow the targeting of new medicines, screening programs or preventive healthcare strategies, which include the use of biologic markers or complex tests driven by algorithms also potentially taking account of patient preferences. The International Society for Pharmacoeconomics and Outcome Research expanded its current work around precision medicine to (1) describe the evolving paradigm of precision medicine with examples of current and evolving applications, (2) describe key stakeholders perspectives on the value of precision medicine in their respective domains, and (3) define the core factors that should be considered in a value assessment framework for precision medicine. With the ultimate goal of improving health of well-defined patient groups, precision medicine will affect all stakeholders in the healthcare system at multiple levels spanning the individual perspective to the societal perspective. For an efficient, timely and practical precision medicine value assessment framework, it will be important to address these multiple perspectives through building consensus among the stakeholders for robust procedures and measures of value aspects, including performance of precision mechanism; aligned reimbursement processes of precision mechanism and subsequent treatment; transparent expectations for evidence requirements and study designs adequately matched to the intended use of the precision mechanism and to the smaller target patient populations; recognizing the potential range of value-generation such as ruling-in and ruling-out decisions.