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Since 2019 the Dutch National Healthcare Institute has operated a coverage with evidence development (CED) program for specific products with insufficient evidence of their clinical benefit: orphan medicinal products (OMPs), medicines with conditional marketing authorization (CMA), and medicines with marketing authorization under exceptional circumstances (AEC). The objective of this study is to give an overview of this program and reflect on learnings, challenges, and opportunities.
Methods
This study is a narrative policy review of the Dutch CED program and describes the different phases and stakeholder involvement. Additionally, an overview of the medicines included in the CED program is presented and put in an international perspective.
Results
The CED program consists of four phases: candidate prescreening, research protocol drafting, signing of process agreement and financial agreement, and controlled access. Stakeholders are involved intensively throughout the process. Since 2019, six medicines have entered the program. The program is used to fill different evidence gaps for various types of medicines and indications. In other countries, these medicines are often included in restricted reimbursement programs.
Conclusions
The CED program is gathering clinical effectiveness data while providing patient access to OMPs, CMA, and AEC products. Important facilitating factors for the program were identified, including the involvement of all stakeholders, the only-in-research approach of data gathering, and the case-by-case evidence generation requirements and duration. Continuous evaluation is needed as the program does not yet include the expected number of medicines, and no conclusion can be drawn so far on the usefulness of the data collection.
Research participants should be informed of genetic test results that could impact their health, particularly when they have expressed interest in receiving such information. Furthermore, the return of genetic test results is essential to improve trust, transparency, and health equity. However, investigators often encounter barriers in returning genetic test results to research participants. We examined genomic research at a large, research-intensive medical school and found less than 6% of protocols included plans to return results to participants. This study describes our development of protocols for returning primary and secondary genetic test results and implementation of a Genomic Return of Results (gROR) service. This arose through a collaboration with experts in community engagement, genetics, and pathology to consider consent adequacy, analytical/clinical validity, and clinical utility when returning results. The gROR service reduces investigator burden and provides participants with genetic information and guidance to address any potential health risks. Genetic results are returned by a genetic counselor at no cost to participants or their family. Investigator costs are subsidized to incentivize the delivery of actionable genetic test results to research participants. Our approach prioritizes transparency, accessibility, and informed decision-making, thereby promoting equitable sharing of genetic knowledge and personalized healthcare interventions.
Do governing elites who engage in undemocratic practices face accountability? We investigate whether American state legislators who publicly acted against the 2020 presidential election outcome sustained meaningful sanctions in response. We theorize that repercussions for undemocratic activities are selective – conspicuous, highly visible efforts to undermine democratic institutions face the strongest ramifications from voters, other politicians, and parties. In contrast, less prominent actions elicit weaker responses. Our empirical analyses employ novel data on state legislators’ anti-election actions and a weighting method for covariate balance to estimate the magnitude of punishments for undemocratic behavior. The results indicate heterogeneity, with the strongest consequences targeting legislators who appeared at the US Capitol on 6 January 2021, and weaker penalties for lawmakers who engaged in other forms of antagonism towards democracy. We conclude that focusing sanctions on conspicuous acts against democratic institutions could leave less apparent – but still detrimental – efforts to undermine elections unchecked, ultimately weakening democratic health.
We introduce and study a class of generalized Meixner-type free gamma distributions $\mu _{t,\theta ,\lambda }$ ($t,\theta>0$ and $\lambda \ge 1$), which includes both the free gamma distributions introduced by Anshelevich and certain scaled free beta prime distributions introduced by Yoshida. We investigate fundamental properties and mixture structures of these distributions. In particular, we consider the Gibbs distribution $\frac {1}{\mathcal {Z}_{t,\theta ,\lambda }} \exp \{-V_{t,\theta ,\lambda }(x)\}$ associated with a family of potentials $V_{t,\theta ,\lambda }$, and show that $\mu _{t,\theta ,\lambda }$ maximizes Voiculescu’s free entropy with potential $V_{t,\theta ,\lambda }$ for parameters $t,\theta>0$ and $1\le \lambda <1+t/\theta $. This result substantially extends the range of classical-free correspondences obtained the potential function, differing from those arising from the Bercovici–Pata bijection. Moreover, we identify algebraic relations involving noncommutative random variables distributed as free gamma distributions.
This article examines Paul’s view of the law with attention to the figure of the pedagogue. It suggests that the law stands in a redemptive-historical role to the coming of Christ. It accomplishes this through a comparison between Seneca’s Moral Epistles and Paul. Seneca’s discussion is a helpful heuristic to elucidate Paul’s teaching on Jewish law. Paul highly values the Jewish law and explains that it leads humans to Christ as a pedagogue, although the law itself does not have the power to make righteous. Scholars offer arguments in support of positive or negative attitudes toward the pedagogue, but the pedagogue’s basic role was to bring a child to the age of maturity and rationality. Paul’s thesis is to argue that the Jewish law functions, historically and ethically, to lead one to Christ. This interpretation suggests that the law plays a positive redemptive-historical role in Galatians 3:19–4:11.
Childbirth-related post-traumatic stress disorder (CB-PTSD) is an underrecognized condition with consequences for mothers and infants. This study aimed to determine risk factors for CB-PTSD symptoms across countries within a stress–diathesis framework, focusing on antenatal, birth-related, and postpartum predictors.
Methods
The INTERSECT cross-sectional survey (April 2021–January 2024) included 11,302 women at 6–12 weeks postpartum. The study was carried out across maternity services in 31 countries. Outcomes were CB-PTSD diagnosis, symptom severity, and perceived traumatic birth, assessed with the City Birth Trauma Scale. Multiple risk factors were assessed, including preexisting vulnerability, pregnancy, birth, and infant-related factors. All models were adjusted for country-level variation as a random effect.
Results
Models explained substantial variance across all outcomes (conditional R2 = 0.53–0.58). Negative birth experience was the strongest predictor (e.g. odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.80–0.84 for diagnosis). Ongoing maternal complications predicted both CB-PTSD diagnosis and symptoms (e.g. OR = 1.61, 95% CI = 1.41–1.84), and major infant complications were associated with CB-PTSD diagnosis (OR = 1.63, 95% CI = 1.29–2.07). Reports of perceived danger to self or infant (criterion A) were linked to higher CB-PTSD symptoms and traumatic birth ratings (e.g., β =0.25, 95% CI = 0.21–0.29). Other predictors reached significance but showed small effects.
Conclusions
Findings support a stress–diathesis framework, showing that while pre-existing vulnerabilities contribute, birth-related stressors exert the strongest influence. Trauma-informed maternity care should prioritize these factors, with attention to women’s appraisals of birth.
Intrinsic capacity, introduced by the WHO, represents a shift in focus from treating disease to maintaining physical and mental capacities individuals as they age. It encompasses five interrelated domains: vitality, sensory, cognition, psychology, and locomotion. Vitality refers to the body’s physiological reserve and is shaped by processes such as energy metabolism, immune function, and neuromuscular integrity. By definition, vitality is closely linked to nutritional status, which plays a central role in maintaining resilience and health in older adults. However, integrating nutritional status into the vitality domain presents several challenges due to inconsistent definitions and varied measurement approaches. This review examines these challenges and explores possibilities for integrating nutritional status in the vitality domain. The absence of standardised nutrition-related indicators limits comparability across studies and constrains the practical application of intrinsic capacity in both research and clinical contexts. To strengthen the role of intrinsic capacity in nutritional monitoring, it is essential to reach consensus on which nutritional indicators to include and how to score them consistently. Addressing these methodological challenges will support the use of intrinsic capacity in identifying early signs of nutritional decline and guiding timely interventions to promote healthy ageing.
Public perceptions of immigration are often inaccurate, yet research lacks conceptual clarity and valid measurement of these misperceptions. Prior work focuses mainly on population innumeracy (misestimating immigrant shares) and cannot distinguish genuine misperceptions from mere guessing. We introduce a survey module that captures multiple dimensions of immigration-related perceptions alongside respondents’ confidence in their estimates. Using population survey data from Switzerland, we develop confidence-weighted indicators that separate misperception from guessing. Although inaccurate perceptions are widespread across several immigration domains, they are less prevalent than often assumed; guessing accounts for a substantial share of observed inaccuracy. This measurement strategy enables more precise empirical tests of theories linking perceptions to political attitudes and behavior.
To compare healthcare survey response rates using two widely utilized recruitment methods: email and the electronic health record (EHR) patient portal.
Materials and methods:
Adults with a prior history of any bariatric surgery were randomly assigned (1:1) to receive a survey invitation via email or through the EHR patient portal. A second reminder was sent using the same method. A third invitation used a crossover approach, switching to the alternate method. We compared survey completion rates, changes in research preference status, and time to survey completion. Predictors of response were assessed using multivariable logistic regression.
Results:
The email group had a 9.9% response rate after the first invitation and 6.5% after the second. The EHR portal group had 8.4% and 4.5% response rates, respectively. Following crossover, the third invitation yielded a 4.4% response for those switched to the EHR portal and 7.5% for those switched to email. The EHR portal group was 27% less likely to complete the survey compared to the email group. Respondents were more likely to be female, non-Hispanic, White, have a recent healthcare encounter, and have recently logged into the portal. Median time to completion was under 24 hours in both groups, with over two-thirds of responses received on the day of or the day after the invitation. A change in research preference status was observed in 2.5% of email and 4.0% of portal participants.
Discussion and conclusion:
Email-based recruitment yielded higher response rates than EHR portal-based recruitment, with most responses occurring shortly after invitation.
This paper is interested in the spread of an autocratic ideology and the emergence of a societal belief. It is often assumed that the greater the capacities of an autocratic regime to inculcate an ideological belief into the minds and hearts of subordinate citizens, the more an autocratic ideology is shared in a given society. The extent of an ideological belief is explained by a direct and immediate function of its indoctrination capacities. The paper does not question this top–down, macro–micro approach, but argues that the spread of an ideology also depends on stabilizing micro–micro interactions and micro–macro linkages. In this light, the paper makes use of James Coleman’s famous explanatory model and theorizes the different partial mechanisms. It pays particular emphasis on the micro–macro mechanism. Borrowing insights from epidemiology, it argues that three classes of parameters should be taken into closer consideration: timing, contact structure, and the contagiousness of an ideology. In empirical terms, the paper illustrates its theoretical reasoning with the dissemination of the North Korean Juche ideology from the 1950s to the early 1970s, which represents an extreme case of a rapidly ideologizing autocracy. The paper relies on secondary sources as well as archival material retrieved from the former embassy of the German Democratic Republic in Pyongyang.
Although forests play a vital role in US climate strategies, US forest area is expected to decline in the coming decades. Policymakers can help arrest or reverse that decline by strengthening incentives for forest carbon sequestration. Increased funding for afforestation, restoration, and bioenergy and wood products market development will likely benefit the forest sector unevenly across geographic, commercial, and demographic dimensions. This review explores the effects of policies – particularly incentives for afforestation and reforestation, carbon credit market participation, and wood products utilization – on US forest communities. We describe this policy landscape and use various data to investigate effects on diverse stakeholders, with special emphasis on the implications for disadvantaged and forest-dependent communities.
Afforestation policies in the South-Central region could significantly enhance carbon dioxide removal while reshaping rural dynamics. Forest carbon credit markets, though crucial for climate goals, may disadvantage small forest owners and communities, instead favoring large corporate entities. Policies promoting wood products in the South-Central region could benefit forest-dependent, high-poverty communities. We also note how policy implementation might ensure an equitable distribution of climate-related benefits among stakeholders in the forest sector.
Substantial experimental research has explored mental contamination – feelings of internal pollution proposed to result from misinterpreting perceived violations. The Mental Contamination Report (MCR) was developed to measure in-the-moment experiences of mental contamination, and has been used in seminal experiments in this domain. However, the MCR has yet to be psychometrically evaluated. The aim of the current study was to evaluate the psychometric properties of the MCR, and if warranted, propose a revised version with improved research utility.
Method:
Data for this study were collected as part of a larger experiment examining the impact of moral self-violation on mental contamination. A sample of 150 undergraduate students completed the MCR, Vancouver Obsessional-Compulsive Inventory-Mental Contamination Subscale, and the Vancouver Obsessional-Compulsive Inventory.
Results:
The original Emotions Subscale of the MCR demonstrated excellent internal consistency (${\rm{\alpha }}$=0.92) but contained emotions non-specific to mental contamination. We conducted an exploratory factor analysis (EFA) of the emotion items to identify which items load more heavily onto a mental contamination-specific factor. The EFA revealed a two-factor solution, with five items items loading strongly on the mental contamination-specific factor. For the 5-item mental contamination-specific Emotions Subscale, we found excellent internal consistency (${\rm{\alpha }}$=0.90), strong known groups validity, F2,147=63.17, p<.001, ηp2=.46, good convergent validity and mixed results for divergent validity. For the Behavioural Urges Subscale, we found overall mixed psychometric properties.
Conclusions:
Based on the results of the psychometric analysis, a revised version of the MCR is proposed.
The meaning of equality is highly contested. As a result, courts across different jurisdictions have developed distinct doctrinal approaches to operationalize the concept. This article argues that four primary equality frameworks can be identified, each reflecting not only different understandings of equality but also varying degrees of judicial deference to the legislature and executive. The first is the equality-as-non-discrimination model, which predominates in most common law jurisdictions and dominates the theoretical discourse on equality. The second, prevalent in many continental European jurisdictions, is the equality-as-reasonableness model, under which courts apply a relatively strict standard of review, even in cases that do not involve suspect classifications. The third, the positive-equality model, recognizes that courts can derive positive obligations from the principle of equality. Finally, the deferential model largely entrusts the definition and implementation of equality to the legislature and executive. This article highlights the normative strengths and weaknesses of each model, arguing that no single approach holds an absolute normative advantage over the others. Instead, the suitability of a particular model depends on the societal and institutional context in which a court operates.
Anhedonia and depression symptoms have been linked to potential deficits in reward learning. However, how anhedonia impacts the ability to adjust and learn about the effort required to obtain rewards remains unclear.
Methods
We examined young people (N = 155, 16–25 years) with a range of depression and anhedonia symptoms using a probabilistic instrumental reward and effort learning task. Participants were asked to learn which options to choose to maximize reward or minimize effort for reward. We compared the exerted effort (button pressing speed) for high (puppy images) vs low (dog images) rewards and collected subjective reports of “liking,” “wanting,” and “willingness to exert effort.” Computational models were fit to the learning data and estimated parameter values were correlated with depression and anhedonia symptoms.
Results
As depression symptoms and consummatory anhedonia increased, reward liking decreased, and as anticipatory anhedonia increased, liking, wanting, and willingness to exert effort for reward decreased.
Participants exerted more effort for high rewards than for low rewards, but anticipatory anhedonia diminished this difference.
Higher consummatory anhedonia was associated with poorer reward and effort learning, and with increased temperature parameter values for both learning types, indicating a higher tendency to make exploratory choices. Higher depression symptoms were associated with lower reward learning accuracy.
Conclusion
We provide novel evidence that anhedonia is associated with difficulties in modulating effort as a function of reward value and with the underexploitation of low effort and high reward options. We suggest that addressing these impairments could be a novel target for intervention in anhedonic young people.
The theory of causal fermion systems represents a novel approach to fundamental physics and is a promising candidate for a unified physical theory. This book offers a comprehensive overview of the theory, structured in four parts: the first lays the necessary mathematical and physical foundations; the second offers an introduction to the theory and the causal action principle; the third describes the mathematical tools for analyzing causal fermion systems; and the fourth gives an outlook on the key physical applications. With relevance across mathematical and theoretical physics, the book is aimed at graduate students and researchers interested in novel approaches to the structure of spacetime and alternative perspectives to the more established quantum field theories. It can be used for advanced courses in the subject or as a reference for research and self-guided study. Exercises are included at the end of each chapter to build and develop key concepts.
China's engagement in Africa since 2000 consists of a diverse set of institutions, activities, relations, investment flows and other economic statecraft events. These have generated opportunities for economic transformation, reviving the prospects for industrialization and job creation in some African countries following decades of neglect. While the case for industrialization-led structural transformation is strong, the proposed means of pursuing this pathway vary, necessitating bold vision and interventions. Whether through infrastructure funding and building, or direct greenfield investments, China is helping lay the foundations for industrialization in Africa, albeit unevenly and slowly. The vectors and outcomes are, however, variegated, calling for a comparative examination. Therefore, the Element illustrates variations in outcomes and the importance of context when considering the vectors of Africa–China engagements, how they contribute to industrialization prospects, and the central role of policy agency, bargaining and contestation. This title is also available as Open Access on Cambridge Core.
This Element analyses issues of abuse in new religious movements (NRMs). It argues that abuse in NRMs is not unique but that certain factors can be intensified in NRM contexts – propensities for separation from wider society, teachings on unique legitimacy and exclusivity, and charismatic authority. First, a historical overview addresses how abuse in NRMs has been approached and understood, linking this to the development of NRM and cultic studies and their preferred terminology. Second, a theoretical framework allows consideration of the ways in which the interlinked structural and cultural factors of religious movements can contribute to the perpetration, legitimisation or concealment of abuse. Finally, the Element presents an applied case study analysing the interplay of these factors in the Jesus Fellowship Church, a UK-based NRM which closed in 2019, partly in recognition of abuses that had occurred. This title is also available as Open Access on Cambridge Core.
Recipients of hematopoietic cell transplantation (HCT) are at increased risk for Clostridioides difficile infection (CDI) and its recurrence, which are associated with significant morbidity. We aimed to characterize risk factors for primary and recurrent CDI in a large cohort of HCT recipients.
Methods:
We conducted a retrospective cohort study of 2725 adults who underwent HCT from 2010–2023 to evaluate the epidemiology, timing, and risk factors for CDI. We compared patients who developed CDI with those who did not, adjusting for patient demographics, comorbidities, transplant factors, medications, and laboratory values. Among patients who developed CDI, we investigated risk factors for recurrent CDI.
Results:
The cumulative 1-year incidence of CDI was 17.8% among allogeneic HCT recipients (181/1016) and 4.1% among autologous recipients (71/1709). Overall CDI incidence increased by 1.4% annually during the study period (95%CI: 1.24–1.53%). Independent risk factors for primary CDI included penicillin antibiotics (aOR 1.51; 95%CI: 1.13–2.02), prior chemotherapy (aOR 8.36; 95%CI: 2.95–23.69 for 1–3 regimens), and umbilical cord blood stem cells (aOR 1.95; 95%CI: 1.07–3.57). Autologous HCT was associated with decreased risk. Among 252 patients with primary CDI, 22 (8.7%) developed recurrence. Macrolide use before index CDI (aOR 7.25; 95%CI: 1.80–29.2) and allogeneic HCT (aOR 31.04; 95%CI: 1.37–731.58) were associated with recurrence.
Conclusion:
CDI is a common, early complication of HCT particularly among allogeneic recipients. Penicillin exposure, prior chemotherapy, and cord blood stem cell source are key risk factors, while macrolide use is associated with recurrence. Our findings highlight potential targets for risk-stratified prevention strategies.