A woman with a rare p.Glu74Gly transthyretin mutation presenting exclusively with a rapidly progressive neuropathy: a case report

Introduction: Familial amyloid polyneuropathy is a rare autosomal dominant disorder caused by mutations in the transthyretin gene, TTR. Diagnosis can be challenging, especially if other family members are not affected or an obvious systemic involvement is lacking. The patients are often misdiagnosed, leading to a delay in the initiation of therapy. Case presentation: A 35-year-old woman of Turkish origin presented to our outpatient clinic with severe polyneuropathy associated with distally pronounced tetraparesis and hypesthesia of 2 to 3 years’ duration. In addition, small nerve fiber involvement with impaired detection of cold temperatures and tingling pain in the lower legs was reported. She did not complain of autonomic dysfunction or visual disturbance. Her family history was empty regarding neuromuscular disorders. The routine diagnostic work-up was unremarkable. A sural nerve biopsy disclosed amyloid deposits, which led to the identification of a rare heterozygous transthyretin mutation (p.Glu74Gly; old classification: p.Glu54Gly). Conclusions: Few cases with this very heterozygous mutation can be found in the literature. In contrast to the case of our patient, all of the previously described patients in the literature presented with additional severe autonomic symptoms, involvement of the eyes and a positive family history. In this case report, we emphasize that, in patients with progressive neuropathy with small fiber involvement, an amyloid neuropathy should be considered in the differential diagnosis, even if the family history is empty and other organs are not affected

Networks of action situations: a systematic review of empirical research

“Action situations”—events, venues, or physically interdependent instances of decision-making—have become a central unit of analysis in the social–environmental sciences, particularly among scholars interested in bridging the social with the biophysical or ecological side of interdependent decisions. A growing body of empirical studies in social–ecological systems research has recently used case and comparative studies to analyse multiple interdependent action situations, structured into networks. In this article, we take stock of this body of empirical research, synthesize the diverse approaches that scholars have taken to assess “networks of action situations”, and identify fruitful paths forward. We conduct a systematic review of the empirical literature in the field, reviewing and summarizing the key characteristics of the empirical studies, including network features, topologies, methods, and data sources used in each case. We summarize and discuss the conceptualizations, methods, diagnostic procedures, and conclusions used in this body of work in a narrative framework synthesis. The review indicates that an increasingly coherent approach is taking shape, but a systematic, protocol-driven, or formalized approach is only partly emerging. We derive future research needs that could help accumulate knowledge from empirical research

Design and quality criteria for archetype analysis

A key challenge in addressing the global degradation of natural resources and the environment is to effectively transfer successful strategies across heterogeneous contexts. Archetype analysis is a particularly salient approach in this regard that helps researchers to understand and compare patterns of (un)sustainability in heterogeneous cases. Archetype analysis avoids traps of overgeneralization and ideography by identifying reappearing but nonuniversal patterns that hold for well-defined subsets of cases. It can be applied by researchers working in inter- or transdisciplinary settings to study sustainability issues from a broad range of theoretical and methodological standpoints. However, there is still an urgent need for quality standards to guide the design of theoretically rigorous and practically useful archetype analyses. To this end, we propose four quality criteria and corresponding research strategies to address them: (1) specify the domain of validity for each archetype, (2) ensure that archetypes can be combined to characterize single cases, (3) explicitly navigate levels of abstraction, and (4) obtain a fit between attribute configurations, theories, and empirical domains of validity. These criteria are based on a stocktaking of current methodological challenges in archetypes research, including: to demonstrate the validity of the analysis, delineate boundaries of archetypes, and select appropriate attributes to define them. We thus contribute to a better common understanding of the approach and to the improvement of the research design of future archetype analyses

Lenalidomide and dexamethasone in relapsed/refractory immunoglobulin light chain (AL) amyloidosis: results from a large cohort of patients with long follow-up.

SummaryLenalidomide and dexamethasone (RD) is a standard treatment in relapsed/refractory immunoglobulin light chain (AL) amyloidosis (RRAL). We retrospectively investigated toxicity, efficacy and prognostic markers in 260 patients with RRAL. Patients received a median of two prior treatment lines (68% had been bortezomib‐refractory; 33% had received high‐dose melphalan). The median treatment duration was four cycles. The 3‐month haematological response rate was 31% [very good haematological response (VGHR) in 18%]. The median follow‐up was 56·5 months and the median overall survival (OS) and haematological event‐free survival (haemEFS) were 32 and 9 months. The 2‐year dialysis rate was 15%. VGHR resulted in better OS (62 vs. 26 months, P < 0·001). Cardiac progression predicted worse survival (22 vs. 40 months, P = 0·027), although N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) increase was frequently observed. Multivariable analysis identified these prognostic factors: NT‐proBNP for OS [hazard ratio (HR) 1·71; P < 0·001]; gain 1q21 for haemEFS (HR 1·68, P = 0·014), with a trend for OS (HR 1·47, P = 0·084); difference between involved and uninvolved free light chains (dFLC) and light chain isotype for OS (HR 2·22, P < 0·001; HR 1·62, P = 0·016) and haemEFS (HR 1·88, P < 0·001; HR 1·59, P = 0·008). Estimated glomerular filtration rate (HR 0·71, P = 0·004) and 24‐h proteinuria (HR 1·10, P = 0·004) were prognostic for renal survival. In conclusion, clonal and organ biomarkers at baseline identify patients with favourable outcome, while VGHR and cardiac progression define prognosis during RD treatment

Archetype analysis in sustainability research : meanings, motivations, and evidence-based policy making

Archetypes are increasingly used as a methodological approach to understand recurrent patterns in variables and processes that shape the sustainability of social-ecological systems. The rapid growth and diversification of archetype analyses has generated variations, inconsistencies, and confusion about the meanings, potential, and limitations of archetypes. Based on a systematic review, a survey, and a workshop series, we provide a consolidated perspective on the core features and diverse meanings of archetype analysis in sustainability research, the motivations behind it, and its policy relevance. We identify three core features of archetype analysis: recurrent patterns, multiple models, and intermediate abstraction. Two gradients help to apprehend the variety of meanings of archetype analysis that sustainability researchers have developed: (1) understanding archetypes as building blocks or as case typologies and (2) using archetypes for pattern recognition, diagnosis, or scenario development. We demonstrate how archetype analysis has been used to synthesize results from case studies, bridge the gap between global narratives and local realities, foster methodological interplay, and transfer knowledge about sustainability strategies across cases. We also critically examine the potential and limitations of archetype analysis in supporting evidence-based policy making through context-sensitive generalizations with case-level empirical validity. Finally, we identify future priorities, with a view to leveraging the full potential of archetype analysis for supporting sustainable development

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline

peer reviewed[en] BACKGROUND AND OBJECTIVES: To determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer disease (AD) biomarkers, cognitive decline, and clinical progression to mild cognitive impairment (MCI). METHODS: This study included patients with clinical SCD and SCD-free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-β (Aβ)42/Aβ40, phosphorylated tau (p-tau181), total tau and Aβ42/p-tau181 levels, longitudinal cognitive composite trajectories, and risk of clinical progression to incident MCI (follow-up M ± SD: 40.6 ± 23.7 months). In addition, we explored group differences between SCD and HC in those without MNPD. RESULTS: In our sample (N = 672, mean age: 70.7 ± 5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline, and a higher risk of progression to incident MCI (HR: 4.07, 95% CI 2.46-6.74) compared with SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95% CI 38.5-75.4) and a negative predictive value of 86.0% (95% CI 81.9-90.1) for the progression of SCD to MCI within 3 years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared with HC participants without MNPD (n = 215; HR: 4.09, 95% CI 2.07-8.09), while AD biomarker levels did not differ significantly between these groups. DISCUSSION: Our results suggest that MNPD are a risk factor for AD-related clinical progression in cognitively normal patients seeking medical counseling because of SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD

Novelty-Related fMRI Responses of Precuneus and Medial Temporal Regions in Individuals at Risk for Alzheimer Disease

BACKGROUND AND OBJECTIVES: We assessed whether novelty-related fMRI activity in medial temporal lobe regions and the precuneus follows an inverted U-shaped pattern across the clinical spectrum of increased Alzheimer disease (AD) risk as previously suggested. Specifically, we tested for potentially increased activity in individuals with a higher AD risk due to subjective cognitive decline (SCD) or mild cognitive impairment (MCI). We further tested whether activity differences related to diagnostic groups were accounted for by CSF markers of AD or brain atrophy. METHODS: We studied 499 participants aged 60-88 years from the German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study (DELCODE) who underwent task-fMRI. Participants included 163 cognitively normal (healthy control, HC) individuals, 222 SCD, 82 MCI, and 32 patients with clinical diagnosis of mild AD. CSF levels of β-amyloid 42/40 ratio and phosphorylated-tau181 were available from 232 participants. We used region-based analyses to assess novelty-related activity (novel > highly familiar scenes) in entorhinal cortex, hippocampus, and precuneus as well as whole-brain voxel-wise analyses. First, general linear models tested differences in fMRI activity between participant groups. Complementary regression models tested quadratic relationships between memory impairment and activity. Second, relationships of activity with AD CSF biomarkers and brain volume were analyzed. Analyses were controlled for age, sex, study site, and education. RESULTS: In the precuneus, we observed an inverted U-shaped pattern of novelty-related activity across groups, with higher activity in SCD and MCI compared with HC, but not in patients with AD who showed relatively lower activity than MCI. This nonlinear pattern was confirmed by a quadratic relationship between memory impairment and precuneus activity. Precuneus activity was not related to AD biomarkers or brain volume. In contrast to the precuneus, hippocampal activity was reduced in AD dementia compared with all other groups and related to AD biomarkers. DISCUSSION: Novelty-related activity in the precuneus follows a nonlinear pattern across the clinical spectrum of increased AD risk. Although the underlying mechanism remains unclear, increased precuneus activity might represent an early signature of memory impairment. Our results highlight the nonlinearity of activity alterations that should be considered in clinical trials using functional outcome measures or targeting hyperactivity

Advancing the research agenda on food systems governance and transformation

The food systems upon which humanity depends face multiple interdependent environmental, social and economic threats in the 21st Century. Yet, the governance of these systems, which determines to a large extent the ability to adapt and transform in response to these challenges, is underresearched. This perspective piece synthesises the findings of two recent reviews of food systems governance and transformations and proposes a comprehensive research agenda for the coming years. These reviews highlight the influence of governance on food systems, methodological obstacles to explaining the effectiveness of governance in realising food sustainability, and conditions that have historically supported food system transformations. We argue that the following steps are key to improving our knowledge of the role of governance in food systems: (1) developing more comparable research designs for building generalisable explanations of the governance elements that are most effective in realising food systems goals; (2) using the lens of polycentricity to help disentangle complex governance networks; (3) giving greater attention to the conditions and pre-conditions associated with historical food system transformations; (4) identifying adaptations that strengthen or weaken path dependency; and, (5) focusing research on how transformations can be supported by institutions that facilitate collective action and stakeholder agency