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Standardized measures to evaluate neurological patients in palliative care are missing. The Integrated Palliative Outcome Scale, a self-report tailored for neurological patients (IPOS Neuro-S8) helps identify symptom burden but lacks validation in German. This study aimed to validate the IPOS Neuro-S8 in severely affected multiple sclerosis (MS) patients.
Methods
This validation study is a secondary analysis of data from a clinical phase II intervention study with severely affected MS patients. The original study enrolled German-speaking patients aged 18 with severe MS who receive an escalating immunotherapeutic agent and/or exhibit a high level of disability were recruited from the administrative district Cologne (#DRKS00021783). In this validation study, we evaluated construct, discriminant, and convergent validity, internal consistency, test–retest reliability, and sensitivity to change of the IPOS Neuro-S8, using the “Hamburger Lebensqualitätsmessinstrument” (HALEMS), and the Hospice and Palliative Care Evaluation supplemented by neurological symptoms (HOPE+) as comparison measures.
Results
Data from 80 MS patients (mean age 56, SD = 11) were analyzed. Exploratory and confirmatory factor analyses revealed a 3-factor structure (r = 0.34–0.63), reflecting distinct clinical patterns, i.e., breath-mouth connection, pain-sleep cycle, and nausea-vomiting link. Significant convergent validity to hypothesized total score of the HOPE+ (rs(78) = 0.71, p < 0.001) and good discriminant validity using the HALEMS total score (rs(78) = 0.48, p < 0.001) were observed. Correlation with physical symptoms of the HALEMS was stronger than with nonphysical aspects. Internal consistency (Cronbach’s α = 0.67) and test–retest reliability (intraclass coefficient = 0.75) were acceptable.
Significance of results
IPOS Neuro-S8 displays promising psychometric properties for assessing palliative care symptoms in severe MS, a model for other severe neurological diseases due to MS's broad central nervous involvement, allowing findings to be transferable to other neurological diseases. A criterion for minimal clinically important difference was established to evaluate the sensitivity to change. Additional validation across different neurological conditions and disease severities is warranted to enhance generalizability and clinical utility.
Between 2015 and 2017, East Arnhem Land recorded the highest rates of avoidable deaths in Australia.(1) In 2018, coronary heart disease emerged as the leading cause of avoidable death among First Nations people, with poor diet contributing to 50% of the total burden.(2) Yolŋŋu people in East Arnhem Land are aware of the health challenges and actively seek community-led support from organisations to create health-promoting food environments. The Arnhem Land Aboriginal Progress Corporation (ALPA), governed by a Yolŋu Board of directors, operate six grocery stores in East Arnhem Land. Through analysis of store sales data more than half of total sugar sales are attributed to table sugar. Despite the successful implementation of strong nutrition policies across their retail stores, which have significantly reduced the sale of sugary products like soft drinks, lollies, and cordial, there has been limited success with reducing purchasing of table sugar. Overall, free sugars from all sugar products purchased remains above the World Health Organization’s recommendations. To tackle this public health issue, the Heart Foundation, in collaboration with ALPA and Miwatj Health Aboriginal Corporation, have embarked on a project aimed at reducing table sugar consumption in East Arnhem Land. Consultations with community members and health professionals in Galiwin ‘ku and Milingimbi were held from July 15 to 19, 2024, to assist in the co-design of culturally relevant nutrition resources. Microsoft Teams was utilised for recording and transcription, and artificial intelligence software for thematic analysis. The consultations explored community perceptions of table sugar, its use, and its health impacts. It was identified that sugar consumption is deeply ingrained, particularly in tea drinking, where large quantities of sugar are consumed daily. The addictive nature of sugar was acknowledged, making it challenging to reduce intake. Thematic analysis revealed that while there is an awareness of sugar’s harmful effects, such as its links to heart disease and diabetes, challenges like food insecurity, addiction, and ingrained consumption habits persist. Community members preferred resources that are culturally sensitive, employ positive storytelling methods, and use both modern (Youtube, TikTok, Instagram and Facebook) and traditional (posters in stores and clinics) media. Suggested strategies included emphasising gradual reduction techniques and involving community to enhance the authenticity of resources. Draft resources will be further refined through a second round of community consultations in late October 2024, with final versions distributed by the end of the year and accessible on the Heart Foundation’s website. Success will be measured through ALPA store sales data on table sugar, website engagement, and social media metrics. This initiative seeks to promote sustainable behaviour change and improve health outcomes in East Arnhem Land.
We investigate the effects of order-of-play (simultaneous, unobserved sequential and fully observed sequential play) and form of presentation (extensive vs. normal) in three simple two person games: battle-of-the-sexes with and without outside option and a three strategy game which differentiates between virtual observability (VO) and iterated elimination of dominated strategies as principles of equilibrium selection. VO predicts that knowledge of the order of play alone will affect the distribution of strategies chosen. We contrast this with the predictions of iterated elimination of dominated strategies. We report results from 1800 one-shot games conducted in 6 sessions with 120 subjects and analysed as panel data. The form of presentation strongly affects the distribution of outcomes and strategies. Information about order of play shifts the distribution of strategies away from the distribution in simultaneous play and towards the distribution in fully observed play, especially in the less complicated games presented in normal order. Order-of-play effects are less evident as complexity of the game increases. Extensive form presentation appears to induce sequential thinking even in simultaneously played games.
We investigate the effects of heterogeneity and incomplete information on aggregate contributions to a public good using the voluntary contribution mechanism. The non-linear laboratory environment has three-person groups as partners under varying conditions of information and communication. Bergstrom, Blum and Varian predict that increasing heterogeneity will have no effect on aggregate contributions in a no-communication environment. Ledyard conjectures a positive effect of incomplete information, a negative effect of heterogeneity, and a positive interaction of heterogeneity and incomplete information. We find that incomplete information has a small but significant negative effect. Heterogeneity has a positive effect on aggregate contributions, but its effects interact unexpectedly with communication. In a no-communication environment, heterogeneity in two dimensions (endowment and preferences) increases contributions substantially while heterogeneity in a single dimension (endowment or preferences) has little effect. In the communication environment we find the reverse. We also find a positive interaction between heterogeneity and incomplete information. Thus we reject the Bergstrom, Blume and Varian invariance result and provide mixed evidence on Ledyard's conjectures.
Here, we present a comprehensive morphological and molecular phylogenetic analysis of Clinostomum sp. (Digenea: Clinostomidae) metacercariae parasitizing two freshwater fish species from Southeast Brazil: Serrasalmus spilopleura (piranha) and Callichthys callichthys (tambuatá). The morphological examination revealed distinct characteristics of metacercariae in each host. Using the cytochrome c oxidase I (COI) gene barcode region, we obtained DNA sequences that allowed for accurate phylogenetic placement. Phylogenetic analyses revealed that Clinostomum sp. HM41 (metacercariae), isolated from S. spilopleura, exhibited 86% similarity to Ithyoclinostomum yamagutii, while Clinostomum sp. HM125 (metacercariae), from C. callichthys, showed 98.7% similarity to Clinostomum sp. Cr_Ha1. The phylogenetic trees constructed through Bayesian Inference and Maximum Likelihood methods indicated high biodiversity within the Clinostomum genus and strong support for distinct lineages. These findings enhance our understanding of the diversity and ecological distribution of Clinostomum species in South American freshwater environments.
With wide-field phased array feed technology, the Australian Square Kilometre Array Pathfinder (ASKAP) is ideally suited to search for seemingly rare radio transient sources that are difficult to discover previous-generation narrow-field telescopes. The Commensal Real-time ASKAP Fast Transient (CRAFT) Survey Science Project has developed instrumentation to continuously search for fast radio transients (duration $\lesssim$ 1 s) with ASKAP, with a particular focus on finding and localising fast radio bursts (FRBs). Since 2018, the CRAFT survey has been searching for FRBs and other fast transients by incoherently adding the intensities received by individual ASKAP antennas, and then correcting for the impact of frequency dispersion on these short-duration signals in the resultant incoherent sum (ICS) in real time. This low-latency detection enables the triggering of voltage buffers, which facilitates the localisation of the transient source and the study of spectro-polarimetric properties at high time resolution. Here we report the sample of 43 FRBs discovered in this CRAFT/ICS survey to date. This includes 22 FRBs that had not previously been reported: 16 FRBs localised by ASKAP to $\lesssim 1$ arcsec and 6 FRBs localised to $\sim 10$ arcmin. Of the new arcsecond-localised FRBs, we have identified and characterised host galaxies (and measured redshifts) for 11. The median of all 30 measured host redshifts from the survey to date is $z=0.23$. We summarise results from the searches, in particular those contributing to our understanding of the burst progenitors and emission mechanisms, and on the use of bursts as probes of intervening media. We conclude by foreshadowing future FRB surveys with ASKAP using a coherent detection system that is currently being commissioned. This will increase the burst detection rate by a factor of approximately ten and also the distance to which ASKAP can localise FRBs.
Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data.
Methods
We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors.
Results
The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms).
Conclusion
The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.
Researchers often aim to assess whether repeated measures of an exposure are associated with repeated measures of an outcome. A question of particular interest is how associations between exposures and outcomes may differ over time. In other words, researchers may seek the best form of a temporal model. While several models are possible, researchers often consider a few key models. For example, researchers may hypothesize that an exposure measured during a sensitive period may be associated with repeated measures of the outcome over time. Alternatively, they may hypothesize that the exposure measured immediately before the current time period may be most strongly associated with the outcome at the current time. Finally, they may hypothesize that all prior exposures are important. Many analytic methods cannot compare and evaluate these alternative temporal models, perhaps because they make the restrictive assumption that the associations between exposures and outcomes remains constant over time. Instead, we provide a tutorial describing four temporal models that allow the associations between repeated measures of exposures and outcomes to vary, and showing how to test which temporal model is best supported by the data. By finding the best temporal model, developmental psychopathology researchers can find optimal windows for intervention.
Coal is declining in the U.S. as part of the clean energy transition, resulting in remarkable air pollution benefits for the American public and significant costs for the industry. Using the AP3 integrated assessment model, we estimate that fewer emissions of sulfur dioxide, nitrogen oxides, and primary fine particulate matter driven by coal’s decline led to $300 billion in benefits from 2014 to 2019. Conversely, we find that job losses driven by less coal plant and mining activity resulted in $7.84 billion in foregone wages over the same timeframe. While the benefits were greatly distributed (mostly throughout the East), costs were highly concentrated in coal communities. Transferring a small fraction of the benefits to workers could cover these costs while maintaining societal net benefits. Forecasting coal fleet damages from 2020 to 2035, we find that buying out or replacing these plants would result in $589 billion in air quality benefits, which considerably outweigh the costs. The return on investment increases when policy targets the most damaging capacity, and net benefits are maximized when removing just facilities where marginal benefits exceed marginal costs. Evaluating competitive reverse auction policy designs akin to Germany’s Coal Exit Act, we find that adjusting bids based on monetary damages rather than based only on carbon dioxide emissions – the German design – provides a welfare advantage. Our benefit–cost analyses clearly support policies that drive a swift and just transition away from coal, thereby clearing the air while supporting communities needing assistance.
Cyber-Physical-Systems provide extensive data gathering opportunities along the lifecycle, enabling data-driven design to improve the design process. However, its implementation faces challenges, particularly in the initial data capturing stage. To identify those, a comprehensive approach combining a systematic literature review and an industry survey was applied. Four groups of interrelated challenges were identified as most relevant to practitioners: data selection, data availability in systems, knowledge about data science processes and tools, and guiding users in targeted data capturing.
Alteration experiments have been performed using RTT7 and synthetic basaltic glasses in MgCl2−CaCl2 salt solution at 190°C. The duration of experiments ranged from 0.25 to 463 days. The alteration products were studied by Scanning Electron Microscope (SEM), Scanning Transmission Electron Microscope (STEM), X-ray diffraction (XRD) and Electron Spectrometry for Chemical Analysis (ESCA). For both glasses, the early alteration product is a hydrotalcite-like compound [Mg6Al2CO3(OH)16·4H2O] in which HPO42−, SO42− and Cl− substitutes for CO32−. The measured basal spacing is 7.68 Å for the hydrotalcite formed from R7T7 glass and 7.62 Å for the hydrotalcite formed from basaltic glass which reflect the high Al/Al + Mg ratios x (0.34 ≤ x ≤ 0.46). The chemical microanalyses show that the hydrotalcite is subsequently covered by a silica-rich gel which evolves into saponite after a few months. These results support the use of basaltic glasses alteration patterns in Mg-rich solution, to understand the long-term behavior of R7T7 nuclear waste glass.
End members and species defined with permissible ranges of composition are presented for the true micas, the brittle micas and the interlayer-cation-deficient micas. The determination of the crystallochemical formula for different available chemical data is outlined, and a system of modifiers and suffixes is given to allow the expression of unusual chemical substitutions or polytypic stacking arrangements. Tables of mica synonyms, varieties, ill-defined materials and a list of names formerly or erroneously used for micas are presented. The Mica Subcommittee was appointed by the Commission on New Minerals and Mineral Names (“Commission”) of the International Mineralogical Association (IMA). The definitions and recommendations presented were approved by the Commission.
We assess the association between self-reported history of periodontal disease diagnosis with self-reported cognitive and functional decline at age ∼60. We also investigate (1) the roles of social background, demographic characteristics, education, and adolescent test scores in confounding that association and (2) the role of cardiovascular disease in mediating that association.
Participants and Methods:
We use data from a nationally representative sample of 13,525 people who participated in the 2021 wave of the High School & Beyond (HSB) cohort study. HSB began in 1980 with a nationally-representative sample of American 10th and 12th grade students; these students have been followed up on six occasions since 1980, yielding extraordinary and prospectively-collected life course data on all key measures for a large, multicultural sample.
In 2021, HSB sample members were evaluated with neuropsychological tests that evaluated list learning and memory, semantic and letter fluency, and working memory. They were also asked to self-report memory and functional decline using the AD8, using a cutoff of 2 or more items for significant concerns. Mild Cognitive Impairment will be identified using an algorithm validated in a similar sample of middle aged participants.
Sample members were also asked in 2021 whether a medical professional had ever diagnosed them with periodontal disease; those responding affirmatively were then asked the years in which they started and stopped having periodontal disease.
Measures of social and economic background; demographic characteristics; and educational contexts, opportunities, and attainments were measured prospectively—and in great detail—in the surveys administered in the 1980s. Critically, almost all sample members completed a series of cognitive tasks during adolescence, allowing us to address a key set of confounders in the relationship between periodontal disease and MCI. Markers of cardiovascular disease were measured in both 2013 and 2021.
We estimate logistic regression models predicting significant cognitive and functional concerns as a function of periodontal disease history; we also estimate models that account for confounders, including social background, demographic characteristics, education, and cognitive skills during adolescence; finally, we estimate models that account for the mediating role of cardiovascular disease. All models account for the clustered sampling design of HSB and employ sampling weights to account for HSB’s complex sampling design and selective attrition from the panel.
Results:
About 15% of the cohort has been diagnosed with periodontal disease, and nearly one in five had significant cognitive and functional concerns.
People with a history of periodontal disease were more likely to report significant cognitive and functional concerns. This association remains substantive and statistically significant after adjusting for confounders. All else equal, the odds of people with a history of periodontal disease having an AD8 score of 2 or higher were about 60% greater than the odds of those not reporting periodontal disease. Very little of this association can be attributed to cardiovascular disease as a mediating pathway.
Conclusions:
People with a history of periodontal disease are at greatly elevated risk of self-reported cognitive and functional concerns at age ∼60. This supports evidence— never before collected at this scale in a long-term, representative cohort study—that oral pathogens may contribute to cognitive well-being over the life course.
We ask about the degree to which the association between (1) the quantity and quality of people’s education and (2) midlife self-reported concerns about cognition and daily function is mediated by occupational complexity. The overarching hypothesis is that amount and quality of education provides people with access to better jobs, including jobs that are more cognitively complex. Occupational complexity, in turn, may be protective against cognitive impairment. If true, this means that part of the poorly-understood connection between education and cognitive impairment can be attributed to occupational complexity.
Participants and Methods:
We use data from a nationally representative sample of 13,525 people who participated in the 2021 wave of the High School & Beyond (HSB) cohort study. HSB began in 1980 with a nationally-representative sample of American 10th and 12th grade students; these students have been followed up on six occasions since 1980, yielding extraordinary and prospectively-collected life course data on all key measures for a large, multicultural sample.
In 2021, HSB sample members were evaluated with neuropsychological tests that evaluated list learning and memory, semantic and letter fluency, and working memory. They were also asked to self-report memory and functional decline using the AD8, using a cutoff of 2 or more items for significant concerns. Mild Cognitive Impairment will be identified using an algorithm validated in a similar sample of middle aged participants.
HSB surveys gathered information about sample members’ labor force activities in every survey between 1980 and 2021, including information sufficient to code verbatim reports of occupations to the standards of the 2010 Standard Occupational Classification. We have linked these codes for sample members’ 2013 and 2021 occupations to the O*Net database, which includes extensive information about the cognitive complexity (and other attributes) of every occupation.
Measures of key confounders—including social and economic background; demographic characteristics; educational contexts, opportunities, and attainments that are associated with labor force outcomes; adolescent achievement test scores; and aspects of midlife occupations besides complexity (e.g., how well they pay)—were measured prospectively and in great detail in the surveys administered between the 1980s and 2021.
We estimate logistic regression models predicting significant cognitive and functional concerns as a function of educational contexts, opportunities, and outcomes; we also estimate models that account for the confounders listed above. Our main focus is on coefficients for education in models that do and do not include occupational complexity as a mediator. All models account for the clustered sampling design of HSB and use sampling weights to account for HSB’s complex sampling design and selective attrition from the panel.
Results:
Nearly one in five cohort members had significant cognitive and functional concerns; rates are lower for non-Latinx Whites and for better educated people. Associations between educational contexts, opportunities, and outcomes (including attainment) are robust, even after adjusting for confounders.
Between one quarter and one third of the conditional association between education and self-reported cognitive and functional concerns can be attributed to occupational complexity.
Conclusions:
Occupational complexity is an important pathway through which more and better education protects people from concerns about cognitive and functional decline at about age 60.
The ubiquity of mobile devices allows researchers to assess people’s real-life behaviors objectively, unobtrusively, and with high temporal resolution. As a result, psychological mobile sensing research has grown rapidly. However, only very few cross-cultural mobile sensing studies have been conducted to date. In addition, existing multi-country studies often fail to acknowledge or examine possible cross-cultural differences. In this chapter, we illustrate biases that can occur when conducting cross-cultural mobile sensing studies. Such biases can relate to measurement, construct, sample, device type, user practices, and environmental factors. We also propose mitigation strategies to minimize these biases, such as the use of informants with expertise in local culture, the development of cross-culturally comparable instruments, the use of culture-specific recruiting strategies and incentives, and rigorous reporting standards regarding the generalizability of research findings. We hope to inspire rigorous comparative research to establish and refine mobile sensing methodologies for cross-cultural psychology.
Debate is ongoing on the efficacy of cognitive behavior therapy (CBT) for myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). With an individual patient data (IPD) meta-analysis we investigated whether the effect of CBT varied by patient characteristics. These included post-exertional malaise (PEM), a central feature of ME/CFS according to many. We searched for randomized controlled trials similar with respect to comparison condition, outcomes and treatment-protocol. Moderation on fatigue severity (Checklist Individual Strength, subscale fatigue severity), functional impairment (Sickness Impact Profile-8) and physical functioning (Short Form-36, subscale physical functioning) was investigated using linear mixed model analyses and interaction tests. PROSPERO (CRD42022358245). Data from eight trials (n = 1298 patients) were pooled. CBT showed beneficial effects on fatigue severity (β = −11.46, 95% CI −15.13 to −7.79); p < 0.001, functional impairment (β = −448.40, 95% CI −625.58 to −271.23); p < 0.001; and physical functioning (β = 9.64, 95% CI 3.30 to 15.98); p < 0.001. The effect of CBT on fatigue severity varied by age (pinteraction = 0.003), functional impairment (pinteraction = 0.045) and physical activity pattern (pinteraction = 0.027). Patients who were younger, reported less functional impairments and had a fluctuating activity pattern benefitted more. The effect on physical functioning varied by self-efficacy (pinteraction = 0.025), with patients with higher self-efficacy benefitting most. No other moderators were found. It can be concluded from this study that CBT for ME/CFS can lead to significant reductions of fatigue, functional impairment, and physical limitations. There is no indication patients meeting different case definitions or reporting additional symptoms benefit less from CBT. Our findings do not support recent guidelines in which evidence from studies not mandating PEM was downgraded.
Help-seeking for mental health problems is facilitated and hindered by several factors at the individual, interpersonal and community level. The most frequently researched factors contributing to differences in help-seeking behaviour are based on classical socio-demographic variables, such as age, gender and education, but explanations for the observed differences are often absent or remain vague. The present study complements traditional approaches in help-seeking research by introducing a milieu approach, focusing on values and political attitudes as a possible explanation for differences in help-seeking for emotional mental health problems.
Methods
A representative cross-sectional survey of N = 3,042 respondents in Germany was conducted through face-to-face interviews about past help-seeking for mental health problems, socio-demographic characteristics and values and political attitudes
Results
Multivariate logistic regression analyses indicated that belonging to a cosmopolitan intellectual milieu group was significantly associated with an increased likelihood of past help-seeking for mental health issues (psychotherapeutic/psychological help-seeking [OR = 2.09, 95% CI: 1.11–3.93, p < 0.05) and primary care (OR = 2.21, 95% CI: 1.15–4.24, p < 0.05]), whereas members of individualist and conservative milieu groups were less likely to report having sought help from a psychotherapist, but not from a general practitioner. Increased odds ratios were also found for a number of socio-demographic variables, such as being aged 26 years and over, a female gender and more than 12 years of formal education. Associations between socio-demographic variables remained significant, and the explained variance of the used models improved considerably when milieu variables were added.
Conclusions
We discuss how milieu-specific patterns were relevant for explaining differences in mental health service use in addition to socio-demographic factors. It seems promising to consider help-seeking from a milieu perspective to improve disparities in access to and the use of psychotherapy as well as to resource allocation.
We present kinematic, radiometric, geochemical and PT data, which help to constrain the tectonometamorphic evolution of the Tripolitza Unit (TPU). The age of both the metamorphic peak (P = 0.4 ±0.2 GPa, T = ca. 310 °C) and top-to-the WNW mylonitic thrusting, attributed to the emplacement of the hanging Pindos nappe, has been constrained at 19 ±2.5 Ma using Rb-Sr on synkinematic white mica of a basal mylonite of NW Crete. This early tectonic event is also documented by the oldest generation of veins, which cut through less metamorphic (T = 240 ±15 °C) late Bartonian/Priabonian Nummulite limestone exposed as olistolith in TPU flysch of central Crete. Calcite of these veins yielded a similar U-Pb age at 20 ±6 Ma. U-Pb dating of matrix calcite, on the other hand, reflect the time of sedimentation (38.4 ±5.7 Ma and 37.6 ±1.2 Ma), which is in line with the faunal content of the black limestone. Geochemical data and U-Pb calcite ages of fibres of the Nummulite test (32.3 ±3.1 Ma and 34.6 ±0.9 Ma) suggest unexpected pseudomorphic fibre replacement during late Priabonian/early Rupelian diagenesis. Additional calcite veins, which developed at ca. 10–11 and 7 – 9 Ma (U-Pb on calcite), are attributed to top-to-the S thrusting and subsequent extension, respectively. The resulting anticlockwise rotation of the shortening direction within the TPU from WNW-ESE at ca. 20 Ma to N-S at ca. 10 Ma has significant implications for the geodynamic evolution of the External Hellenides.