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Background: Although principles of the health promoting school (HPS) approach are followed worldwide, differences between countries in the implementation are reported. The aim of the current study was (1) to examine the implementation of the HPS approach in European countries in terms of different implementation indicators, that is, percentage of schools implementing the HPS approach, implementation of core components, and positioning on so-called HPS-related spectra, (2) to explore patterns of consistency between the implementation indicators across countries, and (3) to examine perceived barriers and facilitators to the implementation of the HPS approach across countries. Methods: This study analyzed data from a survey that was part of the Schools for Health in Europe network's Monitoring Task 2020. The survey was completed by HPS representatives of 24 network member countries. Results: Large variations exist in (the influencing factors for) the implementation of the HPS approach in European countries. Observed patterns show that countries with higher percentages of schools implementing the HPS approach also score higher on the implementation of the core components and, in terms of spectra, more toward implementing multiple HPS core components, add-in strategies, action-oriented research and national-level driven dissemination. In each country a unique mix of barriers and facilitators was observed. Conclusion: Countries committed to implementing the HPS approach in as many schools as possible also seem to pay attention to the quality of implementation. For a complete and accurate measurement of implementation, the use of multiple implementation indicators is desirable.

ObjectivesThe mortuary record at Middle Period site Kalawwasa Rummeytak (CA-SCL-134) (2600-1225 cal BP) in California's southern Santa Clara Valley shows pronounced wealth inequality; Olivella shell bead wealth, as well as other grave goods, are concentrated in the burials of several older adult females. The concentration of wealth among women, along with regional strontium isotopic evidence of male-biased residential shifts in early adulthood, suggests a matrilineal kinship system that practiced matrilocal post-marital residence patterns. We suggest local resource enhancement effects incentivized keeping women in their natal communities and investing more in female offspring.Materials and methodsWith the consent of, and in collaboration with, the Muwekma Ohlone Tribe of the San Francisco Bay Area, this paper employs isotopic analysis (δ15 N and δ13 C, 86 Sr/87 Sr) to examine duration of exclusive breastfeeding, weaning age (complete cessation of breastmilk consumption), early childhood diet, and lifetime residential mobility of individuals interred at Kalawwasa Rummeytak to test the assumption that the site inhabitants favored matrilocality and that female offspring received greater levels of investment in groups with female wealth/status attainment. First molars, third molars, and bone was sampled from 22 individuals.ResultsThe average weaning age for females at Kalawwasa Rummeytak is 36.3 months ± 9.7 (1 SD), or just over 3 years. The average weaning age for males is 31.2 ± 7.9 months (1 SD), or about 2.6 years. Infants at the site were provisioned with supplemental foods dominated by C3 plants and terrestrial herbivores, as well as anadromous fish. After weaning, individuals consumed a diet dominated by acorns, C3 plants, and terrestrial herbivores, with periodic inclusion of anadromous fish. 30% of the sampled population of females exhibit local first molar 87 Sr/86 Sr values, suggesting that Kalawwasa Rummeytak is their natal community. None of the males interred at the site are locals.DiscussionDespite the small sample size often unavoidable in archaeological contexts, we find possible female-biased parental investment strategies. Cessation of breastfeeding (weaning) was, on average, 5 months earlier for males compared to females. There are no differences between females and males in the consumption of supplemental or post-weaning foods. Strontium data suggest a flexible postmarital residence system that favored matrilocality. This may have incentivized greater investment in female offspring.

Summary: Background: Female Lynch syndrome carriers have an increased risk of developing endometrial cancer. Regardless, research on endometrial carcinoma tumorigenesis is scarce and no uniform, evidence-based gynaecological management guidelines exist. We therefore described gynaecological surveillance and surgery outcomes in a nation-wide Lynch syndrome cohort. Methods: For this retrospective cohort study, female Lynch syndrome carriers, prospectively registered in the Dutch Lynch syndrome database (StOET), were included up to February 28th 2022. Carriers were linked to the Dutch national pathology (PALGA) database. The number of carriers with/without gynaecological surveillance, number of index carriers with endometrial carcinoma before Lynch syndrome diagnosis were assessed, as well as uptake of risk-reducing surgery and characteristics of endometrial carcinomas including the requisite for adjuvant therapy according to current guidelines. Overall survival after endometrial carcinoma diagnosis was analyzed using Kaplan Meier time to event analyses, cumulative incidence was calculated after adjusting for competing risks (death and prophylactic hysterectomy). Findings: In total, 1046 registered female Lynch syndrome carriers were eligible for surveillance, of whom 313 (30.0%) did not have surveillance and 21.4% (n = 224 of 1046) opted for prophylactic hysterectomy. In carriers with surveillance, more cases of endometrial carcinoma and hyperplasia were found than in those without (37 endometrial carcinomas (7.3%) and 28 hyperplasias (5.5%) in 506 carriers with surveillance versus 14 (2.6%) and 4 (0.7%) in 540 carriers without surveillance, respectively); carriers with surveillance were generally younger than those without (median 56 years [IQR 48–65] versus median 65 years [IQR 49–75] at database assembly, respectively; p

This article presents outcomes from a Workshop entitled "Bioarchaeology: Taking Stock and Moving Forward," which was held at Arizona State University (ASU) on March 6-8, 2020. Funded by the National Science Foundation (NSF), the School of Human Evolution and Social Change (ASU), and the Center for Bioarchaeological Research (CBR, ASU), the Workshop's overall goal was to explore reasons why research proposals submitted by bioarchaeologists, both graduate students and established scholars, fared disproportionately poorly within recent NSF Anthropology Program competitions and to offer advice for increasing success. Therefore, this Workshop comprised 43 international scholars and four advanced graduate students with a history of successful grant acquisition, primarily from the United States. Ultimately, we focused on two related aims: (1) best practices for improving research designs and training and (2) evaluating topics of contemporary significance that reverberate through history and beyond as promising trajectories for bioarchaeological research. Among the former were contextual grounding, research question/hypothesis generation, statistical procedures appropriate for small samples and mixed qualitative/quantitative data, the salience of Bayesian methods, and training program content. Topical foci included ethics, social inequality, identity (including intersectionality), climate change, migration, violence, epidemic disease, adaptability/plasticity, the osteological paradox, and the developmental origins of health and disease. Given the profound changes required globally to address decolonization in the 21st century, this concern also entered many formal and informal discussions.

Purpose: Adapting the Health Promotion School (HPS) approach to context specifics is acknowledged as being essential for implementation and achieving optimal effectiveness. This study aims to explore implementation variations on seven HPS spectra (such as top-down to bottom-up involvement of stakeholders) on which implementation of the HPS approach can vary, and the factors that relate to navigation on these spectra. Design/methodology/approach: In 2020, fourteen HPS researchers and professionals from ten European countries participated in semi-structured interviews. Findings: Navigation variations on the HPS spectra occurred throughout most spectra. Further, a tendency was found towards spectrum extremes of addressing multiple core-components, implementing non-disruptive Health Promotion (HP) programmes, and evaluating the HPS approach through an action-oriented research approach. Important general factors were resources, staff capacity and time available to staff members for implementing the HPS approach. Some spectra required more specific factors like organisational skills, leadership or a certain level of democracy. Practical implications: The implementation of the HPS approach should be supported by implementation strategies addressing the spectrum-specific factors, but more generic factors such as staff capacity, resources and the level of democracy should also be considered. Originality/value: This study explores navigation variations throughout HPS spectra rather than the HPS approach in general. It also nuances implementation diversity across and within different European contexts.

Abstract Purpose A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. Methods This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. Results 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI − 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (− 1.17 ml/kg, 95% CI − 1.87 to − 0.44). Conclusions IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).

Previous stable isotope research on Middle-to-Late Holocene (6600 cal BP-present) hunter-gatherers of Central California has documented significant regional variation in human paleodiets between the San Francisco Bay Area and Central Valley. In general, this geographically-patterned dietary variation tracks greater consumption of marine food resources in the Bay Area and greater consumption of freshwater and terrestrial food resources in the Central Valley. Using stable carbon and nitrogen isotope analysis of bone collagen, stable carbon isotopes of bone bioapatite, and a large series of AMS dates (5420-2975 cal BP), we examine human paleodiets in 238 burials from CA-CCO-548 (Marsh Creek), located near the Sacramento-San Joaquin Delta, in Central California. Isotopic results support archaeofaunal and paleobotanical findings regarding the dietary importance of terrestrial C3-resources (e.g., artiodactyls, small seeds, acorns) and freshwater fish. The results further indicate that marine resources were of minor importance and could have been acquired from brackish areas near the mouth of the San Francisco Bay estuary located 9 km away or through trade. Although carbon and nitrogen isotopes of bone collagen suggest continuity in the sources of dietary protein over time. Carbon isotopes of bone bioapatite demonstrate a significant temporal shift toward greater consumption of C3 plant resources, such as acorns and small seeds, consistent with resource intensification models. The paleodiet of the CA-CCO-548 population is similar to contemporaneous groups located to the south and northwest, but is distinct from groups within the Delta and San Francisco Bay Area.

Previous stable isotope research on Middle-to-Late Holocene (6600 cal BP-present) hunter-gatherers of Central California has documented significant regional variation in human paleodiets between the San Francisco Bay Area and Central Valley. In general, this geographically-patterned dietary variation tracks greater consumption of marine food resources in the Bay Area and greater consumption of freshwater and terrestrial food resources in the Central Valley. Using stable carbon and nitrogen isotope analysis of bone collagen, stable carbon isotopes of bone bioapatite, and a large series of AMS dates (5420-2975 cal BP), we examine human paleodiets in 238 burials from CA-CCO-548 (Marsh Creek), located near the Sacramento-San Joaquin Delta, in Central California. Isotopic results support archaeofaunal and paleobotanical findings regarding the dietary importance of terrestrial C3-resources (e.g., artiodactyls, small seeds, acorns) and freshwater fish. The results further indicate that marine resources were of minor importance and could have been acquired from brackish areas near the mouth of the San Francisco Bay estuary located 9 km away or through trade. Although carbon and nitrogen isotopes of bone collagen suggest continuity in the sources of dietary protein over time. Carbon isotopes of bone bioapatite demonstrate a significant temporal shift toward greater consumption of C3 plant resources, such as acorns and small seeds, consistent with resource intensification models. The paleodiet of the CA-CCO-548 population is similar to contemporaneous groups located to the south and northwest, but is distinct from groups within the Delta and San Francisco Bay Area.

Abstract Background Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. Methods CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. Discussion The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. Trial registration EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016. Graphical Abstract

Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State-of-the-art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient-specific information on drug accessibility at the tumor tissue level, target binding, and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing.

Abstract An accurate estimated glomerular filtration rate (eGFR) is essential in drug dosing. This study demonstrates the limitations of indexed (ml/min/1.73 m2) and de‐indexed (ml/min) eGFR based drug dosing in patients with obesity or underweight. This systematic study aimed to determine the most appropriate approach to estimate the GFR for standardized eGFR based drug dosing in these patients. (Raw) data of 12 studies were selected to investigate the accuracy and bias of both the indexed and de‐indexed estimations of the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration equation (CKD‐EPI), and of the Cockcroft–Gault (CG) in patients with obesity or underweight. Accuracy was calculated as the proportion of eGFR values within 30% of the measured GFR (P30) using an inert tracer (e.g., iohexol, inulin, 51Cr‐EDTA, or iothalamate clearance). An accuracy of at least 80% was considered acceptable. GFR values estimated with the CG, MDRD, and CKD‐EPI differ significantly within a patient with obesity or underweight regardless of whether it is indexed or de‐indexed. All studies, with two exceptions, show that all three equations are inaccurate for patients with underweight or class II obesity (P30: 55%–94%). De‐indexing eGFR improves not or modestly the accuracy, and mostly remains below the 80% (P30: 62%–100%). CG was highly inaccurate in obese and underweight patients (P30: 7%–82%). Although these results show that CG is obsolete, the accuracy of MDRD and CKD‐EPI is low in patients with obesity or underweight and de‐indexing is not the solution. Better education and more accurate methods for appropriate drug dosing (e.g., measured GFR with inert tracer, therapeutic drug monitoring, or 24‐h creatinine clearance) are recommended.

Abstract Objective Vanishing white matter (VWM) is a leukodystrophy, characterized by stress‐sensitive neurological deterioration and premature death. It is currently without curative treatment. It is caused by bi‐allelic pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for the regulation of the integrated stress response (ISR), a physiological response to cellular stress. Preclinical studies on VWM mouse models revealed that deregulated ISR is key in the pathophysiology of VWM and an effective treatment target. Guanabenz, an α2‐adrenergic agonist, attenuates the ISR and has beneficial effects on VWM neuropathology. The current study aimed at elucidating guanabenz's disease‐modifying potential and mechanism of action in VWM mice. Sephin1, an ISR‐modulating guanabenz analog without α2‐adrenergic agonistic properties, was included to separate effects on the ISR from α2‐adrenergic effects. Methods Wild‐type and VWM mice were subjected to placebo, guanabenz or sephin1 treatments. Effects on clinical signs, neuropathology, and ISR deregulation were determined. Guanabenz's and sephin1's ISR‐modifying effects were tested in cultured cells that expressed or lacked the α2‐adrenergic receptor. Results Guanabenz improved clinical signs, neuropathological hallmarks, and ISR regulation in VWM mice, but sephin1 did not. Guanabenz's effects on the ISR in VWM mice were not replicated in cell cultures and the contribution of α2‐adrenergic effects on the deregulated ISR could therefore not be assessed. Interpretation Guanabenz proved itself as a viable treatment option for VWM. The exact mechanism through which guanabenz exerts its ameliorating impact on VWM requires further studies. Sephin1 is not simply a guanabenz replacement without α2‐adrenergic effects.