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Aim: Bile acids (BAs) are implicated in the pathogenesis of several metabolic syndrome‐related diseases, including insulin resistance (IR) and type 2 diabetes (T2D). It has been reported that IR and T2D are associated with an increased ratio of 12α/non‐12α‐hydroxylated BAs in the circulating BA pool. It is, however, unknown whether the improvement of insulin sensitivity inversely affects BA composition in humans. Therefore, we assessed whether lifestyle‐induced weight loss induces changes in BA metabolism in people with obesity, with or without T2D, and if these changes are associated with metabolic parameters. Materials and Methods: Individual BAs and C4 were quantified by ultra‐high‐performance liquid chromatography‐tandem mass spectrometry in plasma samples collected from two cohorts of people with obesity (OB) and with T2D and obesity (T2D), before and after a lifestyle intervention. Results: Lifestyle‐induced weight loss improved glycaemic control in both cohorts, with plasma BA concentrations not affected by the lifestyle interventions. The ratio of 12α/non‐12α‐hydroxylated BAs remained unchanged in OB (p =.178) and even slightly increased upon intervention in T2D (p =.0147). Plasma C4 levels were unaffected in OB participants (p =.20) but significantly reduced in T2D after intervention (p =.0003). There were no significant correlations between the ratio of 12α/non‐12α‐hydroxylated BAs and glucose, insulin, or homeostatic model assessment‐IR, nor in plasma triglycerides, low‐density lipoprotein cholesterol, lipoprotein (a) in the T2D cohort. Conclusions: Lifestyle‐induced weight loss did improve glycaemic control but did not affect BA concentrations. Improvements in insulin sensitivity were not associated with changes in BA parameters in people with obesity, with or without T2D. [ABSTRACT FROM AUTHOR]

The principle of maximum ignorance posits that the coarse-grained description of a system is maximally agnostic about its underlying microscopic structure. We briefly review this principle for random matrix theory and for the eigenstate thermalization hypothesis. We then apply this principle in holography to construct ensembles of random mixed states. This leads to an ensemble of microstates which models our microscopic ignorance, and which on average reproduces the effective semiclassical physics of a given bulk state. We call this ensemble the state-averaging ansatz. The output of our model is a prediction for semiclassical contributions to variances and higher statistical moments over the ensemble of microstates. The statistical moments provide coarse-grained — yet gravitationally non-perturbative — information about the microstructure of the individual states of the ensemble. We show that these contributions exactly match the on-shell action of known wormhole configurations of the gravitational path integral. These results strengthen the view that wormholes simply parametrize the ignorance of the microstructure of a fundamental state, given a fixed semiclassical bulk description. [ABSTRACT FROM AUTHOR]

Copyright of Historische Zeitschrift is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chemoradiotherapy with cisplatin in a triweekly regimen of 100 mg/m2 body surface area, is used to treat locally advanced head and neck squamous cell carcinoma (HNSCC) with curative intent. Cisplatin dose limiting toxicity (CDLT) occurs often and impedes obtaining the planned cumulative cisplatin dose. A cumulative cisplatin dose of 200 mg/m2 or more is warranted for better survival and locoregional control. Patients with a low skeletal muscle mass (SMM) have a three-fold higher risk of developing CDLT than patients with a normal SMM. SMM can be assessed through measurements on routinely performed diagnostic head and neck CT- or MRI-scans. A weekly regimen of 40 mg/m2 body surface area cisplatin is proposed as a less toxic schedule, which possibly decreases the risk of developing CDLT and enables reaching a higher cumulative cisplatin dose. The aim of this multicenter randomized clinical trial (NL76533.041.21, registered in the Netherlands Trial Register) is to identify whether a regimen of weekly cisplatin increases compliance to the planned chemotherapy scheme in HNSCC patients with low SMM. The primary outcome is the difference in compliance rate, defined as absence of CDLT, between low SMM patients receiving either the weekly or triweekly regimen. Secondary outcomes consist of toxicities, the cumulative cisplatin dose, time to recurrence, incidence of recurrence at two years of follow-up, location of recurrence, 2-year overall, disease free and disease specific survival, quality of life, patient's experiences, and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Cyp2c70-deficient mice have a human-like bile acid (BA) composition due to their inability to convert chenodeoxycholic acid (CDCA) into rodent-specific muricholic acids (MCAs). However, the hydrophobic BA composition in these animals is associated with liver pathology. Al-though Cyp2c70-ablation has been shown to alter gut microbiome composition, the impact of gut bacteria on liver pathology in Cyp2c70−/− mice remains to be established. Therefore, we treated young-adult male and female wild-type (WT) and Cyp2c70−/− mice with antibiotics (AB) with broad specificity to deplete the gut microbiota and assessed the consequences on BA metabolism and liver pathology. Female Cyp2c70−/− mice did not tolerate AB treatment, necessitating premature termination of the experiment. Male Cyp2c70−/− mice did tolerate AB but showed markedly augmented liver pathology after 6 weeks of treatment. Dramatic downregulation of hepatic Cyp8b1 expression (−99%) caused a reduction in the proportions of 12α-hydroxylated BAs in the circulating BA pools of AB-treated male Cyp2c70−/− mice. Interestingly, the resulting increased BA hydrophobicity strongly correlated with various indicators of liver pathology. Moreover, genetic inactivation of Cyp8b1 in livers of male Cyp2c70−/− mice increased liver pathology, while addition of ursodeoxycholic acid to the diet prevented weight loss and liver pathology in AB-treated female Cyp2c70−/− mice. In conclusion, depletion of gut microbiota in Cyp2c70−/− mice aggravates liver pathology at least in part by increasing the hydrophobicity of the circulating BA pool. These findings highlight that the potential implications of AB administration to cholestatic patients should be evaluated in a systematic manner. [ABSTRACT FROM AUTHOR]

Driven quantum systems exhibit a large variety of interesting and sometimes exotic phenomena. Of particular interest are driven conformal field theories (CFTs) which describe quantum many-body systems at criticality. In this paper, we develop both a spacetime and a quantum information geometry perspective on driven 2d CFTs. We show that for a large class of driving protocols the theories admit an alternative but equivalent formulation in terms of a CFT defined on a spacetime with a time-dependent metric. We prove this equivalence both in the operator formulation as well as in the path integral description of the theory. A complementary quantum information geometric perspective for driven 2d CFTs employs the so-called Bogoliubov-Kubo-Mori (BKM) metric, which is the counterpart of the Fisher metric of classical information theory, and which is obtained from a perturbative expansion of relative entropy. We compute the BKM metric for the universal sector of Virasoro excitations of a thermal state, which captures a large class of driving protocols, and find it to be a useful tool to classify and characterize different types of driving. For Möbius driving by the SL(2, ℝ) subgroup, the BKM metric becomes the hyperbolic metric on the disk. We show how the non-trivial dynamics of Floquet driven CFTs is encoded in the BKM geometry via Möbius transformations. This allows us to identify ergodic and non-ergodic regimes in the driving. We also explain how holographic driven CFTs are dual to driven BTZ black holes with evolving horizons. The deformation of the black hole horizon towards and away from the asymptotic boundary provides a holographic understanding of heating and cooling in Floquet CFTs. [ABSTRACT FROM AUTHOR]

We study various aspects of the Carroll limit in which the speed of light is sent to zero. A large part of this paper is devoted to the quantization of Carroll field theories. We show that these exhibit infinite degeneracies in the spectrum and may suffer from non-normalizable ground states. As a consequence, partition functions of Carroll systems are ill-defined and do not lead to sensible thermodynamics. These seemingly pathological properties might actually be a virtue in the context of flat space holography. Better defined is the Carroll regime, in which we consider the leading order term in an expansion around vanishing speed of light without taking the strict Carroll limit. Such an expansion may lead to sensible notions of Carroll thermodynamics. An interesting example is a gas of massless particles with an imaginary chemical potential conjugate to the momentum. In the Carroll regime we show that the partition function of such a gas leads to an equation of state with w = −1. As a separate story, we study aspects of Carroll gravity and couplings to Carrollian energy-momentum tensors. We discuss many examples of solutions to Carroll gravity, including wormholes, Maxwell fields, solutions with a cosmological constant, and discuss the structure of geodesics in a Carroll geometry. The coupling of matter to Carroll gravity also allows us to derive energy-momentum tensors for hypothetical Carroll fluids from expanding relativistic fluids as well as directly from hydrostatic partition functions. [ABSTRACT FROM AUTHOR]

Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70−/− (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70−/− mice with a human-like bile acid composition without affecting insulin sensitivity. [ABSTRACT FROM AUTHOR]

The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. We recently identified SPRING as a post-transcriptional regulator of SREBP activation. Constitutive or inducible global ablation of Spring in mice is not tolerated, and we therefore develop liver-specific Spring knockout mice (LKO). Transcriptomics and proteomics analysis reveal attenuated SREBP signaling in livers and hepatocytes of LKO mice. Total plasma cholesterol is reduced in male and female LKO mice in both the low-density lipoprotein and high-density lipoprotein fractions, while triglycerides are unaffected. Loss of Spring decreases hepatic cholesterol and triglyceride content due to diminished biosynthesis, which coincides with reduced very-low-density lipoprotein secretion. Accordingly, LKO mice are protected from fructose diet-induced hepatosteatosis. In humans, we find common genetic SPRING variants that associate with circulating high-density lipoprotein cholesterol and ApoA1 levels. This study positions SPRING as a core component of hepatic SREBP signaling and systemic lipid metabolism in mice and humans. Hendrix et al show that absence of hepatic Spring dramatically lowers levels of lipids in the liver and plasma in mice, and protects from development of diet-induced steatosis. In line, genetic variation in SPRING is associated with lipid levels in humans. [ABSTRACT FROM AUTHOR]

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24‐dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti‐inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3‐Leiden. CETP mice, a well‐established translational model that develops diet‐induced human‐like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet‐induced hepatic steatosis and inflammation in a strictly LXRα‐dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH. Synopsis: Non‐alcoholic fatty liver disease (NAFLD) affects over 30% of the general population, yet there is currently no medication available for its treatment. This study reports a novel strategy to activate liver X receptors (LXR) via pharmacological Δ24‐dehydrocholesterol reductase (DHCR24) inhibition for the treatment of NAFLD and potentially other cardiometabolic diseases. SH42 inhibits DHCR24 to increase levels of the endogenous LXR agonist desmosterol in the circulation and liver.Inhibition of DHCR24 exerts metabolic and immune benefits in a strictly LXRα‐dependent manner without causing hyperlipidemia.Inhibition of DHCR24 decreases liver collagen content and plasma alanine transaminase levels in an established NAFLD model. [ABSTRACT FROM AUTHOR]

Background: Thyroid cancer (TC) patients are understudied but appear to be at risk for poor physical and psychosocial outcomes. Knowledge of the course and determinants of these deteriorated outcomes is lacking. Furthermore, little is known about mediating biological mechanisms. Objectives: The WaTCh-study aims to; Examine the course of physical and psychosocial outcomes. Examine the association of demographic, environmental, clinical, physiological, and personality characteristics to those outcomes. In other words, who is at risk? Reveal the association of mediating biological mechanisms (inflammation, kynurenine pathway) with poor physical and psychological outcomes. In other words, why is a person at risk? Design and methods: Newly diagnosed TC patients from 13 Dutch hospitals will be invited. Data collection will take place before treatment, and at 6, 12 and 24 months after diagnosis. Sociodemographic and clinical information is available from the Netherlands Cancer Registry. Patients fill-out validated questionnaires at each time-point to assess quality of life, TC-specific symptoms, physical activity, anxiety, depression, health care use, and employment. Patients are asked to donate blood three times to assess inflammation and kynurenine pathway. Optionally, at each occasion, patients can use a weighing scale with bioelectrical impedance analysis (BIA) system to assess body composition; can register food intake using an online food diary; and can wear an activity tracker to assess physical activity and sleep duration/quality. Representative Dutch normative data on the studied physical and psychosocial outcomes is already available. Impact: WaTCh will reveal the course of physical and psychosocial outcomes among TC patients over time and answers the question who is at risk for poor outcomes, and why. This knowledge can be used to provide personalized information, to improve screening, to develop and provide tailored treatment strategies and supportive care, to optimize outcomes, and ultimately increase the number of TC survivors that live in good health. [ABSTRACT FROM AUTHOR]

Lowering intraocular pressure (IOP) by placement of a glaucoma shunt is an effective treatment for glaucoma. However, fibrosis of the outflow site can hamper surgical outcome. In this study, the antifibrotic effect of adding an endplate (with or without microstructured surface topographies) to a microshunt made of poly(styrene‐block‐isobutylene‐block‐styrene) is investigated. New Zealand white rabbits are implanted with a control implant (without endplate) and modified implants. Afterward, bleb morphology and IOP is recorded for 30 days. After killing of the animals, eyes are collected for histology, Addition of an endplate extended bleb survival, Topography‐990 has the longest recorded bleb‐survival time. Histology reveals that the addition of an endplate increases the presence of myofibroblasts, macrophages, polymorphonuclear cells, and foreign body giant cells compared to the control. However, an increased capsule thickness and inflammatory response are observed in the groups with surface topographies, The addition of an endplate results in prolonged bleb survival, demonstrating that engineering of the shape of glaucoma implants could prolong bleb functionality. Future research should further elaborate the effect of surface topographies on long‐term bleb survival, since an increased presence of pro‐fibrotic cells and increased capsule thickness are observed compared to the control. [ABSTRACT FROM AUTHOR]

Copyright of Neue Politische Literatur is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

ice with deletion of Cyp2c70 have a human-like bile acid composition, display age- and sex-dependent signs of hepatobiliary disease and can be used as a model to study interactions between bile acids and the gut microbiota in cholestatic liver disease. In the present study, we rederived Cyp2c70−/− mice as germ-free (GF) and colonized them with a human or a mouse microbiota to investigate whether the presence of a microbiota can be protective in cholangiopathic liver disease associated with Cyp2c70-deficiency. GF Cyp2c70−/− mice showed reduced neonatal survival, liver fibrosis, and distinct cholangiocyte proliferation. Colonization of germ-free breeding pairs with a human or a mouse microbiota normalized neonatal survival of the offspring, and particularly colonization with mouse microbiota from a conventionally raised mouse improved the liver phenotype at 6–10 weeks of age. The improved liver phenotype in conventionalized (CD) Cyp2c70−/− mice was associated with increased levels of tauro-ursodeoxycholic acid (TUDCA) and UDCA, resulting in a more hydrophilic bile acid profile compared with GF and humanized Cyp2c70−/− mice. The hydrophobicity index of biliary bile acids of CD Cyp2c70−/− mice was associated with changes in gut microbiota, liver weight, liver transaminases, and liver fibrosis. Hence, our results indicate that neonatal survival of Cyp2c70−/− mice seems to depend on the establishment of a gut microbiota at birth, and the improved liver phenotype in CD Cyp2c70−/− mice may be mediated by a larger proportion of TUDCA/UDCA in the circulating bile acid pool and/or by the presence of specific bacteria. [ABSTRACT FROM AUTHOR]

We construct worldsheet traversable wormholes by considering the effects of a double-trace deformation, δ L ∼ h ∂ ϕ L ∂ ϕ R , coupling the endpoints of an open string in AdS space. The operator deforming the theory is irrelevant and makes the boundaries bend inward toward the IR. This effect, reminiscent of two-dimensional dilaton gravities, renders the teleportation protocol more efficient and facilitates the transfer of information between the members of the dual Bell pair. We compare our results with those obtained with the standard double-trace deformation, δ L ∼ h ϕ L ϕ R , introduced by Gao, Jafferis and Wall. [ABSTRACT FROM AUTHOR]

We construct operators in holographic two-dimensional conformal field theory, which act locally in the code subspace as arbitrary bulk spacelike vector fields. Key to the construction is an interplay between parallel transport in the bulk spacetime and in kinematic space. We outline challenges, which arise when the same construction is extended to timelike vector fields. We also sketch several applications, including boundary formulations of the bulk Riemann tensor, dreibein, and spin connection, as well as an application to holographic complexity. [ABSTRACT FROM AUTHOR]

Objective: To investigate the incidences of prostate-specific membrane antigen (PSMA) thyroid incidentaloma (PTI) using different methods to define PTI, to compare the incidence of PTI among different PSMA PET tracers, and to evaluate the clinical consequences of PTI. Methods: PSMA PET/CT scans in consecutive patients with primary prostate cancer were analyzed for the presence of PTI using a structured visual (SV) analysis reporting any elevated thyroidal uptake; a semi-quantitative (SQ) analysis using a SUVmax thyroid/bloodpool (t/b) ratio ≥ 2.0 as cutoff; and an analysis of PTI incidence in the clinical reports (RV analysis). Results: A total of 502 patients were included. The incidence of PTIs was 22% in the SV analysis, 7% in the SQ analysis, and 2% in the RV analysis. PTI incidences differed significantly from 29 to 64% (SQ, resp. SV analysis) for [18F]PSMA-1007, 7 to 23% for [68Ga]PSMA-11, 2 to 8% for [18F]DCFPyL, and to 0% for [18F]PSMA-JK-7. The majority of PTI in the SV and SQ analyses consisted of diffuse (72–83%) and/or only slightly elevated thyroidal uptake (70%). Inter-observer agreement in the SV analysis was substantial (kappa = 0.76–0.78). During follow-up (median 16.8 months), there were no thyroid-related adverse events except in three patients. Conclusions: The incidence of PTI varies greatly among different PSMA PET tracers and is strongly dependent on the analysis method applied. PTI may safely be restricted to focal thyroidal uptake with a SUVmax t/b ratio ≥ 2.0. The clinical pursuit of a PTI must be weighed up to the expected outcome of the underlying disease. Key Points: • Thyroid incidentalomas (PTIs) are recognized in PSMA PET/CT. • Incidence of PTI varies greatly among PET tracers and analysis methods. • Incidence of thyroid-related adverse events in PTI cases is low. [ABSTRACT FROM AUTHOR]

Bile acids facilitate the intestinal absorption of dietary lipids and act as signalling molecules in the maintenance of metabolic homeostasis. Farnesoid X receptor (FXR) is a bile acid-responsive nuclear receptor involved in bile acid metabolism, as well as lipid and glucose homeostasis. Several studies have suggested a role of FXR in the control of genes regulating intestinal glucose handling. We applied a novel dual-label glucose kinetic approach in intestine-specific FXR−/− mice (iFXR-KO) to directly assess the role of intestinal FXR in glucose absorption. Although iFXR-KO mice showed decreased duodenal expression of hexokinase 1 (Hk1) under obesogenic conditions, the assessment of glucose fluxes in these mice did not show a role for intestinal FXR in glucose absorption. FXR activation with the specific agonist GS3972 induced Hk1, yet the glucose absorption rate remained unaffected. FXR activation increased the duodenal villus length in mice treated with GS3972, while stem cell proliferation remained unaffected. Accordingly, iFXR-KO mice on either chow, short or long-term HFD feeding displayed a shorter villus length in the duodenum compared to wild-type mice. These findings indicate that delayed glucose absorption reported in whole-body FXR−/− mice is not due to the absence of intestinal FXR. Yet, intestinal FXR does have a role in the small intestinal surface area. [ABSTRACT FROM AUTHOR]

Biomaterials can control cell and nuclear morphology. Since the shape of the nucleus influences chromatin architecture, gene expression and cell identity, surface topography can control cell phenotype. This study provides fundamental insights into how surface topography influences nuclear morphology, histone modifications, and expression of histone‐associated proteins through advanced histone mass spectrometry and microarray analysis. The authors find that nuclear confinement is associated with a loss of histone acetylation and nucleoli abundance, while pathway analysis reveals a substantial reduction in gene expression associated with chromosome organization. In light of previous observations where the authors found a decrease in proliferation and metabolism induced by micro‐topographies, they connect these findings with a quiescent phenotype in mesenchymal stem cells, as further shown by a reduction of ribosomal proteins and the maintenance of multipotency on micro‐topographies after long‐term culture conditions. Also, this influence of micro‐topographies on nuclear morphology and proliferation is reversible, as shown by a return of proliferation when re‐cultured on a flat surface. The findings provide novel insights into how biophysical signaling influences the epigenetic landscape and subsequent cellular phenotype. [ABSTRACT FROM AUTHOR]

Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice. [ABSTRACT FROM AUTHOR]

The spectral form factor is a powerful probe of quantum chaos that diagnoses the statistics of energy levels, but is blind to other features of a theory such as matrix elements of operators or OPE coefficients in conformal field theories. In this paper, we introduce generalized spectral form factors: new probes of quantum chaos sensitive to the dynamical data of a theory. These quantities can be studied using random matrix theory and an effective theory of quantum chaos. We focus our attention on a particular combination of heavy-heavy-heavy OPE coefficients that generalizes the genus-2 partition function of two-dimensional CFTs, for which we define a form factor. Assuming that random matrix theory applies to chaotic CFTs, we probe heavy-heavy-heavy OPE coefficients and find statistical correlations that agree with the OPE Randomness Hypothesis: these coefficients have a random tensor component. The EFT of quantum chaos predicts that the genus-2 form factor displays a ramp and a plateau. Our results suggest that this is a common property of generalized spectral form factors. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) and differentiated thyroid cancer (TC) are two common cancer types with the highest incidence in women. BC and TC can develop synchronous or metachronous and the occurrence of both is higher than expected by chance. This study aimed to examine the association between BC and TC in the Netherlands.Methods: This is a retrospective cohort study during the period of 1989-2020 retrieved from the Netherlands Cancer Registry (NCR). Patients diagnosed with BC-TC and BC alone as control group and TC-BC and TC alone as control group were included. The primary outcome was the standardized incidence ratio (SIR) of BC-TC and TC-BC. Secondary outcomes included data on the demographics, type of malignancy, treatment and overall survival (OS).Results: The incidence of TC among 318.002 women with BC (BC-TC) was 0.1% (423 patients) (SIR = 1.86 (95% CI: 1.40-2.32)) and the incidence of BC among 12,370 patients with TC (TC-BC) was 2.9% (355 patients) (SIR = 1.46 (95% CI: 1.09-1.83)). BC-TC patients were younger compared to the BC alone group at BC diagnosis (55 vs 60 years, p < 0.001). The age-adjusted odds ratio to develop TC was not significantly increased for patients who received chemotherapy and radiotherapy. Most TC cases were synchronous tumors after BC diagnosis (19%) with a TNM stage 1. Only 6% of the BC tumors after TC occurred synchronous with a TNM stage 1 in most cases. The OS of all groups was the most favorable in patients with both BC and TC compared to BC- and TC alone.Conclusion and Relevance: The SIR of TC after BC diagnosis and BC after TC diagnosis was higher than predicted based on the rates of the general population. TC and BC as second primary tumors were diagnosed in an early stage and did not affect overall survival. Therefore, Dutch women who have been treated for BC or TC require no special surveillance for their thyroid- and breast gland. [ABSTRACT FROM AUTHOR]

We present new asymptotic formulas for the distribution of OPE coefficients in conformal field theories. These formulas involve products of four or more coefficients and include light-light-heavy as well as heavy-heavy-heavy contributions. They are derived from crossing symmetry of the six and higher point functions on the plane and should be interpreted as non-Gaussianities in the statistical distribution of the OPE coefficients. We begin with a formula for arbitrary operator exchanges (not necessarily primary) valid in any dimension. This is the first asymptotic formula constraining heavy-heavy-heavy OPE coefficients in d > 2. For two-dimensional CFTs, we present refined asymptotic formulas stemming from exchanges of quasi-primaries as well as Virasoro primaries. [ABSTRACT FROM AUTHOR]

The Eigenstate Thermalization Hypothesis makes a prediction for the statistical distribution of matrix elements of simple operators in energy eigenstates of chaotic quantum systems. As a leading approximation, off-diagonal matrix elements are described by Gaussian random variables but higher-point correlation functions enforce non-Gaussian corrections which are further exponentially suppressed in the entropy. In this paper, we investigate non- Gaussian corrections to the statistical distribution of heavy-heavy-heavy OPE coefficients in chaotic two-dimensional conformal field theories. Using the Virasoro crossing kernels, we provide asymptotic formulas involving arbitrary numbers of OPE coefficients from modular invariance on genus-g surfaces. We find that the non-Gaussianities are further exponentially suppressed in the entropy, much like the ETH. We discuss the implication of these results for products of CFT partition functions in gravity and Euclidean wormholes. Our results suggest that there are new connected wormhole geometries that dominate over the genus-two wormhole. [ABSTRACT FROM AUTHOR]

Purpose: A prostate-specific membrane antigen (PSMA) thyroid incidentaloma (PTI) is an unexpected, PSMA-avid thyroid lesion, newly detected during the investigation of an unrelated condition using PSMA PET/CT. The aim of this study is to examine the incidence and clinical significance of PTI and the associated management strategies since the implementation of the PSMA PET/CT scan. Methods: This study involves a retrospective cohort study of 61 PTI cases depicted on PSMA PET/CT scans performed between January 2016 and July 2021, almost exclusively for (re)staging prostate cancer. The medical records of the included cases were retrospectively reviewed and data of the PSMA PET/CT scans, primary malignancy, thyroid diagnostics, treatment, and follow-up were collected. Results: PTI was reported in 1.1% of the patients who underwent oncologic PSMA PET/CT scans included in this study. Two PTI cases had a histologically proven thyroid cancer: one a benign thyroid lesion and one a metastasis of a renal cell carcinoma. In none of the cases in whom any form of further thyroid workup was withheld, the PTI became clinically relevant during follow-up (median 1.8 years (1.1–3.3)). Six patients (10%) died due to their primary cancer. Conclusion: The incidence of thyroid incidentalomas on PSMA PET/CT was low (1.1%) in this large, two-center experience. Less than half of the PTI cases were analyzed and the risk of malignancy, despite being low, was not negligible. The clinical outcome was good using a standard diagnostic workup for PTI, while the prognosis of the patient was determined by the primary malignancy. The consideration to analyze and treat PTI cases should be part of the shared decision-making in cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the utility of [18F]FDG-PET as an imaging biomarker for pathological response early upon neoadjuvant immune checkpoint blockade (ICB) in patients with head and neck squamous cell carcinoma (HNSCC) before surgery. Methods: In the IMCISION trial (NCT03003637), 32 patients with stage II‒IVb HNSCC were treated with neoadjuvant nivolumab with (n = 26) or without (n = 6) ipilimumab (weeks 1 and 3) before surgery (week 5). [18F]FDG-PET/CT scans were acquired at baseline and shortly before surgery in 21 patients. Images were analysed for SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG). Major and partial pathological responses (MPR and PPR, respectively) to immunotherapy were identified based on the residual viable tumour in the resected primary tumour specimen (≤ 10% and 11–50%, respectively). Pathological response in lymph node metastases was assessed separately. Response for the 2 [18F]FDG-PET-analysable patients who did not undergo surgery was determined clinically and per MR-RECIST v.1.1. A patient with a primary tumour MPR, PPR, or primary tumour MR-RECIST-based response upon immunotherapy was called a responder. Results: Median ΔSUVmax, ΔSUVmean, ΔMTV, and ΔTLG decreased in the 8 responders and were significantly lower compared to the 13 non-responders (P = 0.05, P = 0.002, P < 0.001, and P < 0.001). A ΔMTV or ΔTLG of at least − 12.5% detected a primary tumour response with 95% accuracy, compared to 86% for the EORTC criteria. None of the patients with a ΔTLG of − 12.5% or more at the primary tumour site developed a relapse (median FU 23.0 months since surgery). Lymph node metastases with a PPR or MPR (5 metastases in 3 patients) showed a significant decrease in SUVmax (median − 3.1, P = 0.04). However, a SUVmax increase (median + 2.1) was observed in 27 lymph nodes (in 11 patients), while only 13 lymph nodes (48%) contained metastases in the corresponding neck dissection specimen. Conclusions: Primary tumour response assessment using [18F]FDG-PET-based ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant ICB in HNSCC, outperforming the EORTC criteria, although pseudoprogression is seen in neck lymph nodes. [18F]FDG-PET could, upon validation, select HNSCC patients for response-driven treatment adaptation in future trials. Trial registration: https://www.clinicaltrials.gov/, NCT03003637, December 28, 2016. [ABSTRACT FROM AUTHOR]

Cultivated potato is a clonally propagated autotetraploid species with a highly heterogeneous genome. Phased assemblies of six cultivars including two chromosome-scale phased genome assemblies revealed extensive allelic diversity, including altered coding and transcript sequences, preferential allele expression, and structural variation that collectively result in a highly complex transcriptome and predicted proteome, which are distributed across the homologous chromosomes. Wild species contribute to the extensive allelic diversity in tetraploid cultivars, demonstrating ancestral introgressions predating modern breeding efforts. As a clonally propagated autotetraploid that undergoes limited meiosis, dysfunctional and deleterious alleles are not purged in tetraploid potato. Nearly a quarter of the loci bore mutations are predicted to have a high negative impact on protein function, complicating breeder's efforts to reduce genetic load. The StCDF1 locus controls maturity, and analysis of six tetraploid genomes revealed that 12 allelic variants of StCDF1 are correlated with maturity in a dosage-dependent manner. Knowledge of the complexity of the tetraploid potato genome with its rampant structural variation and embedded deleterious and dysfunctional alleles will be key not only to implementing precision breeding of tetraploid cultivars but also to the construction of homozygous, diploid potato germplasm containing favorable alleles to capitalize on heterosis in F1 hybrids. Cultivated potato is an autotetraploid species with a highly heterogeneous genome. Knowledge of the complexity of the potato genome will be important for breeding. This study reports genome assemblies of six potato cultivars and the construction of potato pan-genome. Comparative genomic analyses reveal extensive allelic diversity in cultivated potato cultivars, including altered coding and transcript sequences, preferential allele expression, structural variation, and pan-genome variation. [ABSTRACT FROM AUTHOR]

We study the parallel transport of modular Hamiltonians encoding entanglement properties of a state. In the case of 2d CFT, we consider a change of state through action with a suitable diffeomorphism on the circle: one that diagonalizes the adjoint action of the modular Hamiltonian. These vector fields exhibit kinks at the interval boundary, thus together with their central extension they differ from usual elements of the Virasoro algebra. The Berry curvature associated to state-changing parallel transport is the Kirillov-Kostant symplectic form on an associated coadjoint orbit, one which differs appreciably from known Virasoro orbits. We find that the boundary parallel transport process computes a bulk symplectic form for a Euclidean geometry obtained from the backreaction of a cosmic brane, with Dirichlet boundary conditions at the location of the brane. We propose that this gives a reasonable definition for the symplectic form on an entanglement wedge. [ABSTRACT FROM AUTHOR]

Objective: The objective was to assess swallowing, mouth opening and speech function during the first year after radiation-based treatment (RT(+)) after introduction of a dedicated preventive rehabilitation program for stage III–IV oropharyngeal carcinoma (OPC). Methods: Swallowing, mouth opening and speech function were collected before and at six- and twelve-month follow-up after RT(+) for OPC as part of ongoing prospective assessments by speech-language pathologists. Results: Objective and patient-perceived function deteriorated until 6 months and improved until 12 months after treatment, but did not return to baseline levels with 25%, 20% and 58% of the patients with objective dysphagia, trismus and speech problems, respectively. Feeding tube dependency and pneumonia prevalence was low. Conclusion: Despite successful implementation, a substantial proportion of patients still experience functional limitations after RT(+) for OPC, suggesting room for improvement of the current rehabilitation program. Pretreatment sarcopenia seems associated with worse functional outcomes and might be a relevant new target for rehabilitation strategies. [ABSTRACT FROM AUTHOR]

Background: Low skeletal muscle mass (SMM) is an adverse prognostic factor for chemotherapy dose‐limiting toxicity (CDLT). In patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), low SMM is a predictor for CDLT. We aimed to validate these findings. Methods: Consecutive LA‐HNSCC patients treated with primary CRT with high‐dose cisplatin were retrospectively included. SMM was measured on pre‐treatment CT‐imaging. A cumulative cisplatin dose below 200 mg/m2 was defined as CDLT. Results: One hundred and fifty three patients were included; 37 (24.2%) experienced CDLT, and 84 had low SMM (54.9%). Patients with low SMM experienced more CDLT than patients with normal SMM (35.7% vs. 10.1%, p < 0.01). Low SMM (OR 3.99 [95% CI 1.56–10.23], p = 0.01) and an eGFR of 60–70 ml/min (OR 5.40 [95% CI 1.57–18.65], p < 0.01) were predictors for CDLT. Conclusion: Pre‐treatment low SMM is associated with CDLT in LA‐HNSCC patients treated with primary CRT. Routine SMM assessment may allow for CDLT risk assessment and treatment optimization. [ABSTRACT FROM AUTHOR]

Background: Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia. Aims: We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors. Methods: In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right‐sided, were detected, as published previously. An average‐risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy. Results: In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size ≥10 mm, whereas (high‐grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4–9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient. Conclusions: Colorectal neoplasia in HL survivors differ from average‐risk controls; classification AN was primarily based on polyp size (≥10 mm) in HL survivors. Longer follow‐up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: To further improve the quality of head and neck cancer (HNC) care, we developed a composite measure defined as "textbook outcome" (TO). Methods: We analyzed a retrospective cohort of patients after curvative‐intent primary surgery, radiotherapy (RT), or chemoradiation (CRT) for HNC between 2015 and 2018 at the Netherlands Cancer Institute. TO was defined as 1) the start of treatment within 30 days, 2a) satisfactory pathologic outcomes, without 30‐day postoperative complications, for the surgically treated group, and 2b), for RT and CRT patients, no unexpected or prolonged hospitalization and toxicity after the completion of treatment as planned. Results: In total, 392 patients with HNC were included. An overall TO was achieved in 9.6% of patients after surgery, 20.6% after RT, and 2.2% after CRT. Two indicators (margins >5 mm and start treatment <30 days) reduced TO radically for both groups. Conclusion: TO can aid the evaluation of the quality of care for HNC patients and guide improvement processes. Level of Evidence: 3 Laryngoscope, 132:78–87, 2022 [ABSTRACT FROM AUTHOR]

Background: A thyroid incidentaloma (TI) is an unexpected, asymptomatic thyroid lesion discovered during the investigation of an unrelated condition. The aim of the present study is to examine the incidence of 18Fluorodeoxyglucose (FDG)-positron emission tomography (PET) TI, the associated management strategies and the outcomes in a tertiary cancer referral center. Methods: This study involves a retrospective cohort study of 1003 patients with TI found on 18FDG-PET/CT scans performed between January 2010 and January 2020 for a nonthyroidal malignancy. The Kaplan–Meier method was used for survival analyses in patients concerning an underlying malignancy, with a prevalence of 5% or higher in this cohort. Logistic- and cox regression analyses were performed to analyze predictors of thyroid malignancy and mortality. A propensity score weighted method was used to control for baseline differences between the intervention (additional TI diagnostics) and control (no TI diagnostics) group. Results: FDG-positive TI occurred in 1.9% (1003/52,693) of the oncologic 18FDG-PET/CT scans performed in our center. Thyroid surgery was performed in 47 patients (6%) and a thyroid malignancy was detected in 31 of them, which is 66% of those who had an operation and 4% of all patients. During the follow-up (median 6 years), 334 deaths (42%) related to different types of cancer (38%) or other causes (4%) were observed. One patient died from medullary thyroid cancer. In multivariate analysis adjusted for age, gender and the type- and stage of nonthyroidal malignancy, were independent predictors of survival (P < .05). Conclusions: The incidence of TI in this tertiary cancer referral center was comparable to current literature. Further thyroid workup was performed in less than half of the patients, and only a minority of patients underwent thyroid surgery. Since only one patient died from thyroid cancer, the strategy to withhold from thyroid diagnostics and treatment seems valid for most TI. Active thyroid treatment might benefit a subgroup of patients in whom the primary nonthyroidal malignancy is successfully treated or presumably stable. A wait-and-see policy with ultrasound follow-up could be an alternative strategy. These considerations should be part of the shared decision making in cancer patients with a TI. [ABSTRACT FROM AUTHOR]

We propose an ansatz for OPE coefficients in chaotic conformal field theories which generalizes the eigenstate thermalization hypothesis and describes any OPE coefficient involving heavy operators as a random variable with a Gaussian distribution. In two dimensions this ansatz enables us to compute higher moments of the OPE coefficients and analyse two and four-point functions of OPE coefficients, which we relate to genus-2 partition functions and their squares. We compare the results of our ansatz to solutions of Einstein gravity in AdS3, including a Euclidean wormhole that connects two genus-2 surfaces. Our ansatz reproduces the non-perturbative correction of the wormhole, giving it a physical interpretation in terms of OPE statistics. We propose that calculations performed within the semi-classical low-energy gravitational theory are only sensitive to the random nature of OPE coefficients, which explains the apparent lack of factorization in products of partition functions. [ABSTRACT FROM AUTHOR]

We discuss some general aspects of commutators of local operators in Lorentzian CFTs, which can be obtained from a suitable analytic continuation of the Euclidean operator product expansion (OPE). Commutators only make sense as distributions, and care has to be taken to extract the right distribution from the OPE. We provide explicit computations in two and four-dimensional CFTs, focusing mainly on commutators of components of the stress-tensor. We rederive several familiar results, such as the canonical commutation relations of free field theory, the local form of the Poincaré algebra, and the Virasoro algebra of two-dimensional CFT. We then consider commutators of light-ray operators built from the stress-tensor. Using simplifying features of the light sheet limit in four-dimensional CFT we provide a direct computation of the BMS algebra formed by a specific set of light-ray operators in theories with no light scalar conformal primaries. In four-dimensional CFT we define a new infinite set of light-ray operators constructed from the stress-tensor, which all have well-defined matrix elements. These are a direct generalization of the two-dimensional Virasoro light-ray operators that are obtained from a conformal embedding of Minkowski space in the Lorentzian cylinder. They obey Hermiticity conditions similar to their two-dimensional analogues, and also share the property that a semi-infinite subset annihilates the vacuum. [ABSTRACT FROM AUTHOR]

We propose that finite cutoff regions of holographic spacetimes represent quantum circuits that map between boundary states at different times and Wilsonian cutoffs, and that the complexity of those quantum circuits is given by the gravitational action. The optimal circuit minimizes the gravitational action. This is a generalization of both the "complexity equals volume" conjecture to unoptimized circuits, and path integral optimization to finite cutoffs. Using tools from holographic T T ¯ , we find that surfaces of constant scalar curvature play a special role in optimizing quantum circuits. We also find an interesting connection of our proposal to kinematic space, and discuss possible circuit representations and gate counting interpretations of the gravitational action. [ABSTRACT FROM AUTHOR]

Introduction: Thyroid cancer is one of the most common carcinomas diagnosed in adolescents and young adults, with a rapidly rising incidence for the past three decades. Surgery is the standard treatment for patients with differentiated thyroid carcinoma (DTC), and when indicated, followed by radioactive iodine (RAI) treatment. The aim of this study was to evaluate the possible effects of RAI therapy on ovarian function and fertility in women. Methods: The PubMed, Embase, and Web of Science databases were systematically searched up to January 2020. In addition, a meta-analyses were performed for anti-Mullerian hormone (AMH) levels after RAI, comparison of AMH levels prior and 1 year after RAI, and pregnancy rates in patient with thyroid cancer receiving RAI compared with patients with thyroid cancer who did not receive RAI. Results: A total of 36 studies were eligible for full-text screening and 22 studies were included. The majority of the studies had a retrospective design. Menstrual irregularities were present in the first year after RAI in 12% and up to 31% of the patients. Approximately 8–16% of the patients experienced amenorrhea in the first year after RAI. Women who received RAI treatment (median dose 3700 MBq [range 1110–40,700 MBq]); had menopause at a slightly younger age compared with women who did not receive RAI treatment, 49.5 and 51 years, respectively (p < 0.001). Pooled AMH of the seven studies reporting AMH concentrations after RAI was 1.79 ng/mL. Of these, four studies reported AMH concentrations prior and 1 year after RAI. The mean difference was 1.50 ng/mL, which was significant. Finally, meta-analysis showed that patients undergoing RAI were not at a decreased risk of becoming pregnant. Conclusions: Most of the studies indicate that RAI therapy for DTC is not associated with a long-term decrease in pregnancy rates although meta-analyses show a significant decrease in AMH levels after RAI therapy. Prospective studies are needed to confirm these results. We recommend counseling patients about the possible effects of 131I and incorporate today's knowledge in multidisciplinary counseling. [ABSTRACT FROM AUTHOR]

Reciprocity between cells and their surrounding extracellular matrix is one of the main drivers for cellular function and, in turn, matrix maintenance and remodelling. Unravelling how cells respond to their environment is key in understanding mechanisms of health and disease. In all these examples, matrix anisotropy is an important element, since it can alter the cell shape and fate. In this work, the objective is to develop and exploit easy-to-produce platforms that can be used to study the cellular response to natural proteins assembled into diverse topographical cues. We demonstrate a robust and simple approach to form collagen substrates with different topographies by evaporating droplets of a collagen solution. Upon evaporation of the collagen solution, a stain of collagen is left behind, composed of three regions with a distinct pattern: an isotropic region, a concentric ring pattern, and a radially oriented region. The formation and size of these regions can be controlled by the evaporation rate of the droplet and initial collagen concentration. The patterns form topographical cues inducing a pattern-specific cell (tenocyte) morphology, density, and proliferation. Rapid and cost-effective production of different self-agglomerated collagen topographies and their interfaces enables further study of the cell shape-phenotype relationship in vitro. Substrate topography and in analogy tissue architecture remains a cue that can and will be used to steer and understand cell function in vitro, which in turn can be applied in vivo, e.g. in optimizing tissue engineering applications. [ABSTRACT FROM AUTHOR]

The ambition of the Netherlands, laid down in the National Plan Open Science, is to achieve 100% open access for academic publications. The ambition was to be achieved by 2020. However, it is to be expected that for the year 2020 between 70% and 75% of the articles will be open access. Until recently, the focus of the Netherlands has been on the gold route - open access via journals and publishers' platforms. This is likely to be costly and it is also impossible to cover all articles and other publication types this way. Since 2015, Dutch Copyright Act has offered an alternative with the implementation of Article 25fa (also known as the 'Taverne Amendment'), facilitating the green route, i.e. open access via (trusted) repositories. This amendment allows researchers to share short scientific works (e.g. articles and book chapters in edited collections), regardless of any restrictive guidelines from publishers. From February 2019 until August 2019 all Dutch universities participated in the pilot 'You Share, We Take Care!' to test how this copyright amendment could be interpreted and implemented by institutions as a policy instrument to enhance green open access and "selfarchiving". In 2020 steps were taken to scale up further implementation of the amendment. This article describes the outcomes of this pilot and shares best practices on implementation and awareness activities in the period following the pilot until early 2021, in which libraries have played an instrumental role in building trust and working on effective implementations on an institutional level. It concludes with some possible next steps for alignment, for example on a European level. [ABSTRACT FROM AUTHOR]

Natural evolution tackles optimization by producing many genetic variants and exposing these variants to selective pressure, resulting in the survival of the fittest. We use high throughput screening of large libraries of materials with differing surface topographies to probe the interactions of implantable device coatings with cells and tissues. However, the vast size of possible parameter design space precludes a brute force approach to screening all topographical possibilities. Here, we took inspiration from Nature to optimize materials surface topographies using evolutionary algorithms. We show that successive cycles of material design, production, fitness assessment, selection, and mutation results in optimization of biomaterials designs. Starting from a small selection of topographically designed surfaces that upregulate expression of an osteogenic marker, we used genetic crossover and random mutagenesis to generate new generations of topographies. [ABSTRACT FROM AUTHOR]

Introduction: Xerostomia is a well-known complication after iodine-131 (131I) therapy for thyroid carcinoma. It is currently insufficiently understood how the dose and biodistribution of 131I relates to salivary gland toxicity, and whether this is consistent for all salivary glands within a single patient. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) was recently introduced as a new tool to evaluate the relative loss of vital acinar cells in individual salivary glands. We aimed to assess gland-specific salivary gland toxicity after 131I-therapy using PSMA PET/CT. Methods: Five patients with differentiated thyroid cancer underwent [68Ga]Ga-PSMA-11 PET/CT to evaluate their eligibility for peptide radioligand therapy with [177Lu]Lu-PSMA-617. Uptake patterns in salivary glands were evaluated visually and quantitatively as an indicator of vital acinar cell loss after prior 131I-therapy. Results: Four of 5 patients demonstrated significant lowered uptake in at least one salivary gland, after receiving at least 2 131I-treatments. Asymmetric loss of vital acinar cells occurred by gland type (parotid/submandibular) and location (right/left). The other salivary glands in these patients and all salivary glands in the fifth patient showed normal uptake, demonstrating high intrapatient and interpatient variability. Conclusions: 131I-therapy can induce salivary gland toxicity with high inter- but also high intrapatient variation among separate gland locations, which can be assessed with PSMA PET/CT. This new technique offers potential to guide further development and evaluation of protective measures in patients receiving 131I-therapy. [ABSTRACT FROM AUTHOR]