A single-center observational study on long-term neurodevelopmental outcomes in children with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. METHODS: This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation. RESULTS: Thirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p < 0.05). CONCLUSIONS: The results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs.

Brain areas activated during visual learning in the cichlid fish Pseudotropheus zebra.

The neural correlates of most cognitive functions in fish are unknown. This project aimed to identify brain regions involved in visual learning in the cichlid fish Pseudotropheus zebra. The expression of the protein pS6 was measured in 19 brain areas and compared between groups of individuals subjected to four different behavioral contexts (control, avoidance, trained, and novelty groups). Control group individuals were sacrificed with minimal interactions. Fish in the avoidance group were chased with a net for an hour, after which they were sacrificed. Individuals in the trained group received daily training sessions to associate a visual object with a food reward. They were sacrificed the day they reached learning criterion. Fish in the novelty group were habituated to one set of visual stimuli, then faced a change in stimulus type (novelty stimulus) before they were sacrificed. Fish in the three treatment groups showed the largest activation of pS6 in the inferior lobes and the tectum opticum compared to the control group. The avoidance group showed additional activation in the preoptic area, several telencephalic regions, the torus semicircularis, and the reticular formation. The trained group that received a food reward, showed additional activation of the torus lateralis, a tertiary gustatory center. The only area that showed strong activation in all three treatment groups was the nucleus diffusus situated within the inferior lobe. The inferior lobe receives prominent visual input from the tectum via the nucleus glomerulosus but so far, nothing is known about the functional details of this pathway. Our study showed for the first time that the inferior lobes play an important role in visual learning and object recognition.

Investigating charge-up and fragmentation dynamics of oxygen molecules after interaction with strong X-ray free-electron laser pulses.

During the last decade, X-ray free-electron lasers (XFELs) have enabled the study of light-matter interaction under extreme conditions. Atoms which are subject to XFEL radiation are charged by a complex interplay of (several subsequent) photoionization events and electronic decay processes within a few femtoseconds. The interaction with molecules is even more intriguing, since intricate nuclear dynamics occur as the molecules start to dissociate during the charge-up process. Here, we demonstrate that by analyzing photoelectron angular emission distributions and kinetic energy release of charge states of ionic molecular fragments, we can obtain a detailed understanding of the charge-up and fragmentation dynamics. Our novel approach allows for gathering such information without the need of complex ab initio modeling. As an example, we provide a detailed view on the processes happening on a femtosecond time scale in oxygen molecules exposed to intense XFEL pulses.

Computer-Generated R.E.N.A.L. Nephrometry Scores Yield Comparable Predictive Results to Those of Human-Expert Scores in Predicting Oncologic and Perioperative Outcomes.

PURPOSE: We sought to automate R.E.N.A.L. (for radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry scoring of preoperative computerized tomography scans and create an artificial intelligence-generated score (AI-score). Subsequently, we aimed to evaluate its ability to predict meaningful oncologic and perioperative outcomes as compared to expert human-generated nephrometry scores (H-scores). MATERIALS AND METHODS: A total of 300 patients with preoperative computerized tomography were identified from a cohort of 544 consecutive patients undergoing surgical extirpation for suspected renal cancer at a single institution. A deep neural network approach was used to automatically segment kidneys and tumors, and geometric algorithms were developed to estimate components of R.E.N.A.L. nephrometry score. Tumors were independently scored by medical personnel blinded to AI-scores. AI- and H-score agreement was assessed using Lin's concordance correlation and their predictive abilities for both oncologic and perioperative outcomes were assessed using areas under the curve. RESULTS: Median age was 60 years (IQE 51-68), and 40% were female. Median tumor size was 4.2 cm and 91.3% had malignant tumors, including 27%, 37% and 24% with high stage, grade and necrosis, respectively. There was significant agreement between H-scores and AI-scores (Lin's ⍴=0.59). Both AI- and H-scores similarly predicted meaningful oncologic outcomes (p <0.001) including presence of malignancy, necrosis, and high-grade and -stage disease (p <0.003). They also predicted surgical approach (p <0.004) and specific perioperative outcomes (p <0.05). CONCLUSIONS: Fully automated AI-generated R.E.N.A.L. scores are comparable to human-generated R.E.N.A.L. scores and predict a wide variety of meaningful patient-centered outcomes. This unambiguous artificial intelligence-based scoring is intended to facilitate wider adoption of the R.E.N.A.L. score.

Fourfold Differential Photoelectron Circular Dichroism.

We report on a joint experimental and theoretical study of photoelectron circular dichroism (PECD) in methyloxirane. By detecting O 1s photoelectrons in coincidence with fragment ions, we deduce the molecule's orientation and photoelectron emission direction in the laboratory frame. Thereby, we retrieve a fourfold differential PECD clearly beyond 50%. This strong chiral asymmetry is reproduced by ab initio electronic structure calculations. Providing such a pronounced contrast makes PECD of fixed-in-space chiral molecules an even more sensitive tool for chiral recognition in the gas phase.

Strong Differential Photoion Circular Dichroism in Strong-Field Ionization of Chiral Molecules.

We investigate the differential ionization probability of chiral molecules in the strong-field regime as a function of the helicity of the incident light. To this end, we analyze the fourfold ionization of bromochlorofluoromethane (CHBrClF) with subsequent fragmentation into four charged fragments and different dissociation channels of the singly ionized methyloxirane. By resolving for the molecular orientation, we show that the photoion circular dichroism signal strength is increased by 2 orders of magnitude.

NMR Relaxometry: The Canonical Case Glycerol.

We present a quantitative description of the proton spin-lattice relaxation rate R1(T,ω) of glycerol including temperatures from 191 to 360 K and a frequency range 10 kHz < ω/2π < 20 MHz covered by the field-cycling technique. The analysis encompasses the data compiled by Noack and co-workers in 1971, so far, the most complete data set (10 kHz > ω/2π < 117 MHz). Applying frequency-temperature superposition, master curves are constructed extending over 15 decades in frequency/time. They are described by contributions reflecting translational and rotational dynamics mediated by inter- and intramolecular relaxation pathways. The rotational part of the spectral density/susceptibility shows high similarity with those reported by dielectric spectroscopy or photon correlation spectroscopy (PCS). In addition to a Cole-Davidson-like peak, a high-frequency "excess wing" has to be accounted for. Quantitative agreement with the PCS susceptibility is found which probes the same order of the rotational correlation function. The translational contribution is reproduced by applying the force-free hard sphere model, describing diffusion of dipolarly coupled spin systems. Rotational and translational time constants are compared to those from other techniques. Our approach is paradigmatic for the analysis of spin relaxation in glass-forming liquids. It also solves long-standing deficiencies regarding the analyses of deuteron relaxation. Moreover, the case of glycerol is special as its large separation of translation and rotation dynamics, probably because of its hydrogen bond network, is not found in nonassociated liquids.

Let us talk about death: gender effects in cancer patients' preferences for end-of-life discussions.

PURPOSE: Patients with advanced cancer often receive suboptimal end-of-life (EOL) care. Particularly males with advanced cancer are more likely to receive EOL care that is more aggressive, even if death is imminent. Critical factors determining EOL care are EOL conversations or advance care planning. However, information about gender-related factors influencing EOL conversations is lacking. Therefore, the current study investigates gender differences concerning the content, the desired time point, and the mode of initiation of EOL conversations in cancer patients. METHODS: In a cross-sectional study, 186 female and male cancer patients were asked about their preferences for EOL discussions using a semi-structured interview, focusing on (a) the importance of six different topics (medical and nursing care, organizational, emotional, social, and spiritual/religious aspects), (b) the desired time point, and (c) the mode of discussion initiation. RESULTS: The importance of EOL topics differs significantly regarding issue (p = 0.002, η2 = 0.02) and gender (p < 0.001, η2 = 0.11). Males wish to avoid the engagement in discussions about death and dying particularly if they are anxious about their end-of-life period. They wish to be addressed regarding the "hard facts" nursing and medical care only. In contrast, females prefer to speak more about "soft facts" and to be addressed about each EOL topic. Independent of gender, the majority of patients prefer to talk rather late: when the disease is getting worse (58%), at the end of their therapy, or when loosing self-sufficiency (27.5%). CONCLUSION: The tendency of patients to talk late about EOL issues increases the risk of delayed or missed EOL conversations, which may be due to a knowledge gap regarding the possibility of disease-associated incapability. Furthermore, there are significant gender differences influencing the access to EOL conversations. Therefore, for daily clinical routine, we suggest an early two-step, gender-sensitive approach to end-of-life conversations.

Strong time dependence of ocean acidification mitigation by atmospheric carbon dioxide removal.

In Paris in 2015, the global community agreed to limit global warming to well below 2 [Formula: see text]C, aiming at even 1.5 [Formula: see text]C. It is still uncertain whether these targets are sufficient to preserve marine ecosystems and prevent a severe alteration of marine biogeochemical cycles. Here, we show that stringent mitigation strategies consistent with the 1.5 [Formula: see text]C scenario could, indeed, provoke a critical difference for the ocean's carbon cycle and calcium carbonate saturation states. Favorable conditions for calcifying organisms like tropical corals and polar pteropods, both of major importance for large ecosystems, can only be maintained if CO[Formula: see text] emissions fall rapidly between 2025 and 2050, potentially requiring an early deployment of CO[Formula: see text] removal techniques in addition to drastic emissions reduction. Furthermore, this outcome can only be achieved if the terrestrial biosphere remains a carbon sink during the entire 21st century.

An automatic procedure that grades some facial skin structural signs: agreements and validation with clinical assessments made by dermatologists.

OBJECTIVE: To confirm the robustness and validity of an automatic scoring system, algorithm-based, that grades the severity of nine facial signs through "selfies" smartphones pictures taken by European Caucasian women through dermatological assessments. METHODS: 157 Caucasian women from three countries (France, Germany, Spain), of different ages (20-75 years), took one "selfie" image by the frontal camera of their smartphones whereas local dermatologists photographed them with the back camera of the same smartphone. The same nine facial signs of these subjects were initially graded by these local dermatologists, using referential Skin Aging Atlases. All 314 "selfies" images were then further automatically analyzed by the algorithm. The severity of facial signs (wrinkles, pigmentation, ptosis, skin folds etc.) were statistically compared to the assessments made by the three dermatologists, taken as ground truth. RESULTS: Highly significant coefficients of correlation (P < 0.001) were found in the three cohorts between the grades provided by the system and those from dermatologists in live. The back camera - of a better resolution than the frontal one - seems affording slightly more significant correlations. However, although significantly correlated, the signs of vascular disorders and cheek skin pores present some disparities that are likely linked to the technical diversity of smartphones or self-shootings, leading to lower coefficients of correlations. CONCLUSION: This automatic scoring system offers a promising approach in the harmonization of Dermatological assessments of skin facial signs and their changes with age or the follow up of anti-aging treatments.

OBJECTIF: De confirmer la validité et la solidité d'un système de scorage automatique qui quantifie la sévérité de neuf signes du visage à partir de photographies de type "selfies" prises par des femmes Caucasiennes Européennes d'âge différents. MÉTHODES: 157 femmes Caucasiennes de trois pays différents (France, Allemagne, Espagne), d'âges différents (20-75 ans) ont pris un « selfie¼ avec la caméra frontale de leur téléphone tandis que le dermatologue local les a photographiées à l'aide de la caméra dorsale du même appareil. Les neuf signes faciaux ciblés par le système de scorage automatique ont été préalablement évalués par trois dermatologues locaux, utilisant des Atlas référentiels du vieillissement cutané. Les 314 images obtenues furent ensuite analysées automatiquement par l'algorithme. Les sévérités des neuf signes (rides, ptose, plis, pigmentation...) ont été ensuite comparées à celles établies par les dermatologues, considérées comme références absolues. RÉSULTATS: De très significatifs coefficients de corrélation (P < 0.001) ont été trouvés dans les trois cohortes entre les scores fournis par le système et ceux issus des évaluations des dermatologues des visages durant la visite des volontaires. La caméra du dos des smartphones - de meilleure résolution que la frontale - semble fournir de légèrement meilleures significativités. Cependant, bien que significativement corrélés, les signes des désordres vasculaires et des pores cutanés des joues montrent quelques disparités, dues possiblement à la diversité technique des smartphones ou celle des prises de vue, conduisant à de plus faibles coefficients de corrélation. CONCLUSION: Ce système de quantification automatique semble offrir une approche prometteuse dans l'harmonisation des évaluations dermatologiques des signes faciaux et leurs modifications liées à l'âge et/ou le suivi de traitements à vocation antivieillissement cutané.

Construction of a hybrid clamped cell for high-pressure neutron-diffraction experiments with a large diamond window.

A hybrid pressure cell was fabricated from commercially available copper-beryllium and custom-made Ni-Cr-Al Russian alloy, tailored for usage as a reaction vessel supplying a volume of about 400 mm3. In order to directly (in situ) monitor pressure and chemical reactions within the chamber, a large diamond window suitable for spectroscopic sample analysis was implemented. The performance of the hybrid cell was validated from high-pressure neutron-diffraction measurements on carbon dioxide.

Kinetics and tissue repair process following fractional bipolar radiofrequency treatment.

INTRODUCTION: Fractionated radiofrequency (RF) tissue tightening is an alternative method to fractionated laser treatment of skin wrinkling, laxity and acne scars, with reduced risk of scarring or persistent pigmentation. The aim of this study was to evaluate and quantify the wound healing process after RF treatment. MATERIALS AND METHODS: 12 patients were treated with a 64-pin fractional bipolar RF device with 60 mJ/pin applied energy. Confocal laser scanning microscopy (CLSM) examination was performed on day 1, day 2, day 7 and day 14 after treatment. Clinical wound healing process was measured and expressed as a percentage. RESULTS: All patients developed erythema, mild edema and crusts at the treated areas. Two weeks after treatment clinical symptoms resolved. During ablation patients reported moderate pain. Directly after ablation microscopic ablation zones could be detected in CLSM. Measurement of MAZ at epidermis, dermo-epidermal junction and papilary dermis showed a constant diameter until two weeks after treatment. Re-epithelization of the MAZ could be detected already 1 week after treatment. However, 2 weeks after ablation the honeycomb pattern of the epidermis was not yet completely restored. DISCUSSION: Bipolar fractionated RF treatment demonstrates clinically a rapid wound healing response. The subepidermal remodelling process still ongoing after 14 days, showing new granulation tissue. Therefore, treatment intervals of at least 14 days should be recommended to allow completion of the remodelling process.

Scaling analysis of the viscoelastic response of linear polymers.

Viscoelastic response in terms of the complex shear modulus G*(ω) of the linear polymers poly(ethylene-alt-propylene), poly(isoprene), and poly(butadiene) is studied for molar masses (M) from 3k up to 1000k and over a wide temperature range starting from the glass transition temperature Tg (174 K-373 K). Master curves G'(ωτα) and G″(ωτα) are constructed for the polymer-specific relaxation. Segmental relaxation occurring close to Tg is independently addressed by single spectra. Altogether, viscoelastic response is effectively studied over 14 decades in frequency. The structural relaxation time τα used for scaling is taken from dielectric spectra. We suggest a derivative method for identifying the different power-law regimes and their exponents along G″(ωτα) ∝ ωε″. The exponent ε″ = ε″(ωτα) ≡ d ln G″(ωτα)/d ln(ωτα) reveals more details compared to conventional analyses and displays high similarity among the polymers. Within a simple scaling model, the original tube-reptation model is extended to include contour length fluctuations (CLFs). The model reproduces all signatures of the quantitative theory by Likhtman and McLeish. The characteristic times and power-law exponents are rediscovered in ε″(ωτα). The high-frequency flank of the terminal relaxation closely follows the prediction for CLF (ε″ = -0.25), i.e., G″(ω) ∝ ω-0.21±0.02. At lower frequencies, a second regime with lower exponent ε″ is observed signaling the crossover to coherent reptation. Application of the full Likhtman-McLeish calculation provides a quantitative interpolation of ε″(ωτα) at frequencies below those of the Rouse regime. The derivative method also allows identifying the entanglement time τe. However, as the exponent in the Rouse regime (ωτe > 1) varies along εeRouse = 0.66 ± 0.04 (off the Rouse prediction εRouse = 0.5) and that at ωτe < 1 is similar, only a weak manifestation of the crossover at τe is found at highest M. Yet, calculating τe/τα= (M/Mo)2, we find good agreement among the polymers when discussing ε″(ωτe). The terminal relaxation time τt is directly read off from ε″(ωτα). Plotting τt/τe as a function of Z = M/Me, we find universal behavior as predicted by the TR model. The M dependence crosses over from an exponent significantly larger than 3.0 at intermediate M to an exponent approaching 3.0 at highest M in agreement with previous reports. The frequency of the minimum in G″(ωτα) scales as τmin ∝ M1.0±0.1. An M-independent frequency marks the crossover to glassy relaxation at the highest frequencies. Independent of the amplitude of G″(ω), which may be related to sample-to-sample differences, the derivative method is a versatile tool to provide a detailed phenomenological analysis of the viscoelastic response of complex liquids.

Diagnostic accuracy of dermatofluoroscopy in cutaneous melanoma detection: results of a prospective multicentre clinical study in 476 pigmented lesions.

BACKGROUND: Early detection is a key factor in improving survival from melanoma. Today, the clinical diagnosis of cutaneous melanoma is based mostly on visual inspection and dermoscopy. Preclinical studies in freshly excised or paraffin-embedded tissue have shown that the melanin fluorescence spectra after stepwise two-photon excitation, a process termed dermatofluoroscopy, differ between cutaneous melanoma and melanocytic naevi. However, confirmation from a larger prospective clinical study is lacking. OBJECTIVES: The primary end point of this study was to determine the diagnostic accuracy of dermatofluoroscopy in melanoma detection. Secondary end points included the collection of data for improving the computer algorithm that classifies skin lesions based on melanin fluorescence and the assessment of safety aspects. METHODS: This was a prospective, blinded, multicentre clinical study in patients with pigmented skin lesions (PSLs) indicated for excision either to rule out or to confirm cutaneous melanoma. All included lesions underwent dermoscopy and dermatofluoroscopy in vivo before lesions were excised and subjected to histopathological examination. RESULTS: In total, 369 patients and 476 PSLs were included in the final analysis. In 101 of 476 lesions (21·2%) histopathology revealed melanoma. The observed sensitivity of dermatofluoroscopy was 89·1% (90 of 101 melanomas identified), with an observed specificity of 44·8%. The positive and negative predictive values were 30·3% and 93·9%, respectively. No adverse events occurred. CONCLUSIONS: Dermatofluoroscopy is a safe and accurate diagnostic method to aid physicians in diagnosing cutaneous melanoma. Limitations arise from largely amelanotic or regressing lesions lacking sufficient melanin fluorescence.

Endogenous cortisol in keratinized matrices: Systematic determination of baseline cortisol levels in hair and the influence of sex, age and hair color.

The measurement of hair cortisol is increasingly used to measure long-term cumulative cortisol levels and investigate its role as an important stress mediator. In this study a comparative statistical analysis of five independent studies (all analyzed in our laboratory) was performed to investigate baseline ranges of cortisol values in hair and evaluate potential influences of sex, age and hair color. Cortisol concentrations in hair of 554 subjects were measured and a comparative statistical analysis was performed. The analysis showed that cortisol levels significantly differ depending on age. The toddler group (7 months (0.6 years) to 3 years) showed significantly higher values (median 10pg/mg, p-value<0.0001, d=0.78) than the adolescent group. The adolescent groups showed significantly lower (p-value<0.0001, d=0.58 and p<0.0001, d=0.13) values (median 2.4pg/mg and 2.8pg/mg) than the adult group (median 5.8pg/mg). Furthermore, in the adult group men showed significantly higher cortisol values than women (p-value<0.05, d=0.17). This effect could not be seen in the adolescent group. Black hair showed higher cortisol concentrations than blond hair (p-value<0.0001, d=1.3). In addition, two rounds of interlaboratory comparisons for hair cortisol samples between four laboratories revealed very consistent results. Our results demonstrate that baseline cortisol levels are generally low in hair thus making a standardized and well-elaborated analytical method indispensable for accurate determination. Age-dependent normative baseline cortisol levels (toddlers, adolescents and adults) are highly recommended based on the comparative analysis comprising five independent studies.

Symmetry Breaking and Strong Persistent Plasma Currents via Resonant Destabilization of Atoms.

The ionization rate of an atom in a strong optical field can be resonantly enhanced by the presence of long-living atomic levels (so-called Freeman resonances). This process is most prominent in the multiphoton ionization regime, meaning that the ionization event takes many optical cycles. Nevertheless, here, we show that these resonances can lead to rapid subcycle-scale plasma buildup at the resonant values of the intensity in the pump pulse. The fast buildup can break the cycle-to-cycle symmetry of the ionization process, resulting in the generation of persistent macroscopic plasma currents which remain after the end of the pulse. This, in turn, gives rise to a broadband radiation of unusual spectral structure, forming a comb from terahertz to visible. This radiation contains fingerprints of the attosecond electron dynamics in Rydberg states during ionization.

Segmental dynamics of polyethylene-alt-propylene studied by NMR spin echo techniques.

Segmental dynamics of a highly entangled melt of linear polyethylene-alt-propylene with a molecular weight of 200 kDa was studied with a novel proton nuclear magnetic resonance (NMR) approach based upon 1H → 2H isotope dilution as applied to a solid-echo build-up function ISE(t), which is constructed from the NMR spin echo signals arising from the Hahn echo (HE) and two variations of the solid-echo pulse sequence. The isotope dilution enables the separation of inter- and intramolecular contributions to this function and allows one to extract the segmental mean-squared displacements in the millisecond time range, which is hardly accessible by other experimental methods. The proposed technique in combination with time-temperature superposition yields information about segmental translation in polyethylene-alt-propylene over 6 decades in time from 10-6 s up to 1 s. The time dependence of the mean-squared displacement obtained in this time range clearly shows three regimes of power law with exponents, which are in good agreement with the tube-reptation model predictions for the Rouse model, incoherent reptation and coherent reptation regimes. The results at short times coincide with the fast-field cycling relaxometry and neutron spin echo data, yet, significantly extending the probed time range. Furthermore, the obtained data are verified as well by the use of the dipolar-correlation effect on the Hahn echo, which was developed before by the co-authors. At the same time, the amplitude ratio of the intermolecular part of the proton dynamic dipole-dipole correlation function over the intramolecular part obtained from the experimental data is not in agreement with the predictions of the tube-reptation model for the regimes of incoherent and coherent reptation.