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Infants are immersed in a world of sounds from the moment their auditory system becomes functional, and experience with the auditory world shapes how their brain processes sounds in their environment. Across cultures, speech and music are two dominant auditory signals in infants' daily lives. Decades of research have repeatedly shown that both quantity and quality of speech input play critical roles in infant language development. Less is known about the music input infants receive in their environment. This study is the first to compare music input to speech input across infancy by analyzing a longitudinal dataset of daylong audio recordings collected in English-learning infants' home environments, at 6, 10, 14, 18, and 24 months of age. Using a crowdsourcing approach, 643 naïve listeners annotated 12,000 short snippets (10 s) randomly sampled from the recordings using Zooniverse, an online citizen-science platform. Results show that infants overall receive significantly more speech input than music input and the gap widens as the infants get older. At every age point, infants were exposed to more music from an electronic device than an in-person source; this pattern was reversed for speech. The percentage of input intended for infants remained the same over time for music while that percentage significantly increased for speech. We propose possible explanations for the limited music input compared to speech input observed in the present (North American) dataset and discuss future directions. We also discuss the opportunities and caveats in using a crowdsourcing approach to analyze large audio datasets. A video abstract of this article can be viewed at https://youtu.be/lFj_sEaBMN4

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence. METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]). CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.

In situ cosmogenic 14C (in situ 14C) in quartz provides a recently developed tool to date exposure of bedrock surfaces of up to ∼ 25 000 years. From outcrops located in east-central Sweden, we tested the accuracy of in situ 14C dating against (i) a relative sea level (RSL) curve constructed from radiocarbon dating of organic material in isolation basins and (ii) the timing of local deglaciation constructed from a clay varve chronology complemented with traditional radiocarbon dating. Five samples of granitoid bedrock were taken along an elevation transect extending southwestwards from the coast of the Baltic Sea near Forsmark. Because these samples derive from bedrock outcrops positioned below the highest postglacial shoreline, they target the timing of progressive landscape emergence above sea level. In contrast, in situ 14C concentrations in an additional five samples taken from granitoid outcrops above the highest postglacial shoreline, located 100 km west of Forsmark, should reflect local deglaciation ages. The 10 in situ 14C measurements provide robust age constraints that, within uncertainties, compare favourably with the RSL curve and the local deglaciation chronology. These data demonstrate the utility of in situ 14C to accurately date ice sheet deglaciation, and durations of postglacial exposure, in regions where cosmogenic 10Be and 26Al routinely return complex exposure results.

ABSTRACT: Background: Spinal Infection (SI) is associated with various comorbidities. The interaction of these comorbidities and their impact on costs and complexity of care has not been fully assessed. Methods: This is a retrospective cohort study of SI patients in an urban hospital system to characterize comorbidities and outcomes in adult patients with SI. Adult patients in our hospital system who were hospitalized with an initial diagnosis of SI between July 1, 2017 and June 30, 2019 were included. Outcomes measures included length of stay (LOS) of the index hospitalization for SI, charges and payments for the index hospitalization, and hospital readmissions within one year after discharge from the index hospitalization. Data was obtained by querying our Electronic Data Warehouse (EDW) using ICD-10-CM and CPT procedure codes. Spearman's correlation was used to summarize the relationships between LOS, charges, and payments. Multivariable linear regression was used to evaluate associations of demographics, comorbidities, and other factors with LOS. Multivariable Cox regression was used to evaluate associations of demographics, comorbidities, and other factors with hospital readmissions. Results: 403 patients with a first diagnosis of SI were identified. The average number of comorbidities per patient was 1.3. 294 (73%) had at least 1 medical comorbidity, and 54 (13%) had 3 or more comorbidities. The most common medical comorbidities were diabetes mellitus (26%), intravenous drug use (IVDU, 26%), and malnutrition (20%). 112 patients (28%) had a surgical site infection (SSI). DM (p

State-of-the-art commercially available 3D laser micro- and nanoprinters using polymeric photoresists based on two- or multi-photon absorption rely on high-power pico- or femtosecond lasers, leading to fairly large and expensive instruments. Lately, we have introduced photoresists based on two-step absorption instead of two-photon absorption, allowing for the use of small and inexpensive continuous-wave 405 nm wavelength GaN semiconductor laser diodes with light-output powers below 1 mW. Here, using the identical photoresist system and similar laser diodes, we report on the design, construction, and characterization of a 3D laser nanoprinter that fits into a shoe box. This shoe box contains all optical components, namely the mounted laser, the collimation- and beam-shaping optics, a miniature MEMS xy-scanner, a tube lens, the focusing microscope objective lens (NA=1.4, 100× magnification), a piezo slip-stick z-stage, the sample holder, a camera monitoring system, LED sample illumination, as well as the miniaturized control electronics employing a microcontroller. We present a gallery of example 3D structures printed with this instrument. We achieve about 100 nm lateral spatial resolution and focus scan speeds of about 1 mm/s. Potentially, our shoe-box-sized system can be made orders of magnitude less expensive than today’ s commercial systems.

Abstract Background Standard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases. Methods For this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified by the most commonly used PET parameter, the maximum tumor voxel normalized by dose and body weight (SUVmax) and also by the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals for SUVmax and SULpeak were used to determine the limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment. Results The mean relative difference of SUVmax and SULpeak in 38 bone tumors of the first cohort were 4.3% and 6.7%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and − 16.3% for SUVmax, and 21.2% and − 17.5% for SULpeak. 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification using SULpeak for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria for SULpeak changed the status of 3 patients compared to the standard Positron Emission Tomography Response Criteria in Solid Tumors of ± 30% SULpeak. Conclusion In evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG SUVmax, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions in these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

PurposeMany MRI sequences are sensitive to motion and its associated artifacts. The linearized geometric solution (LGS), a balanced steady-state free precession (bSSFP) off-resonance signal demodulation technique, is evaluated with respect to motion artifact resilience.Theory and methodsThe mechanism and extent of LGS motion artifact resilience is examined in simulated, flow phantom, and in vivo clinical imaging. Motion artifact correction capabilities are decoupled from susceptibility artifact correction when feasible to permit controlled analysis of motion artifact correction when comparing the LGS with standard and phase-cycle-averaged (complex sum) bSSFP imaging.ResultsSimulations reveal that the LGS demonstrates motion artifact reduction capabilities similar to standard clinical bSSFP imaging techniques, with slightly greater resilience in high SNR regions and for shorter-duration motion. Flow phantom experiments assert that the LGS reduces shorter-duration motion artifact error by ∼24%-65% relative to the complex sum, whereas reconstructions exhibit similar error reduction for constant motion. In vivo analysis demonstrates that in the internal auditory canal/orbits, the LGS was deemed to have less artifact in 24%/49% and similar artifact in 76%/51% of radiological assessments relative to the complex sum, and the LGS had less artifact in 97%/81% and similar artifact in 3%/16% of assessments relative to standard bSSFP. Only 2 of 63 assessments deemed the LGS inferior to either complex sum or standard bSSFP in terms of artifact reduction.ConclusionThe LGS provides sufficient bSSFP motion artifact resilience to permit robust elimination of susceptibility artifacts, inspiring its use in a wide variety of applications.

Obesity is considered to be a chronic complex disease that increases the risk of diabetes, heart diseases and certain cancers. According to the literature, in obese people the gastrointestinal microbiota is disturbed, which could be the cause of the onset of obesity and related diseases. Moreover, there are small non-coding RNAs (microRNAs) that are disturbed in obesity, which are also considered to be a possible mechanism of probiotics' action. Certain microRNAs are involved in the development and metabolism of adipose tissue cells, as well as the secretion and action of insulin, showing that changed expression of certain miRNAs could have a significant impact on the onset and development of obesity and obesity-related diseases. Thus, miRNAs are considered to be possible markers for the diagnosis and prognosis of various metabolic diseases, and possible therapeutic targets for the treatment of obesity and related diseases. Considering the growing need of the healthcare system for nutraceuticals and dietary supplements that present effective and safe medical nutritive therapy in obese individuals, this work aimed to assess the beneficial effects of probiotics on obesity-related microRNAs. In this review, we described the role of microRNAs and probiotics in obesity and the association between probiotics and obesityrelated microRNAs. Circulating miRNAs' profile in obese individuals significantly differs from that of normal-weight individuals. miRNAs such as miR-155, miR-221, miR-24-3p, and miR181a are over-expressed, while miR-26b and 125a are under-expressed in obese patients compared to non-obese individuals. It has been found that supplementation with Bifidobacterium bifidum and Lactobacillus acidophilus could downregulate the expression of miR-155 and miR221, and upregulate the expression of miR-26b. Supplementation with a probiotic formulation containing S. boulardii, L. plantarum 299v, and octacosanol led to the downregulation of miR155 and miR-24-3p expression. miR-125a and miR-181a were upregulated and downregulated, respectively, after the intervention with L. delbrueckii and L. rhamnosus. After reviewing the available literature, we can conclude that probiotics have beneficial effects on microRNAs altered in obesity, which could provide an effective strategy for the management of obesity.

This paper explores the relationship between students' digital competence acquisition, teaching practices, and teacher professional learning activities. We analysed insights provided by 59,452 teachers through SELFIE, an online self-reflection tool for schools' digital capacity. Using ordinary least squares regressions with school fixed effects, we focus on students' digital competence and find that the use of digital technologies in cross-curricular projects is the teaching practice most related to the acquisition of students' digital competence. On the other hand, we also find that teachers' participation in teacher networks is highly correlated with the implementation of cross-curricular projects with digital technologies. The results further suggest that the use of digital technologies for teacher collaboration (in professional learning activities and in implementing cross-curricular projects) can have great potential and importance in the digital age, both for teachers and learners.

BackgroundDuring the SARS-CoV-2 pandemic it was speculated that the virus might be associated with a persistent increase of cardiovascular risk. The present study compares pre- and post-pandemic hospital admission rates for hypertension and coronary artery disease.MethodsSystematic multicentric retrospective cohort analysis of 57.795 hospital admissions in an urban region in Germany during two different periods (pre-pandemic 01–06/2019 vs. post-pandemic era 01–06/2023). Information on hospital admissions for arterial hypertension, chronic coronary syndrome, unstable angina pectoris and acute myocardial infarction were extracted from the hospitals data systems. Additionally, six comorbidities and performed coronary interventions were monitored.ResultsCompared to the pre-pandemic era, there was no increase in hospitalizations for arterial hypertension (516 vs. 483, −6.8%, p = 0.07) or myocardial infarction (487 vs. 349, −23.8%, p

Vitamin D3 regulates a variety of biological processes irrespective of its well-known importance for calcium metabolism. Epidemiological and animal studies indicate a role in immune regulation, intestinal barrier function and microbiome diversity. Here, we analyzed the impact of different vitamin D3- containing diets on C57BL/6 and BALB/c mice, with a particular focus on gut homeostasis and also investigated effects on immune cells in vitro. Weak regulatory effects were detected on murine T cells. By trend, the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 suppressed IFN, GM-CSF and IL-10 cytokine secretion in T cells of C57BL/6 but not BALB/c mice, respectively. Using different vitamin D3-fortified diets, we found a tissue–specific enrichment of mainly CD11b+ myeloid cells but not T cells in both mouse strains e.g. in spleen and Peyer’s Patches. Mucin Reg3γ and Batf expression, as well as important proteins for gut homeostasis, were significantly suppressed in the small intestine of C57BL76 but not BALB/c mice fed with a high-vitamin D3 containing diet. Differences between both mouse stains were not completely explained by differences in vitamin D3 receptor expression which was strongly expressed in epithelial cells of both strains. Finally, we analyzed gut microbiome and again an impact of vitamin D3 was detected in C57BL76 but not BALB/c. Our data suggest strain-specific differences in vitamin D3 responsiveness under steady state conditions which may have important implications when choosing a murine disease model to study vitamin D3 effects.

PurposeSpatially fractionated radiation therapy (SFRT), which delivers highly nonuniform dose distributions instead of conventionally practiced homogeneous tumor dose, has shown high rates of clinical response with minimal toxicities in large-volume primary or metastatic malignancies. However, prospective multi-institutional clinical trials in SFRT are lacking, and SFRT techniques and dose parameters remain variable. Agreement on dose prescription, technical administration, and clinical and translational design parameters for SFRT trials is essential to enable broad participation and successful accrual to rigorously test the SFRT approach. We aimed to develop a consensus for the design of multi-institutional clinical trials in SFRT, tailored to specific primary tumor sites, to help facilitate development and enhance the feasibility of such trials.Methods and materialsPrimary tumor sites with sufficient pilot experience in SFRT were identified, and fundamental trial design questions were determined. For each tumor site, a comprehensive consensus effort was established through disease-specific expert panels. Clinical trial design criteria included eligibility, SFRT technology and technique, dose and fractionation, target- and normal-tissue dose parameters, systemic therapies, clinical trial endpoints, and translational science considerations. Iterative appropriateness rank voting, expert panel consensus reviews and discussions, and public comment posting were used for consensus development.ResultsClinical trial criteria were developed for head and neck cancer and soft-tissue sarcoma. Final consensus among the 22 trial design categories each (a total of 163 criteria) was high to moderate overall. Uniform patient cohorts of advanced bulky disease, standardization of SFRT technologies and dosimetry and physics parameters, and collection of translational correlates were considered essential to trial design. Final guideline recommendations and the degree of agreement are presented and discussed.ConclusionsThis consensus provides design guidelines for the development of prospective multi-institutional clinical trials testing SFRT in advanced head and neck cancer and soft-tissue sarcoma through in-advance harmonization of the fundamental clinical trial design among SFRT experts, potential investigators, and the SFRT community.

The article ‘EGFR/Ras-induced CCL20 production modulates the tumour microenvironment’, written by Andreas Hippe, Stephan Alexander Braun, Péter Oláh, Peter Arne Gerber, Anne Schorr, Stephan Seeliger, Stephanie Holtz, Katharina Jannasch, Andor Pivarcsi, Bettina Buhren, Holger Schrumpf, Andreas Kislat, Erich Bünemann, Martin Steinhoff, Jens Fischer, Sérgio A. Lira, Petra Boukamp, Peter Hevezi, Nikolas Hendrik Stoecklein, Thomas Hoffmann, Frauke Alves, Jonathan Sleeman, Thomas Bauer, Jörg Klufa, Nicole Amberg, Maria Sibilia, Albert Zlotnik, Anja Müller- Homey and Bernhard Homey, was originally published electronically on the publisher’s internet portal on 30 June 2020 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 16 September 2021 to © The Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. Open Access funding enabled and organized by Projekt DEAL.

Purpose: The role of postoperative radiation therapy (PORT) in early stage Merkel cell carcinoma (MCC) is controversial. We analyzed the role of PORT in preventing local recurrences (LR) among patients with low-risk, pathologic stage I MCC based on the location of the primary tumors: head/neck (HN) versus non-HN sites. Methods and Materials: One hundred forty-seven patients with MCC were identified that had “low risk” disease (pathologic T1 primary tumor, negative microscopic margins, negative pathologic node status, no immunosuppression or prior systemic therapy). LR was defined as tumor recurrence within 2 cm of the primary surgical bed, and its frequency was estimated with the cumulative incidence method. Results: Seventy-nine patients received PORT (30 HN, 49 non-HN) with a median dose of 50 Gy (range, 8-64 Gy) and 68 patients were treated with surgery alone (30 HN, 38 non-HN). Overall, PORT was associated with a decreased risk of LR (5-year rate: 0% vs 9.5%; P = .004) with 6 LRs observed in the surgery alone group. Although the addition of PORT significantly reduced LR rates among patients with HN MCC (0% vs. 21%; P = .034), no LRs were observed in patients with non-HN MCC managed with surgery alone. There was no significant difference in MCC-specific survival comparing HN versus non-HN groups, with or without PORT. Conclusions: For low-risk, pathologic stage I MCC of the extremities and trunk, excellent local control rates were achieved with surgery, and PORT is not indicated. However, PORT was associated with a significant reduction in LRs among low-risk MCC of the HN.

Abstract The spatial and temporal distribution of Alpine snow is a sensitive gauge of environmental change. While understanding past snow dynamics is essential for reconstructing past climate and forecasting future trends, reliable snowpack data prior to the instrumental record are scarce. We present a novel pairing of cosmogenic paleothermometry and luminescence photochronometry which constrain the temperature and insolation history of bedrock outcrops at the Gotthard Pass, Switzerland, over the last ∼15,000 years. By coupling these results with cosmogenic 14C‐10Be chronology and modern in situ rock thermometry, we infer a ∼70‐day reduction of snowpack at the topographic mid‐slope. Our data indicate stable environmental conditions throughout the Holocene, followed by a 6.6 ± 2.9°C increase of ground surface temperature, coeval with an order‐of‐magnitude or more increase in ground surface insolation. Bracketing the onset of these changes between 1504 and 1807 CE, our findings tie the snowpack decline with the onset of human industrialization.

IntroductionLung cancer screening (LCS) can reduce lung cancer mortality; however, poor understanding of results may impact patient experience and follow-up. We sought to determine whether an informational handout accompanying LCS results can improve patient-reported outcomes and adherence to follow-up.Study designThis was a prospective alternating intervention pilot trial of a handout to accompany LCS results delivery.Setting/participantsPatients undergoing LCS in a multisite program over a 6-month period received a mailing containing either: 1) a standardized form letter of LCS results (control) or 2) the LCS results letter and the handout (intervention).InterventionA two-sided informational handout on commonly asked questions after LCS created through iterative mixed-methods evaluation with both LCS patients and providers.Outcome measuresThe primary outcomes of 1)patient understanding of LCS results, 2)correct identification of next steps in screening, and 3)patient distress were measured through survey. Adherence to recommended follow-up after LCS was determined through chart review. Outcomes were compared between the intervention and control group using generalized estimating equations.Results389 patients were eligible and enrolled with survey responses from 230 participants (59% response rate). We found no differences in understanding of results, identification of next steps in follow-up or distress but did find higher levels of knowledge and understanding on questions assessing individual components of LCS in the intervention group. Follow-up adherence was overall similar between the two arms, though was higher in the intervention group among those with positive findings (p = 0.007).ConclusionsThere were no differences in self-reported outcomes between the groups or overall follow-up adherence. Those receiving the intervention did report greater understanding and knowledge of key LCS components, and those with positive results had a higher rate of follow-up. This may represent a feasible component of a multi-level intervention to address knowledge and follow-up for LCS.Trial registrationClinicalTrials.gov NCT05265897.