The association between thyroid differentiation score and survival outcomes in papillary thyroid carcinoma.

BACKGROUND: Thyroid differentiation score (TDS), calculated based on mRNA expression levels of 16 genes controlling thyroid metabolism and function, has been proposed as a measure to quantify differentiation in PTC. The objective of this study is to determine whether TDS is associated with survival outcomes across patient cohorts. METHODS: Two independent cohorts of PTC patients were used: 1) the Cancer Genome Atlas (TCGA) thyroid cancer study (N=372), 2) MD Anderson Cancer Center (MDACC) cohort (N=111). The primary survival outcome of interest was progression-free interval (PFI). Association with overall survival (OS) was also explored. The Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. RESULTS: In both cohorts, TDS was associated with tumor and nodal stage at diagnosis as well as tumor driver mutation status. High TDS was associated with longer PFI on univariable analyses across cohorts. After adjusting for overall stage, TDS remained significantly associated with PFI in the MDACC cohort only (aHR 0.67, 95%CI 0.52-0.85). In subgroup analyses stratified by tumor driver mutation status, higher TDS was most consistently associated with longer PFI in BRAFV600E-mutated tumors across cohorts after adjusting for overall stage (TCGA: aHR 0.60, 95% CI: 0.33-1.07; MDACC: aHR 0.59, 95% CI: 0.42-0.82). For OS, increasing TDS was associated with longer OS in the overall MDACC cohort (aHR=0.78, 95% CI:0.63-0.96), where the median duration of follow-up was 12.9 years. CONCLUSION: TDS quantifies the spectrum of differentiation status in PTC and may serve as a potential prognostic biomarker in PTC, mostly promisingly in BRAFV600E-mutated tumors.

Soil Giant Phage: Genome and Biological Characteristics of Sinorhizobium Jumbo Phage.

This paper presents the first in-depth research on the biological and genomic properties of lytic rhizobiophage AP-J-162 isolated from the soils of the mountainous region of Dagestan (North Caucasus), which belongs to the centers of origin of cultivated plants, according to Vavilov N.I. The rhizobiophage host strains are nitrogen-fixing bacteria of the genus Sinorhizobium spp., symbionts of leguminous forage grasses. The phage particles have a myovirus virion structure. The genome of rhizobiophage AP-J-162 is double-stranded DNA of 471.5 kb in length; 711 ORFs are annotated and 41 types of tRNAs are detected. The closest phylogenetic relative of phage AP-J-162 is Agrobacterium phage Atu-ph07, but no rhizobiophages are known. The replicative machinery, capsid, and baseplate proteins of phage AP-J-162 are structurally similar to those of Escherichia phage T4, but there is no similarity between their tail protein subunits. Amino acid sequence analysis shows that 339 of the ORFs encode hypothetical or functionally relevant products, while the remaining 304 ORFs are unique. Additionally, 153 ORFs are similar to those of Atu_ph07, with one-third of the ORFs encoding different enzymes. The biological properties and genomic characteristics of phage AP-J-162 distinguish it as a unique model for exploring phage-microbe interactions with nitrogen-fixing symbiotic microorganisms.

Multiparametric Ultrasound for Focal Testicular Pathology: A Ten-Year Retrospective Review.

Conventional ultrasonography (US), including greyscale imaging and colour Doppler US (CDUS), is pivotal for diagnosing scrotal pathologies, but it has limited specificity. Historically, solid focal testicular abnormalities often led to radical orchidectomy. This retrospective study evaluated the utilisation of contrast-enhanced ultrasound (CEUS) and strain elastography (SE) in investigating intratesticular focal abnormalities. A total of 124 cases were analysed. This study underscored the superior diagnostic capabilities of CEUS in detecting vascular enhancement in all malignant cases, even those with undetectable vascularity by CDUS. It also highlighted the potential of CEUS in identifying distinctive vascular patterns in benign vascular tumours. Definitive confirmation of benignity could be obtained when the absence of enhancement was demonstrated on CEUS. While SE alone offered no distinctive advantage in differentiating between benign and malignant pathologies, we demonstrated that incorporating a combination of CEUS and SE into the evaluation of focal testicular abnormalities could improve diagnostic performance metrics over conventional CDUS. Our findings underscore the role of advanced ultrasound techniques in enhancing the evaluation of focal testicular abnormalities in clinical practice and could aid a shift towards testis-sparing management strategies.

Inhomogeneous terminators on the exoplanet WASP-39 b.

Transmission spectroscopy has been a workhorse technique over the past two decades to constrain the physical and chemical properties of exoplanet atmospheres 1-5. One of its classical key assumptions is that the portion of the atmosphere it probes - the terminator region - is homogeneous. Several works in the past decade, however, have put this into question for highly irradiated, hot (Teq ≳ 1000 K) gas giant exoplanets both empirically 6-10 and via 3-dimensional modelling 11-17. While models predict clear differences between the evening (day-to-night) and morning (night-to-day) terminators, direct morning/evening transmission spectra in a wide wavelength range has not been reported for an exoplanet to date. Under the assumption of precise and accurate orbital parameters on WASP-39 b, here we report the detection of inhomogeneous terminators on the exoplanet WASP-39 b, which allows us to retrieve its morning and evening transmission spectra in the near-infrared (2 - 5 µm) using JWST. We observe larger transit depths in the evening which are, on average, 405±88 ppm larger than the morning ones, also having qualitatively larger features than the morning spectrum. The spectra are best explained by models in which the evening terminator is hotter than the morning terminator by 177 - 57 + 65 K with both terminators having C/O ratios consistent with solar. General circulation models (GCMs) predict temperature differences broadly consistent with the above value and point towards a cloudy morning terminator and a clearer evening terminator.

Brain clocks capture diversity and disparity in aging and dementia.

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of multimodal diversity (geographical, socioeconomic, sociodemographic, sex, neurodegeneration) on the brain age gap (BAG) is unknown. Here, we analyzed datasets from 5,306 participants across 15 countries (7 Latin American countries -LAC, 8 non-LAC). Based on higher-order interactions in brain signals, we developed a BAG deep learning architecture for functional magnetic resonance imaging (fMRI=2,953) and electroencephalography (EEG=2,353). The datasets comprised healthy controls, and individuals with mild cognitive impairment, Alzheimer's disease, and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (fMRI: MDE=5.60, RMSE=11.91; EEG: MDE=5.34, RMSE=9.82) compared to non-LAC, associated with frontoposterior networks. Structural socioeconomic inequality and other disparity-related factors (pollution, health disparities) were influential predictors of increased brain age gaps, especially in LAC (R2=0.37, F2=0.59, RMSE=6.9). A gradient of increasing BAG from controls to mild cognitive impairment to Alzheimer's disease was found. In LAC, we observed larger BAGs in females in control and Alzheimer's disease groups compared to respective males. Results were not explained by variations in signal quality, demographics, or acquisition methods. Findings provide a quantitative framework capturing the multimodal diversity of accelerated brain aging.

Molecular Perspectives in Radioactive Iodine Theranostics: Current Redifferentiation Protocols for Mis-Differentiated Thyroid Cancer.

Thyroid cancer molecular oncogenesis involves functional dedifferentiation. The initiating genomic alterations primarily affect the MAPK pathway signal transduction and generate an enhanced ERK output, which in turn results in suppression of the expression of transcription of the molecules of iodine metabolomics. The clinical end result of these molecular alterations is an attenuation in theranostic power of radioactive iodine (RAI). The utilization of RAI in systemic therapy of metastatic disease requires restoration of the functional differentiation. This concept has been accomplished by modulation of MAPK signaling. Objective responses have been demonstrated in metastatic disease settings. RAI-refractoriness in "differentiated thyroid cancers" remains a clinical problem despite optimized RAI administration protocols. Functional mis-differentiation and associated RAI-indifference are the underlying primary obstacles. MAPK pathway modulation offers a potential for reversal of RAI-indifference and combat refractoriness. This review presents the latest clinical experience and protocols for the redifferentiation of radioiodine-refractory mis-differentiated thyroid cancer, providing a comprehensive overview of the current protocols and intervention strategies used by leading institutions. Timing and techniques of imaging, thyrotropin (TSH) stimulation methods, and redifferentiation agents are presented. The efficacy and limitations of various approaches are discussed, providing an overview of the advantages and disadvantages associated with each of the protocols.

Acute Effect of Transcranial Direct Current Stimulation in Pelvic Floor Muscle Function in Young Healthy Women: Initial Findings of a Randomized Controlled Trial.

INTRODUCTION AND HYPOTHESIS: Transcranial direct current stimulation (tDCS) can enhance muscle function in healthy individuals. However, it is unknown if tDCS associated with pelvic floor muscle training (PFMT) can improve pelvic floor muscle function (PFMF) in healthy women. The aim of this study was to investigate the acute effect of a single session of tDCS in PFMF compared with sham-tDCS in healthy women. METHODS: A double-blind, cross-over, randomized clinical trial was conducted with healthy, nulliparous and sexually active women. PFMF was assessed by bidigital palpation (PERFECT scale) and intravaginal pressure by a manometer (Peritron™). Participants randomly underwent two tDCS sessions (active and sham) 7 days apart. The electrode was positioned equal for both protocols, the anode electrode in the supplementary motor area (M1) and the cathode electrode in the right supraorbital frontal cortex (Fp2). The current was applied for 20 min at 2 mA in active stimulation and for 30 s in sham-tDCS. The tDCS applications were associated with verbal instructions to PFMT in a seated position. After each tDCS session PFMF was reevaluated. RESULTS: Twenty young healthy women (aged 23.4 ± 1.7 years; body mass index 21.7 ± 2.2 kg/m2) were included. No difference was observed in power, endurance, and intravaginal pressure of PFMF (p > 0.05). The number of sustained contractions improved from 3.0 (2.0-3.5) to 4.0 (3.0-5.0) after active-tDCS (p = 0.0004) and was superior to sham-tDCS (p = 0.01). CONCLUSION: The number of sustained contractions of PFM improved immediately after a single active-tDCS session, with a difference compared with the post-intervention result of sham-tDCS in healthy young women.

Initial Management of BRAF V600E-Variant Anaplastic Thyroid Cancer: The FAST Multidisciplinary Group Consensus Statement.

Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease. Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making. Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.

Genome mining leads to the identification of a stable and promiscuous Baeyer-Villiger monooxygenase from a thermophilic microorganism.

Baeyer-Villiger monooxygenases (BVMOs) are NAD(P)H-dependent flavoproteins that convert ketones to esters and lactones. While these enzymes offer an appealing alternative to traditional Baeyer-Villiger oxidations, these proteins tend to be either too unstable or exhibit too narrow of a substrate scope for implementation as industrial biocatalysts. Here, sequence similarity networks were used to search for novel BVMOs that are both stable and promiscuous. Our genome mining led to the identification of an enzyme from Chloroflexota bacterium (strain G233) dubbed ssnBVMO that exhibits i) the highest melting temperature of any naturally sourced BVMO (62.5 ºC), ii) a remarkable kinetic stability across a wide range of conditions, similar to those of PAMO and PockeMO, iii) optimal catalysis at 50 °C, and iv) a broad substrate scope that includes linear aliphatic, aromatic, and sterically bulky ketones. Subsequent quantitative assays using propiophenone demonstrated >95% conversion. Several fusions were also constructed that linked ssnBVMO to a thermostable phosphite dehydrogenase. These fusions can recycle NADPH and catalyze oxidations with sub-stoichiometric quantities of this expensive cofactor. Characterization of these fusions permitted identification of PTDH-L1-ssnBVMO as the most promising protein that could have utility as a seed sequence for enzyme engineering campaigns aiming to develop biocatalysts for Baeyer-Villiger oxidations.

Barriers to and facilitators of implementing colorectal cancer screening evidence-based interventions in federally qualified health centers: a qualitative study.

BACKGROUND: There is an urgent need to increase colorectal cancer screening (CRCS) uptake in Texas federally qualified health centers (FQHCs), which serve a predominantly vulnerable population with high demands. Empirical support exists for evidence-based interventions (EBIs) that are proven to increase CRCS; however, as with screening, their use remains low in FQHCs. This study aimed to identify barriers to and facilitators of implementing colorectal cancer screening (CRCS) evidence-based interventions (EBIs) in federally qualified health centers (FQHCs), guided by the Consolidated Framework for Implementation Research (CFIR). METHODS: We recruited employees involved in implementing CRCS EBIs (e.g., physicians) using data from a CDC-funded program to increase the CRCS in Texas FQHCs. Through 23 group interviews, we explored experiences with practice change, CRCS promotion and quality improvement initiatives, organizational readiness, the impact of COVID-19, and the use of CRCS EBIs (e.g., provider reminders). We used directed content analysis with CFIR constructs to identify the critical facilitators and barriers. RESULTS: The analysis revealed six primary CFIR constructs that influence implementation: information technology infrastructure, innovation design, work infrastructure, performance measurement pressure, assessing needs, and available resources. Based on experiences with four recommended EBIs, participants described barriers, including data limitations of electronic health records and the design of reminder alerts targeted at deliverers and recipients of patient or provider reminders. Implementation facilitators include incentivized processes to increase provider assessment and feedback, existing clinic processes (e.g., screening referrals), and available resources to address patient needs (e.g., transportation). Staff buy-in emerged as an implementation facilitator, fostering a conducive environment for change within clinics. CONCLUSIONS: Using CFIR, we identified barriers, such as the burden of technology infrastructure, and facilitators, such as staff buy-in. The results, which enhance our understanding of CRCS EBI implementation in FQHCs, provide insights into designing nuanced, practical implementation strategies to improve cancer control in a critical setting.

Monitoring handgrip strength to motivate lifestyle choices for patients with diabetes type 2 - a pragmatic randomised controlled trial.

METHODS: Measurement of HGS with Jamar dynamometers was added to annual check-ups for patients with T2DM by diabetes nurses in primary care with feedback about normal values for age and sex in the intervention group. The control group had standard check-ups. Change in self-reported PA level was measured with questionnaires. RESULTS: Seven clinics and 334 patients participated. The intervention led to similar effects on PA in both groups. Patients with T2DM had comparable HGS to the general public. Regression analyses showed statistically significantly higher HGS in the intervention group than in the control group at follow-up and no improvement in PA, HbA1c, or waist circumference. Increased HGS was found for older people, men, and people with normal-to-high inclusion HGS, while patients with low inclusion HGS reduced their strength levels. CONCLUSIONS: Measuring HGS and giving feedback to patients with T2DM can lead to increased HGS but does not seem to affect general PA level, HbA1c, or waist circumference. People over 65 years, men, and people with normal-to-high HGS were influenced positively by the intervention. Patients with low HGS may need personalised support to increase physical activity and improve function.ClinicalTrials registration: NCT03693521.

Streptococcus canis Native Aortic Valve Endocarditis Linked to Cat Exposure: A Case Report and Review.

Streptococcus canis is an uncommon human pathogen, but documented infections have been mostly associated with exposure to dogs. There are only five documented cases of endocarditis secondary to streptococcus canis, with all cases except one documenting exposure to a canine. We present a 74-year-old male with a history of Type 2 diabetes mellitus, CKD 3, moderate aortic stenosis and remote exposure to agent orange, who was found to have Streptococcus canis native valve endocarditis without exposure to a dog. To the best of our knowledge this case is the first case of endocarditis linked to feline exposure.

The impact of environmental factors and contaminants on thyroid function and disease from fetal to adult life: current evidence and future directions.

The thyroid gland regulates most of the physiological processes. Environmental factors, including climate change, pollution, nutritional changes, and exposure to chemicals, have been recognized to impact thyroid function and health. Thyroid disorders and cancer have increased in the last decade, the latter increasing by 1.1% annually, suggesting that environmental contaminants must play a role. This narrative review explores current knowledge on the relationships among environmental factors and thyroid gland anatomy and function, reporting recent data, mechanisms, and gaps through which environmental factors act. Global warming changes thyroid function, and living in both iodine-poor areas and volcanic regions can represent a threat to thyroid function and can favor cancers because of low iodine intake and exposure to heavy metals and radon. Areas with high nitrate and nitrite concentrations in water and soil also negatively affect thyroid function. Air pollution, particularly particulate matter in outdoor air, can worsen thyroid function and can be carcinogenic. Environmental exposure to endocrine-disrupting chemicals can alter thyroid function in many ways, as some chemicals can mimic and/or disrupt thyroid hormone synthesis, release, and action on target tissues, such as bisphenols, phthalates, perchlorate, and per- and poly-fluoroalkyl substances. When discussing diet and nutrition, there is recent evidence of microbiome-associated changes, and an elevated consumption of animal fat would be associated with an increased production of thyroid autoantibodies. There is some evidence of negative effects of microplastics. Finally, infectious diseases can significantly affect thyroid function; recently, lessons have been learned from the SARS-CoV-2 pandemic. Understanding how environmental factors and contaminants influence thyroid function is crucial for developing preventive strategies and policies to guarantee appropriate development and healthy metabolism in the new generations and for preventing thyroid disease and cancer in adults and the elderly. However, there are many gaps in understanding that warrant further research.

[Recommendations for the management of latex allergy in pediatrics]. / Recomendaciones para el manejo de la alergia al látex en pediatría.

Latex allergy, or natural rubber latex allergy (NRLA), is a global health concern, even among the pediatric population, with symptoms varying in severity from mild to potentially life-threatening. Latex is derived from the Hevea Brasiliensis tree, producing twelve million tons annually for use in various everyday and medical products. Despite efforts to mitigate NRLA, its prevalence remains high, especially in at- risk groups such as children with spina bifida. Clinical manifestations include immediate and delayed symptoms, even anaphylactic reactions. Diagnosis involves a detailed medical history and specific tests. Prevention focuses on avoiding exposure, especially in medical and educational settings. Treatment, including immunotherapy, exhibits variable efficacy. NRLA has a strong negative impact on children's quality of life. The objective of this publication is to provide updated information and practical tools for the pediatrician's and allergist's practice.

La alergia al látex del caucho natural (ALCN) es un problema de salud global, incluso en población pediátrica, con síntomas de gravedad variable, desde leves hasta potencialmente mortales. El látex se obtiene del árbol Hevea brasiliensis; se producen doce millones de toneladas anuales que se utilizan en diversos productos cotidianos y médicos. A pesar de los esfuerzos para mitigar la ALCN, su prevalencia sigue siendo alta, especialmente en grupos de riesgo, como niños con espina bífida. Las manifestaciones clínicas incluyen síntomas inmediatos y retardados, hasta reacciones anafilácticas. El diagnóstico requiere una historia clínica detallada y pruebas específicas. La prevención se centra en evitar la exposición, especialmente en entornos médicos y escolares. El tratamiento, incluida la inmunoterapia, muestra eficacia variable. La ALCN tiene un fuerte impacto negativo en la calidad de vida. El objetivo de esta publicación es proveer información actualizada y herramientas prácticas para el consultorio del pediatra y el alergólogo.

Mitochondrial inorganic polyphosphate is required to maintain proteostasis within the organelle.

The existing literature points towards the presence of robust mitochondrial mechanisms aimed at mitigating protein dyshomeostasis within the organelle. However, the precise molecular composition of these mechanisms remains unclear. Our data show that inorganic polyphosphate (polyP), a polymer well-conserved throughout evolution, is a component of these mechanisms. In mammals, mitochondria exhibit a significant abundance of polyP, and both our research and that of others have already highlighted its potent regulatory effect on bioenergetics. Given the intimate connection between energy metabolism and protein homeostasis, the involvement of polyP in proteostasis has also been demonstrated in several organisms. For example, polyP is a bacterial primordial chaperone, and its role in amyloidogenesis has already been established. Here, using mammalian models, our study reveals that the depletion of mitochondrial polyP leads to increased protein aggregation within the organelle, following stress exposure. Furthermore, mitochondrial polyP is able to bind to proteins, and these proteins differ under control and stress conditions. The depletion of mitochondrial polyP significantly affects the proteome under both control and stress conditions, while also exerting regulatory control over gene expression. Our findings suggest that mitochondrial polyP is a previously unrecognized, and potent component of mitochondrial proteostasis.

Myocardial Injury in Patients with Hip Fracture: A HIP ATTACK Randomized Trial Substudy.

BACKGROUND: Myocardial injury after a hip fracture is common and has a poor prognosis. Patients with a hip fracture and myocardial injury may benefit from accelerated surgery to remove the physiological stress associated with the hip fracture. This study aimed to determine if accelerated surgery is superior to standard care in terms of the 90-day risk of death in patients with a hip fracture who presented with an elevated cardiac biomarker/enzyme measurement at hospital arrival. METHODS: The HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) trial was a randomized controlled trial designed to determine whether accelerated surgery for hip fracture was superior to standard care in reducing death or major complications. This substudy is a post-hoc analysis of 1392 patients (from the original study of 2970 patients) who had a cardiac biomarker/enzyme measurement (>99.9% had a troponin measurement and thus "troponin" is the term used throughout the paper) at hospital arrival. The primary outcome was all-cause mortality. The secondary composite outcome included all-cause mortality and non-fatal myocardial infarction, stroke, and congestive heart failure 90 days after randomization. RESULTS: Three hundred and twenty-two (23%) of the 1392 patients had troponin elevation at hospital arrival. Among the patients with troponin elevation, the median time from hip fracture diagnosis to surgery was 6 hours (interquartile range [IQR] = 5 to 13) in the accelerated surgery group and 29 hours (IQR = 19 to 52) in the standard care group. Patients with troponin elevation had a lower risk of mortality with accelerated surgery compared with standard care (17 [10%] of 163 versus 36 [23%] of 159; hazard ratio [HR] = 0.43 [95% confidence interval (CI) = 0.24 to 0.77]) and a lower risk of the secondary composite outcome (23 [14%] of 163 versus 47 [30%] of 159; HR = 0.43 [95% CI = 0.26 to 0.72]). CONCLUSIONS: One in 5 patients with a hip fracture presented with myocardial injury. Accelerated surgery resulted in a lower mortality risk than standard care for these patients; however, these findings need to be confirmed. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.