Survival Outcomes of Total Laryngectomy: Evaluating the Intersection of Race and Social Determinants.

OBJECTIVE: Analyze joint effects of race and social determinants on survival outcomes for patients undergoing total laryngectomy for advanced or recurrent laryngeal cancer at a tertiary care institute. METHODS: Retrospective chart review of adult patients undergoing total laryngectomy for laryngeal cancer at a tertiary care center from 2013 to 2020. Extracted data included demographics, pathological staging and features, treatment modalities, and outcomes such as recurrence, fistula formation, and 2- and 5-year disease-free survival (DFS) and overall survival (OS). Area Deprivation Index (ADI) was calculated for each patient. RESULTS: Among 185 patients identified, 113 were Black (61.1%) and 69 were White (37.3%). No significant differences were observed between racial groups regarding age, gender, ADI, or cancer stage. There was no significant difference in 2-year DFS/OS between groups. ADI was comparable between racial groups, with the majority in the highest deprivation quintile (63.8% of Whites vs. 62.5% of Blacks). No significant differences were observed in gender, race, cancer stage, positive margins, extracapsular extension, or smoking status among ADI quintiles. We observed a significant difference in 2-year DFS stratified by ADI (p = 0.025). Stratifying by ADI and race revealed improved survival of White patients in lower quintiles but higher survival of Black patients in the highest disparity quintile (p = 0.013). CONCLUSION: Overall, survival outcomes by race were comparable among laryngectomy patients, but there was a significant difference in 2-year DFS when stratified by ADI. Further research into survival outcomes related to social determinants is needed to better delineate their effects on head and neck cancer outcomes. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Cytotoxicity assessment of eluates from vacuum-forming thermoplastics.

OBJECTIVES: This study aimed to evaluate possible cytotoxic effects of thermoplastic materials commonly used for occlusal splints and orthodontic appliances. METHODS: Seven thermoplastics were included: three variants of the Essix sheets (C+, Plus, and Tray Rite; Dentsply Sirona), three thermoplastics (Bleach Heavy, Splint, and X-Heavy; Cavex Holland) and Invisalign (Align Technology). Cylindrical specimens (n = 24; 10 mm diameter) were incubated in cell culture medium for 24 h and 14 days. After incubation, the medium was collected, serially diluted, and dosed to primary human gingival fibroblasts in triplicate. Medium processed like the samples was used as negative control. Cell viability was evaluated by XTT and LDH assay to assess metabolic activity and membrane integrity, respectively. Next, cell cycle was assessed with flow cytometry after exposing HGFs to undiluted extracts. RESULTS: The 24-hour and 14-day extracts did not evoke cytotoxicity after 24-hour incubation. No significant differences in cell viability (one-way ANOVA, p > 0.05 ) in the XTT and LDH assays or in cell cycle distribution between the different materials (two-way ANOVA, p > 0.05 ). CONCLUSION: The thermoplastics tested in the study showed no evident in-vitro cytotoxic effects. Further investigation should focus on determining which compounds are released from thermoplastic materials and assessing potential toxicity related to exposure to these compounds. CLINICAL SIGNIFICANCE: Our study adds to the growing body of evidence on the biocompatibility of dental thermoplastics. This can aid clinical decision-making, as thermoplastics are expected to be safe to use in terms of cytotoxicity.

Profiling the endocrine disrupting properties of triazines, triazoles and short-chain PFAS.

Persistent, mobile and toxic (PMT) compounds released to the environment are likely to pollute drinking water sources due to their slow environmental degradation (persistency) and high water solubility (mobility). The aim of the present study was to create in vitro hazard profiles for sixteen triazoles, nine triazines and eleven PFAS based on their agonistic and antagonistic effects in estrogen receptor (ER), androgen receptor (AR) and thyroid hormone receptor (TR) reporter gene assays, their ability to bind human transthyretin (TTR), and their effects on steroidogenesis. The triazole fungicides tetraconazole, bitertanol, fenbuconazole, tebuconazole, cyproconazole, difenoconazole, propiconazole, paclobutrazol and triadimenol had agonistic or antagonistic effects on the ER and AR. Difenoconazole, propiconazole and triadimenol were also found to be TR antagonists. The triazine herbicide ametryn was an ER, AR and TR antagonist. The same nine triazole fungicides and the triazines atrazine, deethyl-atrazine and ametryn affected the secretion of steroid hormones. Furthermore, PFAS compounds PFBS, PFHxS, PFHxA, PFOS, PFOA and GenX and the triazoles bitertanol, difenoconazole and 4-methyl benzotriazole were found to displace T4 from TTR. These results are in line with earlier in vitro and in vivo studies on the endocrine disrupting properties of triazines, triazoles and PFAS. The present study demonstrates that this battery of in vitro bioassays can be used to profile compounds from different classes based on their endocrine disrupting properties as a first step to prioritize them for further research, emission reduction, environmental remediation and regulatory purposes.

Creatinine clearance/eGFR ratio: a simple index for muscle mass related to mortality in ICU patients.

INTRODUCTION: In patients admitted to the intensive care unit (ICU), muscle mass is inversely associated with mortality. Although muscle mass can be estimated with 24-h urinary creatinine excretion (UCE), its use for risk prediction in individual patients is limited because age-, sex-, weight- and length-specific reference values for UCE are lacking. The ratio between measured creatinine clearance (mCC) and estimated glomerular filtration rate (eGFR) might circumvent this constraint. The main goal was to assess the association of the mCC/eGFR ratio in ICU patients with all-cause hospital and long-term mortality. METHODS: The mCC/eGFR ratio was determined in patients admitted to our ICU between 2005 and 2021 with KDIGO acute kidney injury (AKI) stage 0-2 and an ICU stay ≥ 24 h. mCC was calculated from UCE and plasma creatinine and indexed to 1.73 m2. mCC/eGFR was analyzed by categorizing patients in mCC/eGFR quartiles and as continuous variable. RESULTS: Seven thousand five hundred nine patients (mean age 61 ± 15 years; 38% female) were included. In-hospital mortality was 27% in the lowest mCC/eGFR quartile compared to 11% in the highest quartile (P < 0.001). Five-year post-hospital discharge actuarial mortality was 37% in the lowest mCC/eGFR quartile compared to 19% in the highest quartile (P < 0.001). mCC/eGFR ratio as continuous variable was independently associated with in-hospital mortality in multivariable logistic regression (odds ratio: 0.578 (95% CI: 0.465-0.719); P < 0.001). mCC/eGFR ratio as continuous variable was also significantly associated with 5-year post-hospital discharge mortality in Cox regression (hazard ratio: 0.27 (95% CI: 0.22-0.32); P < 0.001). CONCLUSIONS: The mCC/eGFR ratio is associated with both in-hospital and long-term mortality and may be an easily available index of muscle mass in ICU patients.

Are the postmortem concentration changes of the synthetic cannabinoid cumyl-5F-P7AICA and its N-pentanoic acid metabolite dependent on the environmental conditions? - A systematic study following pulmonary administration to pigs.

The number of fatal cases involving synthetic cannabinoids (SCs) is increasing. However, interpretation of postmortem (PM) toxicological findings is challenging, due to unknown PM intervals and possible redistribution processes or instabilities. Only sparse data on SCs are available. Therefore, a controlled pig study was performed to determine the PM stability of cumyl-5F-P7AICA under different environmental conditions. Ten pigs inhalatively received 200µg/kg body weight cumyl-5F-P7AICA each. Six hours later, they were euthanized and biopsies of the main tissues and body fluids were taken. Animals were stored in air or water (n=5 each) and samples were repeatedly taken for three days. Quantification of cumyl-5F-P7AICA and its N-pentanoic acid metabolite (NPA) was performed using standard addition or a fully validated method (blood) followed by LC-MS/MS. Time-dependent concentration changes of cumyl-5F-P7AICA were observed in liver, bile fluid and muscle specimens at both conditions. Concentrations of NPA only changed considerably in duodenum content of animals stored in air. Environment-dependent concentrations changes were only observed for cumyl-5F-P7AICA in kidney and the NPA metabolite in duodenum content. Overall, cumyl-5F-P7AICA and its metabolite seem to be quite stable in PM specimens. Hence, also central blood might be analyzed, if no peripheral blood is available.

Characteristics of Hospitalized Patients With and Without Celiac Disease on a Gluten-Free Diet.

BACKGROUND: Most people maintaining a gluten-free diet (GFD) do not have celiac disease (CD). Comorbidities and associated conditions in this population are largely unknown. AIMS: This study identified demographics, dietary patterns, and diagnoses for patients prescribed a GFD during hospitalization and compared patients with CD to those without CD. METHODS: We performed a retrospective cross-sectional study for hospital admissions with a GFD between Jan 1, 2010 and June 30, 2022, while excluding patients missing demographic data (n = 113). We compared patients with and without a CD diagnosis, including multivariable logistic regression to identify characteristics independently associated with a CD diagnosis. RESULTS: We analyzed 1527 hospitalized patients of all ages. A minority (n = 467, 30.6%) carried a CD diagnosis. Age, sex, body mass index, and Medicare/Medicaid enrollment and additional diagnoses associated with a GFD (e.g., IBS) were not significantly different. The CD cohort was more predominantly white (66.6% vs 58.4%, p = 0.007) and non-Hispanic (62.5% vs. 52.7%, p = 0.001). While hospitalized, patients with CD had fewer additional dietary restrictions (mean 0.33 vs 0.56, p < 0.001) and more frequent micronutrient supplementation (26.6% vs 21.4%, p = 0.03). CD was independently associated with malnutrition (OR 1.86, 95% CI 1.31-2.65) and inversely associated with a vegetarian diet (OR 0.35, 95% CI 0.15-0.81), reduced lactose diet (OR 0.25, 95% CI 0.13-0.50), and Hispanic ethnicity (OR 0.56, 95% CI 0.35-0.90) while controlling for other covariates. DISCUSSION: Two-thirds of hospitalized patients receiving a GFD do not have a diagnosis of CD. Among GFD inpatients, CD is associated with fewer dietary restrictions and independently associated with malnutrition.

The Scanning CONfoCal Ophthalmoscopy foR DIAbetic eye screening (CONCORDIA) study paper 1.

OBJECTIVE: This project was to determine the performance of the Zeiss Clarus 700 (Clarus) and the Optos California (Optos) with staged mydriasis in a Diabetic Eye Screening Programme (DESP). METHODS: Trial participants were recruited from people attending appointments in DESP or Virtual Eye clinics for delayed hospital appointments. Non-mydriatic photographs from the Clarus and Optos cameras were compared to 2-field 45 degrees mydriatic digital photography (the reference standard) and mydriatic photographs compared if the non-mydriatic photos were unassessable (staged mydriasis). RESULTS: 1573 patients were recruited. 76 individuals were withdrawn, leaving 1497 individuals (2993 eyes). For the Clarus and the Optos, the sensitivity for any retinopathy were 94.2% (95% CI: 92.9-95.3%) and 91.9% (95% CI: 90.5-93.2%) with specificities of 87.3% (95% CI: 85.4-89.0%) and 78.1% (95% CI: 75.7-80.3%) respectively. For referable DR the sensitivities for the Clarus and Optos were 86.0% (95% CI: 82.9-88.8%) and 77.6% (95% CI: 73.9-80.9%) with specificities of 92.8% (95% CI: 91.7-93.8%) and 95.4% (95% CI: 94.5-96.2%) respectively. The Clarus and Optos without mydriasis produced 100 (3.3%) and 152 (5.1%) unassessable eyes respectively, and after staged mydriasis 51 (1.7%) and 102 (3.4%) respectively with 52 (1.7%) reference standard images unassessable. CONCLUSIONS: This study reports the performance of the Clarus and the Optos using staged mydriasis in DR screening with wider fields detecting more referable retinopathy peripherally with some reduction in sensitivity centrally for macular lesions.

Role of Early Postoperative Measurement of Copeptin in Prediction of Diabetes Insipidus Following Pituitary Surgery in Adults: a systematic review plus meta-analysis.

PURPOSE: Early diagnosis of Diabetes insipidus (DI), a complication following pituitary surgery, can avoid the catastrophic results such as lethargy or even death. Measurement of Arginine vasopressin (AVP) may help the early diagnosis, but its direct assaying is challenging. Copeptin, which is co-secreted in equimolar quantities to AVP, is suggested to be a reliable marker in prediction of post-op DI. Therefore, this systematic review plus meta-analysis aims to discover this possible role. METHODS: Google Scholar, PubMed, Scopus, Web of Science, Embase, and Cochrane library were systematically searched up to August 2024. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Problem/Population, Intervention, Comparison, and Outcome (PICO) guidelines were used. Two authors independently reviewed the eligible articles and assessed the quality of them. A meta-analysis was conducted to assess the discriminative performance of copeptin. RESULTS: In total, 8 cohort studies including 1255 participants met the inclusion criteria. The median copeptin levels were significantly lower in DI groups compared to non-DI groups in all included studies (P < 0.005). Meta-analysis of AUCs demonstrated that early measurement of copeptin level had an accuracy of 0.791 (SE: 0.0198, 95% CI: 0.752 to 0.830), which was statistically significant (P < 0.001). CONCLUSION: Copeptin level was significantly lower in DI patients than in non-DI patients who underwent pituitary surgery. Early measurement, as soon as possible (from the first hour to 48 hours after the operation), of copeptin after pituitary surgeries has good, but not excellent, accuracy to exclude post-op DI.

foxe1 mutant zebrafish show indications of a hypothyroid phenotype and increased sensitivity to ethanol for craniofacial malformations.

BACKGROUND: FOXE1 mutations in humans are associated with cleft palate and hypothyroidism. We previously developed a foxe1 mutant zebrafish demonstrating mineralization defects in larvae. In the present study, we investigate the thyroid status and skeletal phenotype of adult foxe1 mutants. RESULTS: Mutant fish have increased expression of tshß in the pituitary, and of hepatic dio1 and dio2. In plasma, we found higher Mg levels. Together these findings are indicative of hypothyroidism. We further observed mineralization defects in scales due to enhanced osteoclast activity as measured by increased expression levels of tracp, ctsk, and rankl. Gene-environment interactions in the etiology of FOXE1-related craniofacial abnormalities remain elusive, which prompts the need for models to investigate genotype-phenotype associations. We here investigated whether ethanol exposure increases the risk of developing craniofacial malformations in foxe1 mutant larvae that we compared to wild types. We found in ethanol-exposed mutants an increased incidence of developmental malformations and marked changes in gene expression patterns of cartilage markers (sox9a), apoptotic markers (casp3b), retinoic acid metabolism (cyp26c1), and tissue hypoxia markers (hifaa, hifab). CONCLUSION: Taken together, this study shows that the foxe1 mutant zebrafish recapitulates phenotypes associated with FOXE1 mutations in human patients and a clear foxe1-ethanol interaction.

Improving the endoscopic recognition of early colorectal carcinoma using artificial intelligence: current evidence and future directions.

Background and study aims Artificial intelligence (AI) has great potential to improve endoscopic recognition of early stage colorectal carcinoma (CRC). This scoping review aimed to summarize current evidence on this topic, provide an overview of the methodologies currently used, and guide future research. Methods A systematic search was performed following the PRISMA-Scr guideline. PubMed (including Medline), Scopus, Embase, IEEE Xplore, and ACM Digital Library were searched up to January 2024. Studies were eligible for inclusion when using AI for distinguishing CRC from colorectal polyps on endoscopic imaging, using histopathology as gold standard, reporting sensitivity, specificity, or accuracy as outcomes. Results Of 5024 screened articles, 26 were included. Computer-aided diagnosis (CADx) system classification categories ranged from two categories, such as lesions suitable or unsuitable for endoscopic resection, to five categories, such as hyperplastic polyp, sessile serrated lesion, adenoma, cancer, and other. The number of images used in testing databases varied from 69 to 84,585. Diagnostic performances were divergent, with sensitivities varying from 55.0% to 99.2%, specificities from 67.5% to 100% and accuracies from 74.4% to 94.4%. Conclusions This review highlights that using AI to improve endoscopic recognition of early stage CRC is an upcoming research field. We introduced a suggestions list of essential subjects to report in research regarding the development of endoscopy CADx systems, aiming to facilitate more complete reporting and better comparability between studies. There is a knowledge gap regarding real-time CADx system performance during multicenter external validation. Future research should focus on development of CADx systems that can differentiate CRC from premalignant lesions, while providing an indication of invasion depth.

The Effect of 6 weeks Physical Activity on Cognitive Control and Trait Impulsivity in Multi-problem Young Adults: First Findings of an RCT-study.

This study aimed to report the effect of a 6-week light-active versus moderate-active physical activity intervention embedded in a multimodal day treatment program on selected measures of cognitive control (i.e., response inhibition, error processing, and cognitive interference) and trait impulsivity. A randomized controlled design was implemented, including male multi-problem young adults (aged 18-27) assigned to either light-active (N = 12) or moderate-active physical activity lessons (N = 11). A repeated measures design was used to examine treatment effects between the two groups over time on response inhibition, error processing, and cognitive interference (measured respectively with a Go/NoGo task, a Flanker task, and the Stroop) and trait impulsivity (measured with the Dutch Baratt Impulsiveness Scale). Cognitive control, but not trait impulsivity, improved over time. Specifically, enhancements in inhibition and reduced cognitive interference were observed after 6 weeks. Error processing did not improve, but we did observe improved performance on an error-processing task. No interaction with physical activity intensity was found, suggesting similar treatment effects regardless of intensity. Results should be interpreted with caution due to several limitations, including the small sample size. Overall, due to current limitations (i.e., physical activity embedded in a larger treatment program, small sample size at follow-up, and low intervention adherence), it is not possible to draw any definite conclusions. However, the current findings contribute to a growing body of evidence suggesting potential benefits of physical activity (embedded in a multi-modal day treatment program) in the enhancement of cognitive control deficits in at-risk populations, independent of exercise intensity.

Retrospective evaluation of adjuvant capecitabine dosing patterns in triple negative breast cancer.

BACKGROUND: The CREATE-X trial demonstrated that adjuvant capecitabine was effective in prolonging survival in high-risk triple-negative breast cancer (TNBC) patients. However, the recommended dose is generally not well tolerated by the US population. The goal of this study is to analyze dosing patterns in an ethnically diverse cohort to better characterize tolerability and inform future dosing guidelines. METHODS: In our single-center retrospective study, we evaluated safety and tolerability in TNBC patients undergoing adjuvant capecitabine treatment. The primary endpoint, relative dose intensity (RDI) across eight cycles, was examined alongside subgroup analyses based on age, race, BMI, and initial dose. Secondary endpoints include capecitabine-related side effects and survival. RESULTS: 67 patients who completed adjuvant capecitabine at University of Chicago Medicine (UCM) between January 2017 and November 2022 were eligible. The mean RDI across eight cycles of treatment was 60.2% (95% CI: 0.554-0.650). When compared to the CREATE-X trial, the RDI in our population was significantly lower (0.602 vs. 0.787, p < 0.001). There was no statistically significant difference in average RDI across eight cycles for patients stratified by age, BMI, race, or initial starting dose. The most frequently reported adverse events were hand-foot syndrome (73%), diarrhea (27%), and fatigue (22%), consistent with prior studies. CONCLUSIONS: Our data demonstrates that a significant portion of patients have a lower tolerated dose of capecitabine in comparison to the recommended adjuvant dose. Acknowledging the limitations of our single-center analysis, RDI was not significantly affected by age, race, BMI, or initial starting dose.

Interleukin-5 as a pleiotropic cytokine orchestrating airway type 2 inflammation: Effects on and beyond eosinophils.

Interleukin (IL)-5 is the key cytokine in the maturation, activation, proliferation, migration and survival of eosinophils, which are key effector cells in many upper and lower airway diseases. Through its effects on eosinophils, IL-5 indirectly contributes to various pathophysiological processes including tissue damage, repair and remodelling. Understanding the importance of IL-5 in eosinophil-associated diseases led to the development of anti-IL-5 therapies, which provide clinical benefits across a range of conditions. However, recent evidence suggests that eosinophil-depletion alone may not account for all of the therapeutic effects of anti-IL-5 therapy and that IL-5 may also contribute to disease independently of its effects on eosinophils. Indeed, evidence from ex vivo studies and targeted therapy in vivo demonstrates that IL-5 and its inhibition affects a much broader range of cells beyond eosinophils, including epithelial cells, plasma cells, mast cells, basophils, neutrophils, type 2 innate lymphoid cells, T regulatory cells and fibroblasts. This review will provide an update on the evidence supporting the breadth of IL-5 biology relevant to disease pathogenesis beyond eosinophil-associated inflammation, where there is a need for additional insight, and the clinical implications of a more central role of IL-5 in type 2 inflammation.

The scanning CONfoCal Ophthalmoscopy foR DIAbetic eye screening (CONCORDIA) study paper 2.

PURPOSE: To determine if the Eidon white light 60-degree field Scanning Confocal Ophthalmoscope (SCO) camera was safe to use with staged mydriasis in a Diabetic Eye Screening Programme (DESP). METHODS: The trial participants were recruited from people with diabetes attending appointments in DESP or Virtual Eye clinics for post-Covid delayed hospital appointments. Using staged mydriasis, the SCO images were taken before the pupils were dilated and compared to two-field 45 degrees mydriatic digital photography (the reference standard). Mydriatic SCO images were only compared to the reference standard if the non-mydriatic SCO images were unassessable. RESULTS: 1050 patients were recruited, 35 individuals were withdrawn, the majority (18) due to an imaging protocol deviation leaving 1015 individuals (2029 eyes). Using staged mydriasis, the sensitivity and specificity for any retinopathy was 97.5% (95% CI: 96.4-98.4%) and 82.3% (95% CI: 79.6-84.7%) respectively. The sensitivity and specificity for referable retinopathy was 92.7% (95% CI: 89.9-94.9%) and 85.4% (95% CI: 83.6-87.2%) respectively. The total number of eyes that were unassessable with the Eidon without mydriasis was 85/2029 (4.2%), and after mydriasis was 34/2029 (1.7%) and, with the reference standard, 34/2029 (1.7% - not always the same images) were unassessable. CONCLUSIONS: This study provides promising early results of the performance of the Eidon camera using staged mydriasis in a DESP which needs further evidence from a non-Caucasian population and from cost-effectiveness analyses.

Development and method validation of a sampling technique for a reproducible detection of synthetic cannabinoids in exhaled breath using an in vitro pig lung model.

Alternative matrices, especially exhaled breath (EB), have gained increasing attention for a few years. To interpret toxicological findings, knowledge on the toxicokinetic (TK) properties of a substance in EB is indispensable. Whilst such data are already accessible for various drugs (e.g. Δ9-tetrahydrocannabinol), they are still not available for new psychoactive substances, particularly synthetic cannabinoids (SCs). As SCs raise a high public health concern, the aim of this study was to assess these data in future TK studies in pigs. For this purpose, an in vitro sampling technique of EB was initially developed, being prospectively applied to anesthetized and ventilated pigs for the detection of SCs in a controlled and reproducible manner as exemplified by cumyl-5F-P7AICA. Furthermore, a method for the qualitative and quantitative detection of cumyl-5F-P7AICA in EB using glass fiber filters (GFF) was established und fully validated. Therefore, cumyl-5F-P7AICA (0.5 mg/mL in ethanol abs.) was initially nebulized using a ventilation machine and a breathing tube, as they are also used in surgeries. The aerosol was delivered into a simulated pig lung. To collect EB, a pump was connected to that part of the breathing tube, that contains EB (expiratory limb), and sampling was performed repeatedly (n=6) for 15 min (2 L EB/min) each using GFF. For extraction of the substance, the GFF were macerated with acetone and the remaining experimental components were rinsed with ethanol. After sample preparation, the extracts were analyzed by LC-MS/MS. In the complete experimental setup, about 40% of the initially nebulized cumyl-5F-P7AICA dose was found with 3.6 ± 1.3% being detected in the GFF. Regarding the comparably high loss of substance, the open ventilation system and a conceivable adsorption of the SC in the ventilator have to be considered. However, the herein introduced approach is promising to determine the TK properties of cumyl-5F-P7AICA in EB.

Diagnostic accuracy of Ages and Stages Questionnaire, Third Edition to identify abnormal or delayed gross motor development in high-risk infants.

AIM: To investigate the diagnostic accuracy of parent-completed Ages and Stages Questionnaire, Third Edition (ASQ-3) to identify abnormal or delayed gross motor development in infants born less than 1000 g or less than 28 weeks gestation. METHODS: Prospective cohort study of high-risk infants comparing ASQ-3 as the index test with concurrent score on Alberta Infant Motor Scale (AIMS) as the reference standard, at 4-, 8- and 12-month corrected (post-term) age. Reference standard positivity cut-offs were 'Abnormal motor development' (AIMS Clinical Range) and 'Motor delay' (AIMS score >1 SD below mean, not captured in Clinical Range). RESULTS: Participating infants (n = 191) had mean gestational age (95% confidence interval (CI)) 26.8 weeks (26.6-27.1) and mean birthweight (95% CI) 870 g (844-896). AIMS rated 51%, 31% and 23% of infants as having 'Abnormal motor development' and 12%, 28% and 13% with 'Motor delay', at 4, 8 and 12 months, respectively. Diagnostic accuracy of ASQ-3 to identify abnormal motor development was acceptable for older infants only if 'Monitor' cut-off was used: sensitivity (95% CI) 33% (23-44), 86% (73-95) and 80% (63-92) and specificity (95% CI) 84% (74-92), 76% (66-84), and 76% (67-83) at 4, 8 and 12 months, respectively. ASQ-3 sensitivity to identify motor delay was low. CONCLUSIONS: ASQ-3 has poor sensitivity to identify abnormal or delayed motor development at 4 months. Using the 'Monitor' cut-off improves the diagnostic accuracy of ASQ-3 for identification of older infants with abnormal motor development who are at high risk of motor disability. However, ASQ-3 has poor sensitivity to identify motor delay. Clinical motor assessment of high-risk infants is recommended, particularly in early infancy.

Impact of TP53 loss-of-function alterations on the response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer patients.

Rationale: PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. Methods: The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including TP53-mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P<0.001), a lower median PSA change (-55% vs. -75%, P=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P=0.003) compared to TP53-wildtype patients. Pathogenic alterations in AR, MYC, BRCA1, or BRCA2 as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside TP53-status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (P<0.05). Conclusion: TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.

High-throughput affinity measurements of direct interactions between activation domains and co-activators.

Sequence-specific activation by transcription factors is essential for gene regulation1,2. Key to this are activation domains, which often fall within disordered regions of transcription factors3,4 and recruit co-activators to initiate transcription5. These interactions are difficult to characterize via most experimental techniques because they are typically weak and transient6,7. Consequently, we know very little about whether these interactions are promiscuous or specific, the mechanisms of binding, and how these interactions tune the strength of gene activation. To address these questions, we developed a microfluidic platform for expression and purification of hundreds of activation domains in parallel followed by direct measurement of co-activator binding affinities (STAMMPPING, for Simultaneous Trapping of Affinity Measurements via a Microfluidic Protein-Protein INteraction Generator). By applying STAMMPPING to quantify direct interactions between eight co-activators and 204 human activation domains (>1,500 K ds), we provide the first quantitative map of these interactions and reveal 334 novel binding pairs. We find that the metazoan-specific co-activator P300 directly binds >100 activation domains, potentially explaining its widespread recruitment across the genome to influence transcriptional activation. Despite sharing similar molecular properties (e.g. enrichment of negative and hydrophobic residues), activation domains utilize distinct biophysical properties to recruit certain co-activator domains. Co-activator domain affinity and occupancy are well-predicted by analytical models that account for multivalency, and in vitro affinities quantitatively predict activation in cells with an ultrasensitive response. Not only do our results demonstrate the ability to measure affinities between even weak protein-protein interactions in high throughput, but they also provide a necessary resource of over 1,500 activation domain/co-activator affinities which lays the foundation for understanding the molecular basis of transcriptional activation.