Trends in use of intensive care during hospitalizations at the end-of-life among older adults with advanced cancer.

BACKGROUND: High-intensity end-of-life (EOL) care, marked by admission to intensive care units (ICUs) or in-hospital death, can be costly and burdensome. Recent trends in use of ICUs, life-sustaining treatments (LSTs), and noninvasive ventilation (NIV) during EOL hospitalizations among older adults with advanced cancer and patterns of in-hospital death are unknown. METHODS: We used SEER-Medicare data (2003-2017) to identify beneficiaries with advanced solid cancer (summary stage 7) who died within 3 years of diagnosis. We identified EOL hospitalizations (within 30 days of death), classifying them by increasing intensity of care into: (1) without ICU; (2) with ICU but without LST (invasive mechanical ventilation, tracheostomy, gastrostomy, acute dialysis) or NIV; (3) with ICU and NIV but without LST; and (4) with ICU and LST use. We constructed a multinomial regression model to evaluate trends in risk-adjusted hospitalization, overall and across hospitalization categories, adjusting for sociodemographics, cancer characteristics, comorbidities, and frailty. We evaluated trends in in-hospital death across categories. RESULTS: Of 226,263 Medicare beneficiaries with advanced cancer, 138,305 (61.1%) were hospitalized at EOL [Age, Mean (SD):77.9(7.1) years; 45.5% female]. Overall, EOL hospitalizations remained high throughout, from 78.1% (95% CI: 77.4, 78.7) in 2004 to 75.5% (95% CI: 74.5, 76.2) in 2017. Hospitalizations without ICU use decreased from 49.3% (95% CI: 48.5, 50.2) to 35.0% (95% CI: 34.2, 35.9) while hospitalizations with more intensive care increased, from 23.7% (95% CI: 23.0, 24.4) to 28.7% (95% CI: 27.9, 29.5) for ICU without LST or NIV, 0.8% (95% CI: 0.6, 0.9) to 3.8% (95% CI: 3.4, 4.1) for ICU with NIV but without LST, and 4.3% (95% CI: 4.0, 4.7) to 8.0% (95% CI: 7.5, 8.5) for ICU with LST use. Among those who experienced in-hospital death, the proportion receiving ICU care increased from 46.5% to 65.0%. CONCLUSIONS: Among older adults with advanced cancer, EOL hospitalization rates remained stable from 2004-2017. However, intensity of care during EOL hospitalizations increased as evidenced by increasing use of ICUs, LSTs, and NIV.

PRAME expression in melanoma is negatively regulated by TET2-mediated DNA hydroxymethylation.

Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis. Teaser: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.

Language barriers and healthcare access: a qualitative study in the Volta Region of Ghana.

BACKGROUND: The study explores the language barriers between two language minority populations and healthcare professionals in the Volta Region of Ghana. METHODS: An interpretive description with a qualitative approach to data collection and analysis was used. This study was carried out in the Tafi-Atome and Avatime-Vane communities, the Hohoe Municipal Hospital and the Margaret Marquart Catholic Hospital in the Kpando Municipality. In all, 46 respondents comprising 19 purposively sampled community members (patients) from the two selected communities and 27 conveniently sampled healthcare professionals from the two health facilities were interviewed. The face-to-face in-depth interviews were audio-recorded, transcribed and thematically analysed. RESULTS: The study revealed a barrier in language use between healthcare professionals and patients from the two language minority communities. While healthcare professionals preferred to use English, Akan and Ewe, the patients, on the other hand, preferred their native languages, which are Sideme and Tegbor. The services of unqualified interpreters were utilised by both healthcare professionals and patients. Study participants were aware of these challenges, which prevented the patients from receiving optimum healthcare services, and the healthcare workers from delivering client-centred healthcare services. CONCLUSIONS: The presence of communication challenges emanating from language barriers between healthcare professionals and patients should be considered as a key hindrance to the attainment of the Sustainable Development Goal Three (SDG3), which aims to promote health and well-being at all ages. Therefore, stakeholders in the healthcare delivery system in Ghana need to prioritize stronger communication and translation practices and policies.

Uncovering Nanoindention Behavior of Amorphous/Crystalline High-Entropy-Alloy Composites.

Amorphous/crystalline high-entropy-alloy (HEA) composites show great promise as structural materials due to their exceptional mechanical properties. However, there is still a lack of understanding of the dynamic nanoindentation response of HEA composites at the atomic scale. Here, the mechanical behavior of amorphous/crystalline HEA composites under nanoindentation is investigated through a large-scale molecular dynamics simulation and a dislocation-based strength model, in terms of the indentation force, microstructural evolution, stress distribution, shear strain distribution, and surface topography. The results show that the uneven distribution of elements within the crystal leads to a strong heterogeneity of the surface tension during elastic deformation. The severe mismatch of the amorphous/crystalline interface combined with the rapid accumulation of elastic deformation energy causes a significant number of dislocation-based plastic deformation behaviors. The presence of surrounding dislocations inhibits the free slip of dislocations below the indenter, while the amorphous layer prevents the movement or disappearance of dislocations towards the substrate. A thin amorphous layer leads to great indentation force, and causes inconsistent stacking and movement patterns of surface atoms, resulting in local bulges and depressions at the macroscopic level. The increasing thickness of the amorphous layer hinders the extension of shear bands towards the lower part of the substrate. These findings shed light on the mechanical properties of amorphous/crystalline HEA composites and offer insights for the design of high-performance materials.

Rotating-Hinge Revision Total Knee Arthroplasty Provides Greater Arc of Motion Gains for Patients Who Have Severe Arthrofibrosis.

INTRODUCTION: Arthrofibrosis is a common postoperative total knee arthroplasty (TKA) complication that results in limited range of motion (ROM). There is limited literature on outcomes after revision TKA (rTKA) for arthrofibrosis based on preoperative ROM restriction. The aims of this study were to: (1) examine ROM trajectory after rTKA for arthrofibrosis patients who have severe versus non-severe limitations; (2) compare ROM gains and final arc of motion (AOM) between severe and non-severe cohorts; (2a) compare ROM gain in a severe cohort treated with a rotating hinge (RH) versus a non-rotating hinge (non-RH) construct; and (3) assess the impact of arthrofibrosis severity on patient-reported outcome measures (PROMs). METHODS: Patients were divided into 2 groups: Group A had preoperative ROM < 70o (severe), and Group B had preoperative ROM > 70o (non-severe). Patients were assessed clinically using AOM gain, absolute ROM, Knee injury and Osteoarthritis Outcomes Score for Joint Replacement (KOOS, JR), Lower Extremity Activity Scale (LEAS), and pain scores. Postoperative gains in AOM were compared between both groups. RESULTS: A total of 56 rTKAs (Group A (severe): n = 36, Group B (non-severe): n = 20) were performed for patients who have postoperative fibrosis. Group B had better ROM at the one-year timepoint (Group B: 95.9 ± 22.5 versus Group A: 83.2 ± 25.7). Group A had significantly better improvement in absolute AOM than Group B (31.1 ± 20.9 versus 11.4 ± 25.0, P < 0.01). The RH group demonstrated significantly better absolute AOM gain than the non-RH group (41.3 ± 19.4 versus 18.3 ± 15.2, P < 0.001). However, there were no significant differences in PROMs between Groups A and B or between RH and NRH groups at the final follow-up. DISCUSSION: Final ROM achieved between severe and non-severe arthrofibrosis groups were similar, and patients who have severe arthrofibrosis can expect greater absolute ROM gains and similar functional outcomes than non-severe arthrofibrosis patients. The RH rTKAs provided greater AOM gains for patients who have severe arthrofibrosis, with equivalent functional outcomes to non-RH implants. For severe arthrofibrosis patients, RH designs provided twice the overall ROM gain, however, longer follow-up is necessary to determine whether RH designs have inferior overall implant survivorship.

Pars Interarticularis and Pedicle Stress Injuries in Young Athletes With Low Back Pain: A Retrospective Cohort Study of 902 Patients Evaluated With Magnetic Resonance Imaging.

BACKGROUND: Previous studies have reported that spondylolysis occurs predominantly at the L5 and L4 levels, with defects at higher levels occurring in <5% of cases. However, computed tomography and radiography were the primary imaging modalities in these studies. Current evidence regarding diagnostic imaging for pediatric lumbar spondylolysis suggests that magnetic resonance imaging (MRI) is as accurate as computed tomography in detecting early stress reactions of the pars interarticularis or pedicles without fractures while avoiding radiation exposure. The early detection of spondylolysis results in a higher likelihood of bony union and a decreased likelihood of spondylolisthesis. HYPOTHESIS: The increased use of MRI may reveal a larger proportion of spondylolysis in patients who experience an injury at a higher spinal level than previously reported. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The medical records of 902 pediatric and adolescent athletes (364 female, 538 male) diagnosed with symptomatic pars interarticularis and pedicle stress injuries at 2 academic medical centers between 2016 and 2021 were retrospectively reviewed. All patients had MRI scans taken at the time of diagnosis. Only patients with pars/pedicle edema on MRI were included. Data regarding spondylolysis stage, spinal level of injury, unilateral versus bilateral injury, sport participation, and MRI protocol over the 5-year study period were analyzed. RESULTS: Male patients presented at older ages than female patients (P < .001). Soccer was the most common sport at symptom onset and the second most common single-sport activity among those who specialized (participating in 1 sport year-round at the exclusion of others), behind gymnastics. The mean symptom duration was 4.0 months. Although most patients (83.5%) had exclusively lower lumbar stress injuries, 9.1% of injuries occurred at or above the L3 level. Over half of the patients had active single-level pars/pedicle fractures on MRI, with a mean symptom duration before presentation in this subgroup of 4.0 months. Even when pars/pedicle stress reactions were excluded from analysis, 7.1% of patients were injured at or above the L3 level. CONCLUSION: Among male and female athletes aged 8 to 21 years presenting with symptomatic pars interarticularis and pedicle stress injuries evaluated by MRI at the time of initial diagnosis, there was a higher incidence of upper lumbar stress injuries than previously reported.

Stress granule formation helps to mitigate neurodegeneration.

Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.

The burden of rheumatologic disease in Aboriginal and Torres Strait Islander Australians.

The objective of this article is to summarise the current knowledge regarding the prevalence of six rheumatological conditions in indigenous Australians - rheumatoid arthritis (RA), osteoarthritis (OA), osteoporosis (OSP), systemic lupus erythematosus (SLE), gout and musculoskeletal (MSK) pain. Online medical literature databases were searched for 'indigenous', 'Aboriginal' and 'Torres Strait Islander', as well as the names of the six conditions. Other included search terms were 'crystal', 'urate', 'arthritis' and 'arthropathy'. No limitations were placed on publication data or language. Forty-five articles examining the prevalence of the six conditions were identified. Based on the published literature, SLE appears to have a higher prevalence, while RA appears to have a lower prevalence in indigenous Australians compared to the non-indigenous community. MSK pain is prevalent, has a significant impact on indigenous people and is perceived as an important area of need. There is a paucity of data regarding these conditions in indigenous Australians. This may be impacted by the uncertainty of case ascertainment by self-report, differences in disease phenotypes and prevalence between the metropolitan compared to the rural or remote indigenous population, and difficulty with access to healthcare. Further studies in conjunction with local indigenous communities are needed to accurately determine the burden of rheumatological disease in the indigenous population. This will assist with resource and workforce planning to deliver culturally appropriate interventions. Strategies for future clinical work and research include the development and dissemination of culturally safe rheumatology resources, rheumatology training of Aboriginal Health Workers and wider integration of rheumatology clinics into community-controlled Aboriginal Health Services.

Quercetin enhances decidualization through AKT-ERK-p53 signaling and supports a role for senescence in endometriosis.

BACKGROUND: Patients with endometriosis suffer with chronic pelvic pain and infertility, and from the lack of pharmacologic therapies that consistently halt disease progression. Differences in the endometrium of patients with endometriosis vs. unaffected controls are well-documented. Specifically, shed endometrial tissues (delivered to the pelvic cavity via retrograde menstruation) reveal that a subset of stromal cells exhibiting pro-inflammatory, pro-fibrotic, and pro-senescence-like phenotypes is enhanced in endometriosis patients compared to controls. Additionally, cultured biopsy-derived endometrial stromal cells from endometriosis patients exhibit impaired decidualization, a defined differentiation process required for human embryo implantation and pregnancy. Quercetin, a senolytic agent, shows therapeutic potential for pulmonary fibrosis, a disorder attributed to senescent pulmonary fibroblasts. In rodent models of endometriosis, quercetin shows promise, and quercetin improves decidualization in vitro. However, the exact mechanisms are not completely understood. Therefore, we investigated the effects of quercetin on menstrual effluent-derived endometrial stromal cells from endometriosis patients and unaffected controls to define the signaling pathways underlying quercetin's effects on endometrial stromal cells. METHODS: Menstrual effluent-derived endometrial stromal cells were collected and cultured from unaffected controls and endometriosis patients and then, low passage cells were treated with quercetin (25 µM) under basal or standard decidualization conditions. Decidualization responses were analyzed by measuring the production of IGFBP1 and PRL. Also, the effects of quercetin on intracellular cAMP levels and cellular oxidative stress responses were measured. Phosphokinase arrays, western blotting, and flow cytometry methods were performed to define the effects of quercetin on various signaling pathways and the potential mechanistic roles of quercetin. RESULTS: Quercetin significantly promotes decidualization of control- and endometriosis-endometrial stromal cells. Quercetin substantially reduces the phosphorylation of multiple signaling molecules in the AKT and ERK1/2 pathways, while enhancing the phosphorylation of p53 and total p53 levels. Furthermore, p53 inhibition blocks decidualization while p53 activation promotes decidualization. Finally, we provide evidence that quercetin increases apoptosis of endometrial stromal cells with a senescent-like phenotype. CONCLUSIONS: These data provide insight into the mechanisms of action of quercetin on endometrial stromal cells and warrant future clinical trials to test quercetin and other senolytics for treating endometriosis.

Patients undergoing multiligament knee reconstruction injured during pivoting sports demonstrate similar clinical, functional and return to sport outcomes by 2 years compared with those undergoing anterior cruciate ligament reconstruction.

PURPOSE: This study investigates the clinical and activity-based outcomes after anterior cruciate ligament reconstruction (ACLR) versus multiligamentous knee reconstruction (MLKR) following a pivoting sports injury. METHODS: Fifty MLKR patients were included, of which 20 (40%) were injured during pivoting sports. A further 50 patients undergoing ACLR following an injury during pivoting sports were consecutively recruited for comparison. Patients were assessed before the surgery and at 6-, 12- and 24 months with patient-reported outcome measures (PROMs) including the International Knee Documentation Committee (IKDC) form, Tegner activity scale (TAS) and anterior cruciate ligament return to sport after injury (ACL-RSI) score. Knee movement, the single (SHD) and triple (THD) hop tests for distance, and peak isokinetic knee extensor and flexor strength were assessed, with Limb Symmetry Indices (LSIs) calculated. Outcomes were compared across groups: (1) ACLR (n = 50), (2) MLKR (n = 50) and (3) MLKR due to pivoting sport injury (n = 20). RESULTS: IKDC, TAS and ACL-RSI scores remained lower (p < 0.05) in the full MLKR versus ACLR cohort at all timepoints. Comparing the ACLR and MLKR cohort that had injuries specifically during pivoting sports, the IKDC (p < 0.001) and TAS (p = 0.009) were higher in the ACLR group at 6 months, and the ACL-RSI was higher at 6 (p < 0.001) and 12 (p = 0.007) months, there were no further differences. Hop and knee extensor strength LSIs were lower (p < 0.05) in the full MLKR (versus ACLR) cohort at all timepoints (apart from the 24-month SHD LSI). However, the ACLR group only demonstrated greater LSIs than the pivoting sport MLKR for the SHD at 6 months (p < 0.001), and knee extensor strength at 6 (p < 0.001) and 12 (p < 0.001) months. CONCLUSIONS: While the recovery of patients undergoing MLKR due to a pivoting sports injury is delayed compared with their ACLR counterparts, the clinical outcome and activity profile are similar by 24 months. LEVEL OF EVIDENCE: Level IV.

Cellular immune response to SARS-CoV-2 and clinical presentation in individuals exposed to endemic malaria.

Ghana and other parts of West Africa have experienced lower COVID-19 mortality rates than other regions. This phenomenon has been hypothesized to be associated with previous exposure to infections such as malaria. This study investigated the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the influence of previous malaria exposure. Blood samples were collected from individuals with asymptomatic or symptomatic COVID-19 (n = 217). A variety of assays were used to characterize the SARS-CoV-2-specific immune response, and malaria exposure was quantified using Plasmodium falciparum ELISA. The study found evidence of attenuated immune responses to COVID-19 among asymptomatic individuals, with elevated proportions of non-classical monocytes and greater memory B cell activation. Symptomatic patients displayed higher P. falciparum-specific T cell recall immune responses, whereas asymptomatic individuals demonstrated elevated P. falciparum antibody levels. Summarily, this study suggests that P. falciparum exposure-associated immune modulation may contribute to reduced severity of SARS-CoV-2 infection among people living in malaria-endemic regions.

Hierarchical Phased-Array Antennas Coupled to Al KIDs: A Scalable Architecture for Multi-band Millimeter/Submillimeter Focal Planes.

We present the optical characterization of two-scale hierarchical phased-array antenna kinetic inductance detectors (KIDs) for millimeter/submillimeter wavelengths. Our KIDs have a lumped-element architecture with parallel plate capacitors and aluminum inductors. The incoming light is received with a hierarchical phased array of slot dipole antennas, split into 4 frequency bands (between 125 GHz and 365 GHz) with on-chip lumped-element band-pass filters, and routed to different KIDs using microstriplines. Individual pixels detect light for the 3 higher-frequency bands (190-365 GHz), and the signals from four individual pixels are coherently summed to create a larger pixel detecting light for the lowest frequency band (125-175 GHz). The spectral response of the band-pass filters was measured using Fourier transform spectroscopy (FTS), the far-field beam pattern of the phased-array antennas was obtained using an infrared source mounted on a 2-axis translating stage, and the optical efficiency of the KIDs was characterized by observing loads at 294 K and 77 K. We report on the results of these three measurements.

Surgeon-Applied Stress and a Ligament Tensor Instrument Provide a Similar Assessment of Preresection Flexion Laxity During Robotic Total Knee Arthroplasty.

Background: Robotic-assisted total knee arthroplasty (RA-TKA) allows surgeons to perform intraoperative soft tissue laxity assessments prior to bone resections and is used to alter resections to achieve gap balance. This study compared 2 techniques for flexion gap laxity assessment during RA-TKA. Methods: A prospective study of 50 primary RA-TKAs performed by a single surgeon was conducted between February and October 2023. Following full exposure, anterior tibial dislocation, and osteophyte removal, maximal medial and lateral compartment flexion laxity was quantified to the nearest 0.5 mm by the robotic system using a dynamic, surgeon-applied stress (SURGEON). This data was used to plan a balanced flexion gap by adjusting the femoral component size, rotation, and anterior-posterior translation. Flexion laxity was quantified again after distal femoral and proximal tibial resections using a ligament tensor instrument (TENSOR). These new data were used to plan for the same desired flexion gap using the same variables. Paired-samples t-tests and a simple linear regression were used for analysis. Results: Both methods produced near-identical recommendations for femoral component sizing (mean deviation 0.06 sizes, range -1 to +1 size; P = .569), rotation (deviation mean 1.0°, range -3.0° to +3.0°; P = .741), and anterior-posterior translation (deviation mean 0.13 mm, range -0.5 to +0.5 mm, P = .785). SURGEON femoral component rotation predicted TENSOR rotation (R2 = 0.157; 95% confidence interval = 0.124, 0.633; P = .004). Conclusions: Assessing flexion laxity with a surgeon-applied stress vs a ligament tensor produced near-identical laxity data in RA-TKA, suggesting surgeons may comfortably choose either technique as a reliable method. Level of Evidence: Level III.

Temporal Trends in the Rate of Revision Total Knee Arthroplasty for Prosthetic Joint Infection.

Background: Perioperative practices have been introduced over the last decade to decrease the risk of periprosthetic joint infection (PJI). We sought to determine whether rates of revision total knee arthroplasty (TKA) for PJI decreased during the period 2006-2016. Methods: This observational cohort study used data from the New York Statewide Planning and Research Cooperative System to identify patients undergoing TKA in 2006-2016. Data through 2017 were used to determine if patients underwent revision TKA for PJI (including debridement, antibiotics and implant retention) within 1 year of the primary surgery. A generalized estimating equation model, clustered by hospital, was used to examine the impact of time on likelihood of revision TKA for PJI. Results: In 2006-2016, 233,165 primary TKAs performed were included. Mean age was 66.1 (standard deviation 10.3) years, and 65% were women. Overall, 0.5% of the patients underwent revision TKA for PJI within 1 year of surgery. The generalized estimating equation model showed that for primary TKA performed in 2006-2013, year of surgery did not impact the likelihood of revision TKA for PJI (odds ratio 1.00, 95% confidence interval 0.97-1.03, P = .9221), but that for primary TKA performed in 2014-2016, the likelihood decreased by year (odds ratio 0.76, 95% confidence interval 0.66-0.88, P = .0002). Conclusions: The likelihood of revision TKA for PJI was stable from 2006 to 2013 but declined during the period 2014-2016 across patient and hospital categories. This decline could be due to infection mitigation strategies or other unmeasured factors.

Use of Computer Navigation for Optimal Acetabular Cup Placement in Revision Total Hip Arthroplasty: Case Reports and Surgical Techniques.

Background: The outcomes of revision total hip arthroplasty (rTHA) have become increasingly important as their volume increases. Computer navigation, a reliable method to improve component positioning during primary total hip arthroplasty (THA), is not well studied in the rTHA setting. Given that dislocation rates following rTHA are significantly higher than those of primary THA, component positioning becomes paramount in these cases. Methods: Here, we present two case reports and surgical techniques, one of a 77-year-old man undergoing rTHA for recurrent hip instability following primary THA, and one of a 61-year-old woman undergoing rTHA for severe iliopsoas bursitis who was at increased risk for instability and dislocation given her history of large segment spinal fusion. Results: Both patients achieved optimal acetabular component positioning after rTHA with imageless computer navigation. Conclusions: The use of imageless computer navigation in rTHA provides accurate and reproducible component positioning during acetabular rTHA.

Interpretably deep learning amyloid nucleation by massive experimental quantification of random sequences.

Insoluble amyloid aggregates are the hallmarks of more than fifty human diseases, including the most common neurodegenerative disorders. The process by which soluble proteins nucleate to form amyloid fibrils is, however, quite poorly characterized. Relatively few sequences are known that form amyloids with high propensity and this data shortage likely limits our capacity to understand, predict, engineer, and prevent the formation of amyloid fibrils. Here we quantify the nucleation of amyloids at an unprecedented scale and use the data to train a deep learning model of amyloid nucleation. In total, we quantify the nucleation rates of >100,000 20-amino-acid-long peptides. This large and diverse dataset allows us to train CANYA, a convolution-attention hybrid neural network. CANYA is fast and outperforms existing methods with stable performance across diverse prediction tasks. Interpretability analyses reveal CANYA's decision-making process and learned grammar, providing mechanistic insights into amyloid nucleation. Our results illustrate the power of massive experimental analysis of random sequence-spaces and provide an interpretable and robust neural network model to predict amyloid nucleation.

ASCT2 is a major contributor to serine uptake in cancer cells.

The non-essential amino acid serine is a critical nutrient for cancer cells due to its diverse biosynthetic functions. While some tumors can synthesize serine de novo, others are auxotrophic and therefore reliant on serine uptake. Importantly, despite several transporters being known to be capable of transporting serine, the transporters that mediate serine uptake in cancer cells are not known. Here, we characterize the amino acid transporter ASCT2 (SLC1A5) as a major contributor to serine uptake in cancer cells. ASCT2 is well known as a glutamine transporter in cancer, and our work demonstrates that serine and glutamine compete for uptake through ASCT2. We further show that ASCT2-mediated serine uptake is essential for purine nucleotide biosynthesis and that estrogen receptor α (ERα) promotes serine uptake by directly activating SLC1A5 transcription. Collectively, our work defines an additional important role for ASCT2 as a serine transporter in cancer and evaluates ASCT2 as a potential therapeutic target.

Oral Cavity Squamous Cell Carcinoma: Impact of Clear Margin Distance on Locoregional Control in Patients Undergoing Postoperative Radiotherapy.

INTRODUCTION: Postoperative radiotherapy can improve locoregional control (LC) in oral cavity squamous cell carcinoma (OCSCC) patients with positive resection margins. The present study aimed to evaluate the impact of surgical margin size on LC in this patient population. METHODS: This retrospective study involved 162 patients with OCSCC who underwent postoperative radiotherapy between 2000 and 2020 at the Department of Radiation Oncology, University Hospital Heidelberg and the German Cancer Research Center. The study aimed to determine the impact of different resection margins on LC, as well as overall survival (OS), progression-free survival (PFS), and treatment-related toxicity (CTCAE 4.03). RESULTS: Seventy-seven patients (47.5%) had involved (<1 mm) margins, 22 patients (13.6%) close (≤5 mm) margins, and 63 patients (38.9%) clear (>5 mm) margins. A surgical margin ≤ 5 mm was a significant predictor for worse LC (HR 2.6, 95% CI 1.2, 6.1), but not for OS (HR 1.2, CI 0.7, 1.9) or PFS (HR 1.2, 0.7, 2.0). CONCLUSION: Patients who have narrow resection margins (1-5 mm) experience poor local control and should receive postoperative radiotherapy. It is necessary to conduct further prospective studies to determine whether a narrower margin window could be achieved to better determine the appropriate indication for adjuvant radiotherapy.

Improving Social and Personal Rhythm Dysregulation in Young and Old Adults with Bipolar Disorder: Post-Hoc Analysis of a Feasibility Randomized Controlled Trial Using Virtual Reality-Based Intervention.

Introduction: Rehabilitative interventions employing technology play a crucial role in bipolar disorder (BD) treatment. The study aims to appraise the virtual reality (VR)-based cognitive remediation (CR) and the interpersonal rhythm approaches to treatment outcomes of BD across different age groups. Methods: Post-hoc analysis of a 12-week randomizedcontrolled cross-over feasibility trial involving people with mood disorders (BD, DSM-IV) aged 18-75 years old: thirty-nine exposed to the experimental VR-based CR vs 25 waiting list controls. People with BD relapse, epilepsy or severe eye diseases (due to the potential VR risks exposure) were excluded. Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) was used to measure the outcome. Results: Cases and controls did not statistically significantly differ in age and sex distributions. Personal rhythm scores improved over the study follow-up in the experimental vs the control group (APC = 8.7%; F = 111.9; p < 0.0001), both in young (18-45 years) (APC = 5.5%; F = 70.46; p < 0.0001) and, to a lesser extent, older (>46 years) adults (APC = 10.5%; F = 12.110; p = 0.002). Conclusions: This study observed improved synchronization of personal and social rhythms in individuals with BD after a virtual reality cognitive remediation intervention, particularly in social activity, daily activities, and chronotype, with greater benefits in the younger population.