Actively variable-spectrum optoelectronics with black phosphorus.

Room-temperature optoelectronic devices that operate at short-wavelength and mid-wavelength infrared ranges (one to eight micrometres) can be used for numerous applications1-5. To achieve the range of operating wavelengths needed for a given application, a combination of materials with different bandgaps (for example, superlattices or heterostructures)6,7 or variations in the composition of semiconductor alloys during growth8,9 are used. However, these materials are complex to fabricate, and the operating range is fixed after fabrication. Although wide-range, active and reversible tunability of the operating wavelengths in optoelectronic devices after fabrication is a highly desirable feature, no such platform has been yet developed. Here we demonstrate high-performance room-temperature infrared optoelectronics with actively variable spectra by presenting black phosphorus as an ideal candidate. Enabled by the highly strain-sensitive nature of its bandgap, which varies from 0.22 to 0.53 electronvolts, we show a continuous and reversible tuning of the operating wavelengths in light-emitting diodes and photodetectors composed of black phosphorus. Furthermore, we leverage this platform to demonstrate multiplexed nondispersive infrared gas sensing, whereby multiple gases (for example, carbon dioxide, methane and water vapour) are detected using a single light source. With its active spectral tunability while also retaining high performance, our work bridges a technological gap, presenting a potential way of meeting different requirements for emission and detection spectra in optoelectronic applications.

The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation.

TIMELESS (TIM) in the fork protection complex acts as a scaffold of the replisome to prevent its uncoupling and ensure efficient DNA replication fork progression. Nevertheless, its underlying basis for coordinating leading and lagging strand synthesis to limit single-stranded DNA (ssDNA) exposure remains elusive. Here, we demonstrate that acute degradation of TIM at ongoing DNA replication forks induces the accumulation of ssDNA gaps stemming from defective Okazaki fragment (OF) processing. Cells devoid of TIM fail to support the poly(ADP-ribosyl)ation necessary for backing up the canonical OF processing mechanism mediated by LIG1 and FEN1. Consequently, recruitment of XRCC1, a known effector of PARP1-dependent single-strand break repair, to post-replicative ssDNA gaps behind replication forks is impaired. Physical disruption of the TIM-PARP1 complex phenocopies the rapid loss of TIM, indicating that the TIM-PARP1 interaction is critical for the activation of this compensatory pathway. Accordingly, combined deficiency of FEN1 and the TIM-PARP1 interaction leads to synergistic DNA damage and cytotoxicity. We propose that TIM is essential for the engagement of PARP1 to the replisome to coordinate lagging strand synthesis with replication fork progression. Our study identifies TIM as a synthetic lethal target of OF processing enzymes that can be exploited for cancer therapy.

Replisome dysfunction upon inducible TIMELESS degradation synergizes with ATR inhibition to trigger replication catastrophe.

The structure of DNA replication forks is preserved by TIMELESS (TIM) in the fork protection complex (FPC) to support seamless fork progression. While the scaffolding role of the FPC to couple the replisome activity is much appreciated, the detailed mechanism whereby inherent replication fork damage is sensed and counteracted during DNA replication remains largely elusive. Here, we implemented an auxin-based degron system that rapidly triggers inducible proteolysis of TIM as a source of endogenous DNA replication stress and replisome dysfunction to dissect the signaling events that unfold at stalled forks. We demonstrate that acute TIM degradation activates the ATR-CHK1 checkpoint, whose inhibition culminates in replication catastrophe by single-stranded DNA accumulation and RPA exhaustion. Mechanistically, unrestrained replisome uncoupling, excessive origin firing, and aberrant reversed fork processing account for the synergistic fork instability. Simultaneous TIM loss and ATR inactivation triggers DNA-PK-dependent CHK1 activation, which is unexpectedly necessary for promoting fork breakage by MRE11 and catastrophic cell death. We propose that acute replisome dysfunction results in a hyper-dependency on ATR to activate local and global fork stabilization mechanisms to counteract irreversible fork collapse. Our study identifies TIM as a point of replication vulnerability in cancer that can be exploited with ATR inhibitors.

Programmable Threshold Logic Implementations in a Memristor Crossbar Array.

In this study, we demonstrate the implementation of programmable threshold logics using a 32 × 32 memristor crossbar array. Thanks to forming-free characteristics obtained by the annealing process, its accurate programming characteristics are presented by a 256-level grayscale image. By simultaneous subtraction between weighted sum and threshold values with a differential pair in an opposite way, 3-input and 4-input Boolean logics are implemented in the crossbar without additional reference bias. Also, we verify a full-adder circuit and analyze its fidelity, depending on the device programming accuracy. Lastly, we successfully implement a 4-bit ripple carry adder in the crossbar and achieve reliable operations by read-based logic operations. Compared to stateful logic driven by device switching, a 4-bit ripple carry adder on a memristor crossbar array can perform more reliably in fewer steps thanks to its read-based parallel logic operation.

Black Phosphorus for Mid-Infrared Optoelectronics: Photophysics, Scalable Processing, and Device Applications.

High efficiency mid-infrared (λ = 3-8 µm) light emitters and photodetectors are pivotal for advancing next-generation optoelectronics. However, narrow-bandgap semiconductors face fundamental challenges such as pronounced nonradiative carrier recombination and thermally generated noise, which impede device performance. Recently, two-dimensional layered black phosphorus (BP) and its alloys have attracted substantial interest for mid-infrared device applications, demonstrating superior performance relative to conventional III-V and II-VI semiconductors with similar bandgaps. In this review, we discuss the optical properties of BP, contrasting these with those of covalent compounds. Owing to its inherently self-terminated surface structure and reduced nonradiative recombination, BP exhibits high performance in light emission and photodetection at room temperature. Furthermore, this review highlights recent advances in the large-area processing of BP thin films, paving the way for practical device applications and integration. Finally, we explore ongoing challenges and emerging opportunities in the utilization of BP for functional mid-infrared devices.

Inflammatory Bowel Disease Hospitalizations Are Similar for Patients Receiving Televisit-Delivered Outpatient Care and Those Receiving Traditional In-Person Care.

INTRODUCTION: The coronavirus disease 2019 pandemic resulted in widespread expansion of telehealth. However, there are concerns that telehealth-delivered outpatient care may limit opportunities for managing complications and preventing hospitalizations for patients with inflammatory bowel disease (IBD). We aimed to assess the association between outpatient IBD care delivered through televisit (video or phone) and IBD-related hospitalizations. METHODS: We conducted a case-control study of patients with IBD who had an IBD-related index hospitalization between April 2021 and July 2022 and received their care in the Veterans Health Administration. We matched these hospitalized patients to controls who were not hospitalized based on age, sex, race, Charlson comorbidity index, IBD type, IBD-related emergency department use, IBD-related hospitalizations, and outpatient gastroenterology visits in the preceding year. The variable of interest was the percentage of total clinic visits delivered through televisit in the year before the index hospitalization. We compared the risk of IBD-related hospitalization by exposure to televisit-delivered care using conditional logistic regression. RESULTS: We identified 534 patients with an IBD-related hospitalization and 534 matched controls without an IBD-related hospitalization during the study period. Patients with IBD with a higher percentage of televisit-delivered (vs in-person) outpatient care were less likely to be hospitalized during the study period (for every 10% increase in televisit use, odds ratio 0.97, 95% confidence interval 0.94-1.00; P = 0.03). DISCUSSION: Televisit-delivered outpatient IBD care is not associated with higher risk of IBD-related hospitalization. These findings may reassure clinicians that televisit-delivered outpatient care is appropriate for patients with complex chronic diseases such as IBD.

Treatment preference archetypes in eosinophilic esophagitis and their implications for therapy.

BACKGROUND: Little is known about how patients make decisions about and prioritize, therapies and disease management in eosinophilic esophagitis (EoE). We aimed to systematically identify and characterize patient perspectives and attitudes that influence decision making for EoE management. METHODS: To understand the diverse attitudes and values of EoE patients, we designed a study using the Q-method. We iteratively developed 31 statements related to EoE disease management. Participants sorted statements by ranking from +4 (most agree) to -4 (most disagree). By-person factor analysis, using 2- and 3- factor rotation, revealed distinct preference archetypes. RESULTS: Thirty-four adults with EoE (mean age 40.9, 51.4% male, 82.9% White) were recruited from gastroenterology and allergy clinics from a single center. We identified two treatment-centered archetypes: Medication preference, driven by symptoms and the desire to minimize risk of complications, and Natural treatment preference, focusing on identifying trigger foods and diet adherence. Three-factor analysis revealed an additional archetype: Treatment ambivalent, a view of EoE as a mild and episodic (not chronic) disease with low priority to treat. Comparison by factor revealed 54% of those in the natural preference archetype were recategorized as treatment ambivalent, suggesting that they see natural treatment as a less complicated or milder strategy and may be at risk of nonadherence and reduced treatment uptake. CONCLUSIONS: We identified three distinct treatment preference archetypes among individuals with EoE, underscoring the need for personalized treatment strategies, especially for those favoring natural approaches but masking ambivalence, and may be at risk for nonadherence or loss to follow-up.

Delivery of Outpatient Cirrhosis Care Through Tele-Visit Is Not Associated With Increased Mortality as Compared With Traditional In-Person Visits.

INTRODUCTION: Providers and patients have expressed concern that care provided through telehealth results in poorer outcomes than traditional in-person care. On the contrary, we hypothesized that patients with cirrhosis engaging in video/phone-based outpatient gastroenterology/hepatology tele-visits do not differ in mortality from those receiving in-person outpatient clinic visits. METHODS: This was a retrospective, case-control study using Veterans Health Administration administrative data of veterans with a cirrhosis diagnosis. Cases were patients who died between April 2021 and July 2022 and had a cirrhosis diagnosis for ≥1 year before death. For each case, a control was randomly selected from the pool of patients alive on the date of death of the case (index date) and matched on age, average Model for End-Stage Liver Disease, and number of gastroenterology/hepatology clinic visits in the prior year. Primary exposure variable was % tele-visits (video/phone) out of total visits in the year before the index date, scaled in 10% increments. Conditional logistic regression was used to assess the association between mortality and % tele-visits. A secondary analysis matched on electronic Child-Turcotte-Pugh score rather than Model for End-Stage Liver Disease. RESULTS: Two thousand nine hundred thirty-three cases were identified and matched with 2,933 controls. After adjusting for covariates, tele-visit-based outpatient care was associated with a small reduction in mortality (odds ratio TH = 0.95, 95% confidence interval = 0.94-0.97). Matching on electronic Child-Turcotte-Pugh score did not change the results. DISCUSSION: Our findings suggest that outpatient cirrhosis care by tele-visit is associated with outcomes no worse than traditional in-person visits. This should reassure providers who hesitate to provide virtual care to patients with cirrhosis due to concerns for poorer outcomes.

Clinical Utility of a CT-based AI Prognostic Model for Segmentectomy in Non-Small Cell Lung Cancer.

Background Currently, no tool exists for risk stratification in patients undergoing segmentectomy for non-small cell lung cancer (NSCLC). Purpose To develop and validate a deep learning (DL) prognostic model using preoperative CT scans and clinical and radiologic information for risk stratification in patients with clinical stage IA NSCLC undergoing segmentectomy. Materials and Methods In this single-center retrospective study, transfer learning of a pretrained model was performed for survival prediction in patients with clinical stage IA NSCLC who underwent lobectomy from January 2008 to March 2017. The internal set was divided into training, validation, and testing sets based on the assignments from the pretraining set. The model was tested on an independent test set of patients with clinical stage IA NSCLC who underwent segmentectomy from January 2010 to December 2017. Its prognostic performance was analyzed using the time-dependent area under the receiver operating characteristic curve (AUC), sensitivity, and specificity for freedom from recurrence (FFR) at 2 and 4 years and lung cancer-specific survival and overall survival at 4 and 6 years. The model sensitivity and specificity were compared with those of the Japan Clinical Oncology Group (JCOG) eligibility criteria for sublobar resection. Results The pretraining set included 1756 patients. Transfer learning was performed in an internal set of 730 patients (median age, 63 years [IQR, 56-70 years]; 366 male), and the segmentectomy test set included 222 patients (median age, 65 years [IQR, 58-71 years]; 114 male). The model performance for 2-year FFR was as follows: AUC, 0.86 (95% CI: 0.76, 0.96); sensitivity, 87.4% (7.17 of 8.21 patients; 95% CI: 59.4, 100); and specificity, 66.7% (136 of 204 patients; 95% CI: 60.2, 72.8). The model showed higher sensitivity for FFR than the JCOG criteria (87.4% vs 37.6% [3.08 of 8.21 patients], P = .02), with similar specificity. Conclusion The CT-based DL model identified patients at high risk among those with clinical stage IA NSCLC who underwent segmentectomy, outperforming the JCOG criteria. © RSNA, 2024 Supplemental material is available for this article.

Universal Platform for Robust Dual-Atom Doped 2D Catalysts with Superior Hydrogen Evolution in Wide pH Media.

Layered 2D transition metal dichalcogenides (TMDs) have been suggested as efficient substitutes for Pt-group metal electrocatalysts in the hydrogen evolution reaction (HER). However, poor catalytic activities in neutral and alkaline electrolytes considerably hinder their practical applications. Furthermore, the weak adhesion between TMDs and electrodes often impedes long-term durability and thus requires a binder. Here, a universal platform is reported for robust dual-atom doped 2D electrocatalysts with superior HER performance over a wide pH range media. V:Co-ReS2 on a wafer scale is directly grown on oxidized Ti foil by a liquid-phase precursor-assisted approach and subsequently used as highly efficient electrocatalysts. The catalytic performance surpasses that of Pt group metals in a high current regime (≥ 100 mA cm-2) at pH ≥ 7, with a high durability of more than 70 h in all media at 200 mA cm-2. First-principles calculations reveal that V:Co dual doping in ReS2 significantly reduces the water dissociation barrier and simultaneously enables the material to achieve the thermoneutral Gibbs free energy for hydrogen adsorption.

mFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer - the FROST trial: study protocol for a multicenter, randomized controlled, phase II trial.

BACKGROUND: High-risk stage III colon cancer has a considerably poorer prognosis than stage II and low-risk stage III colon cancers. Nevertheless, most guidelines recommend similar adjuvant treatment approaches for all these stages despite the dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis with intensive adjuvant treatment. Given the the proven efficacy of triplet chemotherapy in metastatic colorectal cancer treatment, the goal of this study is to evaluate the oncologic efficacy and safety of mFOLFIRINOX in comparison to those of the current standard of care, mFOLFOX 6, as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer after radical resection. METHODS: This multicenter, randomized (1:1), open-label, phase II trial will assess and compare the effectiveness and toxicity of mFOLFIRINOX and mFOLFOX 6 in patients with high-risk stage III colon cancer after radical resection. The goal of the trial is to enroll 312 eligible patients, from 11 institutes, aged between 20 and 70 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or between 70 and 75 with an ECOG performance status of 0. Patients will be randomized into two arms - Arm A, the experimental arm, and Arm B, the reference arm - and will receive 12 cycles of mFOLFIRINOX and mFOLFOX 6 every 2 weeks, respectively. The primary endpoint of this study is the 3-year disease-free survival, and secondary endpoints include the 3-year overall survival and treatment toxicity. DISCUSSION: The Frost trial would help determine the oncologic efficacy and safety of adjuvant triplet chemotherapy for high-risk stage III colon cancers and ultimately improve prognoses. TRIAL REGISTRATION: ClinicalTrials.gov NCT05179889, registered on 17 December 2021.

Prognostic value of CT-defined ground-glass opacity in early-stage lung adenocarcinomas: a single-center study and meta-analysis.

OBJECTIVES: The prognostic value of ground-glass opacity at preoperative chest CT scans in early-stage lung adenocarcinomas is a matter of debate. We aimed to clarify the existing evidence through a single-center, retrospective cohort study and to quantitatively summarize the body of literature by conducting a meta-analysis. METHODS: In a retrospective cohort study, patients with clinical stage I lung adenocarcinoma were identified, and the prognostic value of ground-glass opacity was analyzed using multivariable Cox regression. Commercial artificial intelligence software was adopted as the second reader for the presence of ground-glass opacity. The primary end points were freedom from recurrence (FFR) and lung cancer-specific survival (LCSS). In a meta-analysis, we systematically searched Embase and OVID-MEDLINE up to December 30, 2021, for the studies based on the eighth-edition staging system. The pooled hazard ratios (HRs) of solid nodules (i.e., absence of ground-glass opacity) for various end points were calculated with a multi-level random effects model. RESULTS: In a cohort of 612 patients, solid nodules were associated with worse outcomes for FFR (adjusted HR, 1.98; 95% CI: 1.17-3.51; p = 0.01) and LCSS (adjusted HR, 1.937; 95% CI: 1.002-4.065; p = 0.049). The artificial intelligence assessment and multiple sensitivity analyses revealed consistent results. The meta-analysis included 13 studies with 12,080 patients. The pooled HR of solid nodules was 2.13 (95% CI: 1.69-2.67; I2 = 30.4%) for overall survival, 2.45 (95% CI: 1.52-3.95; I2 = 0.0%) for FFR, and 2.50 (95% CI: 1.28-4.91; I2 = 30.6%) for recurrence-free survival. CONCLUSIONS: The absence of ground-glass opacity in early-stage lung adenocarcinomas is associated with worse postoperative survival. CLINICAL RELEVANCE STATEMENT: Early-stage lung adenocarcinomas manifesting as solid nodules at preoperative chest CT, which indicates the absence of ground-glass opacity, were associated with poor postoperative survival. There is room for improvement of the clinical T categorization in the next edition staging system. KEY POINTS: • In a retrospective study of 612 patients with stage I lung adenocarcinoma, solid nodules were associated with shorter freedom from recurrence (adjusted hazard ratio [HR], 1.98; p = 0.01) and lung cancer-specific survival (adjusted HR, 1.937; p = 0.049). • Artificial intelligence-assessed solid nodules also showed worse prognosis (adjusted HR for freedom from recurrence, 1.94 [p = 0.01]; adjusted HR for lung cancer-specific survival, 1.93 [p = 0.04]). • In meta-analyses, the solid nodules were associated with shorter freedom from recurrence (HR, 2.45) and shorter overall survival (HR, 2.13).

Diagnostic performance and prognostic value of CT-defined visceral pleural invasion in early-stage lung adenocarcinomas.

OBJECTIVES: To analyze the diagnostic performance and prognostic value of CT-defined visceral pleural invasion (CT-VPI) in early-stage lung adenocarcinomas. METHODS: Among patients with clinical stage I lung adenocarcinomas, half of patients were randomly selected for a diagnostic study, in which five thoracic radiologists determined the presence of CT-VPI. Probabilities for CT-VPI were obtained using deep learning (DL). Areas under the receiver operating characteristic curve (AUCs) and binary diagnostic measures were calculated and compared. Inter-rater agreement was assessed. For all patients, the prognostic value of CT-VPI by two radiologists and DL (using high-sensitivity and high-specificity cutoffs) was investigated using Cox regression. RESULTS: In 681 patients (median age, 65 years [interquartile range, 58-71]; 382 women), pathologic VPI was positive in 130 patients. For the diagnostic study (n = 339), the pooled AUC of five radiologists was similar to that of DL (0.78 vs. 0.79; p = 0.76). The binary diagnostic performance of radiologists was variable (sensitivity, 45.3-71.9%; specificity, 71.6-88.7%). Inter-rater agreement was moderate (weighted Fleiss κ, 0.51; 95%CI: 0.43-0.55). For overall survival (n = 680), CT-VPI by radiologists (adjusted hazard ratio [HR], 1.27 and 0.99; 95%CI: 0.84-1.92 and 0.63-1.56; p = 0.26 and 0.97) or DL (HR, 1.44 and 1.06; 95%CI: 0.86-2.42 and 0.67-1.68; p = 0.17 and 0.80) was not prognostic. CT-VPI by an attending radiologist was prognostic only in radiologically solid tumors (HR, 1.82; 95%CI: 1.07-3.07; p = 0.03). CONCLUSION: The diagnostic performance and prognostic value of CT-VPI are limited in clinical stage I lung adenocarcinomas. This feature may be applied for radiologically solid tumors, but substantial reader variability should be overcome. CLINICAL RELEVANCE STATEMENT: Although the diagnostic performance and prognostic value of CT-VPI are limited in clinical stage I lung adenocarcinomas, this parameter may be applied for radiologically solid tumors with appropriate caution regarding inter-reader variability. KEY POINTS: • Use of CT-defined visceral pleural invasion in clinical staging should be cautious, because prognostic value of CT-defined visceral pleural invasion remains unexplored. • Diagnostic performance and prognostic value of CT-defined visceral pleural invasion varied among radiologists and deep learning. • Role of CT-defined visceral pleural invasion in clinical staging may be limited to radiologically solid tumors.

An independent comparison of the Novolytix salivary melatonin radioimmunoassay with the new Novolytix salivary melatonin enzyme-linked immunosorbent assay.

The dim light melatonin onset (DLMO) is the current gold standard biomarker of the timing of the central circadian clock in humans and is often assessed from saliva samples. To date, only one commercially available salivary melatonin assay is considered accurate at the low daytime levels required to accurately detect the DLMO (Novolytix RIA RK-DSM2). The aim of this study was to conduct the first independent evaluation of a newly improved enzyme-linked immunosorbent assay (ELISA; Novolytix MLTN-96) and compare it with the recommended radioimmunoassay (RIA)-both in terms of melatonin concentrations and derived DLMOs. Twenty participants (15 females, 18-59 years old) provided saliva samples every 30 min in dim light starting 6 h before their habitual bedtime, yielding a total of 260 saliva samples. Both the RIA and ELISA yielded daytime melatonin concentrations <2 pg/mL, indicating adequate accuracy to detect the DLMO. The melatonin concentrations from the two assays were highly correlated (r = .94, p < .001), although the RIA yielded lower levels of melatonin concentration than the ELISA, on average by 0.70 pg/mL (p = .006). Seventeen DLMOs were calculated from the melatonin profiles and the DLMOs from both assays were not statistically different (p = .36) and were highly correlated (r = .97, p < .001). Two DLMOs derived from the RIA occurred more than 30 min earlier than the DLMO derived from the ELISA. These results indicate that the new Novolytix ELISA is an appropriate assay to use if the Novolytix RIA is not feasible or available.

Morning light treatment for inflammatory bowel disease: a clinical trial.

BACKGROUND: Inflammatory bowel disease (IBD) affects over 3 million Americans and has a relapsing and remitting course with up to 30% of patients experiencing exacerbations each year despite the availability of immune targeted therapies. An urgent need exists to develop adjunctive treatment approaches to better manage IBD symptoms and disease activity. Circadian disruption is associated with increased disease activity and may be an important modifiable treatment target for IBD. Morning light treatment, which advances and stabilizes circadian timing, may have the potential to improve IBD symptoms and disease activity, but no studies have explored these potential therapeutic benefits in IBD. Therefore, in this study, we aim to test the effectiveness of morning light treatment for patients with IBD. METHODS: We will recruit sixty-eight individuals with biopsy-proven IBD and clinical symptoms and randomize them to 4-weeks of morning light treatment or 4-weeks of treatment as usual (TAU), with equivalent study contact. Patient-reported outcomes (IBD-related quality of life, mood, sleep), clinician-rated disease severity, and a biomarker of gastrointestinal inflammation (fecal calprotectin) will be assessed before and after treatment. Our primary objective will be to test the effect of morning light treatment versus TAU on IBD-related quality of life and our secondary objectives will be to test the effects on clinician-rated disease activity, depression, and sleep quality. We will also explore the effect of morning light treatment versus TAU on a biomarker of gastrointestinal inflammation (fecal calprotectin), and the potential moderating effects of steroid use, restless leg syndrome, and biological sex. DISCUSSION: Morning light treatment may be an acceptable, feasible, and effective adjunctive treatment for individuals with active IBD suffering from impaired health-related quality of life. TRIAL REGISTRATION: The study protocol was registered on ClinicalTrials.gov as NCT06094608 on October 23, 2023, before recruitment began on February 1, 2024.

Heightened migraine risk in patients with rheumatoid arthritis: A national retrospective cohort study.

OBJECTIVE: This study aimed to evaluate the association between rheumatoid arthritis (RA) and subsequent migraine risk using the Korean National Health Insurance Service database. BACKGROUND: Migraine may be related to immune dysfunction and previous studies have suggested an association with chronic inflammatory rheumatic diseases; however, the relationship between RA and migraine remains unclear. METHODS: This was a population-based, nationwide, retrospective, longitudinal cohort study. Participants were enrolled from 2010 to 2017 and followed up until 2019. A total of 42,674 patients who had undergone a health checkup within 2 years prior to the initial diagnosis of RA were included in the study, after applying the exclusion criteria (previous migraine, other rheumatic disease, missing variables of interest). A non-RA control was obtained by age and sex-matching (1:5). Finally, 42,644 patients with RA were enrolled, with 213,370 individuals without RA included as controls. Among the patients with RA, 29,744 had seropositive RA (SPRA), and 12,900 had seronegative RA (SNRA). SPRA was defined by the International Classification of Diseases 10th revision (ICD-10) code M05, prescription of disease-modifying anti-rheumatic drugs (DMARDs), and enrollment in a special copayment reduction program. SNRA was defined by the ICD-10 code M06 and prescription of any DMARD. The primary endpoint was the occurrence of migraine incidents, defined using the ICD-10 code of migraine (G43). RESULTS: A total of 22,294 migraine cases (17,912/213,370 [8.3%] in controls and 4382/42,674 [10.2%] in RA) were reported during a mean follow-up of 4.4 years after a 1-year lag period. Patients with RA had a 1.2-fold higher risk of migraine compared with controls (adjusted hazard ratio [aHR] 1.21, 95% confidence interval [CI] 1.17-1.26). Increased risk of migraine was found in both patients with SNRA and SPRA compared with controls (aHR 1.20, CI 1.15-1.24 in SPRA; aHR 1.26, CI 1.19-1.34 in SNRA). Compared to patients with SNRA, those with SPRA did not demonstrate a heightened risk (aHR 0.94, CI 0.88-1.01). A significant interaction was confirmed between covariates (male, current smoker, those with diabetes mellitus, and dyslipidemia) and the risk of migraine (p for interaction of <0.05). CONCLUSION: RA was linked to a higher migraine risk, regardless of seropositivity.

Allosteric Activation of Ubiquitin-Specific Proteases by ß-Propeller Proteins UAF1 and WDR20.

Ubiquitin-specific proteases (USPs) constitute the largest family of deubiquitinating enzymes, whose catalytic competency is often modulated by their binding partners through unknown mechanisms. Here we report on a series of crystallographic and biochemical analyses of an evolutionarily conserved deubiquitinase, USP12, which is activated by two ß-propeller proteins, UAF1 and WDR20. Our structures reveal that UAF1 and WDR20 interact with USP12 at two distinct sites far from its catalytic center. Without increasing the substrate affinity of USP12, the two ß-propeller proteins potentiate the enzyme through different allosteric mechanisms. UAF1 docks at the distal end of the USP12 Fingers domain and induces a cascade of structural changes that reach a critical ubiquitin-contacting loop adjacent to the catalytic cleft. By contrast, WDR20 anchors at the base of this loop and remotely modulates the catalytic center of the enzyme. Our results provide a mechanistic example for allosteric activation of USPs by their regulatory partners.

The TIMELESS effort for timely DNA replication and protection.

Accurate replication of the genome is fundamental to cellular survival and tumor prevention. The DNA replication fork is vulnerable to DNA lesions and damages that impair replisome progression, and improper control over DNA replication stress inevitably causes fork stalling and collapse, a major source of genome instability that fuels tumorigenesis. The integrity of the DNA replication fork is maintained by the fork protection complex (FPC), in which TIMELESS (TIM) constitutes a key scaffold that couples the CMG helicase and replicative polymerase activities, in conjunction with its interaction with other proteins associated with the replication machinery. Loss of TIM or the FPC in general results in impaired fork progression, elevated fork stalling and breakage, and a defect in replication checkpoint activation, thus underscoring its pivotal role in protecting the integrity of both active and stalled replication forks. TIM is upregulated in multiple cancers, which may represent a replication vulnerability of cancer cells that could be exploited for new therapies. Here, we discuss recent advances on our understanding of the multifaceted roles of TIM in DNA replication and stalled fork protection, and how its complex functions are engaged in collaboration with other genome surveillance and maintenance factors.

Relationship between facility number of clinicians and prescribing intensity of psychotropic medications, opioids, and antibiotics in ambulatory practice.

BACKGROUND: Promoting appropriate pharmacotherapy requires understanding the factors that influence how clinicians prescribe medications. While prior work has focused on patient and clinician factors, features of the organizational setting have received less attention, though identifying sources of variation in prescribing may help identify opportunities to improve patient safety and outcomes. OBJECTIVE: To evaluate the relationship between the number of clinicians who prescribe medications in a facility and facility prescribing intensity of six individual medication classes by clinician specialty: benzodiazepines, antipsychotics, antiepileptics, and antidepressants by psychiatrists and antibiotics, opioids, antiepileptics, and antidepressants by primary care clinicians (PCPs). DESIGN: We used 2017 Veterans Health Administration (VHA) administrative data. SUBJECTS: We included patient-clinician dyads of older patients (> 55 years) with an outpatient encounter with a clinician in 2017. Patient-clinician data from 140 VHA facilities were included (n = 13,347,658). Analysis was repeated for years 2014 to 2016. MAIN MEASURES: For each medication, facility prescribing intensity measures were calculated as clinician prescribing intensity averaged over all clinicians at each facility. Clinician prescribing intensity measures included percentage of each clinician's patients prescribed the medication and mean number of days supply per patient among all patients of each clinician. KEY RESULTS: As the number of prescribing clinicians in a facility increased, the intensity of prescribing decreased. Every increase of 10 facility clinicians was associated with a significant decline in prescribing intensity for both specialties for different medication classes: for psychiatrists, declines ranged from 6 to 11%, and for PCPs, from 2 to 3%. The pattern of more clinicians less prescribing was significant across all years. CONCLUSION: Future work should explore the mechanisms that link the number of facility clinicians with prescribing intensity for benzodiazepines, antipsychotics, antiepileptics, antidepressants, antibiotics, and opioids. Facilities with fewer clinicians may need additional resources to avoid unwanted prescribing of potentially harmful or unnecessary medications.

Extended DNA-binding interfaces beyond the canonical SAP domain contribute to the function of replication stress regulator SDE2 at DNA replication forks.

Elevated DNA replication stress causes instability of the DNA replication fork and increased DNA mutations, which underlies tumorigenesis. The DNA replication stress regulator silencing-defective 2 (SDE2) is known to bind to TIMELESS (TIM), a protein of the fork protection complex, and enhances its stability, thereby supporting replisome activity at DNA replication forks. However, the DNA-binding activity of SDE2 is not well defined. Here, we structurally and functionally characterize a new conserved DNA-binding motif related to the SAP (SAF-A/B, Acinus, PIAS) domain in human SDE2 and establish its preference for ssDNA. Our NMR solution structure of the SDE2SAP domain reveals a helix-extended loop-helix core with the helices aligned parallel to each other, consistent with known canonical SAP folds. Notably, we have shown that the DNA interaction of this SAP domain extends beyond the core SAP domain and is augmented by two lysine residues in the C-terminal tail, which is uniquely positioned adjacent to the SAP motif and conserved in the pre-mRNA splicing factor SF3A3. Furthermore, we found that mutation in the SAP domain and extended C terminus not only disrupts ssDNA binding but also impairs TIM localization at replication forks, thus inhibiting efficient fork progression. Taken together, our results establish SDE2SAP as an essential element for SDE2 to exert its role in preserving replication fork integrity via fork protection complex regulation and highlight the structural diversity of the DNA-protein interactions achieved by a specialized DNA-binding motif.