BACKGROUND:Understanding the relationship between different dimensions of nicotine cravings and smoking behavior is crucial for addressing nicotine dependence. This study examined how morning cravings and past-week cravings relate to nicotine intake, as measured by salivary cotinine, and the mediating role of cigarettes per day (CPD) and time to first cigarette (TTFC). METHODS:Data were obtained as part of the Pennsylvania Adult Smoking Study (PASS), a community-based study of adult smokers. Participants (N = 353) completed structured questionnaires assessing smoking behaviors, cravings, and nicotine dependence. Salivary cotinine levels were measured to assess nicotine intake. Regression and path analyses were conducted to evaluate associations among craving phenotypes, smoking behaviors, and nicotine intake. RESULTS:Morning cravings were significantly associated with both TTFC (β = -0.62, p < 0.001) and CPD (β = 0.27, p = 0.001), while past-week cravings were associated only with CPD (β = 0.14, p = 0.01). TTFC and CPD were both predictors of cotinine levels (β = -0.33, p < 0.001 and β = 0.22, p < 0.001, respectively). The total standardized effect of morning cravings on cotinine was 0.27, significantly greater than the effect of past-week cravings (0.05). Path analysis indicated that the influence of morning cravings on cotinine was mediated through both TTFC and CPD, whereas past-week cravings affected cotinine only via CPD. CONCLUSIONS:Morning cravings demonstrate a stronger association with nicotine intake than past-week cravings, primarily through their effect on TTFC and CPD. These findings highlight the importance of targeting morning cravings in smoking cessation interventions. Future research should explore the role of neurobiological mechanisms, such as cortisol dynamics, in shaping nicotine cravings and smoking behavior.

OBJECTIVE:The ORAL Surveillance trial found a dose-dependent increase in venous thromboembolism (VTE) and pulmonary embolism (PE) events with tofacitinib versus tumor necrosis factor inhibitors (TNFi). We aimed to assess VTE incidence over time and explore risk factors of VTE, including disease activity, in ORAL Surveillance. METHODS:Patients with rheumatoid arthritis (RA) aged 50 years or older with at least one additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily (BID) or TNFi. Post hoc, cumulative probabilities and incidence rates (patients with first events/100 patient-years) by 6-month intervals were estimated for adjudicated VTE, deep vein thrombosis, and PE. Cox regression models identified risk factors. Clinical Disease Activity Index leading up to the event was explored in patients with VTE. RESULTS:Cumulative probabilities for VTE and PE were higher with tofacitinib 10 mg BID, but not 5 mg BID, versus TNFi. Incidence rates were consistent across 6-month intervals within treatments. Across treatments, risk factors for VTE included prior VTE, body mass index greater than or equal to 35 kg/m2, older age, and history of chronic lung disease. At the time of the event, most patients with VTE had active disease as defined by Clinical Disease Activity Index. CONCLUSION:Incidences of VTE and PE were higher with tofacitinib (10 > 5 mg BID) versus TNFi and were generally consistent over time. Across treatments, VTE risk factors were aligned with previous studies in the general RA population. These data highlight the importance of assessing VTE risk factors, including age, body mass index, and VTE history, when considering initiation of tofacitinib or TNFi in patients with active RA.

Background Thyroid hormones are of fundamental importance for brain function. While low triiodothyronine levels during acute ischemic stroke (AIS) are associated with worse clinical outcomes, dynamics of thyroid function after AIS remains unknown. Thus, we longitudinally evaluated thyroid hormones after stroke and related them to stroke severity. Methods We prospectively traced thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxin (fT4) levels from the hyper-acute (within 24 h) to acute (3–5 days) and chronic (3–6 months) stages of ischemic stroke using a mixed regression model. Then, we analyzed whether stroke severity at presentation, expressed by National Institute of Health Stroke Scale (NIHSS), is associated with change in thyroid function. Results Forty-five patients were evaluated in hyper-acute and acute stages, while 29 were followed through chronic stage. TSH levels decreased from hyper-acute (2.91 ± 0.65 μIU/mL) to acute (2.86 ± 0.46 μIU/mL) and chronic stages of stroke (1.93 ± 0.35 μIU/m, p = 0.95). fT3 levels decreased from hyper-acute (2.79 ± 0.09 pg/ml) to acute (2.37 ± 0.07 pg/ml) stages, but recovered in chronic stage (2.78 ± 0.10 pg/ml, p < 0.01). fT4 levels decreased from hyper-acute (1.64 ± 0.14 ng/dl) to acute (1.13 ± 0.03 ng/dl) stages, and increased in the chronic stage (1.16 ± 0.08 ng/dl, p = 0.02). One-unit increase in presenting NIHSS was associated with 0.04-unit decrease of fT3 from hyper-acute to the acute stage ( p < 0.01). Conclusion There is a transient decrease of thyroid hormones after ischemic stroke, possibly driven by stroke severity. Larger studies are needed to validate these findings. Correction of thyroid function in acute stroke may be investigated to improve stroke outcomes.

BACKGROUND:This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). METHODS:JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. RESULTS:A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. CONCLUSIONS:Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD.

The safety of tofacitinib in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) has been demonstrated in clinical studies of ≤ 4 and 9.5 years, respectively. Post-marketing surveillance (PMS) data for tofacitinib from spontaneous and voluntary adverse event (AE) reports have been published for RA, but not PsA. To inform the real-world safety profile of tofacitinib in PsA, we evaluated AE reports submitted to the Pfizer safety database (including RA data for context). Endpoints included AEs, serious AEs (SAEs), AEs of special interest (AESIs; serious infections, herpes zoster, cardiovascular events, malignancies, venous thromboembolism), and fatal cases. Exposure was estimated using IQVIA global commercial sales data. Number, frequency, and reporting rates (RRs; number of events/100 patient-years’ [PY] exposure) were summarized by indication and formulation (immediate release [IR] 5 or 10 mg twice daily], modified release [MR] 11 mg once daily, or all tofacitinib). The data-collection period differed by indication (PsA: 14 December 2017 [US approval, IR/MR] to 6 November 2021; RA: 6 November 2012 [US approval, IR] to 6 November 2021; MR approval, 24 February 2016). A total of 73,525 case reports were reviewed (PsA = 5394/RA = 68,131), with 20,706/439,370 PY (PsA/RA) of exposure. More AEs were reported for IR versus MR (IR/MR: PsA = 8349/7602; RA = 137,476/82,153). RRs for AEs (IR/MR: PsA = 59.6/113.4; RA = 44.0/64.8) and SAEs (PsA = 8.1/13.6; RA = 8.0/9.5) were higher with MR versus IR. AE RRs (RA) in the first 4 years after IR approval were 95.9 (IR; 49,439 PY) and 147.0 (MR; 2000 PY). Frequency of SAEs, AESIs, and fatal cases was mostly similar across formulations and indications. The most frequently-reported AE Preferred Terms (PsA/RA) included drug ineffective (20.0

Table S1. Table showing oligonucleotide primer sequence used in RT-PCR Figure S1. Physicochemical characterization of the nanoparticles shows shape, siRNA protection and siRNA release kinetics. Figure S2. Transferrin (Tf) ligand optimization on nanoparticles measured by fluorescence microscopy and fluorescence intensity. Figure S3.Nanoparticle specificity and receptor-mediated uptake studies. Figure S4. Western blotting showing HuRsiRNA4 but not other siRNAs used as controls reduced HuR protein expression. Figure S5. HuR mRNA expression analysis in nanoparticle-treated tumor and normal cells. Figure S6.Semi-quantitative analysis of HuR and HuR-regulated protein expression in A549 cells. Figure S7.Semi-quantitative analysis of HuR and HuR-regulated protein expression in HCC827 cells. Figure S8.Semi-quantitative analysis of HuR and HuR-regulated protein expression in MRC-9 cells. Figure S9. Western blot analysis shows HuR-TfNP treatments induces apoptosis in A549 cells. Figure S10. Molecular imaging showing biodistribution and kinetics of free ICG and ICG-TfNP in tumor-bearing and non-tumor-bearing naive mice respectively. Figure S11. Bioluminescence imaging showing tumor growth measurement over time in A549 tumor-bearing mice. Figure S12. Molecular analysis of HuR-TfNP-treated tumor tissues shows reduction in HuR mRNA and HuR-regulated proteins and induction of apoptosis. Figure S13. Immunohistochemical analysis of HuR-TfNP-treated A549 tumor tissues for changes in morphology, and in expression of HuR, CD31, KI67 and TUNEL positive cells. Figure S14.Immunohistochemical analysis of HuR-TfNP-treated HCC827 tumor tissues for changes in morphology, and in expression of HuR, CD31, and KI67.

This study aimed to create a pediatric sedation scoring system independent of the American Society of Anesthesiology Physical Status (ASA-PS) classification that is predictive of adverse events, facilitates objective stratification, and resource allocation. Multivariable regression and machine learning algorithm analysis of 134,973 sedation encounters logged in to the Pediatric Sedation Research Consortium (PSRC) database between July 2007 and June 2011. Patient and procedure variables were correlated with adverse events with resultant β-regression coefficients used to assign point values to each variable. Point values were then summed to create a risk assessment score. Validation of the model was performed with the 2011 to 2013 PSRC database followed by calculation of ROC curves and positive predictive values. Factors identified and resultant point values are as follows: 1 point: age ≤ 6 months, cardiac diagnosis, asthma, weight less than 5th percentile or greater than 95th, and computed tomography (CT) scan; 2 points: magnetic resonance cholangiopancreatography (MRCP) and weight greater than 99th percentile; 4 points: magnetic resonance imaging (MRI); 5 points: trisomy 21 and esophagogastroduodenoscopy (EGD); 7 points: cough at the time of examination; and 18 points: bronchoscopy. Sum of patient and procedural values produced total risk assessment scores. Total risk assessment score of 5 had a sensitivity of 82.69% and a specificity of 26.22%, while risk assessment score of 11 had a sensitivity of 12.70% but a specificity of 95.29%. Inclusion of ASA-PS value did not improve model sensitivity or specificity and was thus excluded. Higher risk assessment scores predicted increased likelihood of adverse events during sedation. The score can be used to triage patients independent of ASA-PS with site-specific cut-off values used to determine appropriate sedation resource allocation.

When conducting land cover classification, it is inevitable to encounter foggy conditions, which degrades the performance by a large margin. Robustness may be reduced by a number of factors, such as aerial images of low quality and ineffective fusion of multimodal representations. Hence, it is crucial to establish a reliable framework that can robustly understand remote sensing image scenes. Based on multimodal fusion and attention mechanisms, we leverage HRNet to extract underlying features, followed by the Spectral and Spatial Representation Learning Module to extract spectral-spatial representations. A Multimodal Representation Fusion Module is proposed to bridge the gap between heterogeneous modalities which can be fused in a complementary manner. A comprehensive evaluation study of the fog-corrupted Potsdam and Vaihingen test sets demonstrates that the proposed method achieves a mean F1score exceeding 73%, indicating a promising performance compared to State-Of-The-Art methods in terms of robustness.

Robust semantic labeling of high-resolution remote sensing images (RSIs) in foggy conditions is crucial for automatic monitoring of land covers. This remains a challenging task owing to the low interclass differentiation yet high intraclass variance and geometric size diversity. Although conventional convolutional neural networks (CNNs) have demonstrated state-of-the-art (SOTA) performance in semantic segmentation, most networks are primarily concerned with standard accuracy, while the influence on robustness is rarely explored. This letter proposes a reliable framework which is evaluated across various severity levels of fog corruptions. Utilizing HRNet as the backbone to maintain high-resolution representations, we develop a multimodal fusion module (MMF) to exploit the complementary information of lidar and multispectral data. Based on the evaluation experiment on fog corrupted datasets, our model demonstrates promising performance with an average mean Intersection over Union (mIoU) on the clean along with the corrupted datasets exceeding 80 and 56, respectively.

Background: Resident physicians are frequently uncomfortable ordering enteral nutrition (EN) and are unaware of the variety of formulas and supplements available for different disease processes. Many depend on a clinical dietician to assist with recommending EN formulas and patient energy requirements that may not be readily available on patient admission. This creates a barrier to early initiation of EN and non-compliance with Society of Critical Care Medicine and American Society of Parenteral and Enteral Nutrition clinical guidelines. Objective: Internal medicine resident physicians were provided an iPod with a smart phone/device application (EN application) to assist them in choosing EN formulas for patients during their intensive care unit (ICU) rotation. The primary outcome was improved initiation of EN within 24 hours of admission. Secondary outcomes included the following: time to initiate EN, goal calories reached, infections rates, length of stay, mortality, and concordance with clinical guidelines. Design: The study is a quasi-experimental design to improve delivery of EN at an academic medical center in the medical ICU. Data were collected from a retrospective chart review to evaluate the impact of an EN application to assist resident physicians when ordering EN. Results: Use of the EN application reduced the percent of patients with delayed initiation of EN from 61.2% prior to 37.5% ( P < .01). The mean time to initiate EN also improved 44.5 vs 31.9 hours ( P < .01). Patients were also more likely to achieve their daily caloric goal ( P < .01). Conclusion: The use of an EN application to assist internal medicine residents when ordering EN reduced delays in initiation of EN and improved overall delivery of EN to medical ICU patients.

Background: Reactivation of Hepatitis B virus (HBVr) in patients on immunosuppressive therapy (IST) can be prevented by screening for HBV and preemptive antiviral therapy in patients with prior exposure. Some internal medicine (IM) subspecialty guidelines recommend screening for HBV in all patients prior to starting IST while other guidelines do not and there is no consensus. Methods: We conducted a cross sectional survey to assess the current practice of IM sub-specialty physicians in Oklahoma regarding screening for HBV prior to starting IST. Results: There were seventy respondents from different clinical practice settings; 47.2% (33/70) free-standing specialty clinic, 18.6% (20/70) university hospital/VA hospital, 12.9% (9/70) community hospital and 21.4% (15/70) private hospital. Gastroenterologists accounted for 34.3% (24/70), rheumatologists 25.7% (18/70), hematology-oncologists 21.4% (15/70), and dermatologists 18.6% (13/70). Mean number of years of clinical practice was 27.7(SD 11.9 years). The majority of respondents 91.4% (64/70) were aware of an existing guideline within their respective specialty about screening for HBV prior to prescribing IST. There was a statistically significant difference in practice by subspecialty regarding the choice of serological tests for HBV screening and practice regarding care of screening positive patients (P<0.05). Conclusion: There was significant variation in clinical practice regarding HBV screening, choice of HBV serological tests and management of screening positive patients. The extent to which our results are influenced by divergent subspecialty guidelines is unclear. However, it highlights an unmet need for physician education at IM sub-specialty level and a need for consensus on guidelines for prevention of HBVr.

Tumor suppressor ARID1A, a subunit of the chromatin remodeling complex SWI/SNF, regulates cell cycle progression, interacts with the tumor suppressor TP53, and prevents genomic instability. In addition, ARID1A has been shown to foster resistance to cancer therapy. By promoting non-homologous end joining (NHEJ), ARID1A enhances DNA repair. Consequently, ARID1A has been proposed as a promising therapeutic target to sensitize cancer cells to chemotherapy and radiation. Here, we report that ARID1A is regulated by human antigen R (HuR), an RNA-binding protein that is highly expressed in a wide range of cancers and enables resistance to chemotherapy and radiation. Our results indicate that HuR binds ARID1A mRNA, thereby increasing its stability in breast cancer cells. We further find that ARID1A expression suppresses the accumulation of DNA double-strand breaks (DSBs) caused by radiation and can rescue the loss of radioresistance triggered by HuR inhibition, suggesting that ARID1A plays an important role in HuR-driven resistance to radiation. Taken together, our work shows that HuR and ARID1A form an important regulatory axis in radiation resistance that can be targeted to improve radiotherapy in breast cancer patients.

Background Oral direct-acting antivirals (DAAs) provide an exceptional opportunity to treat hepatitis C virus (HCV) infection. Goals We compared the treatment outcomes between specialty and primary care physician (PCP) clinics for patients treated with DAAs. Methods We performed a retrospective analysis of patients treated for HCV in our PCP clinics and specialty; liver and gastroenterology clinics and gastroenterology clinics. We used the two-sided t-test and the chi-square test to compare the means of continuous and categorical variables, respectively. Results Data from a total of 377 patients was analyzed (PCP clinic: n = 185 and specialty clinic: n = 192). There was no significant difference between age, race, and gender. Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores were comparable at baseline. Greater than 90% of the patients achieved sustained virological response (SVR) with no difference between the groups. Conclusions Uncomplicated patients can be treated for hepatitis C by their PCPs with DAAs with similar treatment outcomes to specialty clinics. There should be explicit guidelines on patient eligibility for treatment by PCPs vs. specialists.

Aberrant expression of GLI1 is responsible for aggressive tumor behavior and survival due to its effects on the DNA damage response (DDR). We investigated whether interleukin (IL)-24, a tumor suppressor, inhibits GLI1 and the associated DDR pathway in human NSCLCs. IL-24 treatment reduces mRNA and protein expression of GLI1 in lung tumor cells, but not in normal cells. GLI1 reporter assay and mRNA studies demonstrated that IL-24 regulates GLI1 at the post-transcriptional level by favoring mRNA degradation. Associated with GLI1 inhibition was marked suppression of the ATM-mediated DDR pathway resulting in increased DNA damage, as evidenced by γ-H2AX foci and Comet assay. Furthermore, attenuation of GLI1-associated DDR by IL-24 increased caspase-3 and PARP activity, resulting in cancer cell apoptosis. GLI1 inhibition and overexpression confirmed that IL-24-mediated anti-tumor effects involved the GLI-dependent pathway. Finally, we observed that IL-24-mediated alteration in GLI1 is independent of the canonical hedgehog-signaling pathway. Our study provides evidence that IL-24 treatment induces DNA damage, and reduces GLI1 expression and offers an opportunity for testing IL-24-based therapy for inhibiting GLI1 in lung cancer.

Socioeconomic status (SES) is a major determinant of tobacco use but little is known whether SES affects nicotine exposure and the degree of nicotine dependence. The Pennsylvania Adult Smoking Study is a cross-sectional study of smoke exposure and nicotine dependence among adults conducted in central Pennsylvania between June 2012 and April 2014. The study included several measures of SES, including assessments of education and household income, as well as occupation, home ownership, health insurance, household density and savings accounts. Measurements included saliva for the nicotine metabolites cotinine (COT), 3-‘hydroxycotinine (3HC) and total metabolites (COT +3HC). Puffing behavior was determined using portable smoking topography devices. The income levels of lighter smokers (< 20 cigarettes per day) was $10,000 more than heavier smokers. Higher Fagerström Test for Nicotine Dependence scores were associated with lower income and job status, scores ranged from 5.4 in unemployed, 4.4 in blue-collar, and 3.8 in white-collar workers. In principal components analysis used to derive SES indicators, household income, number in household, and type of dwelling were the major SES correlates of the primary component. Job category was the major correlate of the second component. Lower SES predicted significantly higher adjusted total nicotine metabolite levels in the unemployed group. Job category was significantly associated with total daily puffs, with the highest level in the unemployed, followed by blue-collar workers, after adjustment for income. Among smokers, there was a relationship between lower SES and increased nicotine dependence, cigarettes per day and nicotine exposure, which varied by job type.

Co-administration of functionally distinct anti-cancer agents has emerged as an efficient strategy in lung cancer treatment. However, a specially designed drug delivery system is required to co-encapsulate functionally different agents, such as a combination of siRNA and chemotherapy, for targeted delivery. We developed a folic acid (FA)-conjugated polyamidoamine dendrimer (Den)-based nanoparticle (NP) system for co-delivery of siRNA against HuR mRNA (HuR siRNA) and cis-diamine platinum (CDDP) to folate receptor-α (FRA) -overexpressing H1299 lung cancer cells. The co-delivery of HuR siRNA and CDDP using the FRA-targeted NP had a significantly greater therapeutic effect than did individual therapeutics. Further, the FRA-targeted NP exhibited improved cytotoxicity compared to non-targeted NP against lung cancer cells. Finally, the NP showed negligible toxicity towards normal MRC9 lung fibroblast cells. Thus, the present study demonstrates FRA-targeted Den nanoparticle system as a suitable carrier for targeted co-delivery of siRNA and chemotherapy agents in lung cancer cells.