Rapid Synthesis and Evaluation of Resveratrol-Piperazine Cocrystals by Ultrasound and Microwave Methods.

OBJECTIVE: Resveratrol-piperazine cocrystals have been obtained by ultrasound (US) and microwave-assisted (MW) techniques, using the solution and slurry-based methods, to study the influence of the synthesis method on the resulting cocrystal properties, and scalability of the processes. The potential of these cocrystals is represented by the unique properties of their components, resveratrol, and piperazine, which could be also used in veterinary practice. Resveratrol has antimicrobial, antiviral and anticarcinogenic properties, while piperazine can be used in the treatment of parasitic infections. METHODS: The influence of ultrasound and microwave-assisted treatment was studied by varying synthesis parameters such as reaction time, temperature, and US or MW power. The main advantage of using these methods is represented by shorter synthesis time compared to conventional methods, resulting in the direct formation of the cocrystals. RESULTS: All samples were obtained in high purity, above 97%. Cocrystal yield correlated positively with ultrasound reaction time, while temperature was not found to influence the microwave synthesis yield up to 50°C, in the case of solution-based methods. MW and US-assisted solution-based methods lead to yields between 52.9 and 68.1%. In the case of the slurry-based method, a minimum reaction time of 5 min leads to the formation of cocrystals with high purity. The resveratrol-piperazine cocrystal's solubility and in vitro antibacterial activity were also evaluated, showing promising results. CONCLUSIONS: Ultrasound and microwave-assisted techniques offer a viable alternative for synthesizing resveratrol-piperazine cocrystals with short reaction times, high yield, and purity, suitable for scalable resveratrol-piperazine cocrystals.

Emergency department visits as a potential opportunity to promote primary care attachment and modify utilization patterns - results of a pilot study in Berlin, Germany.

BACKGROUND: Utilization by low acuity patients contributes to emergency department (ED) crowding. Both knowledge deficits about adequate care levels and access barriers in primary care are important promoters of such presentations. Concurrently, not having a general practitioner (GP) increases the likelihood of low-acuity ED utilization. This pilot study thus investigated feasibility, acceptance, and potential effects of an ED-delivered intervention for low-acuity patients with no regular primary care provider, consisting of an educational leaflet on acute care options and an optional GP appointment scheduling service. METHODS: Low-acuity ED consulters not attached to a GP were given an information leaflet about alternative care offers for acute health problems and offered optional personal appointment scheduling at a local GP practice. Patients were surveyed on demographics, medical characteristics, health care utilization, valuation of the intervention, and reasons for not being attached to a GP and visiting the ED. A follow-up survey was conducted after twelve months. Trends in health and health care utilization were evaluated. RESULTS: Between December 2020 and April 2022, n = 160 patients were enrolled, n = 114 were followed up. The study population was characterized by young age (mean 30.6 years) and predominantly good general health. Besides good health, personal mobility was a central reason for not being attached to a GP, but general preference for specialists and bad experiences with primary care were also mentioned. Most frequently stated motives for the ED consultation were subjective distress and anxiety, a belief in the superiority of the hospital, and access problems in primary care. The interventional offers were favorably valued, 52.5% (n = 84) accepted the GP appointment scheduling service offer. At follow-up, GP utilization had significantly increased, while there were no significant changes regarding utilization of other providers, including ED. An additional practice survey showed a 63.0% take-up rate for the appointment service. CONCLUSIONS: With this pilot study, we were able to show that a personalized appointment scheduling service seems to be a promising approach to promote GP attachment and increase primary care utilization in patients without a regular GP in a highly urbanized setting. Further larger-scale studies are needed to investigate potential quantitative effects on ED visits. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00023480); date 2020/11/27.

Cell-cultivated aquatic food products: emerging production systems for seafood.

The demand for fish protein continues to increase and currently accounts for 17% of total animal protein consumption by humans. About 90% of marine fish stocks are fished at or above maximum sustainable levels, with aquaculture propagating as one of the fastest growing food sectors to address some of this demand. Cell-cultivated seafood production is an alternative approach to produce nutritionally-complete seafood products to meet the growing demand. This cellular aquaculture approach offers a sustainable, climate resilient and ethical biotechnological approach as an alternative to conventional fishing and fish farming. Additional benefits include reduced antibiotic use and the absence of mercury. Cell-cultivated seafood also provides options for the fortification of fish meat with healthier compositions, such as omega-3 fatty acids and other beneficial nutrients through scaffold, media or cell approaches. This review addresses the biomaterials, production processes, tissue engineering approaches, processing, quality, safety, regulatory, and social aspects of cell-cultivated seafood, encompassing where we are today, as well as the road ahead. The goal is to provide a roadmap for the science and technology required to bring cellular aquaculture forward as a mainstream food source.

Cortical Layer-Dependent Signaling in Cognition: Three Computational Modes of the Canonical Circuit.

The cerebral cortex performs computations via numerous six-layer modules. The operational dynamics of these modules were studied primarily in early sensory cortices using bottom-up computation for response selectivity as a model, which has been recently revolutionized by genetic approaches in mice. However, cognitive processes such as recall and imagery require top-down generative computation. The question of whether the layered module operates similarly in top-down generative processing as in bottom-up sensory processing has become testable by advances in the layer identification of recorded neurons in behaving monkeys. This review examines recent advances in laminar signaling in these two computations, using predictive coding computation as a common reference, and shows that each of these computations recruits distinct laminar circuits, particularly in layer 5, depending on the cognitive demands. These findings highlight many open questions, including how different interareal feedback pathways, originating from and terminating at different layers, convey distinct functional signals.

Wake-Up Thrombolysis With Negative Diffusion-Weighted Magnetic Resonance Imaging.

This case underscores the importance of treating neurological deficits of an acute stroke presentation despite initial negative diffusion-weighted imaging (DWI), especially in the acute phase when there is high clinical suspicion of stroke. Additionally, it highlights the appropriate use of a WAKE-UP protocol for patients that present with stroke symptoms without a well-defined inception time. A 71-year-old female presented to the emergency department with symptoms of dizziness and double vision upon wake-up. While clinical exam findings revealed left intranuclear ophthalmoplegia (INO) and inability to ambulate due to gait ataxia, magnetic resonance imaging (MRI) was negative for acute stroke. Despite negative DWI MRI, this patient's clinical exam findings of a left INO and gait ataxia were indicative of an ischemic stroke localizing to the medial longitudinal fasciculus (MLF), and the patient received thrombolytics. Repeat MRI about 48 h later revealed an acute infarct in the left midbrain with a DWI lesion in the MLF.

Active follow-up of patients identified with multidrug-resistant gram-negative bacteria to discontinue contact precautions and isolation measures.

It is essential to refrain from unnecessary isolation measures indicated for patients identified with multidrug-resistant gram-negative bacteria (MDR-GNB) and therefore, this study aimed to evaluate whether a pro-active follow-up strategy to discontinue isolation measures of patients identified with MDR-GNB (without carbapenemase production) resulted in reduced isolation days during hospitalization, compared to passive follow-up. A comparison was made between active and passive follow-up strategies over a two-year period after first MDR-GNB identification. Patients could be declared negative after 2 consecutive negative screening cultures. Active follow-up patients received a questionnaire for screening cultures within six months of MDR-GNB identification. Of the 2208 patients included, 1424 patients (64.5%) underwent passive follow-up and 784 patients (35.5%) underwent active follow-up. A significantly higher proportion of active follow-up patients who had sufficient (at least two) screening cultures, were declared MDR-GNB negative compared to those with passive follow-up; 66.9% vs. 20.6% (P<0.001) for adult patients and 76.0% vs. 17.1% (P<0.001) for paediatric patients. A comparison between active follow-up patients with sufficient versus those with active follow-up but insufficient cultures revealed a reduction of isolation days for paediatric patients (median 10.6 vs. 1.6 days; P = 0.031). While this difference was not statistically significant for adults (median 5.3 vs 4.2 isolation days), there was a valuable decrease in the number of isolation days for both adult and paediatric patients under active follow-up with sufficient (≥2) cultures, indicating clinical relevance. Therefore, we recommend an active follow-up strategy of patients identified with an MDR-GNB, to prevent further unneeded infection prevention measures.

Macroplastique Is a Safe and Effective Long-term Surgical Treatment for Stress Urinary Incontinence: Prospective Study with 10-Year Follow-up.

BACKGROUND AND OBJECTIVE: Until a few years ago, a midurethral sling was considered the gold standard for the treatment of female stress urinary incontinence (SUI) after failure of conservative therapies. However, criticisms regarding the rate of mesh exposure and lack of long-term efficacy have led to reconsideration of other surgical procedures. Our aim was to investigate long-term subjective and objective outcomes after injection of Macroplastique, a urethral bulking agent. METHODS: We prospectively enrolled all consecutive women complaining of pure SUI symptoms with urodynamically proven SUI who received a Macroplastique injection. We investigated patient-reported subjective outcomes using International Consultation on Incontinence Questionnaire-Short Form, Urogenital Distress Inventory, Patient Global Impression of Improvement, and Visual Analog Scale (VAS) questionnaires, and the cough stress test to assess objective outcomes. Adverse events were recorded during follow-up. KEY FINDINGS AND LIMITATIONS: At 10 yr after Macroplastique injection, the objective cure rate was 56% and 71% of patients reported that they were satisfied. Long-term data revealed no significant decline in subjective or objective cure rates. No serious complications were reported. Study limitations include the small sample size and the lack of pad tests and bladder diaries for postoperative evaluations. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our study shows that Macroplastique injection can be an effective and safe option for the treatment of female SUI in the long term, even when used in the first-line setting. PATIENT SUMMARY: We evaluated outcomes for women with stress urinary incontinence (SUI) who were treated with an injection of Macroplastique gel into the wall of the urethra to prevent leakage of urine. We found that this is a safe option for treatment of female SUI that is effective in the long term.

The association of cognitive coping style with patient preferences in a patient-led follow-up study among colorectal cancer survivors.

INTRODUCTION: Amidst the rising number of cancer survivors and personnel shortages, optimisation of follow-up strategies is imperative, especially since intensive follow-up does not lead to survival benefits. Understanding patient preferences and identifying the associated patient profiles is crucial. Coping style may be a key determinant in achieving this. Our study aims to evaluate preferences, identify coping styles and their associated factors, and explore the association between coping style and patients' preferences in colorectal cancer (CRC) follow-up. METHODS: In a prospective multicentre implementation study, patients completed the Threatening Medical Situations Inventory (TMSI) to determine their coping style. Simultaneously patients choose their follow-up preferences for the CRC trajectory regarding frequency of tumour marker determination, location of blood sampling, and manner of contact. RESULTS: A total of 188 patients completed the TMSI questionnaire after inclusion. A more intensive follow-up was preferred by 71.5% of patients. Of all patients, 52.0% had a coping style classified as 'blunting' and 34.0% as 'monitoring'. Variables such as a younger age, female gender, higher educational level, and lower ASA scores were associated with having higher monitoring scores. However, there were no significant associations between follow-up preferences and patients' coping styles. CONCLUSION: This study suggests that none of the provided options in a patient-led follow-up are unsuitable for patients who underwent curative surgery for primary CRC, based on coping style determined at baseline. Low-intensity surveillance after curative resection of CRC may, therefore, be suitable for a wide range of patients independent of coping styles.

Evaluating the accuracy of lung-RADS score extraction from radiology reports: Manual entry versus natural language processing.

INTRODUCTION: Radiology scoring systems are critical to the success of lung cancer screening (LCS) programs, impacting patient care, adherence to follow-up, data management and reporting, and program evaluation. LungCT ScreeningReporting and Data System (Lung-RADS) is a structured radiology scoring system that provides recommendations for LCS follow-up that are utilized (a) in clinical care and (b) by LCS programs monitoring rates of adherence to follow-up. Thus, accurate reporting and reliable collection of Lung-RADS scores are fundamental components of LCS program evaluation and improvement. Unfortunately, due to variability in radiology reports, extraction of Lung-RADS scores is non-trivial, and best practices do not exist. The purpose of this project is to compare mechanisms to extract Lung-RADS scores from free-text radiology reports. METHODS: We retrospectively analyzed reports of LCS low-dose computed tomography (LDCT) examinations performed at a multihospital integrated healthcare network in New York State between January 2016 and July 2023. We compared three methods of Lung-RADS score extraction: manual physician entry at time of report creation, manual LCS specialist entry after report creation, and an internally developed, rule-based natural language processing (NLP) algorithm. Accuracy, recall, precision, and completeness (i.e., the proportion of LCS exams to which a Lung-RADS score has been assigned) were compared between the three methods. RESULTS: The dataset includes 24,060 LCS examinations on 14,243 unique patients. The mean patient age was 65 years, and most patients were male (54 %) and white (75 %). Completeness rate was 65 %, 68 %, and 99 % for radiologists' manual entry, LCS specialists' entry, and NLP algorithm, respectively. Accuracy, recall, and precision were high across all extraction methods (>94 %), though the NLP-based approach was consistently higher than both manual entries in all metrics. DISCUSSION: An NLP-based method of LCS score determination is an efficient and more accurate means of extracting Lung-RADS scores than manual review and data entry. NLP-based methods should be considered best practice for extracting structured Lung-RADS scores from free-text radiology reports.

Efficacy of occlusal splint versus sleep hygiene and progressive muscle relaxation on perceived stress and sleep bruxism: A randomized clinical trial.

PURPOSE: The objective was the comparison of an occlusal device (OD), and sleep hygiene and progressive muscle relaxation (SH & PMR) on perceived stress and sleep bruxism activity (burst/episode and episode/hour) in participants with sleep bruxism. MATERIAL AND METHODS: Sixty-six participants with self-reported sleep bruxism were selected and randomly allocated into two groups: OD group or SH & PMR group. Assessment of perceived stress and sleep bruxism activity were the primary outcomes. The Perceived Stress Scale-10 (PSS-10 scale) was used to measure perceived stress and bruxism episodes/hour and bursts/episode recorded by electromyography of masseter and temporalis. These outcomes were assessed at baseline, 1 month, 6 months, and 1 year. The paired t-test assessed changes in PSS-10 scores and sleep bruxism activity within the same group over different time points (baseline, 1 month, 6 months, and 1 year). The unpaired t-test compared scores between two groups (OD and SH & PMR) at each time point to evaluate intervention differences. The chi-square test compared gender distribution between both groups. RESULTS: PSS-10 scores were found to decrease with the OD at 1 month and 6 months compared to baseline and SH & PMR at all subsequent follow-ups. This decrease was not statistically significant (p > 0.05) between the OD and SH & PMR groups at all follow-ups. OD and SH & PMR significantly reduced bruxism episodes/hour and bursts/episode at all follow-ups (p < 0.05). There were no adverse effects related to any intervention. CONCLUSIONS: The OD and SH & PMR both effectively reduced PSS-10 scores over 6 months and significantly decreased bruxism episodes and bursts per episode. Both methods are safe and effective for managing sleep bruxism and reducing stress.

Transition mentorship for spina bifida patients with the JUMP program: a pilot study.

OBJECTIVE: The transition from pediatric to adult care is challenging for patients and families with spina bifida (SB). Lifelong care relationships yield to new care environments that are typically larger, less personal, and less engaged with the nuances of SB care. Adolescence and young adulthood are often characterized by personal and psychological stresses due to factors independent of illness or chronic medical complexity. Surveys have demonstrated that transition is associated with uncertainty, anxiety, and elevated risk of adverse events for many SB patients. To help mitigate this, the authors developed a trial mentorship program between teen patients with SB and undergraduate/medical students. This study analyzes and presents the initial outcomes from this program. METHODS: The authors created the Join, Unite, Motivate, and Prepare (JUMP) program to improve readiness for the transition process. The mentee target population was patients aged 13-19 years receiving care at the authors' SB clinic. Mentors were screened/approved undergraduate/medical students who volunteered to participate and successfully completed online training in mentorship. Upon enrollment, each patient set a combination of clinical, self, and parent/guardian goals using the individualized transition plan. These goals were shared with the mentor, mentee, parent/guardian, and physician. To monitor success, the SB program director routinely met with each mentor to discuss progress made and areas of growth. These included continuous quantitative and qualitative goal setting and failures that needed to be addressed for each agenda. RESULTS: Thirteen mentor-mentee matches were created over 9 months. Of the 13 matches, 6 had more than 5 communications after the initial meeting, and 1 mentor-mentee match is still in contact today. Noted success in the program has been through mentees gaining employment, applying for scholarships, starting college, and connecting with others who are going through similar circumstances. Challenges have arisen through failure to follow-up after the initial office visit, risk with using the virtual platform, and wide geographic dispersion of both mentors and mentees across the authors' state. CONCLUSIONS: Transition from pediatric to adult care for adolescents with SB has proven to be a large hurdle. Easing this process through well-thought-out, interactive processes has the potential to improve readiness, increase patient autonomy, and provide exposure to the adult healthcare community. However, the mentorship model, in the SB setting, has not proven to be the remedy.

Prospective Health Impacts of a Universal Basic Income: Evidence from Community Engagement in South Tyneside, United Kingdom.

Studies have suggested that universal basic income (UBI) has the capacity to have substantial health benefits across the population at national level. Multiple impact pathways have recently been theorized and there are calls for trials to explore these pathways empirically. However, very limited research has taken place at local levels to explore potential context-specific effects, or how these effects could play out in economic, social, and behavioral changes. In order to examine these effects and to think through potential issues and unintended consequences, we brought together citizen engagement groups in Jarrow, South Tyneside, in the northeast of England to explore local people's expectations and positions on the development of UBI policies and pilots prior to their implementation. We found that people's expectations regarding the potential beneficial health impacts of UBI on their communities mapped strongly onto academically theorized impact pathways. They also extended understanding of these pathways in meaningful ways. Our findings add to the literature about UBI and health and provide important insights for the future development of empirical, health focused, UBI research.

Scale-up of Global Child and Youth Mental Health Services: A Scoping Review.

Numerous influential policy and scientific bodies are calling for more rapid advances in the scale-up of child and youth mental health services (CYMHS). A number of CYMHS innovations hold promise for advancing scale-up but little is known about how real-world efforts are progressing. We conducted a scoping review to identify promising approaches to CYMHS scale-up across the globe. Searches were completed in six databases (Academic Search Complete, CINAHL, MEDLINE, PsychInfo, PubMed, and Web of Science). Article selection and synthesis were conducted in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) checklist. A second search focused on low-and-middle-income countries (LMIC) was conducted based on the Cochrane Library recommended search filters of the World Bank listed LMIC countries. Authors used a double coding strategy during the title/abstract and full-text review. Twenty-eight articles meeting the eligibility criteria were identified that described 22 initiatives (in 11 different countries). Our review found the majority of published scale-up studies in CYMHS were not informed by scale-up frameworks in design or reporting. The methods and outcomes used in the identified articles were highly variable and limited our ability to draw conclusions about comparative effectiveness although promising approaches emerged. Successes and failures identified in our review largely reflect consensus in the broader literature regarding the need for strategies to better navigate the complexities of system and policy implementation while ensuring CYMHS interventions fit local contexts.

The landscape of circulating tumor HPV DNA and TTMV-HPVDNA for surveillance of HPV-oropharyngeal carcinoma: systematic review and meta-analysis.

BACKGROUND: Human papilloma virus (HPV) related cancers of the oropharynx are rapidly increasing in incidence and may soon represent the majority of all head and neck cancers. Improved monitoring and surveillance methods are thus an urgent need in public health. MAIN TEXT: The goal is to highlight the current potential and limitations of liquid biopsy through a meta analytic study on ctHPVDNA and TTMV-HPVDNA. It was performed a Literature search on articles published until December 2023 using three different databases: MEDLINE, Embase, and Cochrane Library. Studies that evaluated post-treatment ctHPVDNA and TTMV-HPVDNA in patients with HPV + OPSCC, studies reporting complete data on the diagnostic accuracy in recurrence, or in which the number of true positives, false positives, true negatives, and false negatives was extractable, and methods of detection of viral DNA clearly defined. The meta-analysis was conducted following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) reporting guidelines. The aim of this meta-analysis was to evaluate the sensitivity, specificity, and accuracy of ctHPVDNA and TTMV by ddPCR to define its efficacy in clinical setting for the follow up of HPV-OPSCC. CONCLUSION: The 12 studies included in the meta-analysis provided a total of 1311 patients for the analysis (398 valuated with ctHPVDNA and 913 with TTMV-HPVDNA). Pooled sensitivity and specificity were 86% (95% CI: 78%-91%) and 96% (95% CI: 91%-99%), respectively; negative and positive likelihood ratios were 0.072 (95% CI: 0.057-0.093) and 24.7 (95% CI: 6.5-93.2), respectively; pooled DOR was 371.66 (95% CI: 179.1-918). The area under the curve (AUC) was 0.81 (95% CI, 0.67-0.91). Liquid biopsy for the identification of cell free DNA might identify earlier recurrence in HPV + OPSCC patients. At the present time, liquid biopsy protocol needs to be standardized and liquid biopsy cannot yet be used in clinical setting. In the future, a multidimensional integrated approach which links multiple clinical, radiological, and laboratory data will contribute to obtain the best follow-up strategies for the follow-up of HPV-OPSCC.

European survey on follow-up strategies for unruptured intracranial aneurysms.

Introduction: The increasing detection rates of unruptured intracranial aneurysms (UIA) pose a challenge for both neurovascular centers, tasked with managing a growing pool of patients requiring regular monitoring with imaging, and the healthcare system that must bear the costs of such surveillance. While there is consensus on the need for follow-up of UIA, uncertainties persist regarding the optimal cessation of surveillance, especially when considering diverse patient risk factors and, notably, in cases of treated aneurysms with stable rest perfusion. Detailed guidelines on UIA follow-up are currently lacking, exacerbating these challenges. Research question: We sought to investigate European strategies for follow-up of untreated, microsurgically and endovascularly treated UIA. Material and methods: An online survey consisting of 15 questions about follow-up management of UIA was sent out to the cerebrovascular section of the European Association of Neurosurgical Societies (EANS). Results: The survey response rate was 27.3% (68/249). There was consenus upon the necessity for long-term follow-up of UIA (100% [n = 68]). The recommendation to perform follow-up was inversely correlated with patient age and more prevalent among endovascularly compared to microsurgically treated patients (92.6% [n = 63] vs. 70.6% [n = 48]). A majority recommended continued follow-up of treated aneurysms with stable rest perfusion, with lifelong surveillance in patients under 60 years and continuation for 5-10 years in patients aged 61-80, irrespective of whether they underwent microsurgical (38.3% [n = 23]; 33.3% [n = 20]) or endovascular (41.9% [n = 26]; 30.6% [n = 19]) treatment. Discussion and conclusion: This survey confirmed a European consensus on the necessity of long-term follow-up for untreated UIA. However, significant variations in follow-up strategies, especially for treated UIA and post-treatment rest perfusion, were noted. Despite limited evidence suggesting low risk from aneurysm remnants, respondents favored long-term follow-up, highlighting uncertainty in management. This underscores the need for collaborative research on aneurysm remnants and standardized follow-up protocols for UIA in Europe.

Retreatment and Anti-tuberculosis Therapy Outcomes in Brazil Between 2015 and 2022: A Nationwide Study.

Background: Adherence to anti-tuberculosis treatment (ATT) in Brazil remains a challenge in achieving the goals set by the World Health Organization (WHO). Patients who are lost to follow-up during treatment pose a significant public health problem. This study aimed to investigate the factors associated with unfavorable ATT outcomes among those undergoing retreatment in Brazil. Methods: We conducted an observational study of patients aged ≥18 years with tuberculosis (TB) reported to the Brazilian National Notifiable Disease Information System between 2015 and 2022. Clinical and epidemiologic variables were compared between the study groups (new cases and retreatment). Regression models identified variables associated with unfavorable outcomes. Results: Among 743 823 reported TB cases in the study period, 555 632 cases were eligible, consisting of 462 061 new cases and 93 571 undergoing retreatments (44 642 recurrent and 48 929 retreatments after loss to follow-up [RLTFU]). RLTFU (odds ratio [OR], 3.96 [95% confidence interval {CI}, 3.83-4.1]) was a significant risk factor for any type of unfavorable ATT. Furthermore, RLTFU (OR, 4.93 [95% CI, 4.76-5.11]) was the main risk factor for subsequent LTFU. For death, aside from advanced age, living with HIV (OR, 6.28 [95% CI, 6.03-6.54]) was the top risk factor. Conclusions: Retreatment is a substantial risk factor for unfavorable ATT outcomes, especially after LTFU. The rates of treatment success in RLTFU are distant from the WHO End TB Strategy targets throughout Brazil. These findings underscore the need for targeted interventions to improve treatment adherence and outcomes in persons who experience RLTFU.

Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial.

BACKGROUND: Nivolumab+ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years median follow-up from CheckMate 214. PATIENTS AND METHODS: Patients with aRCC (N=1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. Endpoints included OS, and independent radiology review committee-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients. RESULTS: With 8 years (99.1 months) median follow-up, the HR (95% CI) for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all IMDC risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). Median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1-not estimable (NE) versus 19.8-33.2; ITT], 82.8 versus 19.8 months [54.1-NE versus 16.4-26.4; I/P], and 61.5 versus 33.2 months [27.8-NE versus 24.8-51.4; FAV]). Incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time. CONCLUSIONS: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC.

Assessing Transition Cow Management in Dairy Cows for Improved Health, Milk Production, Pregnancy and Culling Outcomes.

Understanding of the social environment has the potential to benefit dairy cow welfare and production. Our aim was to evaluate the associations of stocking density, calving density, days spent in a pre-partum group before calving (days spent in close-up, DCU) and the number of days from a pen filling event (addition of new cows to the pre-partum pen) on early-lactation health, production, pregnancy and culling outcomes in dairy cows. Data were gathered from 2780 cows in 2 herds. Herd management and reproductive records were analyzed for cows receiving treatment in the first 30 d of lactation (days in milk, DIM) for clinical mastitis, reproductive tract disease, ketosis, milk fever and displaced abomasum. Principal component analysis was used to account for the relationship between gestation length (GL) and DCU and their association with early lactation disease, milk production, pregnancy and culling outcomes. The effect of stocking density, the number of days from a pen filling event to calving and the calving density experienced by a cow in her week of calving was also evaluated. Causal inference was used to correct for confounding bias due to farm identity. The odds of disease in the first 30 DIM increased with stocking density before calving. A quadratic association was found between the first principal component (PC1), representing the combined effect of GL and DCU, and the odds of disease in multiparous cows only. Early lactation milk production and 305 d milk production in multiparous cows increased with PC1 score. Quadratic relationships were found between stocking density at d 8 to 2 before calving with both early lactation and 305 d milk production in multiparous cows but no associations were found in primiparous cows. Calving density showed a quadratic association with 305 d milk production in primiparous cows. The number of days from the last pen filling event to calving was not associated with changes in milk production. Disease occurrence was negatively associated with both early lactation and 305 d milk yield in multiparous cows but only with early lactation milk production in primiparous cows. The occurrence of disease was associated with a delayed time to pregnancy only in primiparous cows while both disease and being in lactation group ≥ 3 were negatively associated with time to pregnancy in multiparous cows. Week 4 milk (W4MK) was positively associated with reduced time to pregnancy in multiparous cows. For primiparous cows, increasing age at calving was associated with increased culling risk, while being in lactation group ≥ 3 was associated with increased culling risk in multiparous cows. Culling risk decreased with increasing W4MK in all cows. These results suggest that gestation length, time spent in close-up and stocking density are important factors influencing disease incidence in early lactation and subsequent lactation performance but had differing effects on primiparous versus multiparous cows. A better understanding of how pre-partum management factors influence postpartum health and milk production can help farms to plan facilities and organize the day-to-day management of cows and will assist in improving cow welfare and productivity.

Impact of completely histological remission on reducing flare-ups in moderate-to-severe, biologics-experienced ulcerative colitis patients with endoscopic remission.

BACKGROUND/PURPOSE: Endoscopic remission is presently recognized as the standard therapeutic target in the treatment of ulcerative colitis (UC). However, achieving histological remission is increasingly viewed as a pivotal objective. This study investigates the effects of attaining completely histological remission on the clinical outcomes for UC patients with a high disease burden who have already reached endoscopic remission. This is the inaugural study to concentrate on this specific patient demographic. METHODS: This retrospective cohort study enrolled moderate-to-severe, biologics-experienced UC patients with completely endoscopic remission (Mayo endoscopic subscore of 0) between June 2017 and October 2023 at Chang Gung Memorial Hospital, Linkou. Patients were classified into histological remission (HR) and non-histological remission (non-HR) groups based on the Nancy index (NI). HR was defined as an NI score of 0, with all other patients categorized as non-HR. The definition of flare-ups was based on both clinical and endoscopic evidence. Comparative analyses focused on baseline characteristics and clinical outcomes at follow-up. RESULTS: A total of 42 patients (HR group: 23, non-HR group: 19) were included. The average follow-up duration was 17.6 months. Baseline characteristics were comparable between the groups. At the end of follow-up, the HR group showed a significantly lower rate of acute flare-ups (26.1% vs. 68.4%, P = 0.006). Although not statistically significant, the HR group also experienced fewer emergency department visits and hospital admissions. CONCLUSIONS: For moderate-to-severe, biologics-experienced UC patients in endoscopic remission, achieving completely histological remission is associated with a substantial reduction in flare-ups, suggesting its potential as a valuable therapeutic target.

Cytotoxic effects of NIR responsive chitosan-polymersome layer coated melatonin-upconversion nanoparticles on HGC27 and AGS gastric cancer cells: Role of the ROS/PI3K/Akt/mTOR signaling pathway.

In this study, a formulation of NaGdF4:Tm/Er@NaGdF4 (core@shell) UCNPs loaded with melatonin drug was synthesized. The novel melatonin-loaded UCNPs were then encapsulated within NIR-responsive biopolymeric chitosan (CS) based polymersome and investigated against gastric cancer (HGC27 & AGS) cells. The photolysis of the ONB moiety and disruption of the disulfide linkage in the polymersome induced by NIR light facilitated by the NaGdF4:Tm/Er@NaGdF4 UCNPs and GSH results in an increased release of melatonin drug. The DLS and zeta potential measurements exhibit a reduced particle size (21.9 ±â€¯3.56 nm) and a low zeta potential (17.91 mV). Furthermore, drug release profiles demonstrated superior melatonin drug release (79.78 %) at pH 5.0 for CS-polymersome-coated melatonin-UCNPs resembling the Hixson-Crowell model. Remarkably, CS-polymersome-coated melatonin-UCNPs exhibit excellent anti-proliferative properties for HGC27 (IC50 = 0.096 µM) and AGS (IC50 = 0.16 µM) cancer cells. The flow cytometry data demonstrate a significant elevation in ROS levels which promoted cell death in both HGC-27 and AGS cells. The observed cell mortality in HGC-27 and AGS cells is primarily caused by the destruction of the nucleus, mtDNA, rupture of disulfide (R-S-S-R) bonds, and nuclear DNA. Contrarily, L929 and HUVECs cells incubated with CS-polymersome coated melatonin-UCNPs (100 µg/mL) reveal a notable cell viability of 88.7 % and 93 % indicating superior biocompatibility. The western blotting analysis revealed the induction of autophagy by CS-polymersome-coated melatonin-UCNPs which subsequently led to apoptosis by regulating the ROS/PI3K/Akt/mTOR molecular signaling pathway.