Effect of hyperglycemia and empagliflozin on markers of cardiorenal injury and inflammation in patients with type 1 diabetes.

AIMS: To investigate the effect of hyperglycemia and empagliflozin on cardiorenal injury and inflammation in patients with uncomplicated type 1 diabetes (T1D). METHODS: Serum cardiac (sST2, Gal-3, cTnT), kidney injury (KIM-1, NGAL), inflammatory (sTNFR1, sTNFR2), and hemodynamic (NT-proBNP, EPO) markers were assessed post-hoc in two separate T1D cohorts. The glycemic clamp trial (NCT02344602) evaluated 49 adults with T1D and 27 controls under euglycemic and acute hyperglycemic conditions. The crossover BETWEEN trial (NCT02632747) investigated empagliflozin 25 mg plus ramipril for 4 weeks compared to placebo-ramipril for 4 weeks in 30 adults with T1D. RESULTS: In the glycemic clamp study, hyperglycemia acutely increased levels of NT-proBNP (p = 0.0003) and sTNFR2 (p = 0.003). BETWEEN participants treated with empagliflozin exhibited a paradoxical subacute rise in NT-proBNP (p = 0.0147) compared to placebo, independent of hematocrit. Individuals with higher baseline levels of sST2 and sTNFR1 had greater empagliflozin-associated reductions in systolic blood pressure and greater activation of renin-angiotensin-aldosterone system (RAAS) mediators, whereas those with higher baseline levels of KIM-1 and sTNFR1 had greater glomerular filtration rate (GFR) dip. CONCLUSION: The protective mechanisms of SGLT2 inhibition on blood pressure, RAAS activation, and renal hemodynamics are apparent in the subset of people with uncomplicated T1D with adverse cardiorenal and inflammatory markers.

When does patient function "Plateau" after total joint arthroplasty? A cohort study.

PURPOSE: With over 100,000 procedures completed per year, hip and knee arthroplasty are two of the most common surgical procedures performed in Canada. There has been literature indicating that patient reported outcome measures (PROM) will start to plateau between six and 12 months. The purpose of this paper was to analyze the trajectory of PROMs following total hip and knee arthroplasty (THA and TKA), as well as assess the impact of any potential confounders on this trajectory. The central research question was: At what point do PROMS plateau among patients that undergo elective THA and TKA? METHODS: This study was a retrospective analysis of data from a prospective database. Patients were eligible if they had undergone an elective, primary THA/TKA with Oxford Scores recorded pre-operatively, and at least at two of the following four time points: six weeks, six months, one year, and two years. RESULTS: Mean pre-operative Oxford scores were 18.0 (7.8) for THA, and 20.1 (7.5) for TKA. For both THA and TKA, there were statistically significant interval improvements in Oxford scores from six weeks [THA: 33.8 (7.9)/TKA: 28.7 (7.8)] to six months [THA: 40.2 (7.3)/TKA: 35.9 (8.3)], and from six months to one year [THA: 41.0 (7.3)/TKA: 37.3 (8.4)], but not from one to two years [THA: 40.0 (8.5)/TKA: 36.4 (9.6)]. CONCLUSIONS: Patients undergoing either primary THA or TKA can expect clinically meaningful improvements in the first six months after surgery. Beyond this time point, there is a plateau in PROMs. These findings are important for both setting patient expectations in pre-operative discussions, and allowing surgeons to have a realistic understanding of their patients' expected post-operative course.

Surgical outcomes of trigonal intraventricular meningiomas: a single-centre study.

Trigonal meningiomas are rare intraventricular tumours that present a surgical challenge. There is no consensus on the optimal surgical approach to these lesions, though the transtemporal and transparietal approaches are most frequently employed. We aimed to examine the approach-related morbidity and surgical nuances in treating trigonal meningiomas. This retrospective review assimilated data from 64 trigonal meningiomas operated over 15 years. Details of clinicoradiological presentation, surgical approach and intraoperative impression, pathology and incidence of various postoperative deficits were recorded. In our study, Trigonal meningiomas most frequently presented with headache and visual deterioration. The median volume of tumours was 63.6cc. Thirty-one meningiomas each (48.4%) were WHO Grade 1 and WHO Grade 2, while 2 were WHO Grade 3. The most frequent approach employed was transtemporal (38 patients, 59.4%), followed by transparietal (22 patients, 34.4%). After surgery features of raised ICP and altered mental status resolved in all patients, while contralateral limb weakness resolved in 80%, aphasia in 60%, seizures in 70%, and vision loss in 46.2%. Eighteen patients (28.13%) developed transient postoperative neurological deficits, with one patient (1.5%) developing permanent morbidity. Surgery for IVMs results in rapid improvement of neurological status, though visual outcomes are poorer in patients with low vision prior to surgery, longer duration of complaints and optic atrophy. The new postoperative deficits in some patients tend to improve on follow up. Transtemporal and transparietal approaches may be employed, based on multiple factors like tumour extension, loculation of temporal horn, size of lesion with no significant difference in their safety profile.

Construing the function of N-terminal domain of D29 mycobacteriophage LysA endolysin in phage lytic efficiency and proliferation.

Endolysins produced by bacteriophages hydrolyze host cell wall peptidoglycan to release newly assembled virions. D29 mycobacteriophage specifically infects mycobacteria including the pathogenic Mycobacterium tuberculosis. D29 encodes LysA endolysin, which hydrolyzes mycobacterial cell wall peptidoglycan. We previously showed that LysA harbors two catalytic domains (N-terminal domain [NTD] and lysozyme-like domain [LD]) and a C-terminal cell wall binding domain (CTD). While the importance of LD and CTD in mycobacteriophage biology has been examined in great detail, NTD has largely remained unexplored. Here, to address NTD's significance in D29 physiology, we generated NTD-deficient D29 (D29∆NTD) by deleting the NTD-coding region from D29 genome using CRISPY-BRED. We show that D29∆NTD is viable, but has a longer latent period, and a remarkably reduced burst size and plaque size. A large number of phages were found to be trapped in the host during the D29∆NTD-mediated cell lysis event. Such poor release of progeny phages during host cell lysis strongly suggests that NTD-deficient LysA produced by D29∆NTD, despite having catalytically-active LD, is unable to efficiently lyse host bacteria. We thus conclude that LysA NTD is essential for optimal release of progeny virions, thereby playing an extremely vital role in phage physiology and phage propagation in the environment.

Adjuvant therapy may improve overall survival in high-risk periampullary adenocarcinomas patients - A match-pair analysis from a multi-institutional cohort study (The MIPPAP study).

BACKGROUND: The role of adjuvant therapy in resected periampullary adenocarcinomas is equivocal due to contrasting data and limited prospective trials. METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP), included data from 8 institutions across India. Of the 1679 pancreatic resections, 736 patients with T3/T4 and/or Node positive adenocarcinomas (considered as high risk for recurrence) were included for analysis. Three (adjuvant): one (observation) matching, using T3/T4 T staging, nodal positivity and ampullary subtype was performed by using the nearest neighbour matching method. RESULTS: Of 736 patients eligible for inclusion, 621 patients were matched of which 458 patients received adjuvant therapy (AT) (predominantly gemcitabine-based) and 163 patients were observed (O). With a median follow-up of 42 months, there was a statistical difference in overall survival in favour of patients receiving AT as compared to those on observation [68.7 months vs. 61.1 months, Hazard ratio: 0.73 (95% CI: 0.54-0.97); p = 0.03]. Besides AT, presence of nodal involvement (median OS: 65.4 months vs not reached; p = 0.04) predicted for inferior OS. CONCLUSIONS: The results of the match-pair analysis suggest that adjuvant therapy improves overall survival in periampullary adenocarcinomas at high risk of recurrence with a greater benefit in T3/T4, node-positive and ampullary subtypes.

Chemoenzymatic Modification of Daptomycin: Aromatic Group Installation on Trp1.

Daptomycin is a cyclic lipodepsipeptide antibiotic used to treat infections caused by Gram-positive pathogens, including multi-drug resistant strains such as methicillin-resistant Staphylococcus au-reus (MRSA) and vancomycin-resistant enterococci (VRE). The emergence of daptomycin-resistant bacterial strains has renewed interest in generating daptomycin analogs. Previous studies have shown that replacing the tryptophan of daptomycin with aromatic groups can generate analogs with enhanced potency. Additionally, we have demonstrated that aromatic prenyltransferases can attach diverse groups to the tryptophan of daptomycin. Here, we report the use of the prenyltransferase CdpNPT to derivatize the tryptophan of daptomycin with a library of benzylic and heterocyclic pyrophosphates. An analytical-scale study revealed that CdpNPT can transfer various aromatic groups onto daptomycin. Subsequent scaled-up and purified reactions indicated that the enzyme can attach aromatic groups to N1, C2, C5 and C6 positions of Trp1 of daptomycin. In vitro antibacterial activity assays using six of these purified compounds identified aromatic substituted daptomycin analogs show potency against both daptomycin-susceptible and resistant strains of Gram-positive bacteria. These findings suggest that installing aromatic groups on the Trp1 of daptomycin can lead to the generation of potent daptomycin analogs.

Trends in Serum Shifts: Unveiling Hyperglycaemia Links PostCOVID-19 Vaccination.

BACKGROUND: Clinical endocrinology has observed emerging endocrine complications following COVID-19 vaccination, amidst successful reductions in COVID-19 hospitalizations and deaths. The Pfizer-BioNTech and Moderna mRNA vaccines have demonstrated efficacy. Reports indicate a potential association between SARS-CoV-2 vaccination and diabetes, exploring interactions with ACE-2 receptors and molecular mimicry. Additionally, altered liver and kidney function tests post-vaccination prompt investigation into their role in predicting type 2 diabetes. This study aims to explore these biochemical abnormalities in a case-control, single-centre prospective study. MATERIALS AND METHODS: This prospective study aimed to evaluate a total of five hundred healthy donors, out of which 203 qualified for final analysis. Participants were selected based on their vaccination status with a COVID-19 vaccine and prior exposure to the SARS-CoV-2 virus. Donors without prior SARS-CoV-2 infection were excluded from the study. Included participants were adults who had received three doses of the COVID-19 vaccine. RESULTS: A total of 203 individuals were included in the study, comprising 104 with type 2 diabetes mellitus (T2DM) and 99 without. Demographic characteristics including age, sex, nationality, Rh factors, ABO blood groups, liver function tests (LFT), kidney function tests (KFT), lactate dehydrogenase (LDH), and mineral ion levels were analysed. Among the participants, the distribution based on HbA1c levels showed 47.8% with HbA1c <7% classified as normal, 38.48% with HbA1c 8-10% classified as high, and 16.64% with HbA1c <10% classified as uncontrolled diabetes. Significant findings included a decrease in magnesium levels to 0.77±0.82 mmol/L (p<0.04*), an increase in LDH levels to 420.70±356.26 µL (p<0.01*), and elevated levels of alkaline phosphatase (143.22 ± 142.62 µL, p<0.001), gamma-glutamyl transferase (GGT) (55.70 ± 32.20 µL, p<0.001), and serum bilirubin (9.23 ± 4.87 µmol/L, p<0.001). Creatinine levels were significantly lower at 116.75 ± 101.94 µmol/L (p#60;0.001), while uric acid levels were significantly elevated at 305.92 ± 145.04 µmol/L (p<0.001) in individuals with uncontrolled HbA1c <10%. A majority of these individuals belonged to the O+ blood group. CONCLUSION: This study underscores significant shifts in serum biomarkers and their complex interplay with mRNA-based SARS-CoV-2 vaccination and diabetes, particularly in uncontrolled cases. The findings suggest potential autoimmune reactions triggered by the self-adjuvant properties of mRNA and polyethylene glycol lipid conjugates. Variations observed among different blood groups may correspond to racial disparities influencing molecular mimicry mechanisms. Despite these insights, the underlying pathophysiological mechanisms remain unclear, highlighting the critical need for further research to validate and expand upon these findings.

Alkyl sulfones: discovery of novel structural types with differentiated opportunities for insect control.

The discovery of novel chemical classes with novel modes of action for insect control form the backbone of innovation with the goal to deliver much-needed solutions into the hands of growers. Over the last decade, alkyl sulfones have emerged as one of the most versatile new classes and are under intensive investigation in many R&D programs in the industry, with Sumitomo Chemicals recently introducing oxazosulfyl as a first active ingredient to the market. In this review, we discuss some of our strategies to invent novel classes based upon ligand-based design, and also show how incorporation of physical chemical properties into our design enabled us to predictably control chewing and sucking pests. © 2024 Society of Chemical Industry.

Estrogen receptor alpha (ER-α) antagonistic activity of phytoconstituents from Potentilla atrosanguinea and Potentilla fulgens in breast cancer.

The Potentilla genus has long been used traditionally as food and a folklore medicine. In the present study, aerial parts of two Potentilla species, Potentilla fulgens and Potentilla atrosanguinea, of western Himalayan origin, were studied for their anti-breast cancer activity. Ethyl acetate (PAA-EA, PFA-EA), methanolic (PAA-ME, PFA-ME) and hydro-methanolic extract (PAA-HM, PFA-HM) of the plants were tested for their antiproliferative activities against MCF-7 and T-47D breast cancer cell lines. The extracts showed good antiproliferative activity against ER-α dominant breast cancer cell line T-47D, having IC50 values 6.19 ± 0.01 to 33.23 ± 0.04 µg/ml. Eight compounds were isolated, characterized, and quantified from ethyl acetate and methanolic extracts by column chromatography, 1D, 2D-NMR, HRMS and TLC densitometric analysis. Two compounds (4 and 6) have shown better antiproliferative activity than standard bazedoxifene and were further evaluated for their ER-α binding affinity via-fluorescence polarization-based competitive binding assay. The antiestrogenic properties of both compounds were assessed using western blotting. Compounds 4 and 6 were found to have significant affinity for the ER-α and managed to decrease its expression by 38 and 54% respectively. Compounds 4 and 6 also had good stability and reactivity as measured by minimal fluctuations in molecular dynamic simulation analysis, a good dock score in molecular docking, and a respectable HOMO-LUMO energy gap in DFT calculations. Compounds 4 and 6 have shown reliable results and can be used in the development of natural product-based anti-breast cancer agents.

Paricalcitol attenuates oxidative stress and inflammatory response in the liver of NAFLD rats by regulating FOXO3a and NFκB acetylation.

The lack of therapeutics along with complex pathophysiology made non-alcoholic fatty liver disease (NAFLD) a research hotspot. Studies showed that the deficiency of Vitamin D plays a vital role in NAFLD pathogenesis. While several research studies focused on vitamin D supplementation in NAFLD, there is still a need to understand the regulatory mechanism of direct vitamin D receptor activation in NAFLD. In the present study, we explored the role of direct Vitamin D receptor activation using paricalcitol in choline-deficient high-fat diet-induced NAFLD rat liver and its modulation on protein acetylation. Our results showed that paricalcitol administration significantly reduced the fat accumulation in HepG2 cells and the liver of NAFLD rats. Paricalcitol attenuated the elevated serum level of alanine transaminase, aspartate transaminase, insulin, low-density lipoprotein, triglyceride, and increased high-density lipoprotein in NAFLD rats. Paricalcitol significantly decreased the increased total protein acetylation by enhancing the SIRT1 and SIRT3 expression in NAFLD liver. Further, the study revealed that paricalcitol reduced the acetylation of NFκB and FOXO3a in NAFLD liver along with a decrease in the mRNA expression of IL1ß, NFκB, TNFα, and increased catalase and MnSOD. Moreover, total antioxidant activity, glutathione, and catalase were also elevated, whereas lipid peroxidation, myeloperoxidase, and reactive oxygen species levels were significantly decreased in the liver of NAFLD after paricalcitol administration. The study concludes that the downregulation of SIRT1 and SIRT3 in NAFLD liver was associated with an increased acetylated NFκB and FOXO3a. Paricalcitol effectively reversed hepatic inflammation and oxidative stress in NAFLD rats through transcriptional regulation of NFκB and FOXO3a, respectively, by inhibiting their acetylation.

Efficiency and Mechanism of Catalytic Siloxane Exchange in Vitrimer Polymers: Modeling and Density Functional Theory Investigations.

Of late, siloxane-containing vitrimers have gained significant interest due to their fast dynamic characteristics over a reasonable temperature range (180-220 °C), making them well-suited for diverse applications. The exchange reaction pathway in the siloxane vitrimers is accountable for the covalent adaptive network, with the reaction's effectiveness being regulated by either organic or organometallic catalysts. However, directly studying the exchange reaction pathway in the bulk phase using experimental approaches is challenging because of the intricate and interconnected structure of these vitrimers. Here, we perform comprehensive density functional theory (DFT) and experimental investigations to discover the detailed catalytic efficacy of siloxane exchange and provide direction for the reaction process using a 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) catalyst. The calculated transition barrier energy and catalytic efficiency of hexamethyldisiloxane and dihydroxy-dimethylsilane exchange derived from the nudged elastic band with transition-state calculations strongly agree with the experimental findings. In addition, Fukui indices, along with partial charges, are employed to evaluate the nucleophilic and electrophilic behaviors of silanol and siloxane molecules. Our analysis revealed that by utilizing the Fukui indices of both the acid and the base, we can make an approximate estimation of the respective kinetics of the SN2 process in the siloxane exchange reaction mechanism. These findings establish a foundation for comprehending a crucial aspect of the exchange mechanism in siloxane vitrimer systems and could aid in the development of novel catalysts.

Evolution of transgender rights in India: Better late than never.

The progress of transgender rights in India has seen significant strides with milestones such as the National Legal Services Authority (NALSA) judgment and the enactment of the Transgender Persons (Protection of Rights) Act in 2019. The NALSA judgment recognized the right of transgender individuals to self-identify their gender. This decision led to the formal recognition of a 'third gender', advancing legislative and social reforms. Prior to this, transgender individuals faced substantial hurdles, including limited access to education, employment, and healthcare due to a lack of legal recognition. Within a few years, The Transgender Persons (Protection of Rights) Act established a framework that safeguards the rights of transgender individuals and prohibits discrimination based on gender. This legislation requires the government to take measures like promoting education, providing vocational training opportunities, ensuring accessible healthcare services, and offering social security support. It also addresses the healthcare needs of transgender individuals thereby contributing to their overall well being. The Support for Marginalised Individuals for Livelihood and Enterprise (SMILE) program and Garima Greh are initiatives that provide spaces and empower a marginalized transgender individuals and promoting their inclusion, justice and empowerment. This article explores the progress pertaining to transgender rights and welfare, while highlighting efforts undertaken by the Indian government.

Effect of N-acetyl cysteine in children with metabolic dysfunction-associated steatotic liver disease-A pilot study.

BACKGROUND: Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), and its sequelae of more severe forms such as metabolic dysfunction-associated steatohepatitis (MASH) is rapidly increasing in children with the rise in obesity. Successful and sustainable treatments for MASLD are lacking in children. We determined the therapeutic effect of N-acetyl cysteine (NAC) on biomarkers of oxidative stress, inflammation and insulin resistance (IR), liver enzymes, liver fat fraction (LFF) and (LS) in children with obesity and biopsy-confirmed MASLD. METHODS: Thirteen children (n = 13; age: 13.6 ± 2.8 years; NAS score >2) underwent a double-blind, placebo-controlled trial of NAC (either 600 or 1200 mg NAC/day) or placebo for 16 weeks. Measurements included LFF (magnetic resonance imaging), LS (ultrasound elastography), and body composition. Erythrocyte glutathione (GSH), liver enzymes, insulin, glucose, adiponectin, high-sensitivity c-reactive protein (hs-CRP), and interleukin-6 (IL-6) were also measured. HOMA-IR was calculated. RESULTS: Sixteen-week NAC treatment improved (baseline adjusted between-group p < .05 for all) markers of inflammation (IL-6 and hs-CRP), oxidative stress (GSH), and insulin resistance (HOMA-IR) and reduced liver enzymes, LFF and LS. Body weight and body composition did not show beneficial changes. CONCLUSIONS: Sixteen-week NAC treatment was well tolerated in children with obesity and MASLD and led to improvements in oxidative stress, inflammation and IR and liver outcomes. The results from this pilot study support further investigation of NAC as a therapeutic agent in children with MASLD.

Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma.

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

One year experience of an emerging nosocomial pathogen Elizabethkingia meningoseptica at a tertiary care hospital in Northern India: A case series.

Elizabethkingia spp. is a rare catalase and oxidase positive nonfermenting, Gram-negative Bacillus that has traditionally been linked to an array of illnesses in immunocompromised individuals. This case series reports seven cases of Elizabethkingia meningoseptica infections from a tertiary care teaching hospital. The subjects ranged in age from 23 to 75 years. Associated risk factors included a recent history of surgery, diabetes mellitus, renal failure, use of mechanical ventilation, and presence of an indwelling central line. All seven cases acquired infection in the intensive care unit, and the isolates were resistant to penicillin, third- and fourth-generation cephalosporins, and aminoglycosides and showed varied susceptibility to piperacillin-tazobactam, carbapenems, and fluoroquinolones.

Short-term S100A8/A9 Blockade Promotes Cardiac Neovascularization after Myocardial Infarction.

Acute-phase inhibition of the pro-inflammatory alarmin S100A8/A9 improves cardiac function post-myocardial infarction (MI), but the mechanisms underlying the long-term benefits of this short-term treatment remain to be elucidated. Here, we assessed the effects of S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 on myocardial neovascularization in mice with induced MI. The treatment significantly reduced S100A9 and increased neovascularization in the myocardium, assessed by CD31 staining. Proteomic analysis by mass-spectrometry showed strong myocardial upregulation of the pro-angiogenic proteins filamin A (~ 10-fold) and reticulon 4 (~ 5-fold), and downregulation of the anti-angiogenic proteins Ras homolog gene family member A (RhoA, ~ 4.7-fold), neutrophilic granule protein (Ngp, ~ 4.0-fold), and cathelicidin antimicrobial peptide (Camp, ~ 4.4-fold) versus controls. In-vitro, ABR-238901 protected against apoptosis induced by recombinant human S100A8/A9 in human umbilical vein endothelial cells (HUVECs). In conclusion, S100A8/A9 blockade promotes post-MI myocardial neovascularization by favorably modulating pro-angiogenic proteins in the myocardium and by inhibiting endothelial cell apoptosis.

Mitigating target interference challenges in bridging immunogenicity assay to detect anti-tocilizumab antibodies.

Aim: An assay to detect anti-tocilizumab antibodies in the presence of high levels of circulating target and drug is needed for immunogenicity assessment in comparative clinical studies. Methods: An assay was developed and validated using a combination of blocking agents and dilutions to overcome target interference challenges. Results: No false-positive signal was detected in serum samples spiked with 350-500 ng/ml of IL-6 receptor. As low as 50 ng/ml of positive control antibodies could be detected in the presence of either 500 ng/ml of IL-6 or 250 µg/ml of the drug product. Assay also demonstrated high sensitivity, selectivity and precision. Conclusion: A robust, easy to perform immunogenicity assay was developed and validated for detecting anti-tocilizumab antibodies.

[Box: see text].

Outcome Prediction Using Multi-Modal Information: Integrating Large Language Model-Extracted Clinical Information and Image Analysis.

Survival prediction post-cystectomy is essential for the follow-up care of bladder cancer patients. This study aimed to evaluate artificial intelligence (AI)-large language models (LLMs) for extracting clinical information and improving image analysis, with an initial application involving predicting five-year survival rates of patients after radical cystectomy for bladder cancer. Data were retrospectively collected from medical records and CT urograms (CTUs) of bladder cancer patients between 2001 and 2020. Of 781 patients, 163 underwent chemotherapy, had pre- and post-chemotherapy CTUs, underwent radical cystectomy, and had an available post-surgery five-year survival follow-up. Five AI-LLMs (Dolly-v2, Vicuna-13b, Llama-2.0-13b, GPT-3.5, and GPT-4.0) were used to extract clinical descriptors from each patient's medical records. As a reference standard, clinical descriptors were also extracted manually. Radiomics and deep learning descriptors were extracted from CTU images. The developed multi-modal predictive model, CRD, was based on the clinical (C), radiomics (R), and deep learning (D) descriptors. The LLM retrieval accuracy was assessed. The performances of the survival predictive models were evaluated using AUC and Kaplan-Meier analysis. For the 163 patients (mean age 64 ± 9 years; M:F 131:32), the LLMs achieved extraction accuracies of 74%~87% (Dolly), 76%~83% (Vicuna), 82%~93% (Llama), 85%~91% (GPT-3.5), and 94%~97% (GPT-4.0). For a test dataset of 64 patients, the CRD model achieved AUCs of 0.89 ± 0.04 (manually extracted information), 0.87 ± 0.05 (Dolly), 0.83 ± 0.06~0.84 ± 0.05 (Vicuna), 0.81 ± 0.06~0.86 ± 0.05 (Llama), 0.85 ± 0.05~0.88 ± 0.05 (GPT-3.5), and 0.87 ± 0.05~0.88 ± 0.05 (GPT-4.0). This study demonstrates the use of LLM model-extracted clinical information, in conjunction with imaging analysis, to improve the prediction of clinical outcomes, with bladder cancer as an initial example.

Perioperative Transfusion Practices in Adults Having Noncardiac Surgery.

Surgical patients are often transfused to manage bleeding and anemia. Best practices for red blood cell (RBC) transfusion administration in patient having noncardiac surgery remains controversial and a robust evaluation and description of perioperative transfusion practices is lacking. We characterized perioperative hemoglobin concentrations and transfusion practices from the prospective VISION cohort which included 39,222 patients aged ≥45 years who had inpatient noncardiac surgery. Variations in transfusion practices were analyzed using hierarchical mixed models, and associations with mortality and complications were evaluated using a nested frailty survival model. Within the cohort, 16.1% (n = 6296) were given perioperative RBC transfusions, with the fraction declining from 20% to 13% over the 6-year study period. The proportion of patients transfused varied by surgery type from 6.4% for low-risk operations (i.e., minor surgery) to 31.5% for orthopedic surgeries. Variations were largely associated with patient hemoglobin concentrations, but also with center (range: 3.7%-27.3%) and country (0.4%-25.3%). Even after adjusting for baseline hemoglobin, comorbidities and type of surgery, both center and country were significant sources of variation in transfusion practices. Among transfused participants, 60.4% (n = 3728/6170) had at least 1 hemoglobin concentration ≤80g/L and 86.0% (n = 5305/6170) had at least 1 hemoglobin concentration ≤90g/L, suggesting that relatively restrictive transfusion strategies were used in most. The proportion of patients receiving at least 1 RBC transfusion declined from 20% to 13% over 6 years. However, there was considerable unexplained variation in transfusion practices.