High Risk Of Progression Research Articles

Cytokines and Pancreatic Ductal Adenocarcinoma: Exploring Their Relationship with Molecular Subtypes and Prognosis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. The current challenge remains the absence of predictive biomarkers. Cytokines are crucial factors in the pathogenesis and prognosis of PDAC. Furthermore, there is growing interest in differentiating between molecular subtypes of PDAC. The aim of our study is to evaluate the association between the analyzed cytokines and the molecular subtypes of PDAC and to determine their prognostic value. Cytokine levels were measured in 73 patients, and molecular subtypes were analyzed in 34 of these patients. Transforming Growth Factor Beta 2 (TGF-β2) levels were independently associated with the basal-like and null subtypes. In patients with locally advanced and metastatic PDAC, elevated levels of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-9, and IL-15 were associated with a higher risk of progression during first-line treatment, and increased levels of IL-1β, IL-6, IL-8, IL-9, and IL-15 were related to increased mortality. Furthermore, a significant association was observed between higher percentiles of IL-6 and IL-8 and shorter progression-free survival (PFS) during first-line treatment, and between higher percentiles of IL-8 and shorter overall survival (OS). In the multivariate analysis, only elevated levels of IL-8 were independently associated with a higher risk of progression during first-line treatment and mortality. In conclusion, the results of our study suggest that cytokine expression varies according to the molecular subtype of PDAC and that cytokines also play a relevant role in patient prognosis.

Artificial intelligence in myopia in children: current trends and future directions.

Myopia is one of the major causes of visual impairment globally, with myopia and its complications thus placing a heavy healthcare and economic burden. With most cases of myopia developing during childhood, interventions to slow myopia progression are most effective when implemented early. To address this public health challenge, artificial intelligence has emerged as a potential solution in childhood myopia management. The bulk of artificial intelligence research in childhood myopia was previously focused on traditional machine learning models for the identification of children at high risk for myopia progression. Recently, there has been a surge of literature with larger datasets, more computational power, and more complex computation models, leveraging artificial intelligence for novel approaches including large-scale myopia screening using big data, multimodal data, and advancing imaging technology for myopia progression, and deep learning models for precision treatment. Artificial intelligence holds significant promise in transforming the field of childhood myopia management. Novel artificial intelligence modalities including automated machine learning, large language models, and federated learning could play an important role in the future by delivering precision medicine, improving health literacy, and allowing the preservation of data privacy. However, along with these advancements in technology come practical challenges including regulation and clinical integration.

Progression predictors of clinically isolated syndrome to multiple sclerosis: A prospective study in China

ObjectivesClinically isolated syndrome (CIS) is a preclinical phase of multiple sclerosis (MS). The progression rate of CIS to clinical definite MS (CDMS) varies significantly across different populations, and identifying predictors of progression is crucial for early diagnosis and treatment. We aimed to investigate predictors of progression from CIS to CDMS in a Chinese cohort. MethodsA single-center cohort study was conducted with newly diagnosed patients with CIS in China between 2018 and 2021. All patients underwent a comprehensive clinical evaluation, including neurological examination, magnetic resonance imaging, and laboratory tests. Follow-up assessments were conducted at regular intervals to monitor disease progression. Progression to CDMS was defined according to the 2017 McDonald criteria. Age, sex, Expanded Disability Status Scale (EDSS) score, number of patients with magnetic resonance imaging gadolinium-enhancing (Gd+) lesions, T2 lesions and Gd+ lesions count, CSF cell count, CSF total protein, CSF and serum neurofilament light chain (NfL), progranulin (PGRN) and Th17-related cytokines (IL-6, IL-17, IL-21, IL-22, IL-23 and TGF-β) were measured for association with risk of progression to CDMS. ResultsA total of 96 CIS patients were recruited in the study. During the at least 24 months follow-up period, 57 (59.38 %) CIS patients progressed to CDMS, while 39 (40.62 %) patients without progression remained stable as CIS. Multivariate analysis revealed that younger age at onset (OR= 43.43, 95 % CI= 1.76–1071.68, p<0.021), higher CSF elevated protein (OR=58.64, 95 % CI=2.72–1264.51, p=0.009), higher CSF NfL levels (OR= 97.00, 95 % CI= 4.68–2012.99, p=0.003) and higher CSF IL-23 levels (OR= 412.02, 95 % CI=6.56–25869.60, p=0.004) were associated with high risk of progression to CDMS. ConclusionYounger age at onset, elevated CSF NfL, IL-23 and protein levels might be progression predictors of CIS to CDMS in Chinese population.

Circulating interleukin-8 and osteopontin are promising biomarkers of clinical outcomes in advanced melanoma patients treated with targeted therapy

BackgroundCirculating cytokines can represent non-invasive biomarkers to improve prediction of clinical outcomes of cancer patients. Here, plasma levels of IL-8, CCL4, osteopontin, LIF and BDNF were determined at baseline (T0), after 2 months of therapy (T2) and, when feasible, at progression (TP), in 70 melanoma patients treated with BRAF and MEK inhibitors. The association of baseline cytokine levels with clinical response, progression-free survival (PFS) and overall survival (OS) was evaluated.MethodsCytokine concentrations were measured using the xMAP technology. Their ability to discriminate between responding (Rs) and non-responding (NRs) patients was assessed by Receiver Operating Characteristics analysis. PFS and OS were estimated with the Kaplan–Meier method. The Cox proportional hazard model was used in the univariate and multivariate analyses to estimate crude and adjusted hazard ratios with 95% confidence intervals.ResultsCCL4 and LIF were undetectable in the majority of samples. The median osteopontin concentration at T0 and T2 was significantly higher in NRs than in Rs. The median T0 and T2 values of IL-8 were also higher in NRs than in Rs, although the statistical significance was not reached. No differences were detected for BDNF. In 39 Rs with matched T0, T2, and TP samples, osteopontin and IL-8 significantly decreased from T0 to T2 and rose again at TP, while BDNF levels remained unchanged. In NRs, none of the cytokines showed a significant decrease at T2. Only osteopontin demonstrated a good ability to discriminate between Rs and NRs. A high IL-8 T0 level was associated with significantly shorter PFS and OS and higher risk of progression and mortality, and remained an independent negative prognostic factor for OS in multivariate analysis. An elevated osteopontin T0 concentration was also significantly associated with worse OS and increased risk of death. Patients with high IL-8 and high osteopontin showed the lowest PFS and OS, and in multivariate analysis this cytokine combination remained independently associated with a three- to six-fold increased risk of mortality.ConclusionCirculating IL-8 and osteopontin appear useful biomarkers to refine prognosis evaluation of patients undergoing targeted therapy, and deserve attention as potential targets to improve its clinical efficacy.

Prognostic significance of residual tumor at restaging transurethral bladder resection in high-risk non-muscle-invasive bladder cancer.

To assess prognostic significance of residual tumor at repeat transurethral resection (reTUR) in contemporary non-muscle-invasive bladder cancer (NMIBC) patients. Patients were identified retrospectively from eight referral centers in France, Italy and Spain. The cohort included consecutive patients with high or very-high risk NMIBC who underwent reTUR and subsequent adjuvant BCG therapy. A total of 440 high-risk NMIBC patients were screened, 29 (6%) were upstaged ≥ T2 at reTUR and 411 were analyzed (T1 stage: n = 275, 67%). Residual tumor was found in 191 cases (46%). In patients with T1 tumor on initial TURBT, persistent T1 tumor was found in 18% of reTUR (n = 49/275). In patients with high-grade Ta tumor on initial TURBT, T1 tumor was found in 6% of reTUR (n = 9/136). In multivariable logistic regression analysis, we found no statistical association between the use of photodynamic diagnosis (PDD, p = 0.4) or type of resection (conventional vs. en bloc, p = 0.6) and the risk of residual tumor. The estimated 5-yr recurrence and progression-free survival were 56% and 94%, respectively. Residual tumor was significantly associated with a higher risk of recurrence (p < 0.001) but not progression (p = 0.11). Only residual T1 tumor was associated with a higher risk of progression (p < 0.001) with an estimated 5-yr progression-free survival rate of 76%. ReTUR should remain a standard for T1 tumors, irrespective of the use of en bloc resection or PDD and could be safely omitted in high-grade Ta tumors. Persistent T1 tumor at reTUR should not exclude these patients from conservative management, and further studies are needed to explore the benefit of a third resection in this subgroup.

In vivo analysis of ankle joint kinematics and ligament deformation of chronic ankle instability patients during level walking.

Introduction: Chronic ankle instability (CAI) carries a high risk of progression to talar osteochondral lesions and post-traumatic osteoarthritis. It has been clinically hypothesized the progression is associated with abnormal joint motion and ligament elongation, but there is a lack of scientific evidence. Methods: A total of 12 patients with CAI were assessed during level walking with the use of dynamic biplane radiography (DBR) which can reproduce the in vivo positions of each bone. We evaluated the uninjured and CAI side of the tibiotalar and subtalar joint for three-dimensional kinematics differences. Elongation of the anterior talofibular ligament (ATFL), calcaneofibular ligament (CFL), and posterior talofibular ligament (PTFL) were also calculated bilaterally. Results: For patients with CAI, the dorsiflexion of the tibiotalar joint had reduced (21.73° ± 3.90° to 17.21° ± 4.35°), displacement of the talus increased (2.54 ± 0.64mm to 3.12 ± 0.55mm), and the inversion of subtalar joint increased (8.09° ± 2.21° to 11.80° ± 3.41°). Mean ATFL elongation was inversely related to mean dorsiflexion angle (CAI: rho = -0.82, P < 0.001; Control: rho = -0.92, P < 0.001), mean ATFL elongation was related to mean anterior translation (CAI: rho = 0.82, P < 0.001; Control: rho = 0.92, P < 0.001), mean CFL elongation was related to mean dorsiflexion angle (CAI: rho = 0.84, P < 0.001; Control: rho = 0.70, P < 0.001), and mean CFL elongation was inversely related to mean anterior translation (CAI: rho = -0.83, P < 0.001; Control: rho = -0.71, P < 0.001). Furthermore, ATFL elongation was significantly (CAI: rho = -0.82, P < 0.001; Control: rho = -0.78, P < 0.001) inversely correlated with CFL elongation. Discussion: Patients with CAI have significant changes in joint kinematics relative to the contralateral side. Throughout the stance phase of walking, ATFL increases in length during plantarflexion and talar anterior translation whereas the elongation trend of CFL was the opposite. This understanding can inform the development of targeted therapeutic exercises aimed at balancing ligament tension during different phases of gait. The interrelationship between two ligaments is that when one ligament shortens, the other lengthens. The occurrence of CAI didn't change this trend. Surgeons might consider positioning the ankle in a neutral sagittal plane to ensure optimal outcomes during ATFL and CFL repair.

Magnetic resonance imaging insights from active surveillance of women with ductal carcinoma in situ

New approaches are needed to determine which ductal carcinoma in situ (DCIS) is at high risk for progression to invasive ductal carcinoma (IDC). We retrospectively studied DCIS patients who declined surgery (2002–2019), and received endocrine therapy (ET) and breast MRI. Baseline MRI and changes at 3 months and 6 months were analyzed by recursive partitioning to stratify IDC risk. Sixty-two patients (63 DCIS; 1 bilateral) with a mean follow-up of 8.5 years were included. Fifty-one percent remained on active surveillance (AS) without evidence of IDC, with a mean duration of 7.6 years. A decision tree based on MRI features of lesion distinctness and background parenchymal enhancement (BPE) at baseline and change after 3 months of ET stratified patients into low, intermediate, and high risk for progression to IDC. MRI imaging features in patients treated with ET and undergoing AS, may help determine which DCIS lesions are at low versus high risk for IDC.

Analysis of long-term results of conservative and surgical treatment in patients with locally advanced squamous cell carcinoma of the nasal cavity and paranasal sinuses

Introduction. Surgical intervention with subsequent chemoradiation therapy is one of the treatment standards in squamous cell carcinoma of the nasal cavity and paranasal sinuses. However, the question of the optimal therapy for this pathology remains open.Aim. To compare treatment results in patients with locally advanced squamous cell carcinoma of the nasal cavity and paranasal sinuses after conservative and surgical treatment.Materials and methods. The study included 86 patients with squamous cell carcinoma of the nasal cavity and paranasal sinuses, stages III–Iva, who between 2000 and 2020 received treatment at the N.N. Blokhin National medical Research Oncology Center. Surgical treatment with subsequent radiation or chemoradiation therapy was performed in 31 patients, conservative treatment (radiation or chemoradiation therapy) was performed in 55 patients.Results. Five-year overall survival in the conservative treatment group was 46.2 %, in the surgical treatment group – 59.7 % (р = 0.081); 5-year progression-free survival was 17 and 50.5 %, respectively (p = 0.002). In patients with Т3N0 tumor who received surgical treatment, 5-year progression-free survival was significantly higher than in patients who received conservative treatment (p &lt;0,05). Comparison of overall survival and progression-free survival of patients who achieved objective response (complete response + partial response) after conservative treatment (n =36) and after surgical treatment (n = 31) did not show statistically significant differences (р = 0.469 and р = 0.183, respectively). The overall 5-year survival rate in the salvage surgery treatment group (24/55) was 63.1 % compared with 59.7 % in the surgical treatment group (n = 31), there were also no significant differences (p = 0.95). In patients with T3 tumor who received conservative treatment in this study, higher risk of progression was observed compared to patients who underwent surgical treatment.Conclusion. Surgical intervention remains an important treatment method for patients with locally advanced squamous cell carcinoma of the nasal cavity and paranasal sinuses, especially in cases of smaller tumor extent. Conservative therapy seems promising but large-scale prospective controlled randomized clinical trials are necessary to confirm its effectiveness and safety in various patient groups.

Nirmatrelvir/Ritonavir (Paxlovid) Use Among Individuals at Risk of Severe COVID-19: An Analysis of the National COVID Cohort Collaborative (N3C).

Paxlovid is effective in reducing COVID-19 hospitalization and mortality. This study characterized Paxlovid use and evaluated racial/ethnic disparities over time among community-dwelling adults at high risk of progression to severe COVID-19 disease. This retrospective cohort study used the National COVID Cohort Collaborative (N3C) data and included individuals aged 18 years or older diagnosed with COVID-19 between January 2022 and December 2023. The study cohort included nonhospitalized individuals who were at high risk of COVID-19 progression, and selected the first COVID-19 episode in each quarter, including reinfection episodes. Paxlovid use was defined as receiving Paxlovid within ±5 days of a COVID-19 diagnosis. We used descriptive statistics to characterize Paxlovid use overall and by calendar quarter and race/ethnicity. We used a generalized estimating equations (GEE) models to quantify the association of race/ethnicity with Paxlovid use controlling for age, gender, and clinical characteristics. Among 1 264 215 individuals at high risk of disease progression (1 404 607 episodes), Paxlovid use increased from 1.2% in January-March 2022 to 35.1% in October-December 2023. Paxlovid use was more common among non-Hispanic White individuals (23.9%) than non-Hispanic Black (16.5%) and Latinx/e (16.7%) patients. After adjusting age, gender, and clinical characteristics, Paxlovid use was less likely among non-Hispanic Black (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.68-0.70) and Latinx/e (OR 0.72, CI 0.71-0.73) patients than non-Hispanic White patients. Among a large, diverse cohort of community-dwelling individuals with COVID-19, nearly two out of three eligible individuals did not receive Paxlovid, and minoritized racial/ethnic groups were less likely to use Paxlovid than their non-Hispanic White individuals.

Feasibility of in-home monitoring for people with glaucoma: the I-TRAC mixed-methods study.

Glaucoma is a chronic disease of the optic nerve and a leading cause of severe visual loss in the UK. Once patients have been diagnosed, they need regular monitoring at hospital eye services. Recent advances in technology mean patients with glaucoma can now monitor their disease at home. This could be more convenient for patients and potentially reduce costs and increase capacity for the NHS. However, it is uncertain whether self-monitoring would be acceptable or possible for patients with glaucoma. The objectives were to: identify which patients are most appropriate for home monitoring; understand views of key stakeholders (patients, clinicians, researchers) on whether home glaucoma monitoring is feasible and acceptable; develop a conceptual framework for the economic evaluation of home glaucoma monitoring; and explore the need for and provide evidence on the design of a future study to evaluate the clinical and cost-effectiveness of digital technologies for home monitoring of glaucoma. In-home Tracking of glaucoma: Reliability, Acceptability, and Cost (I-TRAC) was a multiphase mixed-methods feasibility study with key components informed by theoretical and conceptual frameworks. Expert glaucoma specialists in the UK recruited through professional glaucoma societies; study site staff and patient participants recruited through three UK hospital eye services (England, Scotland, Northern Ireland); and UK research teams recruited though existing networks. Home tonometer that measures intraocular pressure and a tablet computer with a visual function application. Patients were asked to use the technology weekly for 12 weeks. Forty-two patients were recruited. Retention and completion of follow-up procedures was successful, with 95% (n = 40) completing the 3-month follow-up clinic visits. Adherence to the interventions was generally high [adherence to both devices (i.e. ≥80% adherence) was 55%]. Overall, patients and healthcare professionals were cautiously optimistic about the acceptability of digital technologies for home monitoring of patients with glaucoma. While most clinicians were supportive of the potential advantages glaucoma home monitoring could offer, concerns about the technologies (e.g. reliability and potential to miss disease progression) and how they would fit into routine care need to be addressed. Additionally, clarity is required on defining the ideal population for this intervention. Plans for how to evaluate value for money in a future study were also identified. However, the study also highlighted several unknowns relating to core components of a future evaluative study that require addressing before progression to a definitive effectiveness trial. The main limitation relates to our sample and its generalisability, for example, the over-representation of educated persons of white ethnicity who were generally experienced with technology and research motivated. The In-home Tracking of glaucoma: Reliability, Acceptability, and Cost study has demonstrated 'cautious optimism' when considering patients' and healthcare professionals' views on the acceptability of digital technologies for home monitoring of patients with glaucoma. However, the study also highlighted several unknowns relating to the research question and design of a future evaluative study that require addressing before progression to a randomised controlled trial. Further research is required to determine the appropriate population (i.e. low vs. high risk of progression) and further refine the intervention components and delivery for planning of future evaluation studies. This study is registered as Research Registry #6213. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129248) and is published in full in Health Technology Assessment; Vol. 28, No. 44. See the NIHR Funding and Awards website for further award information.

Liquid Biopsy and 18F-FDG PET/CT Derived Parameters as Predictive Factors of Osimertinib Treatment in Advanced EGFR-Mutated NSCLC

ObjectivesDespite the outstanding results achieved by osimertinib for the treatment of advanced EGFR-mutated NSCLC, the development of resistance is almost inevitable. While molecular mechanism responsible for osimertinib resistance are being mostly revealed, the definition of predictive biomarkers is crucial in order to identify patients at higher risk of progression and optimize treatment strategy. Materials and MethodsThis is a prospective single-center study aimed to assess the potential role of liquid biopsy and 18F-FDG PET/CT derived metabolic parameters as noninvasive predictive biomarkers of osimertinib outcomes in advanced EGFR-mutated NSCLC patients. Patients underwent blood samples for ctDNA analysis at baseline, after 15 days and 1 month (t1) of osimertinib. 18F-FDG PET/CT was performed at baseline and after 1 month of osimertinib. ResultsSeventy-two advanced EGFR-mutated NSCLC patients treated with osimertinib in first (n = 63) and in second-line (n = 9) were prospectively enrolled. Baseline positive shedding status was significantly associated with a shorter progression-free survival (PFS) (9.5 vs. 29.2 months, P = .031). The achievement of an early metabolic response (MR) after 1 month of treatment led to a significantly improved PFS (16.8 vs. 5.5 months, P = .038) and OS (35.2 vs. 15.3 months, P = .047). Early MR was significantly correlated with subsequent radiologic response (P = .010). All 18F-FDG PET/CT baseline parameters were significantly related to baseline EGFR activating mutation allele frequency. Both clearance and no detection of EGFR at t1 were significantly associated with MR (P = .001 and P = .004, respectively). ConclusionMolecular and 18F-FDG PET/CT derived metabolic parameters might represent a useful tool to predict osimertinib outcome in advanced EGFR-mutated NSCLC patients.

IgA Nephropathy – Current and Future Perspectives in Treatment

Abstract Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy in our adult population and is associated with a high lifetime risk of kidney failure. Recent years have succeeded in describing the pathogenesis of IgAN at the molecular level, where immune complexes containing specific galactose deficient IgA1 play an essential role. The gold standard in the diagnosis of IgAN remains renal biopsy followed by determination of a prognostic score using the Oxford classification. A fundamental goal in the management of patients with IgAN is to optimize supportive therapy involving active lifestyle modification and renoprotective medications. The reno-protective drug menu has recently been expanded to include effective sodium-glucose cotransporter 2 inhibitors (SGLT2i), and additional agents are on the way. However, despite maximal supportive therapy, a wide range of patients remain at high risk of disease progression and require the deployment of immunomodulatory drugs. To date, however, we do not have high potency agents that are well tolerated and safe. This has led to the initiation of many studies to target the inflammatory process at different pathogenetic levels. In this article, we summarize the current standards in the treatment of IgAN and present new promising options in the management of this disease.

Systems biology and novel biomarkers for the early detection of diabetic kidney disease.

Diabetic kidney disease is the most common driver of chronic kidney disease (CKD)-associated mortality and kidney replacement therapy. Despite recent therapeutic advances (SGLT2 inhibitors, finerenone), the residual kidney and mortality risk remains high for patients already diagnosed of having CKD (i.e., estimated glomerular filtration rate &lt;60 ml/min/1.73 m2 or urinary albumin:creatinine ratio &gt;30 mg/g). The challenge for the near future is to identify patients at higher risk of developing CKD to initiate therapy before CKD develops (primary prevention of CKD) and to identify patients with CKD and high risk of progression or death, in order to intensify therapy. We now discuss recent advances in biomarkers that may contribute to identify such high-risk individuals for clinical trials of novel primary prevention or treatment approaches for CKD. The most advanced biomarker from a clinical development point of view is the urinary peptidomics classifier CKD273, that integrates prognostic information from 273 urinary peptides and identifies high risk individuals before CKD develops.

Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies

BackgroundConverging evidence suggests that markers of Alzheimer’s disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes.ObjectivesWe sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay.DesignAll participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aβ+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aβ−) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks.SettingThe A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia.ParticipantsOlder participants (ages 65–85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25–30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6–18) were eligible to continue in screening. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ− were enrolled into the LEARN Study (n=553).MeasurementsBaseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo).ResultsHigher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aβ− and A4 Aβ+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models.ConclusionsIn a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

Real-world effectiveness of sotrovimab in preventing hospitalization and mortality in high-risk patients with COVID-19 in the United States: A cohort study from the Mayo Clinic electronic health records.

To describe outcomes of high-risk patients with coronavirus disease 2019 (COVID-19) treated with sotrovimab, other monoclonal antibodies (mAbs), or antivirals, and patients who did not receive early COVID-19 treatment. We also evaluate the comparative effectiveness of sotrovimab versus no treatment in preventing severe clinical outcomes. This observational retrospective cohort study analyzed Mayo Clinic electronic health records. Non-hospitalized adult patients diagnosed with COVID-19 from May 26, 2021 and April 23, 2022 and at high risk of COVID-19 progression were eligible. The primary outcome was 29-day all-cause hospitalization and/or death. Outcomes were described for patients treated with sotrovimab, other mAbs, or antivirals, and eligible but untreated patients, and compared between sotrovimab-treated and propensity score (PS)-matched untreated cohorts. We included 35,485 patients (sotrovimab, 1369; other mAbs, 6488; antivirals, 133; high-risk untreated, 27,495). A low proportion of patients treated with sotrovimab (n = 33/1369, 2.4%), other mAbs (n = 147/6488, 2.3%), or antivirals (n = 2/133, 1.5%) experienced all-cause hospitalization or death. Among high-risk untreated patients, the percentage of all-cause hospitalization or death was 3.3% (n = 910/27,495). In the PS-matched analysis, 2.5% (n = 21/854) of sotrovimab-treated patients experienced all-cause hospitalization and/or death versus 2.8% (n = 48/1708) of untreated patients (difference, -0.4%; p = 0.66). Significantly fewer sotrovimab-treated patients required intensive care unit admission (0.5% vs 1.8%; difference, -1.3%; p = 0.002) or respiratory support (3.5% vs 8.7%; difference, -5.2%; p < 0.001). There was no significant difference in the proportion of sotrovimab-treated and PS-matched untreated patients experiencing 29-day all-cause hospitalization or mortality, although significantly fewer sotrovimab-treated patients required intensive care unit admission or respiratory support.

Sporadic non-ampullary duodenal adenoma with high grade dysplasia: A rare case report

Duodenal adenomatous polyps are usually classified according to the mucin phenotype into intestinal (89.1%) and gastric type (10.9%). The intestinal-type polyps are morphologically divided into tubular and tubulo-villous adenomas, whereas the gastric-type into pyloric gland adenomas and foveolar adenomas. The duodenal adenomas are also clinically categorised into sporadic duodenal adenomas and adenomas associated with genetic syndromes for instance familial adenomatous polyposis (FAP), or MUTYH associated adenomatous polyposis (MAP). Sporadic duodenal adenomas are less common than FAP related adenomas and are usually recognized in elderly men in their 6 to 8 decade of life. The large non-ampullary solitary duodenal adenomas ≥ 20 mm in diameter with high grade dysplasia show a significantly high risk of progression to adenocarcinoma and therefore, must be treated immediately. Our case, is a middle-aged female who presented with symptoms and had an exophytic duodenal mass of about 60mm in diameter, microscopically showing tubulo-villous intestinal pattern with high grade dysplasia and no breach in muscularis mucosae, thereby making it a case with distinct presentation and characteristics.

Evaluation of Triglyceride-Glucose Index Elevation as a Biomarker and Risk Factor in Laryngeal Squamous Cell Carcinoma.

Insulin resistance is associated with increased levels of IGF-1. IGF-1 has been shown to increase the risk of laryngeal squamous cell carcinoma. The Triglyceride-glucose index (TyG index) is a marker of insulin resistance. Our study aimed to investigate the relationship between the TyG index and laryngeal squamous cell carcinoma. Retrospective cohort study. Two tertiary care academic hospitals. The study included 53 patients with laryngeal squamous cell carcinoma (Group 1) and 48 healthy volunteers (Group 2). Laryngeal cancer patients were divided into two groups according to their stage. Stages I and II were named Group 1A, and Stages III and IV were called Group 1B. The TyG index was calculated as ln [fasting Triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. The effect of the TyG index on laryngeal cancer was investigated on the parameters of sex, age, body mass index, and stage of the disease. There were no significant differences in age, sex, and BMI between the groups. The TyG index of group 1 (4.75 ± 0.33) was significantly higher than that of group 2 (4.59 ± 0.15). The TyG index value of group 1B (4.84 ± 0.31) was significantly higher than both group 1A (4.61 ± 0.32) and group 2 (4.59 ± 0.15). There was no significant difference between the TyG index values of group 1A (4.61 ± 0.32) and group 2 (4.59 ± 0.15). The TyG index may be a promising laryngeal squamous cell carcinoma biomarker. People with a higher TyG index may have a higher incidence of laryngeal squamous cell carcinoma and a higher risk of progression.

Nirmatrelvir-Ritonavir (Paxlovid)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses nirmatrelvir-ritonavir (Paxlovid), 150 mg nirmatrelvir; 100 mg ritonavir, tablets, co-packaged for oral use. Indication: For the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

Baseline C-reactive Protein as a Risk Factor for Cryptococcal Meningitis and Death in HIV-associated Cryptococcal Antigenemia With CrAg Titer as an Effect Modifier.

Persons with HIV and cryptococcal antigenemia are at high risk of progression to cryptococcal meningitis or death. Baseline cryptococcal antigen (CrAg) plasma titer ≥1:160 is a known risk factor for poor outcomes, but other risk factors are unknown. In HIV-associated cryptococcal meningitis, baseline serum C-reactive protein (CRP) concentrations are positively associated with increased mortality. We hypothesized that CRP might also be associated with meningitis or death in persons with cryptococcal antigenemia. We measured plasma CrAg titers and CRP concentrations on cryopreserved serum from prospectively enrolled persons with HIV and cryptococcal antigenemia. Using time-to-event analyses, we compared 24-week meningitis-free survival in persons with normal CRP (<8 mg/L) and elevated CRP (≥8 mg/L). Logistic regression was used to assess how CRP concentration and CrAg titer might interact as covariates. Of the 94 persons with elevated CRP, 19 (20.2%) developed meningitis or death, whereas of the 88 persons with normal CRP, 8 (9.1%) developed meningitis or death (P = .035). Persons with CrAg titer <1:160 and normal CRP had an ∼5% (3/61) event rate, whereas those with CrAg titer <1:160 but elevated CRP had an ∼20% (12/59) event rate. Importantly, we identified a statistically significant interaction effect between CrAg titer and CRP groups, in which elevated CRP increased risk in the low CrAg titer group (odds ratio, 1.54; 95% confidence interval, 1.16-2.04), but this effect was not present in high CrAg titer group (odds ratio, 0.78; 95% confidence interval, .53-1.15). Our findings demonstrate that CrAg titer may modify the direction of effect of CRP with meningitis-free survival; future studies should account for this interaction.

Immunosuppression, tonsillectomy and remissions in high-risk IgA-nephropathy

To evaluate the efficacy of immunosuppressive therapy (IST) and tonsillectomy (TE) in patients with high-risk IgA nephropathy (IgAN). Materials and мethods. The retrospective study cohort included cases with primary IgAN (n=213, age 34±11 years, male 52%) at high risk of progression with clinical and morphological data collected. The follow-up was 26 (10; 61) months. The association of IST without TE (IST; n=141) or with TE (IST+TE; n=72) with the development of complete (PR), partial (PR) and overall (PR or PR, OR) remissions was investigated. The incidence of achieving early PR or OR in the IST and IST+TE groups was 65.2% and 86.1%, respectively (p=0.002). The probability of early PR or OR was significantly increased in the IST+TE group compared to IST [HR 1.714 (1.214-2.420) and HR 3.410 (1.309-8.880), respectively]. IST+TE was associated with a 3- to 4-fold increase in the likelihood of PR or OR at the end of follow-up [HR 2.575 (1.679-3.950) and HR 4.768 (2.434-9.337), respectively]. Analyses using pseudorandomisation methods yielded similar results. TE may be effective for remission induction in high-risk IgAN.