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INTRODUCTION: Several recent randomized trials evaluated the impact of adjuvant immune checkpoint inhibitor (ICI)-based therapy on post-surgical outcomes in renal cell carcinoma (RCC), with disparate results. The objective of this consensus statement is to provide data-driven guidance regarding the use of ICIs after complete resection of clear-cell RCC in a Canadian context. METHODS: An expert panel of genitourinary medical oncologists, urologic oncologists, and radiation oncologists with expertise in RCC management was convened in a dedicated session during the 2022 Canadian Kidney Cancer Forum in Toronto, Canada. Topic statements on the management of patients after surgery for RCC, including counselling, risk stratification, indications for medical oncology referral, appropriate followup, eligibility and management for adjuvant ICIs, as well as treatment options for patients with recurrence who receive dadjuvant immunotherapy, were discussed. Participants were asked to vote if they agreed or disagreed with each statement. Consensus was achieved if greater than 75% of participants agreed with the topic statement. RESULTS: A total of 22 RCC experts voted on 14 statements. Consensus was achieved on all topic statements. The panel felt patients with clear-cell RCC at increased risk of recurrence after surgery, as per the Keynote-564 group definitions, should be counselled about recurrence risk by a urologist, should be informed about the potential role of adjuvant ICI systemic therapy, and be offered referral to discuss risks and benefits with a medical oncologist. The panel felt that one year of pembrolizumab is currently the only regimen that should be considered if adjuvant therapy is selected. Panelists emphasized current opinions are based on disease-free survival given the available results. Significant uncertainty regarding the benefit and harms of adjuvant therapy remains, primarily due to a lack of consistent benefit observed across similar trials of adjuvant ICI-based therapies and immature overall survival (OS) data. CONCLUSIONS: This consensus document provides guidance from Canadian RCC experts regarding the potential role of ICI-based adjuvant systemic therapy after surgery. This rapidly evolving field requires frequent evidence-based re-evaluation.

The role of upfront cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors is unclear.To evaluate the relationship between upfront CN and clinical outcomes in the setting of mRCC treated with immune checkpoint inhibitors or targeted therapy.Using the International Metastatic RCC Database Consortium, we retrospectively identified patients diagnosed with de novo mRCC treated with immune checkpoint inhibitors or targeted therapy.Overall survival (OS) was compared between the two groups using the Kaplan-Meier method and multivariable Cox regressions adjusting for known prognostic factors.We identified a total of 4639 eligible patients with mRCC. Among the 4202 patients treated with targeted therapy and 437 patients treated with immune checkpoint inhibitors, 2326 (55%) and 234 (54%) patients received upfront CN prior to treatment start. In multivariable analyses, CN was associated with significantly better OS in both the immune checkpoint inhibitor-treated (hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.41-0.90, p = 0.013) and the targeted therapy treatment (HR: 0.72; 95% CI, 0.67-0.78, p 0.001) group. There was no difference in OS benefit of CN between the immune checkpoint inhibitor and targeted therapy treatment groups (interaction p = 0.6). Limitations include selection of patients from large academic centers and the retrospective nature of the study.Upfront CN is associated with a significant OS benefit in selected patients treated by either immune checkpoint inhibitors or targeted therapy, and still has a role in selected patients in the era of immune checkpoint inhibitors.Before effective systemic therapies were available for metastatic kidney cancer, surgical removal of the primary (kidney) tumor was the mainstay of treatment. The role of removing the primary tumor has recently been called into question given that more effective systemic therapies have become available. In this study, we find that removal of the primary kidney tumor still has a benefit for selected patients treated with highly effective modern systemic therapies, including targeted therapies and immune checkpoint inhibitors.

Procedural dermatology includes invasive conventional dermatologic surgeries which involve significant use of knife and suture, minimally invasive procedures and device-based procedures. Device-based procedures are the easiest to learn and are less prone to human errors due to automation but can lead to monotony, while conventional surgeries require significant skill, craftsmanship and interest. There has been a recent shift in the approach to procedural dermatology as a therapeutic option with complementary and combination models replacing the conventional hierarchical model in which procedures were last in the step-ladder approach. The demand for both conventional dermatologic surgeries and minimally invasive cosmetic procedures is increasing. Unfortunately, this demand has not been met with adequate supply. Consequently, the number of trained professionals with expertise in these procedures is very limited; they are far outnumbered by unqualified practitioners. A limited number of dermatologic surgeons practicing conventional surgeries has resulted in huge waiting lists for vitiligo surgeries, inappropriate excisions for skin cancers and poor cosmetic outcomes of excisions without proper knowledge of flaps and grafts. Increasingly procedures are being performed by inadequately trained personnel, resulting in complications. There is also an absence of good quality research on the subject of procedural dermatology, which has resulted in a lack of standardisation of various procedures and knowledge about the efficacy of various drug-procedure and procedure-procedure combinations. An increasing variety of gimmicky but costly procedures are being offered to the public without much evidence of efficacy. Individual institutional and broad policy directives are needed to address these issues. Special emphasis is required on formal hands-on procedural dermatology training during residency and beyond it.

Various overlapping risk factors lead to coronary artery disease (CAD). The atherogenic index of plasma (AIP) is a marker for CAD severity and progression. However, little is known about its contribution to the residual risk of CAD observed in the absence of all typical risk factors.A prospective cohort study of 366 Indian patients undergoing coronary computed tomography (CT) angiography and diagnosed with stable CAD. Diabetes, hypertension, hypercholesterolemia, smoking, previous CAD, alcohol or lipid-lowering medication intake, renal, liver or thyroid dysfunction were exclusion criteria. Coronary stenosis was graded using the CAD-reporting and data system (CAD-RADS™) system. Lipid profile, HbA1c, uric acid, highly sensitive C-reactive protein (hsCRP) and anthropometric measurements were taken. AIP, triglyceride/high-density lipoprotein cholesterol (HDLc) and total cholesterol (Tc)/HDLc ratios were calculated. Independent predictors of CAD severity and the occurrence of major adverse cardiac events (MACE) during 2.57 (0.52) years of follow-up were identified using logistic regression and Cox proportional hazards regression.Sixty patients experienced a MACE during a cumulative 887.03 person-years. HbA1c, uric acid, hsCRP, Tc/HDLc and AIP were independent predictors of severe coronary lesions (CAD-RADS 4,5) on multivariate analysis with odds ratio 4.52 (2.37-8.61), 1.41 (1.08-1.84), 1.33 (1.09-1.62), 1.76 (1.27-2.44) and 1.29 (1.11-1.50), respectively. Only AIP and Tc/HDLc were independent predictors of MACE with hazard ratios of 1.41 (1.20-1.65) and 1.78 (1.33-2.39) besides patient age and CAD severity.AIP is associated with both the severity of CAD and the occurrence of MACE within 3 years. It could serve as an effective marker of residual risk of CAD in patients devoid of traditional risk factors. Lipid-profile ratios, such as AIP are cost-effective and accessible parameters suitable for low and middle-income settings.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

Liposomes composed of sulfated lactosyl archaeol (SLA) have been shown to be a safe and effective vaccine adjuvant with a multitude of antigens in preclinical studies. In particular, SLA-adjuvanted SARS-CoV-2 subunit vaccines based on trimeric spike protein antigens were shown to be immunogenic and efficacious in mice and hamsters. With the continued emergence of SARS-CoV-2 variants, we sought to evaluate next-generation vaccine formulations with an updated antigenic identity. This was of particular interest for the widespread Omicron variant, given the abundance of mutations and structural changes observed within its spike protein compared to other variants. An updated version of our resistin-trimerized SmT1 corresponding to the B.1.1.529 variant was successfully generated in our Chinese Hamster Ovary (CHO) cell-based antigen production platform and characterized, revealing some differences in protein profile and ACE2 binding affinity as compared to reference strain-based SmT1. We next evaluated this Omicron-based spike antigen for its immunogenicity and ability to generate robust antigen-specific immune responses when paired with SLA liposomes or AddaS03 (a mimetic of the AS03 oil-in-water emulsion adjuvant system found in commercialized SARS-CoV-2 protein vaccines). Immunization of mice with vaccine formulations containing this updated antigen with either adjuvant stimulated neutralizing antibody responses favouring Omicron over the reference strain. Cell-mediated responses, which play an important role in the neutralization of intracellular infections, were induced to a much higher degree with the SLA adjuvant relative to the AddaS03-adjuvanted formulations. As such, updated vaccines that are better capable of targeting towards SARS-CoV-2 variants can be generated through an optimized combination of antigen and adjuvant components.

Complete Supplementary Information for the manuscript, including Supplemental Figures 1-16 and tables 1-4.

Recent years have seen the emergence of conditionally activated diagnostics and therapeutics that leverage protease-cleavable peptide linkers to enhance their specificity for cancer. However, due to a lack of methods to measure and localize protease activity directly within the tissue microenvironment, the design of protease-activated agents has been necessarily empirical, yielding suboptimal results when translated to patients. To address the need for spatially resolved protease activity profiling in cancer, we developed a new class of in situ probes that can be applied to fresh-frozen tissue sections in a manner analogous to immunofluorescence staining. These activatable zymography probes (AZP) detected dysregulated protease activity in human prostate cancer biopsy samples, enabling disease classification. AZPs were leveraged within a generalizable framework to design conditional cancer diagnostics and therapeutics and showcased in the Hi-Myc mouse model of prostate cancer, which models features of early pathogenesis. Multiplexed screening against barcoded substrates yielded a peptide, S16, that was robustly and specifically cleaved by tumor-associated metalloproteinases in the Hi-Myc model. In situ labeling with an AZP incorporating S16 revealed a potential role of metalloproteinase dysregulation in proliferative, premalignant Hi-Myc prostatic glands. Systemic administration of an in vivo imaging probe incorporating S16 perfectly classified diseased and healthy prostates, supporting the relevance of ex vivo activity assays to in vivo translation. We envision AZPs will enable new insights into the biology of protease dysregulation in cancer and accelerate the development of conditional diagnostics and therapeutics for multiple cancer types.Significance:Visualization of protease activity within the native tissue context using AZPs provides new biological insights into protease dysregulation in cancer and guides the design of conditional diagnostics and therapeutics.

BACKGROUND: Patients with chronic kidney disease are commonly excluded from clinical trials. The impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer has not been previously studied. OBJECTIVE: This study aimed to investigate the impact of chronic kidney disease on outcomes in patients with locally advanced rectal cancer. DESIGN: This is a multi-institutional, retrospective cohort study. SETTINGS: This study was conducted at academic and community cancer centers participating in the Canadian Health Outcomes Research Database Consortium Rectal Cancer Database. PATIENTS: Consecutive patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation before curative-intent surgery from 2005 to 2013 were selected. MAIN OUTCOME MEASURES: Disease-free survival, overall survival, pathologic complete response, and neoadjuvant chemotherapy/radiotherapy completion rate were the primary outcomes measured. RESULTS: A total of 1254 patients were included. Median age was 62, and 29%/69% had clinical stage II and III disease. Median estimated creatinine clearance was 93 mL/min, with 11%

The systemic immune-inflammation index (SII) is a novel parameter and its role in the prognosis of sepsis has never been explored previously.We retrospectively assessed 267 patients with blood-culture confirmed sepsis. Clinical and laboratory data recorded at intensive care unit (ICU) admission were analyzed. Outcomes of interest included in-hospital mortality and length-of-stay (LOS) in the ICU. Sequential Organ Failure Assessment (SOFA) scores, SII, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) were calculated. Multivariable regression analysis was used to identify independent predictors of LOS and mortality. Area under receiver operator characteristic (AUROC) curves were used to determine optimum cutoffs, and the incremental effect of SII on the SOFA score was assessed using model discrimination and calibration properties.There were 76 (28.5%) non-survivors. SII, NLR, and PLR were independent predictors of sepsis mortality, with adjusted odds ratios of 1.51 (1.24-1.84), 1.67 (1.30-2.13) and 1.24 (1.11-1.39). SII and SOFA score were independent predictors of LOS. SII had an AUROC of 0.848, and the optimum cutoff was 564 with a sensitivity and specificity of 85.5% and 71.2%. The addition of SII to the model had a significant incremental effect on the predictive ability of SOFA score (Net Reclassification Index = 0.084,The SII is an inexpensive parameter that can be used in addition to clinical sepsis scores to improve the accuracy of patient assessment.

Deep neural networks (DNNs) have shown success in image classification, with high accuracy in recognition of everyday objects. Performance of DNNs has traditionally been measured assuming human accuracy is perfect. In specific problem domains, however, human accuracy is less than perfect and a comparison between humans and machine learning (ML) models can be performed. In recognising everyday objects, humans have the advantage of a lifetime of experience, whereas DNN models are trained only with a limited image dataset. We have tried to compare performance of human learners and two DNN models on an image dataset which is novel to both, i.e. histological images. We thus aim to eliminate the advantage of prior experience that humans have over DNN models in image classification. Ten classes of tissues were randomly selected from the undergraduate first year histology curriculum of a Medical School in North India. Two machine learning (ML) models were developed based on the VGG16 (VML) and Inception V2 (IML) DNNs, using transfer learning, to produce a 10-class classifier. One thousand (1000) images belonging to the ten classes (i.e. 100 images from each class) were split into training (700) and validation (300) sets. After training, the VML and IML model achieved 85.67 and 89% accuracy on the validation set, respectively. The training set was also circulated to medical students (MS) of the college for a week. An online quiz, consisting of a random selection of 100 images from the validation set, was conducted on students (after obtaining informed consent) who volunteered for the study. 66 students participated in the quiz, providing 6557 responses. In addition, we prepared a set of 10 images which belonged to different classes of tissue, not present in training set (i.e. out of training scope or OTS images). A second quiz was conducted on medical students with OTS images, and the ML models were also run on these OTS images. The overall accuracy of MS in the first quiz was 55.14%. The two ML models were also run on the first quiz questionnaire, producing accuracy between 91 and 93%. The ML models scored more than 80% of medical students. Analysis of confusion matrices of both ML models and all medical students showed dissimilar error profiles. However, when comparing the subset of students who achieved similar accuracy as the ML models, the error profile was also similar. Recognition of ‘stomach’ proved difficult for both humans and ML models. In 04 images in the first quiz set, both VML model and medical students produced highly equivocal responses. Within these images, a pattern of bias was uncovered–the tendency of medical students to misclassify ‘liver’ tissue. The ‘stomach’ class proved most difficult for both MS and VML, producing 34.84% of all errors of MS, and 41.17% of all errors of VML model; however, the IML model committed most errors in recognising the ‘skin’ class (27.5% of all errors). Analysis of the convolution layers of the DNN outlined features in the original image which might have led to misclassification by the VML model. In OTS images, however, the medical students produced better overall score than both ML models, i.e. they successfully recognised patterns of similarity between tissues and could generalise their training to a novel dataset. Our findings suggest that within the scope of training, ML models perform better than 80% medical students with a distinct error profile. However, students who have reached accuracy close to the ML models, tend to replicate the error profile as that of the ML models. This suggests a degree of similarity between how machines and humans extract features from an image. If asked to recognise images outside the scope of training, humans perform better at recognising patterns and likeness between tissues. This suggests that ‘training’ is not the same as ‘learning’, and humans can extend their pattern-based learning to different domains outside of the training set.

This study examines the relationship between behavioral biases (herd behavior bias, overconfidence bias, and loss aversion bias) and the Big Five Personality traits. An exploratory study is devised to explore the links between biases and personality. The study develops a structured test battery to measure the biases. The items measuring overconfidence, loss aversion, and herd behavior bias was conceptualized and validated in the study. The test battery was sent out to 294 investors, and with a response percentage of 68%, 200 respondents returned the survey. The study employed confirmatory factor analysis (CFA) to validate the psychological biases questionnaire and employed structural equation modeling for path analysis. Two of the big five personality traits, i.e., Extraversion and Openness to experience, reported a significant causal relationship with all three biases.

5068 Background: Anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICI) are now a standard of care in metastatic renal cell carcinoma (mRCC). Older adults were underrepresented in registration trials and given that immunological senescence may affect the anti-tumor activity of ICIs, there is uncertainty about the efficacy of ICIs in this population. Here we provide real world data on outcomes of older adults with mRCC treated with ICIs. Methods: Patients with mRCC treated with a PD-1/PD-L1 ICI either as monotherapy or as a combination treatment from 2000 to 2019 were included. Older adult was defined as ≥ 70-years at the time of ICI treatment. Descriptive statistics were summarized in means, medians and proportions. Efficacy was assessed by survival analysis, including overall survival (OS), time to treatment failure (TTF), and overall response rate (ORR). Multivariate analyses adjusted for imbalances in IMDC risk factors. P < 0.05 was considered statistically significant. Results: Of 1427 patients, 397 (28%) were older adults. Mean age of older vs. younger adults was 74 (70-92) vs. 60 (22-69) years. Groups were comparable in terms of gender (Female 28.5% vs. 26.1%, p = 0.36), rates of nephrectomy (21% vs. 18.3%, p = 0.24) and presence of sarcomatoid features (12.3% vs. 17.8%, p = 0.14). Proportion of IMDC risk-groups between older vs. younger adults were as follows: 15.4% vs. 18.2% for favorable, 61.2% vs. 59.1% for intermediate, and 23.4% vs. 22.7% for poor; there was no statistical difference (p = 0.55). ICI was used as 1st line in 40%, 2nd line in 48.5% and 3rd line in 11.5% patients; older adults were less likely to be treated with ICI in 1st line (32.2% vs. 43%, p < 0.01). In terms of survival, older adults had poorer median OS (25.1m vs. 30.8m, p < 0.01) but similar median TTF (6.9m vs. 6.9m, p = 0.40) compared to younger adults. In multivariate analyses, older age was not a predictor of either worse OS (aHR = 1.02, p = 0.86) or TTF (aHR = 0.95, p = 0.59). Older adults had a lower ORR compared to younger (24% vs. 31%, p = 0.01), which was mainly driven by responses in 1st line (31% vs. 44%, p = 0.02) and not observed in 2nd/3rd line (20% vs. 20%, p = 0.86). Conclusions: On multivariate analyses, older adults with mRCC treated with ICI had no difference in OS and TTF when compared to younger adults, despite having lower ORR in 1st line. Our data supports that older age is not an independent risk factor for survival; thus, treatment selection should not be based solely on chronological age.

Objective: Breast Cancer is the leading cause of mortality and morbidity amongst Indian females. Breast self-examination (BSE) as an early detection modularity can have a profound effect on lowering mortality, if it is practiced regularly. The aim of this study was to assess the knowledge, attitude, and practice of Breast Self-examination amongst Indian women, aged 30 years and above. Methods: A validated questionnaire, consisting 35 questions measuring ‘Knowledge, Attitudes and Practice of Breast Self-Examination’ was widely circulated amongst 1000 females throughout India and responses were collected for a duration of 3 weeks, from 2nd, September 2020 to 23rd,September 2020. Results: Despite having knowledge about the technique of performing BSE, the respondents did not have a positive attitude towards it and were reluctant to practice BSE. A total of 54.4%, 15.1%, 21.3% and 9.2% of respondents were from the Northern, Southern, Western and Eastern regions of India, respectively. The overall median (IQR) KAP score was 70.0 (16.0) out of a maximum of 110. The knowledge, attitude and practice domain scores were 22.0 (5.0), 36.0 (7.0), and 13.0 (8.0) out of a maximum of 30, 52 and, 28, respectively. All three individual score domains were significantly correlated with each other and the total score.Conclusion: Despite having knowledge about the technique of performing BSE, the respondents did not have a positive attitude towards it and were reluctant to practice BSE.

Background: The fracture of lower end radius is the most common fracture of the upper extremity encountered in practice and constitutes 10 to 20% of all the fractures and 75% of all forearm fractures. In spite of various new advances, closed reduction and cast immobilization has been the mainstay of treatment of these fractures, but malunion of fracture and subluxation /dislocation of distal radioulnar joint resulting in poor functional and cosmetic results is the usual outcome. Recently, the volar locked plate osteosynthesis is considered as the “gold standard” in treatment of ‘unstable’ distal radius fractures. The present study proposed to evaluate the role of volar locking plate fixation in the management of intra-articular and extra-articular volar fractures of distal end radius and to evaluate the clinical, functional and radiological outcomes.Aim and Objectives: To study the improvement in clinical, functional and radiological outcomes of volar locked plate fixation in a distal end radius fracture.Materials and Methods: A prospective study was undertaken in a Tertiary Hospital from September 2016 to September 2018, 30 patients (age >20 yrs) with volar fracture of lower end of radius i.e. AO types A 2.3, B 3.1, B 3.2, B 3.3 operated with volar locked plating. The patients were followed up at 2nd, 6th, 12th and 24th postoperative weeks. Radiological & clinical, functional outcomes were assessed by using Stewart score & PRWE (Patient–rated wrist evaluation questionnaire) score respectively. Data collected of these 30 patients were statistically analysed using ANOVA chi – square test.Results: Clinical and Functional outcome by Patient Rated Wrist Evaluation scoring system shows maximum no. of patients come in Good and Excellent grading i.e. 17(56.7%) and 8(26.7%) out of 30 patients, along with this 1(3.3%) Fair and 4(13.3%) Poor result. Radiological outcome by Stewart I scoring system is Maximum no. of cases shows Good and Excellent results i.e. 20(66.7%) and 6(20%) out of 30 patients. With this 1(3.3%) Fair and 3(10%) Poor result.Conclusion: Open reduction and internal fixation with volar locked plating has satisfactory functional and radiological outcome with minimal complications and thus it is an excellent modality to treat volar fractures of distal end radius.

Clavicle fracture is a common traumatic injury around shoulder girdle due to their subcutaneous position. It is caused by either low-energy or high-energy impact. Fractures of the clavicle have been traditionally treated non-operatively. Although many methods of closed reduction have been described, it is recognized that reduction is practically impossible to maintain and a certain amount of deformity and disability is expected in adults. 30 patients with mid-shaft clavicle fracture were systematically randomized (alternate patient) into either operative treatment with plate fixation or non-operative treatment with clavicle brace and sling. All fractures were classified using Robinson’s classification for clavicle fractures and only Type 2A2 and 2B1 were considered for the study. Patients were followed up at 3wks, 6wks, 3rd month & 6th month. Functional outcomes were assessed according to the Constant and Murley Scoring and radiologically. Maximum number (90%) of patients had Robinson’s Type 2B1 fracture. The mean duration of hospital stay for patients in Group A(operative) and Group B(non operative) was 3.67 ± 0.90 days and 1.73 ± 0.46 days respectively. In Group A, the mean duration of trauma to surgery was 3.13 ± 2.64 days. While the mean operative time was 104.87 ± 13.52 minutes. The duration of union was significantly lesser in Group A as compared to Group B according to Chi-Square test (p0.05). Primary open reduction and internal fixation with pre-contoured clavicle plate for displaced, middle third clavicle fractures provide a more rigid fixation and allows early mobilization whereas conservative treatment require longer periods of immobilization till fracture union. Functional outcomes are better with surgical management of middle third clavicle fractures with pre-contoured locking compression plate. The successful use of locking compression plate for middle third fractures of clavicle requires careful assessment of fracture pattern, patient selection, meticulous operative technique, appropriate choice of fixation, judicious internal fixation, careful post-operative monitoring and aggressive early institution rehabilitation. So, there is need to individualize the treatment as per the need and functional demand of the patient to give the optimum outcome.

Introduction: The prevalence of type 2 diabetes mellitus (T2DM) is increasing steadily, assuming an epidemic proportion throughout the world. Most of this increased burden will come from developing countries. Studies show an increasing role of inflammation in the pathophysiology of diabetes. Estimation of neutrophil-lymphocyte ratio (NLR) could be a simple, inexpensive marker to stratify at-risk diabetes patients. This study aimed to estimate the NLR and CRP levels as a measure of systemic inflammation in diabetics compared to healthy controls. We also investigated if NLR was lower in diabetics with good glycemic control. Methods: A cross-sectional comparative study, conducted in a tertiary hospital on 60 patients with T2DM and 69 healthy controls after voluntary informed consent. Anthropometric parameters, fasting plasma glucose, Lipid profile, CBC, CRP, and HbA1c were measured for all participants. Results: The diabetic group showed significantly higher waist circumference(p=0.007) mean TG (p=0.003), VLDL-c (p=0.001), LDL-c (p=0.010), TG/HDL-c (p=0.001), HbA1c (p=0.00001), MPV (p=0.002), NLR (p=0.006), and CRP (p=0.004) values and lower HDL-c values (p=0.039) as compared to the control group. No significant difference was seen in BMI, Waist -Hip ratio, total cholesterol, and total cholesterol/HDL-c values between the two groups. Among the diabetics, only HDL-c (p=0.018) and TG/HDL-c ratio (p=0.049) differed significantly with glycemic control.Conclusion: Diabetics had higher inflammatory markers (NLR, CRP) as compared to controls. Dyslipidemia (high TG, low HDL-c with high TG/HDL-c) and a higher waist circumference were seen in diabetics. Diabetics with fair control of glycemia (HbA1c < 7%) did not demonstrate lower NLR levels indicating that meticulous glycemic control may not ameliorate the chronic inflammation seen in diabetics until dyslipidemia is corrected.Â

Archaeosomes composed of sulfated lactosyl archaeol (SLA) glycolipids from stereoisomerically pure archaeol (1) are vaccine adjuvants that can boost immunogenicity and vaccine efficacy in preclinical models. Herein, we report a new synthesis of 2,3-bis((3,7,11,15-tetramethylhexadecyl)oxy) propan-1-ol (3) by treating (±)-3-benzyloxy-1,2-propanediol with a mesylated phytol derivative through a double nucleophilic substitution reaction, followed by reductive debenzylation. Three SLA archaeosomes from archaeols of different chiral purities were prepared, and the effect of stereochemistry on their adjuvanticity toward ovalbumin was investigated. It was found that all SLA archaeosomes induced strong humoral and cell-mediated antigen-specific immune responses following immunization of C57BL/6NCrl mice, with no significant differences, irrespective of the chiral purities. The responses were comparable or better than those obtained using mimetics of approved adjuvants. The performance of SLA archaeosomes during immunization and their lack of dependence on the stereochemistry of archaeol points toward a promising, safe, scalable, and economically viable vaccine adjuvant system.

Recent years have seen the emergence of conditionally activated diagnostics and therapeutics that leverage protease-cleavable peptide linkers to enhance their specificity for cancer. However, due to a lack of methods to measure and localize protease activity directly within the tissue microenvironment, the design of protease-activated agents has been necessarily empirical, yielding suboptimal results when translated to patients. To address the need for spatially resolved protease activity profiling in cancer, we developed a new class of in situ probes that can be applied to fresh-frozen tissue sections in a manner analogous to immunofluorescence staining. These activatable zymography probes (AZP) detected dysregulated protease activity in human prostate cancer biopsy samples, enabling disease classification. AZPs were leveraged within a generalizable framework to design conditional cancer diagnostics and therapeutics and showcased in the Hi-Myc mouse model of prostate cancer, which models features of early pathogenesis. Multiplexed screening against barcoded substrates yielded a peptide, S16, that was robustly and specifically cleaved by tumor-associated metalloproteinases in the Hi-Myc model. In situ labeling with an AZP incorporating S16 revealed a potential role of metalloproteinase dysregulation in proliferative, premalignant Hi-Myc prostatic glands. Systemic administration of an in vivo imaging probe incorporating S16 perfectly classified diseased and healthy prostates, supporting the relevance of ex vivo activity assays to in vivo translation. We envision AZPs will enable new insights into the biology of protease dysregulation in cancer and accelerate the development of conditional diagnostics and therapeutics for multiple cancer types. Significance: Visualization of protease activity within the native tissue context using AZPs provides new biological insights into protease dysregulation in cancer and guides the design of conditional diagnostics and therapeutics.

Background: The diagnostics in field of lung pathology with advent of bronchoscopic modalities comprises of BAL, BB, TBNA and TBLB. As the detection of malignancy at the earliest has taken so much importance in terms of treatment, prognosis and life expectancy use of cytological bronchoscopic modalities have come to an age and has promised early, accurate diagnosis and better patient outcome. In India as cases of lung diseases continues to increase, the use of cytology has a special role and in particular neoplastic lesions, infectious diseases and in ILD cases. TBNA technique should be encouraged due to its superior sensitivity. Materials and Methods: This study of BAL, BB, TBNA was done during routine diagnostic bronchoscopies at Government tertiary care centre and comparing their results with TBLB as gold standard. The study consisted of clinically diagnosed / suspected cases of lung lesions. The BAL/TBNA/BB cytology and TBLB specimens were taken by the pulmonologist. The clinical, radiological and bronchoscopic data was assessed. Only the cases where BAL, BB, TBNA and TBLB were received simultaneously were included. Investigations done were complete blood count, random blood sugar, blood urea, serum creatinine, electrolytes, HIV evaluation and Chest X-ray/ CT. Results: In our study of 200 cases, 62 were neoplastic and 109 non-neoplastic on and in 29 cases no abnormality was detected. Out of 62, 46 are of squamous cell carcinoma, 10 of adenocarcinoma and others were 06 in number. The non-neoplastic cases includes 06 cases of acute inflammatory lesions, 29 cases of Tuberculosis, 34 cases of Interstitial pneumonia, 6 cases of sarcoidosis, 1 case of fungal infection, and 17 cases of nonspecific inflammation. On combining TBNA with BAL and BB, overall sensitivity was 62.6% with total positive cases 114. For neoplastic lesions combined sensitivity for all BAL, BB and TBNA was 53.8% (n=62), and for non- neoplastic sensitivity was 73.9%. For assessing the level of agree

As the world in which we live becomes more complex and contested, economically and politically but also in terms of rapid and long-lasting environmental change, design education faces new demands and challenges. We frame and situate these in terms of what we call “design futures literacies.” At stake in such a framing is a rethinking of design’s priorities in the context of climate change and resource use and reuse in futures that are uncertain, contingent and emergent. The article positions design as having shifted away from a techno-modernist design solutionism and to how it may engage in shaping futures through experimentation and exploration in the critical and productive engagement with techno-cultural life. These arguments are located within the prior experience of the transdisciplinary team of co-authors as well as a European level project between four leading design universities. The article takes up their first work package on the co-creation of a Lexicon for Design Futures Literacies and early experimentation towards generating resources and experience for its wider use. The article addresses the largely under articulated relations between language and design (from lexis to discourse). First, we present the development of an alphabetic, lexical semantic set and core grouping of design and futures terms. This vocabulary, drawn from a range of sources and experiences, is linked to the design of a related lexically centred card game. Second, the focus on vocabulary was extended to a section on situating lexis in cultural historical contexts, 3-dimensional haptic form giving and the language of abstraction. This was achieved via reference to a design narrative fiction experiment on emerging technologies and a historical costume annotation project as a prompt for making connections between items from the lexicon and modelling abstract forms in clay. Third, in collaboration with a government ministry and a design council, students developed four future digital urban living scenarios with trust as their central focus. “Languaging” the future was embodied in physical scenarios open to the public, connected to a professional seminar and to international research events where verbal descriptions, explanations and reflections were voiced by the students alongside their educator-researcher. The article closes with suggestions that there is further opportunity for attention to lexis and multimodal discourse modes in shaping design futures literacies, within and across the project but also in practice, in policy and for and as design pedagogy.

Archaeosomes, composed of sulphated lactosyl archaeol (SLA) glycolipids, have been proven to be an effective vaccine adjuvant in multiple preclinical models of infectious disease or cancer. In addition to efficacy, the stability of vaccine components including the adjuvant is an important parameter to consider when developing novel vaccine formulations. To properly evaluate the potential of SLA glycolipids to be used as vaccine adjuvants in a clinical setting, a comprehensive evaluation of their stability is required. Herein, we evaluated the long term stability of preformed empty SLA archaeosomes prior to admixing with antigen at 4 °C or 37 °C for up to 6 months. In addition, the stability of adjuvant and antigen was evaluated for up to 1 month following admixing. Multiple analytical parameters evaluating the molecular integrity of SLA and the liposomal profile were assessed. Following incubation at 4 °C or 37 °C, the SLA glycolipid did not show any pattern of degradation as determined by mass spectroscopy, nuclear magnetic resonance (NMR) and thin layer chromatography (TLC). In addition, SLA archaeosome vesicle characteristics, such as size, zeta potential, membrane fluidity and vesicular morphology, were largely consistent throughout the course of the study. Importantly, following storage for 6 months at both 4 °C and 37 °C, the adjuvant properties of empty SLA archaeosomes were unchanged, and following admixing with antigen, the immunogenicity of the vaccine formulations was also unchanged when stored at both 4 °C and 37 °C for up to 1 month. Overall this indicates that SLA archaeosomes are highly stable adjuvants that retain their activity over an extended period of time even when stored at high temperatures.

With the persistence of the SARS-CoV-2 pandemic and the emergence of novel variants, the development of novel vaccine formulations with enhanced immunogenicity profiles could help reduce disease burden in the future. Intranasally delivered vaccines offer a new modality to prevent SARS-CoV-2 infections through the induction of protective immune responses at the mucosal surface where viral entry occurs. Herein, we evaluated a novel protein subunit vaccine formulation containing a resistin-trimerized prefusion Spike antigen (SmT1v3) and a proteosome-based mucosal adjuvant (BDX301) formulated to enable intranasal immunization. In mice, the formulation induced robust antigen-specific IgG and IgA titers, in the blood and lungs, respectively. In addition, the formulations were highly efficacious in a hamster challenge model, reducing viral load and body weight loss. In both models, the serum antibodies had strong neutralizing activity, preventing the cellular binding of the viral Spike protein based on the ancestral reference strain, the Beta (B.1.351) and Delta (B.1.617.2) variants of concern. As such, this intranasal vaccine formulation warrants further development as a novel SARS-CoV-2 vaccine.

With the persistence of the SARS-CoV-2 pandemic and the emergence of novel variants, the development of novel vaccine formulations with enhanced immunogenicity profiles could help reduce disease burden in the future. Intranasally delivered vaccines offer a new modality to prevent SARS-CoV-2 infections through the induction of protective immune responses at the mucosal surface where viral entry occurs. Herein, we evaluated a novel protein subunit vaccine formulation containing a resistin-trimerized prefusion Spike antigen (SmT1v3) and a proteosome-based mucosal adjuvant (BDX301) formulated to enable intranasal immunization. In mice, the formulation induced robust antigen-specific IgG and IgA titers, in the blood and lungs, respectively. In addition, the formulations were highly efficacious in a hamster challenge model, reducing viral load and body weight loss. In both models, the serum antibodies had strong neutralizing activity, preventing the cellular binding of the viral Spike protein based on the ancestral reference strain, the Beta (B.1.351) and Delta (B.1.617.2) variants of concern. As such, this intranasal vaccine formulation warrants further development as a novel SARS-CoV-2 vaccine.

We sought to evaluate the association of steroids with nonalcoholic fatty liver disease (NAFLD) among patients with inflammatory bowel disease (IBD).Patients with IBD are at increased risk of NAFLD. Steroids may have a role in the pathogenesis of NAFLD.We searched MEDLINE (through PubMed) and Embase for studies from inception to July 2021. We included published interventional and observational studies of adults 18 years or older with ulcerative colitis or Crohn's disease. We reported odds ratios, 95% confidence intervals, and generated forest plots. A random effects model generated a summary effect estimate. Publication bias was assessed by funnel plot and Egger's test. Study quality was examined using modified Newcastle-Ottawa scale (NOS) and Agency for Healthcare Research and Quality (AHRQ).A total of 12 observational studies with 3497 participants were included. NAFLD was identified in 1017 (29.1%) patients. The pooled odds ratio for the development of NAFLD in steroid users versus non-users was 0.87 (95% confidence interval: 0.72-1.04). There was no significant heterogeneity between studies (I²=0.00%, P=0.13). No publication bias was detected by funnel plot or Egger's test (P=0.24). Findings were consistent among subgroup analyses stratified by study quality.In this meta-analysis, steroids were not associated with NAFLD in patients with IBD. Steroids may not need to be withheld from patients with IBD for the purposes of preventing NAFLD. Additional prospective studies that systematically document steroid exposure and important confounders among patients with IBD are warranted.

Purpose: The aim of this study was to test the discomfort experienced during intravitreal injections with eyelid retraction between an eyelid speculum, cotton-tipped applicator (CTA), and unimanual eyelid retraction techniques. Methods: In total, 99 patients receiving intravitreal bevacizumab were enrolled into this prospective study. Participants were randomized to one of the three methods, given subconjunctival 2% lidocaine and then injected in the superior temporal quadrant. Immediately after the procedure, each patient was given a visual analog scale (VAS) to rate their discomfort. Results: The mean pain scores for eyelid retraction with unimanual, CTA, and speculum groups were 0.788 (standard deviation [SD] 0.70, 95% confidence interval [CI] 0.448–1.128), 0.945 (SD 1.28, 95% CI 0.600–1.291), and 1.561 (SD 1.28, 95% CI 1.210–1.912), respectively. A one-way analysis of variance (ANOVA) test revealed a significant difference between the groups (P = 0.006). Post hoc analysis also revealed a difference in mean pain scores between the speculum and both the CTA and the unimanual methods. Conclusion: Our study shows that the unimanual and CTA methods for eyelid retraction are significantly less painful for patients compared to the speculum method. Patient comfort is of the utmost importance as intravitreal injections are performed millions of times a year with most patients requiring multiple injections.

Nanoparticles have emerged as a powerful drug-delivery material to enhance the specificity of drug actions, while reducing the systemic side effects. These particles ranges from 1 to 100nm with one or more dimensions. These are mainly classified into the organic, inorganic and carbon based particles. The objective of this study is the ultimate goal of the cosmetic industries when using nanocarriers is to deliver the right amount of ingredients to the desired parts of the body, and to attain long term stability. Research within the cosmetics industry has revealed that when nanomaterials are engineered into cosmetic products, they can enhance the benefits of active ingredients. Constantly more and more innovative application of materials resulting from the use nanotechnology is being recognized. An exceptionally unique nanomaterial, carbon nanobuds have been identified with combined properties of carbon nanotubes and fullerenes.