Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity.

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.

Central memory CD8+ T cells derive from stem-like Tcf7hi effector cells in the absence of cytotoxic differentiation.

Central memory CD8+ T cells (Tcm) control systemic secondary infections and can protect from chronic infection and cancer as a result of their stem-cell-like capacity to expand, differentiate, and self-renew. Central memory is generally thought to emerge following pathogen clearance and to form based on the de-differentiation of cytolytic effector cells. Here, we uncovered rare effector-phase CD8+ T cells expressing high amounts of the transcription factor Tcf7 (Tcf1) that showed no evidence of prior cytolytic differentiation and that displayed key hallmarks of Tcm cells. These effector-phase Tcf7hi cells quantitatively yielded Tcm cells based on lineage tracing. Mechanistically, Tcf1 counteracted the differentiation of Tcf7hi cells and sustained the expression of conserved adult stem-cell genes that were critical for CD8+ T cell stemness. The discovery of stem-cell-like CD8+ T cells during the effector response to acute infection provides an opportunity to optimize Tcm cell formation by vaccination.

Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy.

Checkpoint blockade mediates a proliferative response of tumor-infiltrating CD8+ T lymphocytes (TILs). The origin of this response has remained elusive because chronic activation promotes terminal differentiation or exhaustion of tumor-specific T cells. Here we identified a subset of tumor-reactive TILs bearing hallmarks of exhausted cells and central memory cells, including expression of the checkpoint protein PD-1 and the transcription factor Tcf1. Tcf1+PD-1+ TILs mediated the proliferative response to immunotherapy, generating both Tcf1+PD-1+ and differentiated Tcf1-PD-1+ cells. Ablation of Tcf1+PD-1+ TILs restricted responses to immunotherapy. Tcf1 was not required for the generation of Tcf1+PD-1+ TILs but was essential for the stem-like functions of these cells. Human TCF1+PD-1+ cells were detected among tumor-reactive CD8+ T cells in the blood of melanoma patients and among TILs of primary melanomas. Thus, immune checkpoint blockade relies not on reversal of T cell exhaustion programs, but on the proliferation of a stem-like TIL subset.

Spurious Hyperphosphatemia in a Patient with Chronic Kidney Disease - a Rare Case of Alteplase Contamination.

Spurious hyperphosphatemia, a rare occurrence, typically arises from substances in a patient's blood interfering with the colorimetric method for serum phosphate measurement. We present a case of factitious hyperphosphatemia caused by alteplase-contaminated blood samples in an 88-year-old CKD patient on hemodialysis, leading to misleadingly high phosphorus levels. Thorough investigations ruled out other etiologies, highlighting the necessity of stringent adherence to blood collection protocols to prevent sample contamination and avert erroneous laboratory results. This unique cause of hyperphosphatemia should be considered in the differential diagnosis when encountering unexplained elevations in phosphorus levels, particularly in the context of normal blood calcium levels.

Reporting Practices of Serum Protein Electrophoresis in Pakistan - a Multicenter Survey.

BACKGROUND: Serum Protein Electrophoresis (SPE) is crucial for the diagnosis and follow-up of monoclonal gammopathy (MG), as it helps to separate and identify these paraproteins. Currently, Pakistan lacks standardized guidelines for SPE reporting and analytical performance. This survey aims to analyze reporting variations from Consultant Chemical Pathologists in Pakistani laboratories. METHODS: This cross-sectional survey was conducted by the section of Chemical Pathology, Department of Pathology and Laboratory Medicine, at Aga Khan University Hospital, Karachi. A previously validated and published tool was used with some modifications to assess analytical techniques, reporting patterns, and interpretations provided with SPE by different laboratories. Frequency and percentages were calculated for each response and descriptive results were also evaluated. Differences between laboratories were also assessed qualitatively. RESULTS: Out of the eight laboratories contacted, seven participated in the survey, yielding a response rate of 87.5%. Immunofixation Electrophoresis (IFE) was used by all labs for serum immunotyping. All labs reported a new small abnormal band in patients with no known monoclonal gammopathy or with a known M-protein. Variations were found in terminologies used to label paraprotein, terminologies used to report normal and pathological SPE patterns, electrophoretic technique, methods for quantifying paraprotein in the gamma region on SPE and for albumin quantification. Similarly, the number of decimal places reported, reporting of multiple monoclonal proteins and small paraprotein in the beta region or monoclonal proteins less than 1 g/L, approach for screening, number of fractions reported in gamma region and reporting of interferences were also not standardized and var-iations were noticed. CONCLUSIONS: Our survey highlighted variations in practices of SPE reporting. These differences in laboratory practices could result in inconsistent test results, which could adversely affect patient care.

Insights from semi-structured interviews on integrating artificial intelligence in clinical chemistry laboratory practices.

BACKGROUND: Artificial intelligence (AI) is gradually transforming the practises of healthcare providers. Over the last two decades, the advent of AI into numerous aspects of pathology has opened transformative possibilities in how we practise laboratory medicine. Objectives of this study were to explore how AI could impact the clinical practices of professionals working in Clinical Chemistry laboratories, while also identifying effective strategies in medical education to facilitate the required changes. METHODS: From March to August 2022, an exploratory qualitative study was conducted at the Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan, in collaboration with Keele University, Newcastle, United Kingdom. Semi-structured interviews were conducted to collect information from diverse group of professionals working in Clinical Chemistry laboratories. All interviews were audio recorded and transcribed verbatim. They were asked what changes AI would involve in the laboratory, what resources would be necessary, and how medical education would assist them in adapting to the change. A content analysis was conducted, resulting in the development of codes and themes based on the analyzed data. RESULTS: The interviews were analysed to identify three primary themes: perspectives and considerations for AI adoption, educational and curriculum adjustments, and implementation techniques. Although the use of diagnostic algorithms is currently limited in Pakistani Clinical Chemistry laboratories, the application of AI is expanding. All thirteen participants stated their reasons for being hesitant to use AI. Participants stressed the importance of critical aspects for effective AI deployment, the need of a collaborative integrative approach, and the need for constant horizon scanning to keep up with AI developments. CONCLUSIONS: Three primary themes related to AI adoption were identified: perspectives and considerations, educational and curriculum adjustments, and implementation techniques. The study's findings give a sound foundation for making suggestions to clinical laboratories, scientific bodies, and national and international Clinical Chemistry and laboratory medicine organisations on how to manage pathologists' shifting practises because of AI.

Indirect Reference Intervals of Serum Calcium in Pakistani Children Using KOSMIC, Bhattacharya, and Hoffman Approach.

BACKGROUND: Reference intervals (RIs) of serum calcium vary based on age, population demographics, and methods of assessment. However, conventional approaches to establish serum calcium (Ca)RIs pose ethical and practical challenges, especially in the pediatric population. Hence, the use of indirect approaches is beneficial. This study was carried out to estimate the RIs of serum Ca using three indirect approaches in the pediatric and adolescent population of Pakistan. METHODS: Data mining laboratory information systems, for serum Ca results from 2013 - 2021 was done on a target population ranging from birth to 18 years of age. The population was grouped into three categories based on age (birth - 1 year, 2 - 4 years, and 5 - 18 years), as defined previously by Tahmasebi et al. in the CALIPER cohort. Pre-validated indirect algorithms, 'KOSMIC', Bhattacharya, and Hoffman, were used for analyzing the RIs. RESULTS: A total of non-duplicate 40,914 serum Ca tests were retrieved over a period of 6 years, including 38.7% (n = 15,830) from birth - 1 year, 16.3% (n = 6,641) from > 1 - 4 years, and 45.2% (n = 18443) from > 4 - 18 years respectively. The three methods revealed comparable performance with the direct RIs reported by Tahmasebi et al. in the CALIPER cohort. Keeping a stringent total allowable error of 1 mg/dl for Serum Ca as given by Clinical Laboratory Improvement Amendments (CLIA) the KOSMIC method outperformed the other two when compared to Tahmasebi, Houman, et al. Conclusions: The study advocates the use of the indirect approach for calculating RIs for serum calcium in the pediatric population, especially to aid clinical decision making in a low resource setting, due to its ability to reproduce results in line with the direct approach in a more economical, practical, and feasible way.

Pathogen-specific Treg cells expand early during mycobacterium tuberculosis infection but are later eliminated in response to Interleukin-12.

Thymically derived Foxp3⁺ regulatory T (Treg) cells have a propensity to recognize self-peptide:MHC complexes, but their ability to respond to epitope-defined foreign antigens during infectious challenge has not been demonstrated. Here we show that pulmonary infection with Mycobacterium tuberculosis (Mtb), but not Listeria monocytogenes (Lm), induced robust lymph node expansion of a highly activated population of pathogen-specific Treg cells from the pre-existing pool of thymically derived Treg cells. These antigen-specific Treg cells peaked in numbers 3 weeks after infection but subsequently underwent selective elimination driven, in part, by interleukin-12-induced intrinsic expression of the Th1-cell-promoting transcription factor T-bet. Thus, the initial Mtb-induced inflammatory response promotes pathogen-specific Treg cell proliferation, but these cells are actively culled later, probably to prevent suppression during later stages of infection. These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity.

CT-based radiomics stratification of tumor grade and TNM stage of clear cell renal cell carcinoma.

OBJECTIVES: To evaluate the utility of CT-based radiomics signatures in discriminating low-grade (grades 1-2) clear cell renal cell carcinomas (ccRCC) from high-grade (grades 3-4) and low TNM stage (stages I-II) ccRCC from high TNM stage (stages III-IV). METHODS: A total of 587 subjects (mean age 60.2 years ± 12.2; range 22-88.7 years) with ccRCC were included. A total of 255 tumors were high grade and 153 were high stage. For each subject, one dominant tumor was delineated as the region of interest (ROI). Our institutional radiomics pipeline was then used to extract 2824 radiomics features across 12 texture families from the manually segmented volumes of interest. Separate iterations of the machine learning models using all extracted features (full model) as well as only a subset of previously identified robust metrics (robust model) were developed. Variable of importance (VOI) analysis was performed using the out-of-bag Gini index to identify the top 10 radiomics metrics driving each classifier. Model performance was reported using area under the receiver operating curve (AUC). RESULTS: The highest AUC to distinguish between low- and high-grade ccRCC was 0.70 (95% CI 0.62-0.78) and the highest AUC to distinguish between low- and high-stage ccRCC was 0.80 (95% CI 0.74-0.86). Comparable AUCs of 0.73 (95% CI 0.65-0.8) and 0.77 (95% CI 0.7-0.84) were reported using the robust model for grade and stage classification, respectively. VOI analysis revealed the importance of neighborhood operation-based methods, including GLCM, GLDM, and GLRLM, in driving the performance of the robust models for both grade and stage classification. CONCLUSION: Post-validation, CT-based radiomics signatures may prove to be useful tools to assess ccRCC grade and stage and could potentially add to current prognostic models. Multiphase CT-based radiomics signatures have potential to serve as a non-invasive stratification schema for distinguishing between low- and high-grade as well as low- and high-stage ccRCC. KEY POINTS: • Radiomics signatures derived from clinical multiphase CT images were able to stratify low- from high-grade ccRCC, with an AUC of 0.70 (95% CI 0.62-0.78). • Radiomics signatures derived from multiphase CT images yielded discriminative power to stratify low from high TNM stage in ccRCC, with an AUC of 0.80 (95% CI 0.74-0.86). • Models created using only robust radiomics features achieved comparable AUCs of 0.73 (95% CI 0.65-0.80) and 0.77 (95% CI 0.70-0.84) to the model with all radiomics features in classifying ccRCC grade and stage, respectively.

Development and validation of standard and real patient gallstone library using Fourier transform infra-red spectroscopy.

BACKGROUND: Analysis of the constituents of gallstones using various spectroscopic techniques assists in identification of the pathogenesis of gallstones. In the current study, using Fourier Transform Infra-Red (FTIR) Spectroscopy, a Gallstone Standard Library (GSL) and a Gallstone Real Patients' Library (GRPL) were developed and validated for gallstone composition analysis. METHODS: The study was conducted at the Department of Pathology & Laboratory Medicine, Aga Khan University, Pakistan. Pure standards (cholesterol, calcium carbonate, bilirubin and bile salts) and gallstone specimens were analyzed using FTIR Nicolet iS-5 Spectrometer from Thermo Fisher Scientific, USA. Thermo Scientific™ QCheck™ algorithm, embedded within the OMNIC™ software, was used to identify the unique spectral fingerprint of the patient samples to match with known, standard material. Matching of > 75% was considered acceptable. Validation for accuracy of the library was performed for twenty analyzed gallstones at an international reference lab. RESULTS: Concerted search analysis was performed against the developed GSL consisting of 71 "pure component" spectrum divided into 5 types to generate the library. For the Gallstone Real Patient Library (GRPL), 117 patient samples were analyzed. Ninety-eight gall stones (83.8%) out of 117 stones matched with the developed GSL. Majority stones were mixed stones (95.92%), with cholesterol being the primary component (91.83%). Results of the developed library were 100% in agreement with the reports received from the external reference lab. CONCLUSIONS: The library developed displayed good consistency and can be used for detection of gallstone composition in Pakistan and replace the traditional labor- and time-intensive chemical method of gallstone analysis.

Forecasting COVID-19 Testing Load Using Google Trends: Experience from a Lower Middle-Income Country with over 10 Million Diagnostic Tests.

BACKGROUND: The ability to forecast changing trends of COVID-19 can help drive efforts to sustain the increasing burden on the healthcare system, specifically the clinical laboratories. We aimed to assess whether the trends of SARS-CoV-2 testing in Pakistan can be predicted using COVID-19 symptoms as search terms and analyzing the data from Google Trends. METHODS: The number of weekly SARS-CoV-2 tests performed were retrieved from online COVID-19 data resource. Google Trends data for the search terms with most common COVID-19 symptoms was analyzed for cross-correlation with the number of tests performed nationally. RESULTS: A total of 10,066,255 SARS-CoV-2 diagnostic tests were analyzed. Search terms of fever, headache, and shortness of breath displayed a statistically significant correlation with total number of tests performed with a 1-week time lag. CONCLUSIONS: Google Trends data can be used to forecast the changing trends in COVID-19 testing. This information can be used for careful planning and arrangements to meet increased diagnostic and healthcare demands in difficult times.

Reference Intervals of Serum TSH from Mixed Distributions Using Truncation Points and the Kolmogorov-Smirnov Distance.

BACKGROUND: Serum TSH reference intervals (RIs) are methodology, population, and age specific. However, the ethical and practical challenges restrict the establishment of pediatric RIs using conventional approaches and advocates the use of indirect data mining-based algorithms. This study was carried out to estimate the reference interval of neonatal serum TSH in Pakistani population using an indirect approach. METHODS: A data mining of serum TSH results of neonates (≤ 1 month of age) from 2013 - 2018 was done. Two subgroups on the basis of age from birth to 5 days and 6 - 30 days were assessed. The German study group's pre-validated indirect algorithm 'KOSMIC' was utilized for the statistical analysis. RESULTS: A total of non-duplicate 82,299 neonatal serum TSH tests were retrieved over a period of 6 years, including 88% (n = 70,788) aged 0 - 5 days and 12% (n = 11,511) ranging from 6 days to 1 month. The estimated RIs for the first age partition was 0.7 (90% CI 0.6 - 0.8) to 15.5 (90% CI 12.9 - 16.2) and for the second group 0.7 (90% CI 0.5 - 0.9) to 7.8 (90% CI 6.1 - 9.9) µIU/mL. CONCLUSIONS: This study revealed age related trends in serum TSH. The study advocates the need for population specific RIs owing to the significant variations noted on comparison with previously published literature. Precise RIs become vital particularly when serum TSH is undertaken as a confirmatory test for presumptive positive results on newborn screening for congenital hypothyroidism.

ACTH-secreting parotid acinic cell carcinoma unusually reported as a paraneoplastic syndrome.

Paraneoplastic syndromes, induced by an immunological cross-reaction or hormone/peptide secretion, are an atypical presentation of tumors. Some tumors, such as small cell lung cancer and bronchial carcinoid, can be adrenocorticotropic hormone (ACTH) secreting tumors. Less commonly, parotid acinic cell carcinoma can be ACTH-secreting tumor leading to Cushing's syndrome. Few literature cases have described ACTH related paraneoplastic syndrome of parotid adenocarcinoma. Because of the rarity of the condition, little is known about the management and prognosis of this phenomenon. In this report, we highlighted the case of a 59-year-old male with a past medical history of parotid adenocarcinoma treated with surgery, chemotherapy, and radiation therapy presented with clinical and biochemical signs of hyperaldosteronism. Abdominal ultra-sound, computed tomography, and magnetic resonance imaging showed hepatic mass. Liver biopsy with immunohistochemistry confirmed the presence of parotid adenocarcinoma secreting ACTH. He is on paclitaxel and carboplatin medication with good clinical response.

Artificial Intelligence-Based Portable Bioelectronics Platform for SARS-CoV-2 Diagnosis with Multi-nucleotide Probe Assay for Clinical Decisions.

In the context of the recent pandemic, the necessity of inexpensive and easily accessible rapid-test kits is well understood and need not be stressed further. In light of this, we report a multi-nucleotide probe-based diagnosis of SARS-CoV-2 using a bioelectronics platform, comprising low-cost chemiresistive biochips, a portable electronic readout, and an Android application for data acquisition with machine-learning-based decision making. The platform performs the desired diagnosis from standard nasopharyngeal and/or oral swabs (both on extracted and non-extracted RNA samples) without amplifying the viral load. Being a reverse transcription polymerase chain reaction-free hybridization assay, the proposed approach offers inexpensive, fast (time-to-result: ≤ 30 min), and early diagnosis, as opposed to most of the existing SARS-CoV-2 diagnosis protocols recommended by the WHO. For the extracted RNA samples, the assay accounts for 87 and 95.2% test accuracies, using a heuristic approach and a machine-learning-based classification method, respectively. In case of the non-extracted RNA samples, 95.6% decision accuracy is achieved using the heuristic approach, with the machine-learning-based best-fit model producing 100% accuracy. Furthermore, the availability of the handheld readout and the Android application-based simple user interface facilitates easy accessibility and portable applications. Besides, by eliminating viral RNA extraction from samples as a pre-requisite for specific detection, the proposed approach presents itself as an ideal candidate for point-of-care SARS-CoV-2 diagnosis.

An objective approach to evaluate novice robotic surgeons using a combination of kinematics and stepwise cumulative sum (CUSUM) analyses.

BACKGROUND: Current evaluation methods for robotic-assisted surgery (ARCS or GEARS) are limited to 5-point Likert scales which are inherently time-consuming and require a degree of subjective scoring. In this study, we demonstrate a method to break down complex robotic surgical procedures using a combination of an objective cumulative sum (CUSUM) analysis and kinematics data obtained from the da Vinci® Surgical System to evaluate the performance of novice robotic surgeons. METHODS: Two HPB fellows performed 40 robotic-assisted hepaticojejunostomy reconstructions to model a portion of a Whipple procedure. Kinematics data from the da Vinci® system was recorded using the dV Logger® while CUSUM analyses were performed for each procedural step. Each kinematic variable was modeled using machine learning to reflect the fellows' learning curves for each task. Statistically significant kinematics variables were then combined into a single formula to create the operative robotic index (ORI). RESULTS: The inflection points of our overall CUSUM analysis showed improvement in technical performance beginning at trial 16. The derived ORI model showed a strong fit to our observed kinematics data (R2 = 0.796) with an ability to distinguish between novice and intermediate robotic performance with 89.3% overall accuracy. CONCLUSIONS: In this study, we demonstrate a novel approach to objectively break down novice performance on the da Vinci® Surgical System. We identified kinematics variables associated with improved overall technical performance to create an objective ORI. This approach to robotic operative evaluation demonstrates a valuable method to break down complex surgical procedures in an objective, stepwise fashion. Continued research into objective methods of evaluation for robotic surgery will be invaluable for future training and clinical implementation of the robotic platform.

An audit of transfusion reaction monitoring and reporting at a cancer hospital in Pakistan - a step towards haemovigilance.

OBJECTIVE: To monitor the frequencies of different adverse transfusion reactions and to assess the compliance of clinical staff with the process of sending proper transfusion reaction workup within the specified time. METHODS: The retrospective audit was conducted at the blood bank of Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, and comprised all transfusion reaction forms received from July 1, 2017, to June 30, 2018. The forms were analysed for type of blood component, time in which it was received by the blood bank, whether or not the form was completely filled, whether or not all required samples were provided, and the type of reaction. RESULTS: Of the 12,787 units dispensed and transfused, 50(0.39%) transfusion reactions were noted. Allergic was the most frequent type 24(48%). Red cells accounted for 38(76%) of the reactions. In 58(95%) cases, reaction forms were completely filled. Blood bags in 36(59%) and post-transfusion ethylenediaminetetra acetic acid samples in 35(57.3%) cases were received at blood bank within 2 hours of reaction. CONCLUSIONS: Incidence of transfusion reactions was found to be low as there was good compliance with procedures on the part of the clinical staff.

Prognostic Value of Serum Procalcitonin in COVID-19 Patients: A Systematic Review.

BACKGROUND: This study is aimed at reviewing the published literature on the prognostic role of serum procalcitonin (PCT) in COVID-19 cases. DATA RETRIEVAL: We systematically reviewed the literature available on PubMed, MEDLINE, LitCovid NLM, and WHO: to assess the utility of PCT in prognosis of coronavirus disease. Scrutiny for eligible studies comprising articles that have evaluated the prognostic utility of PCT and data compilation was undertaken by two separate investigators. Original articles in human subjects reporting the prognostic role of PCT in adult COVID-19 patients were included. The Quality in Prognosis Studies (QUIPS) tool was utilized to assess the strength of evidence. Results were reported as narrative syntheses. RESULTS: Out of the total 426 citations, 52 articles passed through screening. The quality of evidence and methodology of included studies was overall acceptable. The total sample size of the studies comprised of 15,296 COVID-19-positive subjects. Majority of the studies were from China, i.e., 40 (77%). The PCT cut-off utilized was 0.05 ng/mL by 18 (35%) studies, followed by 0.5 ng/mL by 9 (17.5%). Eighty five percent (n = 44) studies reported statistically significant association (p value < 0.05) between PCT and severity. CONCLUSION: Procalcitonin appears as a promising prognostic biomarker of COVID-19 progression in conjunction with the clinical context. HOW TO CITE THIS ARTICLE: Ahmed S, Jafri L, Hoodbhoy Z, Siddiqui I. Prognostic Value of Serum Procalcitonin in COVID-19 Patients: A Systematic Review. Indian J Crit Care Med 2021;25(1):77-84.

Presepsin as a Predictive Biomarker of Severity in COVID-19: A Systematic Review.

BACKGROUND: The aim of this review is to evaluate the global scientific literature on the utility of plasma presepsin (PSP) as a prognostic biomarker in a homogeneous group of coronavirus disease 2019 (COVID-19) positive cases. DATA RETRIEVAL: A systematic review utilizing Medline (PubMed interface), LitCovid NLM, World Health Organization (WHO)-global literature on coronavirus disease, and EBSCO CINAHL Plus was undertaken. The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group guidelines. The quality of individual evidence and possible risk of bias were assessed using the Quality in Prognosis Studies (QUIPS) tool. A narrative synthesis-based conclusion was compiled. RESULTS: A total of three articles passed through the predefined screening criteria and were included in the review. Methodological quality was evaluated to be acceptable. The aggregate study population was summed up to be 167 COVID-19 positive cases, who had undergone analysis of plasma PSP levels for the prediction of severity and mortality. Based on different PSP cutoffs utilized, a statistically significant association between PSP and COVID-19 severity was reported. CONCLUSION: PSP appears as a promising prognostic biomarker of COVID-19 progression. As data are scarce on its utility, large cross-sectional studies are needed. HOW TO CITE THIS ARTICLE: Ahmed S, Mansoor M, Shaikh MS, Siddiqui I. Presepsin as a Predictive Biomarker of Severity in COVID-19: A Systematic Review. Indian J Crit Care Med 2021;25(9):1051-1054.

Fostering teaching-learning through workplace based assessment in postgraduate chemical pathology residency program using virtual learning environment.

BACKGROUND: The principle of workplace based assessment (WBA) is to assess trainees at work with feedback integrated into the program simultaneously. A student driven WBA model was introduced and perception evaluation of this teaching method was done subsequently by taking feedback from the faculty as well as the postgraduate trainees (PGs) of a residency program. METHODS: Descriptive multimethod study was conducted. A WBA program was designed for PGs in Chemical Pathology on Moodle and forms utilized were case-based discussion (CBD), direct observation of practical skills (DOPS) and evaluation of clinical events (ECE). Consented assessors and PGs were trained on WBA through a workshop. Pretest and posttest to assess PGs knowledge before and after WBA were conducted. Every time a WBA form was filled, perception of PGs and assessors towards WBA, time taken to conduct single WBA and feedback were recorded. Faculty and PGs qualitative feedback on perception of WBA was taken via interviews. WBA tools data and qualitative feedback were used to evaluate the acceptability and feasibility of the new tools. RESULTS: Six eligible PGs and seventeen assessors participated in this study. A total of 79 CBDs (assessors n = 7 and PGs n = 6), 12 ECEs (assessors n = 6 and PGs n = 5), and 20 DOPS (assessors n = 6 and PGs n = 6) were documented. PGs average pretest score was 55.6%, which was improved to 96.4% in posttest; p value< 0.05. Scores of annual assessment before and after implementation of WBA also showed significant improvement, p value 0.039, Overall mean time taken to evaluate PG's was 12.6 ± 9.9 min and feedback time 9.2 ± 7.4 min. Mean WBA process satisfaction of assessors and PGs on Likert scale of 1 to 10 was 8 ± 1 and 8.3 ± 0.8 respectively. CONCLUSION: Both assessors and fellows were satisfied with introduction and implementation of WBA. It gave the fellows opportunity to interact with assessors more often and learn from their rich experience. Gain in knowledge of PGs was identified from the statistically significant improvement in PGs' assessment scores after WBA implementation.

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination.

Human colorectal cancer (CRC) is a frequent neoplasia in Western countries, and its metastatic progression is a major cause of cancer-related death. In search of specific molecules upregulated in CRC, with possible clinical relevance, we performed a differential gene-profiling analysis in surgery-derived CRC samples and adjacent uninvolved intestinal mucosa. The chemokine CX3CL1 and its specific receptor CX3CR1 were significantly upregulated in tumors. Higher expression of CX3CL1 and CX3CR1 was confirmed by immunohistochemistry in 100 CRC tumor samples (stages I-III). Unexpectedly, high immune scores of CX3CL1 did not correlate with the density of tumor-infiltrating CD3(+) T cells or CD68(+) macrophages. Coexpression of ligand and receptor by tumor cells (axis-positive tumors) significantly associated with longer disease-free (p = 0.01) and disease-specific survival (p = 0.001). Conversely, axis-negative tumors (with low expression of both ligand and receptor) had increased risk of tumor relapse (p = 0.02), and increased likelihood of metachronous metastasis (p = 0.001), including after stage adjustment (p = 0.006). Transduction of CX3CL1 and CX3CR1 in CRC tumor cell lines induced cell aggregation that strongly inhibited in vitro migration in chemotaxis assays. In a mouse model of spleen-liver metastases, cancer dissemination to liver was dramatically reduced in CX3CL1-CX3CR1-expressing tumors, and ligand-receptor interaction was confirmed in cancer cells in vivo by fluorescence resonance energy transfer analysis. In conclusion, tumoral expression of the CX3CL1-CX3CR1 chemokine axis functions as a retention factor, increasing homotypic cell adhesion and limiting tumor spreading to metastatic sites. Lack or low levels of expression of CX3CL1-CX3CR1 by tumor cells identifies a group of CRC patients at increased risk of metastatic progression.