Investigating the Glucagon-like Peptide-1 and Its Receptor in Human Brain: Distribution of Expression, Functional Implications, Age-related Changes and Species Specific Characteristics.

Introduction: Emerging evidence has shown that the glucagon-like peptide-1 (GLP-1) agonist can be used to treat Alzheimer disease; however, knowledge of its neural targets is limited. To understand the neural substrates of GLP-1, we have done whole brain mapping for GLP-1 and its receptor (GLP-1R), in 30 human brains. Methods: GLP-1 expression was studied by immuno-histochemistry and confirmed by the western blot method. The GLP-1R gene expression was studied by reverse transcription polymerase chain reaction. Results: GLP-1 expression was observed in most of the cortical areas (maximum in frontal, prefrontal and parietal cortex), diencephalon, and brainstem, but not in the cerebellum. Protein expression studies validated these results. The highest expression of GLP-1R was found in the frontal cortex. The orbitofrontal cortex and cerebellum had negligible expression. Hippocampus demonstrated a significant presence of GLP-1R but patchy immunoreactivity to GLP-1. GLP-1R presence in most of the human cortical regions and absence in the cerebellum is the major deviation from the animal brain. Sites that might be of interest in Alzheimer have been identified. GLP-1 demonstrated an age-related decline in most of the areas after the fifth decade. At 60 years, GLP-1 was not found in any of the cortical areas except in the prefrontal cortex; however, it was present in the sub-cortical areas. Conclusion: Age-related profiling of GLP-1 in various brain areas has been analyzed, which can have an important bearing on understanding Alzheimer disease. This study provides a detailed description of GLP-1 and an brain mapping for the first time and may lead to novel treatment options targeting the GLP-1 receptors. Highlights: Glucagon like peptide-1 (GLP-1) agonist can be used for treating Alzheime'rs disease.GLP-1 gene expression was seen in cortical areas, diencephalon and brainstem, but not in cerebellum.Hippocampus demonstrated significant presence of GLP-1R but patchy immunoreactivity to GLP-1.GLP-1 demonstrated age related decline in most of the areas after fifth decade.A detailed description of GLP-1 and amp; GLP-1R locations was given which may lead to novel treatment options. Plain Language Summary: Emerging evidence has shown that the glucagon like peptide-1 (GLP1-1) agonist can be used for treating Alzheimer's disease but knowledge of its neural targets is limited. To understand the neural substrates of GLP-1, we have done whole brain mapping for GLP-1 and its receptor (GLP-1R), in 30 human brains. GLP-1 expression was studied by immuno-histochemistry and confirmed by western blot method. GLP-1R gene expression was studied by RT-PCR. GLP-1 expression was seen in most of the cortical areas (maximum in frontal, prefrontal & amp; parietal cortex), diencephalon and brainstem, but not in cerebellum. Protein expression studies validated these results. Highest expression of GLP-1R was found in the frontal cortex. The orbito-frontal cortex and cerebellum had negligible expression. Hippocampus demonstrated significant presence of GLP-1R but patchy immunoreactivity to GLP-1. GLP-1R presence in most of the human cortical regions and absence in cerebellum is the major deviation from the animal brain. Sites which might be of interest in Alzheimer's have been identified. GLP-1 demonstrated age related decline in most of the areas after 5 th decade. At 60 years GLP-1 was not found in any of the cortical areas except in the prefrontal cortex but it was present in the sub-cortical areas. Age related profiling of GLP-1 in various brain areas has been analysed, which can have important bearing on understanding the Alzheimer's. This study provides detailed description of GLP-1 and ations by complete human brain mapping for the first time and may lead to novel treatment options targeting the GLP-1 receptors.

A single-center review of pre-exposure prophylaxis with tixagevimab-cilgavimab in solid organ transplant recipients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to negatively impact solid organ transplant recipients (SOTr). Data on the use of tixagevimab-cilgavimab (tix-cil) in vaccinated SOTr during circulation of Omicron and its subvariants are limited. Therefore, this single-center review was conducted to evaluate tix-cil efficacy in multiple organ transplant groups during a study period where Omicron B.1.1.529, BA.2.12.1, and BA.5 predominated. METHODS: In this single-center retrospective study, we evaluated the incidence of COVID-19 infection in adult SOTr who did or did not receive pre-exposure prophylaxis (PrEP) with tix-cil. SOTr were included if they were at least 18 years of age and met emergency use authorization criteria for tix-cil use. The primary outcome analyzed was the incidence of COVID-19 infection. RESULTS: Ninety SOTr met inclusion criteria and comprised of two groups, tix-cil PrEP (n = 45) and no tix-cil PrEP (n = 45). Of SOTr who received tix-cil PrEP, three (6.7%) developed COVID-19 infection, compared to eight (17.8%) in the no tix-cil PrEP group (p = .20). Of the 11 SOTr diagnosed with COVID-19, 15 (82.2%) were fully vaccinated against COVID-19 prior to transplantation. Moreover, 18.2% and 81.8% of the COVID-19 cases observed were asymptomatic and mild-to-moderate, respectively. DISCUSSION: Our study results, which included months when BA.5 was in increased circulation, suggest no significant difference in COVID-19 infection with or without use of tix-cil PrEP in our solid organ transplant groups. As the COVID-19 pandemic continues to evolve, clinical utility of tix-cil should be evaluated against new, emerging strains.

Somatic loss of ATM is a late event in pancreatic tumorigenesis.

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Intraparenchymal metastases as a cause for local recurrence of pancreatic cancer.

Using CODA, a technique for three-dimensional reconstruction of large tissues, Kiemen et al. report observation of a microscopic focus of pancreatic cancer found in the vasculature of grossly normal human pancreas tissue resected adjacent to a large tumour. They use TP53 and SMAD4 staining to relate the small focus to the primary tumour. This report describes a represents a probable case of intraparenchymal metastasis of pancreatic cancer, revealing a probable cause of local recurrence.

Algal bioplastics: current market trends and technical aspects.

Abstract: Plastics are undebatably a hot topic of discussion across international forums due to their huge ecological footprint. The onset of COVID-19 pandemic has exacerbated the issue in an irreversible manner. Bioplastics produced from renewable sources are a result of lookout for sustainable alternatives. Replacing a ton of synthetic plastics with biobased ones reduces 1.8 tons CO2 emissions. Here, we begin with highlighting the problem statement-Plastic accumulation and its associated negative impacts. Microalgae outperforms plants and microbes, when used to produce bioplastic due to superior growth rate, non-competitive nature to food, and simultaneous wastewater remediation. They have minimal nutrient requirements and less dependency on climatic conditions for cultivation. These are the reasons for current boom in the algal bioplastic market. However, it is still not at par in price with the petroleum-based plastics. A brief market research has been done to better evaluate the current global status and future scope of algal bioplastics. The objective of this review is to propose possible solutions to resolve the challenges in scale up of bioplastic industry. Various bioplastic production technologies have been comprehensively discussed along with their optimization strategies. Overall studies discussed show that in order to make it cost competitive adopting a multi-dimensional approach like algal biorefinery is the best way out. A holistic comparison of any bio-based alternative with its conventional counterpart is imperative to assess its impact upon commercialization. Therefore, the review concludes with the life cycle assessment of bioplastics and measures to improve their inclusivity in a circular economy.

Clostridioides difficile Toxin B PCR Cycle Threshold as a Predictor of Toxin Testing in Stool Specimens from Hospitalized Adults.

Rapid, accurate detection of Clostridioides difficile toxin may potentially be predicted by toxin B PCR cycle threshold (tcdB Ct). We investigated the validity of this approach in an inpatient adult population. Patients who tested positive by C. difficile PCR (Cepheid GeneXpert) from December 2016 to October 2020 (n = 368) at a tertiary medical center were included. All stool samples were further tested by rapid glutamate dehydrogenase (GDH)/toxin B EIA and cell cytotoxin neutralization assay (CCNA). Receiver operating characteristic curves were analyzed. The area under the curve for tcdB Ct predicting toxin result by EIA was 0.795 (95% confidence interval (CI) 0.747−0.843) and by CCNA was 0.771 (95% CI 0.720−0.822). The Youden Ct cutoff for CCNA was ≤27.8 cycles (sensitivity 65.0%, specificity 77.2%). For specimens with Ct ≤ 25.0 cycles (n = 115), CCNA toxin was positive in >90%. The negative predictive value of tcdB Ct for CCNA was no greater than 80% regardless of cutoff chosen. In summary, very low Ct values (≤25.0) could have limited value as a rapid indicator of positive toxin status by CCNA in our patient population. A broad distribution of Ct values for toxin-negative and toxin-positive specimens precluded more robust prediction. Additional data are needed before broader application of Ct values from qualitatively designed assays to clinical laboratory reporting.

Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance.

Pathogenic germline CDKN2A variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). CDKN2A variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of CDKN2A VUSs is needed to reclassify variants and inform clinical management. Twenty-nine germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. Twelve of the 29 CDKN2A VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of CDKN2A VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic/likely pathogenic CDKN2A in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, CDKN2A VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.

Predicting clinical outcomes in COVID-19 using radiomics on chest radiographs.

OBJECTIVES: For optimal utilization of healthcare resources, there is a critical need for early identification of COVID-19 patients at risk of poor prognosis as defined by the need for intensive unit care and mechanical ventilation. We tested the feasibility of chest X-ray (CXR)-based radiomics metrics to develop machine-learning algorithms for predicting patients with poor outcomes. METHODS: In this Institutional Review Board (IRB) approved, Health Insurance Portability and Accountability Act (HIPAA) compliant, retrospective study, we evaluated CXRs performed around the time of admission from 167 COVID-19 patients. Of the 167 patients, 68 (40.72%) required intensive care during their stay, 45 (26.95%) required intubation, and 25 (14.97%) died. Lung opacities were manually segmented using ITK-SNAP (open-source software). CaPTk (open-source software) was used to perform 2D radiomics analysis. RESULTS: Of all the algorithms considered, the AdaBoost classifier performed the best with AUC = 0.72 to predict the need for intubation, AUC = 0.71 to predict death, and AUC = 0.61 to predict the need for admission to the intensive care unit (ICU). AdaBoost had similar performance with ElasticNet in predicting the need for admission to ICU. Analysis of the key radiomic metrics that drive model prediction and performance showed the importance of first-order texture metrics compared to other radiomics panel metrics. Using a Venn-diagram analysis, two first-order texture metrics and one second-order texture metric that consistently played an important role in driving model performance in all three outcome predictions were identified. CONCLUSIONS: Considering the quantitative nature and reliability of radiomic metrics, they can be used prospectively as prognostic markers to individualize treatment plans for COVID-19 patients and also assist with healthcare resource management. ADVANCES IN KNOWLEDGE: We report on the performance of CXR-based imaging metrics extracted from RT-PCR positive COVID-19 patients at admission to develop machine-learning algorithms for predicting the need for ICU, the need for intubation, and mortality, respectively.

Frame to Improve the Fit of N95 Filtering Face Mask Respirators.

OBJECTIVE: Test a device that can improve upon the seal of filtering face mask respirators (FFRs). METHODS: A 3-D prototype for a fit improvement frame (FIF) was created and quantitative fit testing was performed for FFRs with and without the FIF. RESULTS: Thirty eight volunteers underwent fit testing. The overall fit pass rate was 100% for the 3M model 1860 masks, 50% for the 3M model 8511 masks, 13% for the BYD CARE model DE2322, and 7% for the Honeywell DC300N95. When using the FIF the overall passing rate increase to 87% for the DE2322 + FIF (P < 0.01) and for the DC300N95 + FIF the passing rate increase to 73% (P < 0.01). CONCLUSION: The FIF is effective in improving the mask fit of a common flat fold N95 masks and potentially other N95 masks.

Examination of ATM, BRCA1, and BRCA2 promoter methylation in patients with pancreatic cancer.

BACKGROUND: Pancreatic cancer is a lethal disease with a poor 5-year survival rate. Pathogenic germline variants in the coding regions of ATM, BRCA1, and BRCA2 are found in up to 4.8% of pancreatic cancer patients. Germline promoter methylation and gene silencing arising from a germline variant or through other mechanisms have been described as a cause of tumor suppressor gene inactivation. METHODS: We measured the level of promoter methylation of the ATM, BRCA1, and BRCA2 genes in peripheral blood lymphocytes from 655 patients with pancreatic cancer using real-time PCR. RESULTS: No evidence of germline promoter methylation of any of these genes was found. Promoter methylation levels were minimal with no patient having promoter methylation greater than 3.4%, 3.3%, and 7.6% for ATM, BRCA1 and BRCA2, respectively, well below levels found in patients who have inherited promoter methylation (∼50%). CONCLUSIONS: We found no evidence of germline promoter methylation for the pancreatic susceptibility genes ATM, BRCA1 and BRCA2 in patients with pancreatic cancer. This study reveals that constitutive germline methylation of promoter CpG islands is rare in pancreatic cancer.

The time to offer treatments for COVID-19.

Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.

Machine learning based predictors for COVID-19 disease severity.

Predictors of the need for intensive care and mechanical ventilation can help healthcare systems in planning for surge capacity for COVID-19. We used socio-demographic data, clinical data, and blood panel profile data at the time of initial presentation to develop machine learning algorithms for predicting the need for intensive care and mechanical ventilation. Among the algorithms considered, the Random Forest classifier performed the best with [Formula: see text] for predicting ICU need and [Formula: see text] for predicting the need for mechanical ventilation. We also determined the most influential features in making this prediction, and concluded that all three categories of data are important. We determined the relative importance of blood panel profile data and noted that the AUC dropped by 0.12 units when this data was not included, thus indicating that it provided valuable information in predicting disease severity. Finally, we generated RF predictors with a reduced set of five features that retained the performance of the predictors trained on all features. These predictors, which rely only on quantitative data, are less prone to errors and subjectivity.

The Importance of Understanding the Stages of COVID-19 in Treatment and Trials.

COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan, China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease and the importance of timing for investigation and use of various agents. We considered articles related to COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the medRxiv preprint server. We identified relevant stages of COVID-19 including three periods: pre-exposure, incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or currently in use is likely to provide benefit rather than harm.

Role of Cyclooxygenase-2 in colorectal cancer patients.

Cyclooxygenase-2 (COX-2) is an inducible enzyme which triggers the biosynthesis of prostaglandins. COX-2 is activated in response to inflammatory stimuli and is one of the major molecules that is involved in the development and progression of colorectal cancer (CRC). Consistent with such a conceptual framework, it has been shown that COX-2 inhibitors prevent the carcinogenesis of CRC and aid in the treatment of sporadic or familial cases of CRC as shown by an overall increase in the survival rate. However, prolonged use of these inhibitors is associated with increase risk of development of cardiovascular complications, implying that further research is required to identify COX-2 inhibitors that are associated with lower risks of such complications.

A Cross-Sectional Study Examining the Seroprevalence of Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies in a University Student Population.

PURPOSE: The aim of the study was to determine the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in a university student population. METHODS: This was a cross-sectional survey study based on the World Health Organization population-based seroepidemiological investigational protocol for SARS-CoV-2 conducted between April 29, 2020, and May 8, 2020, examining SARS-CoV-2 antibody prevalence among 790 university students in Los Angeles, CA. Participants completed a questionnaire on potential risk factors before blood sampling. Samples were analyzed using the EUROIMMUN Anti-SARS-CoV-2 ELISA (IgG) for the qualitative detection of IgG class antibodies to SARS-CoV-2 in human serum or plasma. RESULTS: The estimated prevalence of SARS-CoV-2 antibody was 4.0% (3.0%, 5.1%). Factors associated with having a positive test included history of anosmia and/or loss of taste (95% CI: 1.4-9.6). A history of respiratory symptoms, with or without fever, was not associated with a positive antibody test. CONCLUSIONS: Prevalence of SARS-CoV-2 antibodies in the undergraduate and graduate student university population was similar to community prevalence.

Clostridium difficile disease in solid organ transplant recipients: a recommended treatment paradigm.

PURPOSE OF REVIEW: Organ transplant recipients have an increased incidence of Clostridium difficile disease and lower clinical response rates compared with the general population. Transplant specific treatment approaches are not defined. Therefore, a review of therapeutics in the transplant population is needed. RECENT FINDINGS: A literature review on the current therapies for C. difficile was performed focusing on the evidence in transplant recipients and immunosuppressed populations. SUMMARY: Transplant patients warrant an aggressive approach to treatment. The authors propose a suggested treatment paradigm for therapy.

Generation and characterization of a cell line from an intraductal tubulopapillary neoplasm of the pancreas.

Intraductal tubulopapillary neoplasm (ITPN) is a distinct precancerous lesion in the pancreas with unique clinical and molecular features. Although in vitro studies in two-dimensional culture have led to numerous important insights in pancreatic cancer, such models are currently lacking for precancerous lesions. In this study, we report the generation and characterization of a cell line from a human pancreatic ITPN. Neoplastic cells were initially cultured in a three-dimensional organoid system, followed by transfer to two-dimensional culture. RNA sequencing revealed a gene expression profile consistent with pancreatic ductal origin, and whole genome sequencing identified many somatic mutations (including in genes involved in DNA repair and Wnt signaling) and structural rearrangements. In vitro characterization of the tumorigenic potential demonstrated a phenotype between that of normal pancreatic ductal cells and cancer cell lines. This cell line represents a valuable resource for interrogation of unique ITPN biology, as well as precancerous pancreatic lesions more generally.

ATM Serine/Threonine Kinase and its Role in Pancreatic Risk.

Next-generation sequencing has led to the recent discovery of several novel pancreatic cancer susceptibility genes. These genes include ataxia telangiectasia mutated (ATM), a serine/threonine kinase that is an integral component of DNA repair. Pathogenic germline ATM variants are frequently identified in patients with pancreatic ductal adenocarcinoma (PDAC) with and without a family history of the disease. Loss of ATM is also a frequent somatic event in the development of PDAC. These discoveries have advanced our understanding of the genetic basis of pancreatic cancer risk and will impact patient care through appropriate patient-risk stratification; personalized screening and early detection efforts; and, for some, targeted therapy.