Hematoxylin and Eosin Architecture Uncovers Clinically Divergent Niches in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the only cancers with an increasing incidence rate and is often associated with intra- and peri-tumoral scarring, referred to as desmoplasia. This scarring is highly heterogeneous in extracellular matrix (ECM) architecture and plays complex roles in both tumor biology and clinical outcomes that are not yet fully understood. Using hematoxylin and eosin (H&E), a routine histological stain utilized in existing clinical workflows, we quantified ECM architecture in 85 patient samples to assess relationships between desmoplastic architecture and clinical outcomes such as survival time and disease recurrence. By utilizing unsupervised machine learning to summarize a latent space across 147 local (e.g., fiber length, solidity) and global (e.g., fiber branching, porosity) H&E-based features, we identified a continuum of histological architectures that were associated with differences in both survival and recurrence. Furthermore, we mapped H&E architectures to a CO-Detection by indEXing (CODEX) reference atlas, revealing localized cell- and protein-based niches associated with outcome-positive versus outcome-negative scarring in the tumor microenvironment. Overall, our study utilizes standard H&E staining to uncover clinically relevant associations between desmoplastic organization and PDAC outcomes, offering a translatable pipeline to support prognostic decision-making and a blueprint of spatial-biological factors for modeling by tissue engineering methods.

Spatial phenotyping of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma with sparse tumor B-cells and a favorable prognosis. Variant growth patterns of NLPHL, however, often show advanced stage, progression to T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) and a worse prognosis. We studied the tumor microenvironment (TME) of NLPHL and THRLBCL using highplex imaging and spatial profiling at the single cell level. Our findings show distinct differences in TME composition and spatial configuration that differ among typical and variant NLPHL and THRLBCL. Typical NLPHL show abundant helper T-cell subsets, while THRLBCL show abundant cytotoxic T-cells and macrophages. Tumor B-cell size and content is lowest in typical NLPHL, followed by variant NLPHL, and highest in THRLBCL, whereas an opposite trend characterized TME B-cells. CD4/CD8 double-positive T-cells are seen in all NLPHL but not in the majority of THRLBCL and are spatially distant from LP-cells and TFH-rosettes. The differences in macrophage/monocyte content in distinguishing NLPHL pattern E from THRLBCL is further corroborated in independent cohorts of cases. Our results validate the current approach to classification and in addition provide novel insights that could be leveraged to refine clinical management for patients with this spectrum of lymphomas.

Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872-0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes.

Posterior reversible encephalopathy syndrome: A rare complication of rituximab therapy in rheumatoid arthritis.

Rituximab, a murine-human chimeric monoclonal antibody targeting CD20-positive B lymphocytes, has established itself as an effective and relatively safe biologic therapy for patients with refractory rheumatoid arthritis. Most common side effects associated with its use include infusion related reactions and cytopenia. Rare adverse effects such as progressive multifocal leukoencephalopathy and posterior reversible encephalopathy syndrome (PRES) have also been reported. Diagnosis of PRES following rituximab treatment requires a high index of suspicion correlated with clinical and radiological features in individuals at risk. Early diagnosis and prompt treatment is associated with a favorable prognosis. We present a case of a young man who developed PRES following rituximab administration on account of active rheumatoid arthritis. Timely diagnosis and prompt treatment ensured his uneventful recovery without residual neurological deficit.

Tinnitus and biopsychosocial ramifications of COVID-19 associated with severe suicide attempt-a case report.

The COVID-19 disease has been linked to multiple physical and mental health consequences which may be partially attributed to multi-system modulation by inflammatory cytokines. Post-acute sequelae (PASC) of SARS-CoV-2 infection, colloquially known as "Long Covid", has become an established entity. However, screening guidelines and interventions for COVID-19 survivors remain elusive. The neuropsychiatric sequelae of COVID-19 seem to originate from a cumulation of biopsychosocial factors which may predispose individuals to acute psychiatric decompensation irrespective of a previously diagnosed mental illness. We present a case report which illustrates how cognitive issues and medical complaints may negatively interact resulting in significant depression and a severe suicide attempt.

Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.

Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.

Exploring Intra and Interorganizational Integration Efforts Involving the Primary Care Sector - A Case Study from Ontario.

Background: The primary care sector is uniquely positioned to lead the coordination of providers and organizations across health and social care sectors. This study explores whether intraorganizational (professional) integration within a primary care team might be related to interorganizational integration between primary care and other community partners involved in caring for complex patients. Methods: Two care coordination initiatives (Health Links) were selected - one led by a primary care team with a high level of intraorganizational integration as assessed by the Collaborative Practice Assessment Tool (CPAT), and the other led by a primary care team with a low level of intraorganizational integration. A case study design involving a social network approach was used to assess interorganizational integration across six types of relationships including regular contact, perceived level of integration, referrals, information sharing, joint care planning, and shared resources. Results: Compared to the high-CPAT led case, the low-CPAT led case had higher density (more ties among organizations) in terms of regular contact, integration, and sharing of resources, whereas the opposite was true for the referral, information sharing, and joint care planning networks. Network centralization (extent to which network activity is influenced by one or a group of organizations) was higher for the high-CPAT case compared to the low-CPAT case in the integration, referrals, and joint care planning networks, while the low-CPAT case had higher centralization with regard to regular contact, information sharing, and shared resources. Conclusion: The interplay between intra and interorganizational integration remains unclear. We found no consistent differences in the patterns of ties across the six types of networks examined between the two cases. Assessing changes in network metrics for different organizations in each case over time, and supplementing network findings through in-depth interviews with network members are key next steps to consider.

Small Fiber Neuropathy Associated With the Moderna SARS-CoV-2 Vaccine.

Efforts of controlling viral transmission began soon after the first cases of coronavirus disease 2019 (COVID-19) infections were identified. Initial efforts were related to contact precautions, hand hygiene, and mask-wearing; however, it was soon evident that a robust global immunization drive was the most effective way to curb disease transmission. In the United States, the first doses of COVID-19 vaccines were rolled out soon after the FDA granted emergency use authorization for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. What this also meant was that many of the routine phases that any new drug or vaccine goes through before being released publicly were bypassed. Over the past two years, various side effects and reactions have been seen after COVID-19 vaccine administration, the most common being local injection site events (e.g., pain, redness, swelling) and systemic effects (e.g., fatigue, headaches, myalgias). We report the case of a 64-year-old female who developed bilateral lower extremity numbness and tingling within weeks of receiving the third dose of Moderna SARS-CoV-2 vaccine. The patient underwent extensive testing to ascertain the diagnosis. She had negative autonomic testing and normal nerve conduction study/electromyography (EMG), which did not reveal large fiber neuropathy. Eventually, the patient underwent a skin biopsy, which revealed small fiber neuropathy. This case report highlights the importance of keeping a broad differential for rare side effects, such as small fiber neuropathy, that are currently being seen and reported in the literature.

Enoxacin-based derivatives: antimicrobial and antibiofilm agent: a biology-oriented drug synthesis (BIODS) approach.

Background: To find alternative molecules against Klebsiella pneumonia, Proteus mirabilis and methicillin-resistant Staphylococcus aureus, new enoxacin derivatives were synthesized and screened. Methods: All derivatives exhibited promising antibacterial activities as compared to standard enoxacin (2 µg/ml) and standard cefixime (82 µg/ml). Compounds 2, 3 and 5 significantly downregulated the gene expression of biofilm-forming genes. Conclusion: Based on our results, these molecules may serve as potential drug candidates to cure several bacterial infections in the future.

Multiplex imaging of human induced pluripotent stem cell-derived neurons with CO-Detection by indEXing (CODEX) technology.

BACKGROUND: Human induced pluripotent stem cell (iPSC) models have been hailed as a breakthrough for understanding disease and developing new therapeutics. The major advantage of iPSC-derived neurons is that they carry the genetic background of the donor, and as such could be more predictive for clinical translation. However, the development of these cell models is time-consuming and expensive and it is thus critical to maximize readout of markers for immunocytochemistry. One option is to use a highly multiplexed fluorescence imaging assay, like CO-Detection by indEXing (CODEX), which allows detection of 50 + targets in situ. NEW METHOD: This paper describes the development of CODEX in neuronal cell cultures derived from human iPSCs. RESULTS: We differentiated human iPSCs into mixed neuronal and glial cultures on glass coverslips. We then developed and optimized a panel of 21 antibodies to phenotype iPSC-derived neuronal subtypes of cortical, dopaminergic, and striatal neurons, as well as astrocytes, and pre-and postsynaptic proteins. COMPARISON WITH EXISTING METHODS: Compared to standard immunocytochemistry, CODEX oligo-conjugated fluorophores circumvent antibody host interactions and allow for highly customized multiplexing. CONCLUSION: We show that CODEX can be applied to iPSC neuronal cultures and developed fixation and staining protocols for the neurons to sustain the multiple wash-stain cycles of the technology. Furthermore, we demonstrate both cellular and subcellular resolution imaging of multiplexed markers in the same sample.

Examining the Long-Term Sequelae of SARS-CoV2 Infection in Patients Seen in an Outpatient Psychiatric Department.

Background: The acute phase of Coronavirus disease-19 (COVID-19) is well known. However, there is now an increasing number of patients suffering from the post-acute sequelae of COVID-19 (PASC Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis), including neuropsychiatric symptoms. The purpose of this report is to describe the sociodemographic, diagnostic and treatment characteristics of patients evaluated in an outpatient psychiatric setting for PASC. Methods: A retrospective review of 30 individuals with documented COVID-19 illness treated at a university hospital-based Post-COVID-19 Recovery Program were referred to an outpatient psychiatric department for consultation and treatment from December 2020 to July 2021. All individuals complained of neuropsychiatric symptoms including anxiety, depression, fatigue and cognitive problems. Data on sociodemographic characteristics, psychiatric diagnosis, prominent psychological themes and treatment prescribed were described and, where applicable, analyzed with SPSS software. Results: The study population consisted of patients between 25 and 82 years old, with a predominance of women between 46 and 60 years. Approximately half of the patient population had a primary diagnosis of major depressive disorder, often combined with prominent anxiety. Over two-thirds of the patient population reported a combination of depression, fatigue and cognitive complaints, predominantly memory and slowed processing speed. Prominent stressors and psychological themes included social and occupational decline, isolation, lack of empathy and understanding from family, friends and employers, and apprehension about future ability to return to their baseline level of function. Treatments recommended included individual and group psychotherapy, medication and cognitive rehabilitation. Modafinil and antidepressants, often in combination, were the most commonly used medications, intended to target the pervasive fatigue, depressive, and anxiety these individuals were facing. Conclusion: Clinical experience from this patient population underscored the significant medical, emotional, neurocognitive and functional sequelae of PASC. Management of these individuals requires a collaborative approach with the availability of psychotherapeutic interventions, pharmacologic treatment, neurocognitive assessment and remediation to address these symptoms.

Prebiotic potential of enzymatically prepared resistant starch in reshaping gut microbiota and their respond to body physiology.

The increase in consumer demand for high-quality food products has led to growth in the use of new technologies and ingredients. Resistant starch (RS) is a recently recognised source of fibre and has received much attention for its potential health benefits and functional properties. However, knowledge about the fate of RS in modulating complex intestinal communities, the microbial members involved in its degradation, enhancement of microbial metabolites, and its functional role in body physiology is still limited. For this purpose, the current study was designed to ratify the physiological and functional health benefits of enzymatically prepared resistant starch (EM-RSIII) from maize flour. To approve the beneficial health effects as prebiotic, EM-RSIII was supplemented in rat diets. After 21 days of the experiment, EM-RSIII fed rats showed a significant reduction in body weight gain, fecal pH, glycemic response, serum lipid profile, insulin level and reshaping gut microbiota, and enhancing short-chain fatty acid compared to control. The count of butyrate-producing and starch utilizing bacteria, such as Lactobacillus, Enterococcus, and Pediococcus genus in rat's gut, elevated after the consumption of medium and high doses of EM-RSIII, while the E. coli completely suppressed in high EM-RSIII fed rats. Short-chain fatty acids precisely increased in feces of EM-RSIII feed rats. Correlation analysis demonstrated that the effect of butyrate on functional and physiological alteration on the body had been investigated during the current study. Conclusively, the present study demonstrated the unprecedented effect of utilising EM-RSIII as a diet on body physiology and redesigning gut microorganisms.

Microbial Pretreatment of Chicken Feather and Its Co-digestion With Rice Husk and Green Grocery Waste for Enhanced Biogas Production.

To utilize wastes and residues sustainably and excellently, there is a need to fend for efficient methods and resources for biogas production. Use of poultry waste for biogas production represents one of the most important routes toward reaching global renewable energy targets. The current study involves microbial pretreatment of chicken feather waste, followed by its co-digestion with rice husk and green grocery waste in batch and continuous reactors, respectively. Microbial pretreatment of chicken feathers by keratinase secreting Pseudomonas aeruginosa was an effective and eco-friendly approach to make its recalcitrant structure available as a raw substrate for biogas production. The current study also addressed the enhancement and stability of anaerobic digestion by co-digestion. Results demonstrated that biogas production was increased by microbial pretreatment of chicken feathers and that the percentage increase in biogas yield was 1.1% in microbialy pretreated feathers compared to mono-digestion (non-pretreated feathers) in batch fermentation. The highest yield of biogas was obtained in a batch reactor having co-digestion of pretreated rice husk and microbial pretreated chicken feathers. The co-digestion of chicken feathers hydrolysate with green grocery waste in continuous fermentation mode has also enhanced the biogas yield as compared to average of mono-digestion (chicken feather hydrolysate and green grocery waste) and, therefore, improve the efficiency of the overall process.

Homeless Shelters: HIV Testing During the Atlanta Tuberculosis Outbreak (2008-2018).

People experiencing homelessness are at increased risk of tuberculosis (TB) and HIV. We examined the impact of integrating HIV testing and mandatory TB screening on HIV test uptake (HTU) during a multishelter TB outbreak in Atlanta, Georgia (2008-2018). Overall HTU was low; however, the intervention led to a reversal of declining HTU trend (rate ratio = 1.11; 95% confidence interval = 1.04, 1.19). Concerted efforts to increase HIV testing access and uptake alongside robust TB control efforts may increase progress toward the goals of End TB and Ending the HIV Epidemic. (Am J Public Health. 2022;112(6):881-885. https://doi.org/10.2105/AJPH.2022.306801).

cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment.

BACKGROUND: Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear. METHODS: Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells. RESULTS: In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients. CONCLUSIONS: Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.

Examining the extent and factors associated with interprofessional teamwork in primary care settings.

Despite growing emphasis on adopting team-based models of primary care to facilitate patient access to a diverse range of care providers, our understanding of team functioning within primary care teams remains limited. This study examined interprofessional teamwork within primary care practices (Family Health Teams [FHT] and Community Health Centers - [CHC]) in Ontario and explored team-level and organizational factors associated with interprofessional teamwork. Interprofessional teamwork was measured using the Collaborative Practice Assessment Tool (CPAT), which was completed by providers in each participating team. The CPAT responses of 988 providers representing on average 12 professions (sd = 2.1) across 66 teams (44 FHTs and 22 CHCs) were included in the analysis. The average CPAT score was 46.6 (sd = 2.5). CHCs had significantly higher CPAT scores than FHTs (mdiff = 1.7, p = .02). Using diverse communication mechanisms to share information, increasing quality improvement capacities, and age of practice, had a statistically significant positive association with CPAT scores. Increasing team size, using centralized administrative processes, a high level of information exchange, and having a mixed governance board were significantly negatively associated with CPAT score. Findings illustrate factors associated with interprofessional teamwork and offer insight into the comparative performance of two team-based primary care models in Ontario.

Factors Affecting E-Shopping Behaviour: Application of Theory of Planned Behaviour.

E-shopping is a rapidly growing phenomenon among different individuals who intend to shop online. However, a trust deficit in the E-shopping environment has always been a critical issue in the brick-and-click mode of shopping, being one of the main reasons for E-cart abandonment in E-commerce. This empirical study is aimed at investigating the perceived effect of website trust on E-shopping intentions and behaviour, drawing upon the theory of planned behaviour (TPB). Data were collected through self-administered questionnaires from working adults who shop for garments online. Structural equation modelling was used to evaluate the model fit and assumptions. Our findings suggest that website trust and E-shopping attitude play substantial roles in building E-shopping intentions and actual behaviours. Both are the significant predictors of the behaviour mediated by E-shopping intentions. However, E-shopping intentions did not mediate between subjective norms and E-shopping behaviour, when working adults decide to purchase garments online.

Impact of COVID-19 Pandemic on Treatment of Pediatric Oncology Patients: Report from Resource-limited Setting.

The aim of this study was to determine how the COVID-19 pandemic impacted on the effective management; and the outcome of pediatric oncology patients in Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore. Data was retrospectively reviewed from 15 March to 15 June 2020 after the approval of Institutional Review Board Committee. A total of 258 patients on active oncology treatment between the study period were included. The total number of patients whose treatment was affected were 118 (45.7%), while 140 (54.3%) patients received treatment in time. There was total 34 (13.2%) patients relapsed, 23 (67.6%) patients in which treatment delayed, and 11 (32.4%) patients in which their treatment not delayed; while, n=218 (84.5%) were in remission, and 6 (2.3%) patients absconded. COVID-19 pandemic caused a sudden impediment in the treatment of pediatric oncology patients, and is likely to affect the long-term survival outcome of pediatric oncology patients. Key Words: Chemotherapy, Radiotherapy, Surgery, Long term outcome.

The Impact of Private Standards on Corporate Social Responsibility Compliance and Rural Workers' Motivation in Developing Countries: A Study of Mango Farms in Pakistan.

This study examines the role of a private standard on corporate social responsibility (CSR) compliance in the Pakistani mango industry and how this compliance affects rural workers' motivation. Pakistan is the fifth largest mango producer in the world and the fourth largest exporter in global mango trade; also, mango is the biggest fruit crop within the country. Mango trade is subject to trade terms, where buyers decide the conditions of trade agreements by means of codes of conduct. The key dimensions of the codes involved in agrofood trade are food safety, traceability, worker welfare, and environmental consideration, issues which are all connected with CSR. Private standards ensure compliance with these codes of conduct. This study draws on interviews and a questionnaire survey with certified mango producers and farm workers in Pakistan. The mango industry also involves other stakeholders such as government institutes and NGOs; interviews were also conducted with their representatives. Given that this study is an impact assessment research, the researcher designed a theoretical framework using a mixed method approach to investigate the rationale behind acquiring the standard by the mango growers in Pakistan and what impact (if any) this shift has generated with regard to the farm workers' job satisfaction and motivation. This study is the first to empirically examine good agricultural practices in Pakistan and evaluate their impact. This study shows that private standards play a significant role in ensuring compliance, and CSR practices implemented through them were found to be positively related to the rural workers' job satisfaction and motivation. Furthermore, this study has made separate contributions to theory, methodology, and practice. The production of the synergistic model for improving compliance is among the key highlights of the study. The findings of this study can extend to other agriculture and primary production industry workers in Pakistan and even beyond to other developing countries' rural agriculture workers.