Non-Small Cell Lung Cancer-Tumor Biology.

Lung cancer is one of the leading causes of cancer-related mortality worldwide among men and women [...].

Gender differences in appointments to pathology department interim chair positions and subsequent advancement to permanent chair positions.

Females are under-represented as departmental chairs in academic medical centers and identifying ways to increase their numbers in this position would be useful. A previous study of women chairs of pathology showed that 35% of permanent chairs had previously been interim chairs, suggesting that the interim position was a common pathway for women to advance to a permanent chair position. We sought to determine whether it might also be true for males and if not, possible reasons for the difference. Between January 2016 and June 2022, the Association of Pathology Chairs identified 50 people who had served as interim pathology department chairs. Males served as interim chairs more often than females (66% vs 34%), but, within this time frame, female interim chairs were more likely to become permanent chairs than males (47% of females compared to 27% of males). To better understand the difference in the rate of advancement from interim to permanent chair, we surveyed the 50 individuals who had served as interim chairs to explore gender differences in backgrounds, reasons for serving as interim chairs and reasons for seeking or not seeking the permanent chair position. No significant gender differences were found except that male interim chairs were older (59.2 years) than female interim chairs (50.4 years). This study affirms that serving as an interim chair is a common pathway for females to become permanent chairs, while it is less so for males, although the reasons for this difference could not be determined.

The phenotype of academic pathology chairs.

Academic pathology departments across the United States vary greatly in terms of size, clinical workloads and research activity. It is therefore not surprising that their chairs may be an equally diverse group. However, to our knowledge, little is formally known about the "phenotype" (academic credentials, leadership background, and subspecialty focus) or career pathways of these individuals. Using a survey tool, this study sought to determine whether or not dominant phenotypes or trends. Several predominant findings emerged including: race (80% Whites), gender (68% males), dual degrees (41% MD/PhDs), years in practice (56% being in practice >15 years at time of first chair appointment), rank upon appointment (88% holding the rank of professor), and funded research (67% holding research funding). While Anatomic and Clinical Pathology (AP/CP) certified chairs represented 46% of the cohort, 30% were AP-only and another 10% were Anatomic Pathology and Neuropathology (AP/NP) certified. For subspecialty focus, neuropathology (13%) and molecular pathology (15%) were disproportionately represented compared to the general population of pathologists. Previous leadership roles on the path to chairmanship included vice chair (41%), division chief (39%), residency program director (29%), or fellowship director (27%). Many (41%) had not participated in any formal business or leadership training. This information may influence training or experience pursued by individuals aspiring to academic pathology leadership. It also highlights the challenges of suboptimal diversity in race and gender, as well as the professional backgrounds of academic pathology chairs and may suggest consideration of alternate pathways to leadership.

TIMP-1 Dependent Modulation of Metabolic Profiles Impacts Chemoresistance in NSCLC.

The development of chemoresistance remains a significant barrier to treating NSCLC. Alteration of cancer cell metabolism is an important mechanism for chemoresistance. This study explored the role of aberrant metabolism in TIMP-1-mediated chemoresistance. Bioinformatics analysis identified an association of high TIMP-1 with altered energy metabolism. We have defined the role of depolarized mitochondria through a reduction in lactate secretion, higher ROS levels in TIMP-1 KD cells and reduced GSH levels. TIMP-1 modulates the metabolic profile via acetylation of mitochondrial STAT3 and its interaction with CD44. Intriguingly, monomers of acetylated STAT3 were critical for altered metabolism, whereas STAT3 dimers abrogated this function. Further, the mitochondrial metabolic profile was also altered in a cisplatin-resistant clone of A549 cells. We also correlated the immunoexpression of CD44, STAT3 and TIMP-1 in patient samples. This study provided evidence that TIMP-1 alters the metabolic profile by modulating mitochondrial metabolism via the CD44-STAT3 axis through its effects on STAT3 acetylation. It also lent further support to the critical role of TIMP-1 in chemoresistance. Interrogation of the TCGA-LUAD dataset revealed perturbations in the critical modulator that can alter metabolic states in cancer cells. Higher expression of a five-gene signature, including TIMP-1, correlated with immunosuppressive cells and was found to be associated with overall survival. This study identified several metabolic mechanisms that could influence therapeutic options and prognosis in NSCLC patients.

Clinical validation of a multiplex PCR-based detection assay using saliva or nasopharyngeal samples for SARS-Cov-2, influenza A and B.

The COVID-19 pandemic has resulted in significant diversion of human and material resources to COVID-19 diagnostics, to the extent that influenza viruses and co-infection in COVID-19 patients remains undocumented and pose serious public-health consequences. We optimized and validated a highly sensitive RT-PCR based multiplex-assay for the detection of SARS-CoV-2, influenza A and B viruses in a single-test. This study evaluated clinical specimens (n = 1411), 1019 saliva and 392 nasopharyngeal swab (NPS), tested using two-assays: FDA-EUA approved SARS-CoV-2 assay that targets N and ORF1ab gene, and the PKamp-RT-PCR based assay that targets SARS-CoV-2, influenza viruses A and B. Of the 1019 saliva samples, 17.0% (174/1019) tested positive for SARS-CoV-2 using either assay. The detection rate for SARS-CoV-2 was higher with the multiplex assay compared to SARS-specific assay [91.9% (160/174) vs. 87.9% (153/174)], respectively. Of the 392 NPS samples, 10.4% (41/392) tested positive for SARS-CoV-2 using either assay. The detection rate for SARS-CoV-2 was higher with the multiplex assay compared to SARS-specific assay [97.5% (40/41) vs. 92.1% (39/41)], respectively. This study presents clinical validation of a multiplex-PCR assay for testing SARS-CoV-2, influenza A and B viruses, using NPS and saliva samples, and demonstrates the feasibility of implementing the assay without disrupting the existing laboratory workflow.

Clinical and molecular assessment of an onco-immune signature with prognostic significance in patients with colorectal cancer.

Understanding the complex tumor microenvironment is key to the development of personalized therapies for the treatment of cancer including colorectal cancer (CRC). In the past decade, significant advances in the field of immunotherapy have changed the paradigm of cancer treatment. Despite significant improvements, tumor heterogeneity and lack of appropriate classification tools for CRC have prevented accurate risk stratification and identification of a wider patient population that may potentially benefit from targeted therapies. To identify novel signatures for accurate prognostication of CRC, we quantified gene expression of 12 immune-related genes using a medium-throughput NanoString quantification platform in 93 CRC patients. Multivariate prognostic analysis identified a combined four-gene prognostic signature (TGFB1, PTK2, RORC, and SOCS1) (HR: 1.76, 95% CI: 1.05-2.95, *p < 0.02). The survival trend was captured in an independent gene expression data set: GSE17536 (177 patients; HR: 3.31, 95% CI: 1.99-5.55, *p < 0.01) and GSE14333 (226 patients; HR: 2.47, 95% CI: 1.35-4.53, *p < 0.01). Further, gene set enrichment analysis of the TCGA data set associated higher prognostic scores with epithelial-mesenchymal transition (EMT) and inflammatory pathways. Comparatively, a lower prognostic score was correlated with oxidative phosphorylation and MYC and E2F targets. Analysis of immune parameters identified infiltration of T-reg cells, CD8+ T cells, M2 macrophages, and B cells in high-risk patient groups along with upregulation of immune exhaustion genes. This molecular study has identified a novel prognostic gene signature with clinical utility in CRC. Therefore, along with prognostic features, characterization of immune cell infiltrates and immunosuppression provides actionable information that should be considered while employing personalized medicine.

Optical genome mapping identifies rare structural variations as predisposition factors associated with severe COVID-19.

Impressive global efforts have identified both rare and common gene variants associated with severe COVID-19 using sequencing technologies. However, these studies lack the sensitivity to accurately detect several classes of variants, especially large structural variants (SVs), which account for a substantial proportion of genetic diversity including clinically relevant variation. We performed optical genome mapping on 52 severely ill COVID-19 patients to identify rare/unique SVs as decisive predisposition factors associated with COVID-19. We identified 7 SVs involving genes implicated in two key host-viral interaction pathways: innate immunity and inflammatory response, and viral replication and spread in nine patients, of which SVs in STK26 and DPP4 genes are the most intriguing candidates. This study is the first to systematically assess the potential role of SVs in the pathogenesis of COVID-19 severity and highlights the need to evaluate SVs along with sequencing variants to comprehensively associate genomic information with interindividual variability in COVID-19 phenotypes.

Alteration in Nasopharyngeal Microbiota Profile in Aged Patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is an infectious virus that causes coronavirus disease 2019 (COVID-19) transmitted mainly through droplets and aerosol affecting the respiratory tract and lungs. Little is known regarding why some individuals are more susceptible than others and develop severe symptoms. In this study, we analyzed the nasopharyngeal microbiota profile of aged patients with COVID-19 (asymptomatic vs. symptomatic) vs. healthy individuals. We examined the nasopharynx swab of 84 aged-matched patients, out of which 27 were negative asymptomatic (NegA), 30 were positive asymptomatic (PA), and 27 patients were positive symptomatic (PSY). Our analysis revealed the presence of abundant Cyanobacterial taxa at phylum level in PA (p-value = 0.0016) and PSY (p-value = 0.00038) patients along with an upward trend in the population of Litoricola, Amylibacter, Balneola, and Aeromonas at the genus level. Furthermore, to know the relationship between the nasal microbiota composition and severity of COVID-19, we compared PA and PSY groups. Our data show that the nasal microbiota of PSY patients was significantly enriched with the signatures of two bacterial taxa: Cutibacterium (p-value = 0.045) and Lentimonas (p-value = 0.007). Furthermore, we also found a significantly lower abundance of five bacterial taxa, namely: Prevotellaceae (p-value = 7 × 10-6), Luminiphilus (p-value = 0.027), Flectobacillus (p-value = 0.027), Comamonas (p-value = 0.048), and Jannaschia (p-value = 0.012) in PSY patients. The dysbiosis of the nasal microbiota in COVID-19 positive patients might have a role in contributing to the severity of COVID-19. The findings of our study show that there is a strong correlation between the composition of the nasal microbiota and COVID-19 severity. Further studies are needed to validate our finding in large-scale samples and to correlate immune response (cytokine Strome) and nasal microbiota to identify underlying mechanisms and develop therapeutic strategies against COVID-19.

Next-Generation Sequencing (NGS) in COVID-19: A Tool for SARS-CoV-2 Diagnosis, Monitoring New Strains and Phylodynamic Modeling in Molecular Epidemiology.

This review discusses the current testing methodologies for COVID-19 diagnosis and explores next-generation sequencing (NGS) technology for the detection of SARS-CoV-2 and monitoring phylogenetic evolution in the current COVID-19 pandemic. The review addresses the development, fundamentals, assay quality control and bioinformatics processing of the NGS data. This article provides a comprehensive review of the obstacles and opportunities facing the application of NGS technologies for the diagnosis, surveillance, and study of SARS-CoV-2 and other infectious diseases. Further, we have contemplated the opportunities and challenges inherent in the adoption of NGS technology as a diagnostic test with real-world examples of its utility in the fight against COVID-19.

Making a Difference: Adaptation of the Clinical Laboratory in Response to the Rapidly Evolving COVID-19 Pandemic.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2, led to unprecedented demands assigned to clinical diagnostic laboratories worldwide, forcing them to make significant changes to their regular workflow as they adapted to new diagnostic tests and sample volumes. Herein, we summarize the modifications/adaptation the laboratory had to exercise to cope with rapidly evolving situations in the current pandemic. In the first phase of the pandemic, the laboratory validated 2 reverse transcription polymerase chain reaction-based assays to test ∼1000 samples/day and rapidly modified procedures and validated various preanalytical and analytical steps to overcome the supply chain constraints that would have otherwise derailed testing efforts. Further, the pooling strategy was validated for wide-scale population screening using nasopharyngeal swab samples and saliva samples. The translational research arm of the laboratory pursued several initiatives to understand the variable clinical manifestations that this virus presented in the population. The phylogenetic evolution of the virus was investigated using next-generation sequencing technology. The laboratory has initiated the formation of a consortium that includes groups investigating genomes at the level of large structural variants, using genome optical mapping via this collaborative global effort. This article summarizes our journey as the laboratory has sought to adapt and continue to positively contribute to the unprecedented demands and challenges of this rapidly evolving pandemic.

SalivaSTAT: Direct-PCR and Pooling of Saliva Samples Collected in Healthcare and Community Setting for SARS-CoV-2 Mass Surveillance.

OBJECTIVES: Limitations of widespread current COVID-19 diagnostic testing exist in both the pre-analytical and analytical stages. To alleviate these limitations, we developed a universal saliva processing protocol (SalivaSTAT) that would enable an extraction-free RT-PCR test using commercially available RT-PCR kits. METHODS: We optimized saliva collection devices, heat-shock treatment, and homogenization. Saliva samples (879) previously tested using the FDA-EUA method were reevaluated with the optimized SalivaSTAT protocol using two widely available commercial RT-PCR kits. A five-sample pooling strategy was evaluated as per FDA guidelines. RESULTS: Saliva collection (done without any media) showed performance comparable to that of the FDA-EUA method. The SalivaSTAT protocol was optimized by incubating saliva samples at 95 °C for 30-min and homogenization, followed by RT-PCR assay. The clinical sample evaluation of 630 saliva samples using the SalivaSTAT protocol with PerkinElmer (600-samples) and CDC (30-samples) RT-PCR assay achieved positive (PPA) and negative percent agreements (NPAs) of 95.0% and 100%, respectively. The LoD was established as ~60-180 copies/mL by absolute quantification. Furthermore, a five-sample-pooling evaluation using 250 saliva samples achieved a PPA and NPA of 92% and 100%, respectively. CONCLUSION: We have optimized an extraction-free RT-PCR assay for saliva samples that demonstrates comparable performance to FDA-EUA assay (Extraction and RT-PCR).

Guideline-Adherent Clinical Validation of a Comprehensive 170-Gene DNA/RNA Panel for Determination of Small Variants, Copy Number Variations, Splice Variants, and Fusions on a Next-Generation Sequencing Platform in the CLIA Setting.

We describe the clinical validation of a targeted DNA and RNA-based next-generation sequencing (NGS) assay at two clinical molecular diagnostic laboratories. This assay employs simultaneous DNA and RNA analysis of all coding exons to detect small variants (single-nucleotide variants, insertions, and deletions) in 148 genes, amplifications in 59 genes, and fusions and splice variants in 55 genes. During independent validations at two sites, 234 individual specimens were tested, including clinical formalin-fixed, paraffin-embedded (FFPE) tumor specimens, reference material, and cell lines. Samples were prepared using the Illumina TruSight Tumor 170 (TST170) kit, sequenced with Illumina sequencers, and the data were analyzed using the TST170 App. At both sites, TST170 had ≥98% success for ≥250× depth for ≥95% of covered positions. Variant calling was accurate and reproducible at allele frequencies ≥5%. Limit of detection studies determined that inputs of ≥50 ng of DNA (with ≥3.3 ng/µl) and ≥50 ng RNA (minimum of 7 copies/ng) were optimal for high analytical sensitivity. The TST170 assay results were highly concordant with prior results using different methods across all variant categories. Optimization of nucleic acid extraction and DNA shearing, and quality control following library preparation is recommended to maximize assay success rates. In summary, we describe the validation of comprehensive and simultaneous DNA and RNA-based NGS testing using TST170 at two clinical sites.

Infection and Immune Memory: Variables in Robust Protection by Vaccines Against SARS-CoV-2.

SARS-CoV-2 is the cause of a recent pandemic that has led to more than 3 million deaths worldwide. Most individuals are asymptomatic or display mild symptoms, which raises an inherent question as to how does the immune response differs from patients manifesting severe disease? During the initial phase of infection, dysregulated effector immune cells such as neutrophils, macrophages, monocytes, megakaryocytes, basophils, eosinophils, erythroid progenitor cells, and Th17 cells can alter the trajectory of an infected patient to severe disease. On the other hand, properly functioning CD4+, CD8+ cells, NK cells, and DCs reduce the disease severity. Detailed understanding of the immune response of convalescent individuals transitioning from the effector phase to the immunogenic memory phase can provide vital clues to understanding essential variables to assess vaccine-induced protection. Although neutralizing antibodies can wane over time, long-lasting B and T memory cells can persist in recovered individuals. The natural immunological memory captures the diverse repertoire of SARS-CoV-2 epitopes after natural infection whereas, currently approved vaccines are based on a single epitope, spike protein. It is essential to understand the nature of the immune response to natural infection to better identify 'correlates of protection' against this disease. This article discusses recent findings regarding immune response against natural infection to SARS-CoV-2 and the nature of immunogenic memory. More precise knowledge of the acute phase of immune response and its transition to immunological memory will contribute to the future design of vaccines and the identification of variables essential to maintain immune protection across diverse populations.

Clinical Validation of a Sensitive Test for Saliva Collected in Healthcare and Community Settings with Pooling Utility for Severe Acute Respiratory Syndrome Coronavirus 2 Mass Surveillance.

The clinical performance of saliva compared with nasopharyngeal swabs (NPSs) has shown conflicting results in healthcare and community settings. In the present study, a total of 429 matched NPS and saliva sample pairs, collected in either healthcare or community setting, were evaluated. Phase-1 (protocol U) tested 240 matched NPS and saliva sample pairs; phase 2 (SalivaAll protocol) tested 189 matched NPS and saliva sample pairs, with an additional sample homogenization step before RNA extraction. A total of 85 saliva samples were evaluated with both protocols. In phase-1, 28.3% (68/240) samples tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from saliva, NPS, or both. The detection rate from saliva was lower compared with that from NPS samples (50.0% versus 89.7%). In phase-2, 50.2% (95/189) samples tested positive for SARS-CoV-2 from saliva, NPS, or both. The detection rate from saliva was higher compared with that from NPS samples (97.8% versus 78.9%). Of the 85 saliva samples evaluated with both protocols, the detection rate was 100% for samples tested with SalivaAll, and 36.7% with protocol U. The limit of detection with SalivaAll protocol was 20 to 60 copies/mL. The pooled testing approach demonstrated a 95% positive and 100% negative percentage agreement. This protocol for saliva samples results in higher sensitivity compared with NPS samples and breaks the barrier to using pooled saliva for SARS-CoV-2 testing.

Prognostic and therapeutic implications of extracellular matrix associated gene signature in renal clear cell carcinoma.

Complex interactions in tumor microenvironment between ECM (extra-cellular matrix) and cancer cell plays a central role in the generation of tumor supportive microenvironment. In this study, the expression of ECM-related genes was explored for prognostic and immunological implication in clear cell renal clear cell carcinoma (ccRCC). Out of 964 ECM genes, higher expression (z-score > 2) of 35 genes showed significant association with overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS). On comparison to normal tissue, 12 genes (NUDT1, SIGLEC1, LRP1, LOXL2, SERPINE1, PLOD3, ZP3, RARRES2, TGM2, COL3A1, ANXA4, and POSTN) showed elevated expression in kidney tumor (n = 523) compared to normal (n = 100). Further, Cox proportional hazard model was utilized to develop 12 genes ECM signature that showed significant association with overall survival in TCGA dataset (HR = 2.45; 95% CI [1.78-3.38]; p < 0.01). This gene signature was further validated in 3 independent datasets from GEO database. Kaplan-Meier log-rank test significantly associated patients with elevated expression of this gene signature with a higher risk of mortality. Further, differential gene expression analysis using DESeq2 and principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters between ECM-rich high-risk and ECM-poor low-risk patients. Geneset enrichment analysis (GSEA) identified significant perturbations in homeostatic kidney functions in the high-risk group. Further, higher infiltration of immunosuppressive T-reg and M2 macrophages was observed in high-risk group patients. The present study has identified a prognostic signature with associated tumor-promoting immune niche with clinical utility in ccRCC. Further exploration of ECM dynamics and validation of this gene signature can assist in design and application of novel therapeutic approaches.

Positive Job Search Experience for New Pathologists Seeking First Employment Between 2017 and 2019.

CONTEXT.­: An aging population calls for an adequate response in the workforce of medical professionals. The field of pathology has seen a downward trend in numbers of graduating US allopathic medical students choosing the specialty. Concerns about the job market after residency and fellowship graduation may be a contributing factor. OBJECTIVE.­: To provide an update on the trends emerging from a survey of pathology graduates' job search experience for their first nonfellowship position. DESIGN.­: Data from an annual job search survey sent by the College of American Pathologists Graduate Medical Education Committee between 2017 and 2019 to College of American Pathologists junior members and fellows in practice 3 years or less actively looking for a nonfellowship position was analyzed. Various indicators of the job search experience were compared year to year and with the previously published 2012 to 2016 benchmark data. RESULTS.­: Analysis revealed positive trends between the 2017 to 2019 data and the 2012 to 2016 benchmark data, including participants' perceiving more ease in finding a position, improved availability of jobs in their subspecialty choice, and higher ratings of satisfaction with the position accepted, as well as a greater proportion of respondents finding a position within 6 months of initiating their job search. CONCLUSIONS.­: The job market for pathology residents and fellows looking for their first nonfellowship position has improved with respect to multiple indicators, such as ease of finding a position, length of job search, and satisfaction with the position accepted when comparing 2017 to 2019 data with the 2012 to 2016 benchmark data.

Immunogenomic Gene Signature of Cell-Death Associated Genes with Prognostic Implications in Lung Cancer.

Lung cancer is one of the leading causes of death worldwide. Cell death pathways such as autophagy, apoptosis, and necrosis can provide useful clinical and immunological insights that can assist in the design of personalized therapeutics. In this study, variations in the expression of genes involved in cell death pathways and resulting infiltration of immune cells were explored in lung adenocarcinoma (The Cancer Genome Atlas: TCGA, lung adenocarcinoma (LUAD), 510 patients). Firstly, genes involved in autophagy (n = 34 genes), apoptosis (n = 66 genes), and necrosis (n = 32 genes) were analyzed to assess the prognostic significance in lung cancer. The significant genes were used to develop the cell death index (CDI) of 21 genes which clustered patients based on high risk (high CDI) and low risk (low CDI). The survival analysis using the Kaplan-Meier curve differentiated patients based on overall survival (40.4 months vs. 76.2 months), progression-free survival (26.2 months vs. 48.6 months), and disease-free survival (62.2 months vs. 158.2 months) (Log-rank test, p < 0.01). Cox proportional hazard model significantly associated patients in high CDI group with a higher risk of mortality (Hazard Ratio: H.R 1.75, 95% CI: 1.28-2.45, p < 0.001). Differential gene expression analysis using principal component analysis (PCA) identified genes with the highest fold change forming distinct clusters. To analyze the immune parameters in two risk groups, cytokines expression (n = 265 genes) analysis revealed the highest association of IL-15RA and IL 15 (> 1.5-fold, p < 0.01) with the high-risk group. The microenvironment cell-population (MCP)-counter algorithm identified the higher infiltration of CD8+ T cells, macrophages, and lower infiltration of neutrophils with the high-risk group. Interestingly, this group also showed a higher expression of immune checkpoint molecules CD-274 (PD-L1), CTLA-4, and T cell exhaustion genes (HAVCR2, TIGIT, LAG3, PDCD1, CXCL13, and LYN) (p < 0.01). Furthermore, functional enrichment analysis identified significant perturbations in immune pathways in the higher risk group. This study highlights the presence of an immunocompromised microenvironment indicated by the higher infiltration of cytotoxic T cells along with the presence of checkpoint molecules and T cell exhaustion genes. These patients at higher risk might be more suitable to benefit from PD-L1 blockade or other checkpoint blockade immunotherapies.

Infections of the lung: a predictive, preventive and personalized perspective through the lens of evolution, the emergence of SARS-CoV-2 and its pathogenesis.

The long evolutionary battle between humans and pathogens has played an important role in shaping the current network of host-pathogen interactions. Each organ brings new challenges from the perspective of a pathogen to establish a suitable niche for survival while subverting the protective mechanisms of the host. Lungs, the organ for oxygen exchange, have been an easy target for pathogens due to its accessibility. The organ has evolved diverse capabilities to provide the flexibility required for an organism's health and at the same time maintain protective functionality to prevent and resolve assault by pathogens. The pathogenic invasions are strongly challenged by healthy lung architecture which includes the presence and activity of the epithelium, mucous, antimicrobial proteins, surfactants, and immune cells. Competitively, the pathogens in the form of viruses, bacteria, and fungi have evolved an arsenal of strategies that can over-ride the host's protective mechanisms. While bacteria such as Mycobacterium tuberculosis (M. tuberculosis) can survive in dormant form for years before getting active in humans, novel pathogens can wreak havoc as they pose a high risk of morbidity and mortality in a very short duration of time. Recently, a coronavirus strain SARS-CoV-2 has caused a pandemic which provides us an opportunity to look at the host manipulative strategies used by respiratory pathogens. Their ability to hide, modify, evade, and exploit cell's processes are key to their survival. While pathogens like M. tuberculosis have been infecting humans for thousands of years, SARS-CoV-2 has been the cause of the recent pandemic. Molecular understanding of the strategies used by these pathogens could greatly serve in design of predictive, preventive, personalized medicine (PPPM). In this article, we have emphasized on the clinically relevant evasive strategies of the pathogens in the lungs with emphasis on M. tuberculosis and SARS-CoV-2. The molecular basis of these evasive strategies illuminated through advances in genomics, cell, and structural biology can assist in the mapping of vulnerable molecular networks which can be exploited translationally. These evolutionary approaches can further assist in generating screening and therapeutic options for susceptible populations and could be a promising approach for the prediction, prevention of disease, and the development of personalized medicines. Further, tailoring the clinical data of COVID-19 patients with their physiological responses in light of known host-respiratory pathogen interactions can provide opportunities to improve patient profiling and stratification according to identified therapeutic targets.

Factors Influencing US Allopathic Medical Students to Choose Pathology as a Specialty.

The SARS-CoV-2 pandemic has highlighted the crucial role of pathologists in the health care system at a time of significant decline in the number of US medical students matching to pathology residency positions. To understand this decline, a national survey of fourth-year US allopathic medical students was conducted to assess experiences, knowledge, and attitudes of pathology and factors that impact specialty choice. Participating in a separate pathology course did not increase the probability of choosing pathology. Experiences significantly associated with choosing pathology included clinical or research opportunities in pathology during the last 2 years of medical school, autopsy observation/participation, and participation in pathology interest groups. Many respondents felt they were not sufficiently exposed to pathology to consider it as a specialty. Those who considered pathology but did not choose it were less likely to report understanding the activities of pathologists and being recruited by pathology faculty and more likely to express a preference for more direct patient contact as compared to those entering pathology. In general, respondents agreed that pathology has a good work-life balance and a satisfying degree of intellectual challenge. On the other hand, respondents generally agreed that information on social media and perception of the pathology job market do not seem to be positive and few agreed that pathology is a highly regarded specialty. We identify steps to address these issues and increase the number of US medical students choosing pathology as a specialty crucial to the future of medicine and public health.

Widely Disseminated Cryptococcosis Manifesting in a Previously Undiagnosed Human Immunodeficiency Virus (HIV)-Positive 18-Year-Old.

BACKGROUND After initial infection with HIV, loss of CD4+ T cells progresses along a predictable timeline. The clinical latency stage lasts an average of 10 years, until the CD4+ T cell count falls below 200 cells/uL or the patient develops an AIDS-defining opportunistic infection/cancer. This report describes an unusual opportunistic infection in a young patient with no prior clinical evidence of HIV infection. CASE REPORT An 18-year-old man presented with fever, abdominal pain, and dyspnea for the previous 2 weeks and was symptomatically treated for gastroenteritis. He presented 2 weeks later with extreme fatigue, and a CT scan revealed diffuse lymphadenopathy. He was transferred to a regional hospital, but upon arrival and prior to detailed investigative work-up, he developed cardiac arrest. Despite maximal resuscitative efforts, he died approximately 8 h after admission. At autopsy, diffuse lymphadenopathy, splenomegaly, and pulmonary congestion were noted. Disseminated cryptococcal infection involving almost every organ system was identified at autopsy. A postmortem HIV-1 antibody test was positive. The cause of death was severe immunodeficiency as a result of advanced HIV infection resulting in disseminated cryptococcal infection, with cerebral edema, herniation, and respiratory failure. CONCLUSIONS This patient's non-specific symptoms in conjunction with his rapid decline made arriving at a correct diagnosis challenging. Only during autopsy was the disseminated fungal infection discovered, leading to suspicion of HIV infection. HIV autopsies are not uncommon, but the clinical history is usually known beforehand. This case report highlights the importance of considering HIV-related conditions in patients presenting with this array of symptoms, as well as to alert healthcare providers and staff to the need for increased biosafety precautions.