Rickettsia Phylogenomics: Unwinding the Intricacies of Obligate Intracellular Life

BACKGROUND: Completed genome sequences are rapidly increasing for Rickettsia, obligate intracellular alpha-proteobacteria responsible for various human diseases, including epidemic typhus and Rocky Mountain spotted fever. In light of phylogeny, the establishment of orthologous groups (OGs) of open reading frames (ORFs) will distinguish the core rickettsial genes and other group specific genes (class 1 OGs or C1OGs) from those distributed indiscriminately throughout the rickettsial tree (class 2 OG or C2OGs). METHODOLOGY/PRINCIPAL FINDINGS: We present 1823 representative (no gene duplications) and 259 non-representative (at least one gene duplication) rickettsial OGs. While the highly reductive (approximately 1.2 MB) Rickettsia genomes range in predicted ORFs from 872 to 1512, a core of 752 OGs was identified, depicting the essential Rickettsia genes. Unsurprisingly, this core lacks many metabolic genes, reflecting the dependence on host resources for growth and survival. Additionally, we bolster our recent reclassification of Rickettsia by identifying OGs that define the AG (ancestral group), TG (typhus group), TRG (transitional group), and SFG (spotted fever group) rickettsiae. OGs for insect-associated species, tick-associated species and species that harbor plasmids were also predicted. Through superimposition of all OGs over robust phylogeny estimation, we discern between C1OGs and C2OGs, the latter depicting genes either decaying from the conserved C1OGs or acquired laterally. Finally, scrutiny of non-representative OGs revealed high levels of split genes versus gene duplications, with both phenomena confounding gene orthology assignment. Interestingly, non-representative OGs, as well as OGs comprised of several gene families typically involved in microbial pathogenicity and/or the acquisition of virulence factors, fall predominantly within C2OG distributions. CONCLUSION/SIGNIFICANCE: Collectively, we determined the relative conservation and distribution of 14354 predicted ORFs from 10 rickettsial genomes across robust phylogeny estimation. The data, available at PATRIC (PathoSystems Resource Integration Center), provide novel information for unwinding the intricacies associated with Rickettsia pathogenesis, expanding the range of potential diagnostic, vaccine and therapeutic targets

Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19

IMPORTANCE: Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking. OBJECTIVE: To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022. EXPOSURE: Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19. MAIN OUTCOMES AND MEASURES: Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up. RESULTS: Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13). CONCLUSIONS AND RELEVANCE: In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer

Development and validation of a disease risk stratification system for patients with haematological malignancies: a retrospective cohort study of the European Society for Blood and Marrow Transplantation registry

BACKGROUND: Diagnosis and remission status at the time of allogeneic haematopoietic stem-cell transplantation (HSCT) are the principal determinants of overall survival following transplantation. We sought to develop a contemporary disease-risk stratification system (DRSS) that accounts for heterogeneous transplantation indications. METHODS: In this retrospective cohort study we included 55 histology and remission status combinations across haematological malignancies, including acute leukaemia, lymphoma, multiple myeloma, and myeloproliferative and myelodysplastic disorders. A total of 47 265 adult patients (aged ≥18 years) who received an allogeneic HSCT between Jan 1, 2012, and Dec 31, 2016, and were reported to the European Society for Blood and Marrow Transplantation registry were included. We divided EBMT patients into derivation (n=25 534), tuning (n=18 365), and geographical validation (n=3366) cohorts. Disease combinations were ranked in a multivariable Cox regression for overall survival in the derivation cohort, cutoff for risk groups were evaluated for the tuning cohort, and the selected system was tested on the geographical validation cohort. An independent single-centre US cohort of 660 patients transplanted between Jan 1, 2010, and Dec 31, 2015 was used to externally validate the results. FINDINGS: The DRSS model stratified patients in the derivation cohort (median follow-up was 2·1 years [IQR 1·0-3·2]) into five risk groups with increasing mortality risk: low risk (reference group), intermediate-1 (hazard ratio for overall survival 1·26 [95% CI 1·17-1·36], p<0·0001), intermediate-2 (1·53 [1·42-1·66], p<0·0001), high (2·03 [1·86-2·22], p<0·0001), and very high (2·87 [2·63-3·13], p<0·0001). DRSS levels were also associated with a stepwise increase in risk across the tuning and geographical validation cohort. In the external validation cohort (median follow-up was 5·7 years [IQR 4·5-7·1]), the DRSS scheme separated patients into 4 risk groups associated with increasing risk of mortality: intermediate-2 risk (hazard ratio [HR] 1·34 [95% CI 1·04-1·74], p=0·025), high risk (HR 2·03 [95% CI 1·39-2·95], p=0·00023) and very-high risk (HR 2·26 [95% CI 1·62-3·15], p<0·0001) patients compared with the low risk and intermediate-1 risk group (reference group). Across all cohorts, between 64% and 65% of patients were categorised as having intermediate-risk disease by a previous prognostic system (ie, the disease-risk index [DRI]). The DRSS reclassified these intermediate-risk DRI patients, with 855 (6%) low risk, 7111 (51%) intermediate-1 risk, 5700 (41%) intermediate-2 risk, and 375 (3%) high risk or very high risk of 14 041 patients in a subanalysis combining the tuning and internal geographic validation cohorts. The DRI projected 2-year overall survival was 62·1% (95% CI 61·2-62·9) for these 14 041 patients, while the DRSS reclassified them into finer prognostic groups with overall survival ranging from 45·7% (37·4-54·0; very high risk patients) to 73·1% (70·1-76·2; low risk patients). INTERPRETATION: The DRSS is a novel risk stratification tool including disease features related to histology, genetic profile, and treatment response. The model should serve as a benchmark for future studies. This system facilitates the interpretation and analysis of studies with heterogeneous cohorts, promoting trial-design with more inclusive populations. FUNDING: The Varda and Boaz Dotan Research Center for Hemato-Oncology Research, Tel Aviv University