Large-scale Structure-Informed multiple sequence alignment of proteins with SIMSApiper.

SUMMARY: SIMSApiper is a Nextflow pipeline that creates reliable, structure-informed MSAs of thousands of protein sequences in time-frames faster than standard structure-based alignment methods. Structural information can be provided by the user or collected by the pipeline from online resources. Parallelization with sequence identity based subsets can be activated to significantly speed up the alignment process. Finally, the number of gaps in the final alignment can be reduced by leveraging the position of conserved secondary structure elements. AVAILABILITY AND IMPLEMENTATION: The pipeline is implemented using Nextflow, Python3 and Bash. It is publicly available on github.com/Bio2Byte/simsapiper. SUPPLEMENTARY INFORMATION: All data is available on GitHub.

Payer-Negotiated Price Variation and Relationship to Surgical Outcomes for the Most Common Cancers at NCI-Designated Cancer Centers.

BACKGROUND: Federal rules mandate that hospitals publish payer-specific negotiated prices for all services. Little is known about variation in payer-negotiated prices for surgical oncology services or their relationship to clinical outcomes. We assessed variation in payer-negotiated prices associated with surgical care for common cancers at National Cancer Institute (NCI)-designated cancer centers and determined the effect of increasing payer-negotiated prices on the odds of morbidity and mortality. MATERIALS AND METHODS: A cross-sectional analysis of 63 NCI-designated cancer center websites was employed to assess variation in payer-negotiated prices. A retrospective cohort study of 15,013 Medicare beneficiaries undergoing surgery for colon, pancreas, or lung cancers at an NCI-designated cancer center between 2014 and 2018 was conducted to determine the relationship between payer-negotiated prices and clinical outcomes. The primary outcome was the effect of median payer-negotiated price on odds of a composite outcome of 30 days mortality and serious postoperative complications for each cancer cohort. RESULTS: Within-center prices differed by up to 48.8-fold, and between-center prices differed by up to 675-fold after accounting for geographic variation in costs of providing care. Among the 15,013 patients discharged from 20 different NCI-designated cancer centers, the effect of normalized median payer-negotiated price on the composite outcome was clinically negligible, but statistically significantly positive for colon [aOR 1.0094 (95% CI 1.0051-1.0138)], lung [aOR 1.0145 (1.0083-1.0206)], and pancreas [aOR 1.0080 (1.0040-1.0120)] cancer cohorts. CONCLUSIONS: Payer-negotiated prices are statistically significantly but not clinically meaningfully related to morbidity and mortality for the surgical treatment of common cancers. Higher payer-negotiated prices are likely due to factors other than clinical quality.

The Cardiovascular Event Risk Associated with Tyrosine Kinase Inhibitors and the Lipid Profile in Patients with Chronic Myeloid Leukemia.

BACKGROUND: Second- and third-generation tyrosine kinase inhibitors (TKIs) are now available to treat chronic-phase chronic myeloid leukemia (CP-CML) in the first and second line. However, vascular adverse events (VAEs) have been reported for patients with CML treated with some TKIs. METHODS: We retrospectively evaluated the cumulative incidence (CI) and cardiovascular risk for 210 patients included in the Canarian Registry of CML. RESULT: With a mean follow up of 6 years, 19/210 (9.1%) patients developed VAEs, all of whom presented at least one cardiovascular risk factor at diagnosis. The mean time to VAE presentation was 54 months from the start of TKI treatment. We found a statistically significant difference between the CI for nilotinib-naïve vs. nilotinib-treated patients (p = 0.005), between dasatinib-naïve and dasatinib-treated patients (p = 0.039), and for patients who received three lines of treatment with first-line imatinib vs. first-line imatinib (p < 0.001). From the multivariable logistic regression analyses, the Framingham risk score (FRS) and patients with three lines of TKI with first-line imatinib were the only variables with statistically significant hazard ratios for VAE development. Significant increases in HDL-C and total cholesterol may also be predictive for VAE. CONCLUSIONS: In conclusion, it is important to estimate the cardiovascular risk at the diagnosis of CML as it can help determine whether a patient is likely to develop a VAE during TKI treatment.

Assessment of Mayaro virus vector competence of the mosquito Aedes aegypti (Linnaeus, 1762) populations in Argentine using dose-response assays.

Mayaro virus (MAYV; Alphavirus: Togaviridae) is an emerging pathogen in Latin America, causing fever and polyarthritis. Sporadic outbreaks of MAYV have occurred in the region, with reported human cases being imported to Europe and North America. Although primarily a risk for those residing in the Amazon basin's tropical forests, recent reports highlight that urbanization would increase the risk of MAYV transmission in Latin America. Urban emergence depends on human susceptibility and the ability of mosquitos like Aedes aegypti  (Linnaeus, 1762) (Diptera: Culicidae) to transmit MAYV. Despite the absence of active MAYV transmission in Argentine, the risk of introduction is substantial due to human movement and the presence of Ae. aegypti in the region. This study aimed to evaluate the susceptibility of different Argentine Ae. aegypti populations to MAYV genotype L (MAYV-L) using dose-response assays and determine barriers to virus infection, dissemination and transmission. Immature mosquito stages were collected in Buenos Aires, Córdoba and Rosario cities. Female Ae. aegypti (F2) were orally infected by feeding on five concentrations of MAYV-L, ranging from 1.0 to 6.0 log10 PFU/mL. Abdomens, legs and saliva were analysed using viral plaque assays. Results revealed that MAYV-L between infection and dissemination were associated with viral doses rather than the population origin. Infection rates varied between 3% and 65%, with a 50% infectious dose >5.5 log10 PFU/mL. Dissemination occurred at 39%, with a 50% dissemination dose of ~6.0 log10 PFU/mL. Dissemination among infected mosquitoes ranged from 60% to 86%, and transmission from disseminated mosquitoes ranged from 11% to 20%. Argentine Ae. aegypti populations exhibited a need for higher viral doses of MAYV-L than those typically found in humans to become infected. In addition, only a small proportion of infected mosquitoes were capable of transmitting the virus. Understanding MAYV transmission in urban areas is crucial for public health interventions.

[Dengue in Argentina: confirmation of our worst suspicions] / Dengue en Argentina: la confirmación de nuestras peores sospechas

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Private Equity Investment in Surgical Care.

OBJECTIVE: To characterize the extent of private equity investment affecting surgical care. SUMMARY BACKGROUND DATA: Over the last decade, investor-backed, for-profit private equity groups have invested in healthcare at an unprecedented rate, but the breadth of these investments affecting surgical practice remains largely unknown. METHODS: Four nationally representative databases were used to identify all merger/acquisitions involving surgical practices between 2015-2019, determine private equity investment in those transactions, and link the acquisitions with a physician dataset. RESULTS: 1,542 unique transactions were identified, of which 539 were financed by private equity. 58 transactions were then classified into their respective categories within surgical care: digestive disease, orthopedics, urology, vascular surgery, and plastic/cosmetic surgery. These transactions accounted for 199 practice sites and 1,405 physicians, averaging 24.2 physicians per transaction. Acquisition activity peaked in 2017 with a total of 63 practices involved. Digestive disease, urology, and orthopedic surgery accounted for the most activity. General surgeons were involved in a small share of the digestive disease practice acquisitions. Three "surgery-adjacent" categories were also identified: anesthesiology, ambulatory surgery centers, and surgical staffing firms. Among these, anesthesia was the largest category in terms of practices (194) and physicians (2,660) involved in transactions across the study period. Medical Service Organizations (MSOs) were a key mechanism through which private equity firms invested in surgical care. CONCLUSIONS: Private equity has engaged in substantial investment within surgical specialties, creating increased practice consolidation. These investments affect all levels of medical care and have notable implications for patients, practitioners, and policymakers.

Serological survey reveals enzootic circulation of St. Louis encephalitis and West Nile viruses in semiarid Monte ecosystem of Argentina.

St. Louis encephalitis virus (SLEV) and West Nile virus (WNV) are arboviruses transmitted by Culex mosquitoes and amplified in avian hosts. The present study aimed to investigate the presence and seasonal circulation of SLEV and WNV in La Rioja province, within the semiarid ecoregion of the Monte, Argentina. Over a two-year period, avian sera were collected and tested for neutralizing antibodies against SLEV and WNV. Our results reveal the enzootic activity of both viruses in this challenging environment. SLEV seroprevalence was 4.5% (35/778), with higher activity in spring (2016) and autumn (2017). WNV seroprevalence was 3.5% (27/778), peaking during the summer 2016-2017. Greater seroprevalence for SLEV in 2016 was detected for the Lark-like Brushrunner (Coryphistera alaudina) and the Short-billed Canastero (Asthenes baeri) and in 2017 for the Black-crested Finch (Lophospingus pusillus) and Lark-like Brushrunner, whereas for WNV greater seroprevalence in 2016 was detected for the Picui Ground Dove (Columbina picui) and in 2017 for the Lark-like Brushrunner and Band-tailed Seedeater (Catamenia analis). Additionally, five avian individuals experienced seroconversion during the sampling period, namely the Lark-like Brushrunner and White-fronted Woodpecker (Melanerpes cactorum) for SLEV, and the Lark-like Brushrunner, Greater Wagtail Tyrant (Stigmatura budytoides) and Many-colored Chaco Finch (Saltatricula multicolor) for WNV. The study highlights the persistence and circulation of these viruses in a semiarid ecosystem, raising questions about overwintering mechanisms and transmission dynamics. This research contributes to understanding arbovirus ecology in diverse environments. Further investigations are needed to assess the specific mechanisms facilitating virus persistence in the Monte ecoregion.

DNMT3A/TET2/ASXL1 Mutations are an Age-independent Thrombotic Risk Factor in Polycythemia Vera Patients: An Observational Study.

BACKGROUND: Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes (DNMT3A, TET2, and ASXL1). The objective of this study was to confirm this observation in a larger series of PV patients. METHODS: PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias. RESULTS: Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort (p = 0.007), as well as in low-risk patients (p = 0.039) and older patients (p = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation. CONCLUSION: Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.

Emergence of genotype III St. Louis encephalitis virus in the western United States potentially linked to a wetland in Argentina.

St. Louis encephalitis virus (SLEV) is endemic in the Americas and its transmission networks involve Culex mosquitoes and avian species. In 2015, a human encephalitis outbreak took place in Arizona and California, indicating the re-emergence of this pathogen in the US. Viral strains isolated in that outbreak belong to genotype III SLEV previously detected only in South America. In this study, genotype III SLEV was detected in mosquitoes collected in Mar Chiquita Lagoon (Córdoba, Argentina), an overwintering site for numerous migratory bird species. The genotype III SLEV sequence detected in this site shares the closest known ancestor with those introduced in Arizona in 2015. Our results highlight the potential significance of wetlands as key sites for arbovirus maintenance and emergence.

Expanding Access to High-Quality Cancer Care Through Policy-California Cancer Care Equity Act.

This Viewpoint describes key domains in which the California Cancer Care Equity Act may benefit patients, recommends potential improvements to further expand access and reduce disparities, and suggests possible safeguards to monitor and minimize unintended consequences.

Association of social determinants of health International Classification of Disease, Tenth Edition clinical modification codes with outcomes for emergency general surgery and trauma admissions.

BACKGROUND: Patients with Acute Care Surgery needs (ie, emergency general surgery diagnosis or trauma admission) are at particularly high risk for nonmedical patient-related factors that can be important drivers of healthcare outcomes. These social determinants of health are typically ascertained at the geographic area level (ie, county or neighborhood) rather than at the individual patient level. Recently, the International Classification of Diseases Tenth Revision, Tenth Edition created codes to capture health hazards related to patient socioeconomic and psychosocial circumstances. We sought to characterize the impact of these social determinants of health-related codes on perioperative outcomes among patients with acute care surgery needs. METHODS: Patients diagnosed between 2017 and 2020 with acute care surgery needs (ie, emergency general surgery diagnosis or a trauma admission) were identified in the California Department of Healthcare Access and information Patient Discharge database. Data on concomitant social determinants of health-related codes (International Classification of Diseases Tenth Revision, Tenth Edition Z55-Z65), which designated health hazards related to socioeconomic and psychosocial (socioeconomic and psychosocial, respectively) circumstances, were obtained. After controlling for patient factors, including age, sex, race, payer type, and admitting hospital, the association of socioeconomic and psychosocial codes with perioperative outcomes and hospital disposition was analyzed. RESULTS: Among 483,280 with an acute care surgery admission (emergency general surgery: n = 289,530, 59.9%; trauma: n = 193,705, 40.1%) mean age was 56.5 years (standard deviation: 21.5) and 271,911 (56.3%) individuals were male. Overall, 16,263 (3.4%) patients had a concomitant socioeconomic and psychosocial diagnosis code. The percentage of patients with a concurrent social determinants of health International Classification of Diseases Tenth Revision, Tenth Edition diagnosis increased throughout the study period from 2.6% in 2017 to 4.4% in 2020. Patients that were male (odds ratio 1.89; 95% confidence interval 1.82, 1.96), insured by Medicaid (odds ratio 5.43; 95% confidence interval 5.15, 5.72) or self-pay (odds ratio 3.04; 95% confidence interval 2.75, 3.36) all had higher odds of having an social determinants of health International Classification of Diseases Tenth Revision, Tenth Edition diagnosis. Black race did not have a significant association with an social determinants of health International Classification of Diseases Tenth Revision, Tenth Edition diagnosis (odds ratio 0.99; 95% confidence interval 0.94, 1.04); however, Hispanic (odds ratio 0.44; 95% confidence interval 0.43, 0.46) and Asian (odds ratio 0.40; 95% confidence interval 0.36, 0.44) race/ethnicity was associated with a lower odds of having an social determinants of health International Classification of Diseases Tenth Revision, Tenth Edition diagnosis. After controlling for competing risk factors on multivariable analyses, the risk-adjusted probability of hospital postoperative death was 3.1% (95% confidence interval 2.8, 3.4) among patients with a social determinants of health diagnosis versus 5.9% (95% confidence interval 5.9, 6.0) (odds ratio 0.48; 95% confidence interval 0.44, 0.54) among patients without a social determinants of health diagnosis. Risk-adjusted complications were 26.7% (95% confidence interval 26.1, 37.3) among patients with a social determinants of health diagnosis compared with 31.9% (95% confidence interval 31.7, 32.0) (odds ratio 0.74; 95% confidence interval 0.71, 0.77) among patients without a social determinants of health diagnosis. CONCLUSION: International Classification of Diseases Tenth Revision, Tenth Edition social determinants of health code use was low, with only 3.4% of patients having documentation of a socioeconomic and psychosocial circumstance. The presence of an International Classification of Diseases Tenth Revision, Tenth Edition social determinants of health code was not associated with greater odds of complications or death; however, it was associated with longer length of stay and higher odds of being discharged to a skilled nursing facility.

Association Between Historical Redlining and Access to High-Volume Hospitals Among Patients Undergoing Complex Cancer Surgery in California.

BACKGROUND: We sought to determine the impact of historical redlining on travel patterns and utilization of high-volume hospitals (HVHs) among patients undergoing complex cancer operations. METHODS: The California Department of Health Care Access and Information database was utilized to identify patients who underwent esophagectomy (ES), pneumonectomy (PN), pancreatectomy (PA), or proctectomy (PR) for cancer between 2010 and 2020. Patient ZIP codes were assigned Home Owners' Loan Corporation grades (A: 'Best'; B: 'Still Desirable'; C: 'Definitely Declining'; and D: 'Hazardous/Redlined'). A clustered multivariable regression was used to assess the likelihood of patients undergoing surgery at an HVH, bypassing the nearest HVH, and total real driving time and travel distance. RESULTS: Among 14,944 patients undergoing high-risk cancer surgery (ES: 4.7%, n = 1216; PN: 57.8%, n = 8643; PD: 14.4%, n = 2154; PR: 23.1%, n = 3452), 782 (5.2%) individuals resided in the 'Best', whereas 3393 (22.7%) individuals resided in redlined areas. Median travel distance was 7.8 miles (interquartile range [IQR] 4.1-14.4) and travel time was 16.1 min (IQR 10.7-25.8). Overall, 10,763 (ES: 17.4%; PN: 76.0%; PA: 63.5%; PR: 78.4%) patients underwent surgery at an HVH. On multivariable regression, patients residing in redlined areas were less likely to undergo surgery at an HVH (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.54-0.82) and were more likely to bypass the nearest hospital (OR 1.80, 95% CI 1.44-2.46). Notably, Medicaid insurance, minority status, limited English-language proficiency, and educational level mediated the disparities in access to HVH. CONCLUSION: Surgical disparities in access to HVH among patients from historically redlined areas are largely mediated by social determinants such as insurance and minority status.

Association of ICD-10 Clinical Modification Codes for Social Determinants of Health with Surgical Outcomes and Hospital Charges Among Cancer Patients.

INTRODUCTION: We sought to characterize the impact of social determinants of health (SDOH)-related codes on outcomes among patients with a cancer diagnosis. METHODS: Patients diagnosed with lung, pancreas, colon, or rectal cancer between 2017 and 2020 were identified in the California Department of Healthcare Access and Information Patient Discharge Database. Data on concomitant SDOH-related codes (International Classification of Diseases, Tenth Revision [ICD-10] Z55-Z65) designating health hazards related to socioeconomic and psychosocial circumstances were obtained. The association of these SDOH codes with postoperative outcomes was evaluated. RESULTS: Among 10,421 patients who underwent an operation from 2017 to 2020, median age was 66 years (interquartile range [IQR] 56-75) and nearly half of the cohort was male (n = 551,252.9%). In total, 102 (1%) patients had a concurrent ICD-10 SDOH diagnosis. After controlling for competing risk factors, the risk-adjusted probability of in-hospital death was 4.1% (95% confidence interval [CI] 1.0-7.2) among patients with an SDOH diagnosis compared with 2.9% (95% CI 2.5-3.2) among patients without an SDOH diagnosis (odds ratio [OR] 1.52, 95% CI 0.63-3.66; p = 0.258); postoperative complications were 27.0% (95% CI 20.0-34.1) compared with 24.9% (95% CI 24.1-25.6) among patients without an SDOH diagnosis (OR 1.15, 95% CI 0.73-1.82; p = 0.141), and length of stay was 10.6 days (95% CI 10.0-11.2) compared with 9.4 days (95% CI 9.3-9.5) among patients without an SDOH diagnosis. Patients with an SDOH diagnosis had a 5.19 (95% CI 3.23-8.34; p < 0.005) higher odds of being discharged to a skilled nursing facility versus patients without an SDOH diagnosis. CONCLUSION: Uptake and utilization of ICD-10 SDOH was 1% among California patients with lung, pancreas, colon, or rectal cancer. Patients with a concomitant ICD-10 SDOH code had longer length of stay and had higher odds of being discharged to a skilled nursing facility.

Circulation of picobirnavirus in Neotropical free-ranging mammals.

Picobirnavirus (PBV) is a family of non-enveloped double-stranded RNA viruses with bisegmented genomes. Segment 1 encodes the capsid protein and segment 2 encodes RNA-dependent RNA polymerase. They exhibit high genomic heterogeneity and infect a wide range of vertebrate hosts, including humans. The objective of this study was to expand our knowledge of the circulation of PBV in free-living animals from two regions (Brazil and Argentina) of the Atlantic Forest. Fecal samples were analyzed from free-living animals: tapir, brocket deer, peccary, and different species of rodents and marsupials. A total of 133 samples were collected and analyzed by RT-PCR, of which 44 (33.08%) were PBV-positive. Nine amplicons were sequenced, five species from Argentina and four from Brazil, and phylogenetic analysis was performed. The nucleotide and amino acid identities of the PBV strains detected in animals from Argentina and Brazil were between 66.3% and 82.5% and between 55.3% and 74.2%, respectively. The analysed strains presented conserved nucleotide blocks without distinction of the host species. The phylogenetic tree showed that PBV strains from Atlantic Forest animals belonging to genogroup I were grouped into different clusters, without defining groups according to host species (human or animal) or the geographical area of detection. This is the first study on PBV in free-living animals in the Atlantic Forest. Our analysis suggested that PBV strains can infect different animal species, leading to PBV transmission between animals and humans. This reinforces the hypothesis of previous crossover points in the ecology and evolution of heterologous PBV strains.

Modeling and updating the occurrence of Aedes aegypti in its southern limit of distribution in South America.

Aedes aegypti is the main vector of arboviruses in the world. This mosquito species is distributed from tropical to temperate regions. In Argentina, it has been reported in 20 out of 23 provinces and reaches its southernmost distribution in the world. Its distribution and persistence are affected by meteorological, demographic and environmental factors, such as temperature, precipitation, and population. The aim of this study was to update and model the occurrence of Aedes aegypti in its southern limit of distribution in Argentina. To this end, a total of 37 sites were inspected in La Pampa and Río Negro provinces. Generalized Linear Models were used to explain the occurrence of Aedes aegypti based on meteorological, environmental and demographic variables. Aedes aegypti was found in 11 cities of La Pampa province where it had not been previously reported, but was not found in any of the cities evaluated in Río Negro province. The averaged model explaining the occurrence of Aedes aegypti included the minimum temperature, precipitation and interactions between maximum temperature and precipitation as explanatory variables. Although precipitation was statistically significant, other factors such as minimum temperature are also important in modeling the occurrence of Aedes aegypti in its southernmost distribution limit.

Optimizing care delivery in expanding health systems: Views from clinical leaders.

INTRODUCTION: In response to intense market pressures, many hospitals have consolidated into systems. However, evidence suggests that consolidation has not led to the improvements in clinical quality promised by proponents of mergers. The challenges to delivering care within expanding health systems and the opportunities posed to surgical leaders remains largely unexplored. METHODS: Semistructured interviews with 30 surgical leaders at teaching hospitals affiliated with health systems from August-December 2019. Interviews were transcribed verbatim and coded in an iterative process using MaxQDA software. Attitudes and strategies toward redesigning health care delivery across expanding systems were analyzed using thematic analysis. RESULTS: Leaders reported challenges to redesigning care delivery across the system ranging from resource constraints (e.g. hospital beds and operating rooms) to evolving market demands (e.g., patient preferences to receive care close to home). However, participants also highlighted that system expansion provided multiple opportunities to increase access (e.g. decant low-complexity care to affiliated centers) and improve quality of care (e.g. standardize best practices) for diverse populations including the potential to leverage their health system to expand access and improve quality. CONCLUSIONS: Though evidence suggests that hospital consolidation has not led to redesigned care delivery or improved clinical quality at a national level, leaders are pursuing varying sets of strategies aimed at leveraging system expansion in order to improve access and quality of care.

Fluorinated Man9 as a High Mannose Mimetic to Unravel Its Recognition by DC-SIGN Using NMR.

Lectins are capable of reading out the structural information contained in carbohydrates through specific recognition processes. Determining the binding epitope of the sugar is fundamental to understanding this recognition event. Nuclear magnetic resonance (NMR) is a powerful tool to obtain this structural information in solution; however, when the sugar involved is a complex oligosaccharide, such as high mannose, the signal overlap found in the NMR spectra precludes an accurate analysis of the interaction. The introduction of tags into these complex oligosaccharides could overcome these problems and facilitate NMR studies. Here, we show the preparation of the Man9 of high mannose with some fluorine tags and the study of the interaction with its receptor, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). This fluorinated ligand has allowed us to apply heteronuclear two-dimensional (2D) 1H,19F STD-TOCSYreF NMR experiments, using the initial slope approach, which has facilitated the analysis of the Man9/DC-SIGN interaction, unequivocally providing the binding epitope.