Trypanosome RNA helicase KREH2 differentially controls non-canonical editing and putative repressive structure via a novel proposed 'bifunctional' gRNA in mRNA A6.

U-insertion/deletion (U-indel) RNA editing in trypanosome mitochondria is directed by guide RNAs (gRNAs). This editing may developmentally control respiration in bloodstream forms (BSF) and insect procyclic forms (PCF). Holo-editosomes include the accessory RNA Editing Substrate Binding Complex (RESC) and RNA Editing Helicase 2 Complex (REH2C), but the specific proteins controlling differential editing remain unknown. Also, RNA editing appears highly error prone because most U-indels do not match the canonical pattern. However, despite extensive non-canonical editing of unknown functions, accurate canonical editing is required for normal cell growth. In PCF, REH2C controls editing fidelity in RESC-bound mRNAs. Here, we report that KREH2, a REH2C-associated helicase, developmentally controls programmed non-canonical editing, including an abundant 3' element in ATPase subunit 6 (A6) mRNA. The 3' element sequence is directed by a proposed novel regulatory gRNA. In PCF, KREH2 RNAi-knockdown up-regulates the 3' element, which establishes a stable structure hindering element removal by canonical initiator-gRNA-directed editing. In BSF, KREH2-knockdown does not up-regulate the 3' element but reduces its high abundance. Thus, KREH2 differentially controls extensive non-canonical editing and associated RNA structure via a novel regulatory gRNA, potentially hijacking factors as a 'molecular sponge'. Furthermore, this gRNA is bifunctional, serving in canonical CR4 mRNA editing whilst installing a structural element in A6 mRNA.

A retrospective cohort study of socioeconomic deprivation and post-liver transplant survival in adults.

The Area Deprivation Index is a granular measure of neighborhood socioeconomic deprivation. The relationship between neighborhood socioeconomic deprivation and recipient survival following liver transplantation (LT) is unclear. To investigate this, the authors performed a retrospective cohort study of adults who underwent LT at the University of Washington Medical Center from January 1, 2004, to December 31, 2020. The primary exposure was a degree of neighborhood socioeconomic deprivation as determined by the Area Deprivation Index score. The primary outcome was posttransplant recipient mortality. In a multivariable Cox proportional analysis, LT recipients from high-deprivation areas had a higher risk of mortality than those from low-deprivation areas (HR: 1.81; 95% CI: 1.03-3.18, p =0.04). Notably, the difference in mortality between area deprivation groups did not become statistically significant until 6 years after transplantation. In summary, LT recipients experiencing high socioeconomic deprivation tended to have worse posttransplant survival. Further research is needed to elucidate the extent to which neighborhood socioeconomic deprivation contributes to mortality risk and identify effective measures to improve survival in more socioeconomically disadvantaged LT recipients.

Artificial Intelligence in Facial Plastic and Reconstructive Surgery: A Systematic Review.

Artificial intelligence (AI) is a technology that is evolving rapidly and is changing the world and medicine as we know it. After reviewing the PROSPERO database of systematic reviews, there is no article related to this topic in facial plastic and reconstructive surgery. The objective of this article was to review the literature regarding AI applications in facial plastic and reconstructive surgery.A systematic review of the literature about AI in facial plastic and reconstructive surgery using the following keywords: Artificial Intelligence, robotics, plastic surgery procedures, and surgery plastic and the following databases: PubMed, SCOPUS, Embase, BVS, and LILACS. The inclusion criteria were articles about AI in facial plastic and reconstructive surgery. Articles written in a language other than English and Spanish were excluded. In total, 17 articles about AI in facial plastic met the inclusion criteria; after eliminating the duplicated papers and applying the exclusion criteria, these articles were reviewed thoroughly. The leading type of AI used in these articles was computer vision, explicitly using models of convolutional neural networks to objectively compare the preoperative with the postoperative state in multiple interventions such as facial lifting and facial transgender surgery.In conclusion, AI is a rapidly evolving technology, and it could significantly impact the treatment of patients in facial plastic and reconstructive surgery. Legislation and regulations are developing slower than this technology. It is imperative to learn about this topic as soon as possible and that all stakeholders proactively promote discussions about ethical and regulatory dilemmas.

Association of the rs1126616 and rs9138 Variants in the SPP1 Gene among Mexican Patients with Systemic Lupus Erythematosus and Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a multisystem disease considered a prototype of the main autoimmune disease and presents serious complications, such as lupus nephritis (LN), which generates a significant impact on morbidity and mortality. The SPP1 gene encodes the osteopontin (OPN) protein, which plays a crucial role in the regulation of inflammation and immunity. The variants rs1126616 and rs9138 of this gene have been associated with the inflammatory response. The study aims to analyze the association of the rs1126616 and rs9138 variants of the SPP1 gene in SLE Mexican-Mestizo patients without LN (SLE-LN). In this cross-sectional study, a total of 171 genomic DNA samples from SLE patients were clinically confirmed, of which 111 were SLE without LN, 60 were SLE with LN, and 100 healthy individuals were included as reference group. The rs1126616 variant was genotyped using PCR-RFLPs, and the rs9138 variant was genotyped using qPCR TaqMan. The TT genotype, the recessive model [OR 2.76 (95% CI 1.31-5.82), p = 0.011], and the T allele [OR 2.0 (95% CI 1.26-3.16), p = 0.003] of the rs1126616 variant are risk factors for SLE with LN. By contrast, the rs9138 variant did not show statistically significant differences among SLE patients stratified by LN. In our study of SLE Mexican-Mestizo patients with and without NL, demographic and clinical characteristics do not differ from other SLE populations, and the TT genotype of the rs1126616 variant of the SPP1 gene confers a risk factor for the presentation of LN. Otherwise, the rs9138 variant did not show association with NL.

Comparative Analysis of Clinical Practice Guidelines for the Pharmacological Treatment of Type 2 Diabetes Mellitus in Latin America.

PURPOSE OF REVIEW: Type 2 diabetes mellitus (T2DM) is one of the leading causes of death and disability in the world. The majority of diabetes deaths (> 80%) occur in low- and middle-income countries, which are predominant in Latin America. Therefore, the purpose of this article is to compare the clinical practice guideline (CPG) for the pharmacological management of T2DM in Latin America (LA) with international reference guidelines. RECENT FINDINGS: Several LA countries have recently developed CPGs. However, the quality of these guidelines is unknown according to the AGREE II tool and taking as reference three CPGs of international impact: American Diabetes Association (ADA), European Diabetes Association (EASD), and Latin American Diabetes Association (ALAD). Ten CPGs were selected for analysis. The ADA scored > 80% on the AGREE II domains and was selected as the main comparator. Eighty percent of LA CPGs were developed before 2018. Only one was not recommended (all domains < 60%). The CPGs in LA have good quality but are outdated. They have significant gaps compared to the reference. There is a need for improvement, as proposing updates every three years to maintain the best available clinical evidence in all guidelines.

State of pediatric liver transplantation in the United States and achieving zero wait list mortality with ideal outcomes: A statement from the Starzl Network for Excellence in Pediatric Transplant Surgeon's Working Group.

BACKGROUND: Liver transplant is a life-saving therapy that can restore quality life for several pediatric liver diseases. However, it is not available to all children who need one. Expertise in medical and surgical management is heterogeneous, and allocation policies are not optimally serving children. Technical variant grafts from both living and deceased donors are underutilized. METHODS: Several national efforts in pediatric liver transplant to improve access to and outcomes from liver transplant for children have been instituted and include adjustments to allocation policies, UNOS-sponsored collaborative improvement projects, and the emergence of national learning networks to study ongoing challenges in the field the Surgical Working group of the Starzl Network for Excellence in Pediatric Transplantation (SNEPT) discusses key issues and proposes potential solutions to eliminate the persistent wait list mortality that pediatric patients face. RESULTS: A discussion of the factors impacting pediatric patients' access to liver transplant is undertaken, along with a proposal of several measures to ensure equitable access to life-saving liver transplant. CONCLUSIONS: Pediatric liver transplant wait list mortality can and should be eliminated. Several measures, including collaborative efforts among centers, could be leveraged to acheive this goal.

Association of abnormal p-wave parameters with brain MRI morphology: The atherosclerosis risk in communities neurocognitive study (ARIC-NCS).

BACKGROUND: Recent evidence indicates that abnormal P-wave parameters (PWPs)-ECG markers of atrial myopathy-are associated with incident dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. However, the mechanisms remain unclear and may include subclinical vascular brain injury. Hence, we evaluated the association of abnormal PWPs with brain MRI correlates of vascular brain injury in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). METHODS: ARIC-NCS participants who underwent 3T brain MRI scans in 2011-2013 were included. PWPs were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, lacunar infarcts, cerebral microhemorrhages, brain volumes, and white matter disease (WMD) volume. We used weighted multivariable logistic and linear regression to evaluate the associations of abnormal PWPs with brain MRI outcomes. RESULTS: Among 1715 participants (mean age, 76.1 years; 61% women; 29% Black), 797 (46%) had ≥1 abnormal PWP. After multivariable adjustment, including adjusting for prevalent AF, abnormal P-wave terminal force in lead V1 (aPTFV1) and prolonged P-wave duration (PPWD) were associated with increased odds of both cortical (OR 1.41; 95% CI, 1.14 to 1.74 and OR 1.30; 95% CI, 1.04 to 1.63, respectively) and lacunar infarcts (OR 1.36; 95% CI, 1.15 to 1.63 and OR 1.37; 95% CI, 1.15 to 1.65, respectively). Advanced interatrial block (aIAB) was associated with higher odds of subcortical microhemorrhage (OR 2.04; 95% CI, 1.36 to 3.06). Other than a significant association between aPTFV1 with lower parietal lobe volume, there were no other significant associations with brain or WMD volume. CONCLUSION: In this exploratory analysis of a US community-based cohort, ECG surrogates of atrial myopathy are associated with a higher prevalence of brain infarcts and microhemorrhage, suggesting subclinical vascular brain injury as a possible mechanism underlying the association of atrial myopathy with dementia.

High level of infection prevention and control in surveyed hospitals in Colombia, 2021.

Objective: This study aimed to determine the performance of infection prevention and control (IPC) programs in eight core components in level 2 and level 3 hospitals across all provinces in Colombia. Methods: This cross-sectional study used self-assessed IPC performance data voluntarily reported by hospitals to the Ministry of Health and Social Protection during 2021. Each of the eight core components of the World Health Organization's checklist in the Infection Prevention and Control Assessment Framework contributes a maximum score of 100, and the overall IPC performance score is the sum of these component scores. IPC performance is graded according to the overall score as inadequate (0-200), basic (201-400), intermediate (401-600) or advanced (601-800). Results: Of the 441 level 2 and level 3 hospitals, 267 (61%) reported their IPC performance. The median (interquartile range [IQR]) overall IPC score was 672 (IQR: 578-715). Of the 267 hospitals reporting, 187 (70%) achieved an advanced level of IPC. The median overall IPC score was significantly higher in private hospitals (690, IQR: 598-725) than in public hospitals (629, IQR: 538-683) (P < 0.001). Among the core components, scores were highest for the category assessing IPC guidelines (median score: 97.5) and lowest for the category assessing workload, staffing and bed occupancy (median score: 70). Median overall IPC scores varied across the provinces (P < 0.001). Conclusions: This countrywide assessment showed that 70% of surveyed hospitals achieved a self-reported advanced level of IPC performance, which reflects progress in building health system resilience. Since only 61% of eligible hospitals participated, an important next step is to ensure the participation of all hospitals in future assessments.

Bloodstream infections and antibiotic resistance at a regional hospital, Colombia, 2019-2021.

Objectives: To assess antibiotic susceptibility of World Health Organization (WHO) priority bacteria (Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Salmonella spp., Staphylococcus aureus, and Streptococcus pneumoniae) in blood cultures at the Orinoquía regional hospital in Colombia. Methods: This was cross-sectional study using routine laboratory data for the period 2019-2021. Data on blood samples from patients suspected of a bloodstream infection were examined. We determined: the total number of blood cultures done and the proportion with culture yield; the characteristics of patients with priority bacteria; and the type of bacteria isolated and antibiotic resistance patterns. Results: Of 25 469 blood cultures done, 1628 (6%) yielded bacteria; 774 (48%) of these bacteria were WHO priority pathogens. Most of the priority bacteria isolated (558; 72%) were gram-negative and 216 (28%) were gram-positive organisms. Most patients with priority bacteria (666; 86%) were hospitalized in wards other than the intensive care unit, 427 (55%) were male, and 321 (42%) were ≥ 60 years of age. Of the 216 gram-positive bacteria isolated, 205 (95%) were Staphylococcus aureus. Of the 558 gram-negative priority bacteria isolated, the three most common were Escherichia coli (34%), Klebsiella pneumoniae (28%), and Acinetobacter baumannii (20%). The highest resistance of Staphylococcus aureus was to oxacillin (41%). For gram-negative bacteria, resistance to antibiotics ranged from 4% (amikacin) to 72% (ampicillin). Conclusions: Bacterial yield from blood cultures was low and could be improved. WHO priority bacteria were found in all hospital wards. This calls for rigorous infection prevention and control standards and continued surveillance of antibiotic resistance.

[Voluntary interruption of pregnancy and sexual and reproductive health in migrant women in BarranquillaInterrupção voluntária da gravidez e saúde sexual e reprodutiva em mulheres migrantes em Barranquilla]. / Interrupción voluntaria del embarazo y salud sexual y reproductiva en mujeres migrantes en Barranquilla.

Objective: Identify knowledge about and barriers to effective access to voluntary interruption of pregnancy (VIP), and to sexual and reproductive health (SRH) services in general, among women from Venezuela (Venezuelan migrants and Colombian returnees). Methods: Qualitative study of 20 semi-structured interviews with women from Venezuela who are residents of Barranquilla and who carry out leadership activities in communities or who participate in or benefit from those activities. The interviews included opinions and experiences related to access to VIP, and to SRH in general, as well as suggestions for improving access for migrant women. The relationship between access to these services and the migration process was explored, as well as the role of social organizations. Results: A lack of information on SRH-related rights was identified as the main access barrier to VIP. Other identified barriers were: attitude towards VIP, excessive steps involved in accessing medical care, difficulties in admission to the social security system, lack of training and care in SRH, and xenophobia in hospitals. The interviewees said they did not understand the legal framework in Colombia and did not know the channels for safe abortion care. Conclusions: Despite the efforts of institutions and international cooperation, Venezuelan migrant women in Barranquilla are in a situation of vulnerability due to their lack of access to sexual and reproductive health, including voluntary interruption of pregnancy. Implementing strategies for comprehensive care for migrants will improve current health conditions and the effective enjoyment of SRH-related rights.

Objetivo: Identificar os conhecimentos e as barreiras para o acesso efetivo das mulheres provenientes da Venezuela (migrantes venezuelanas e retornadas colombianas) à interrupção voluntária da gravidez (IVG) e aos serviços de saúde sexual e reprodutiva (SSR) em geral. Métodos: Estudo qualitativo de 20 entrevistas semiestruturadas com mulheres provenientes da Venezuela, residentes em Barranquilla, que atuam na liderança comunitária ou que participam (ou se beneficiam) das atividades. As entrevistas compreenderam as dimensões de opiniões e experiências relacionadas ao acesso à IVG e aos serviços de SSR em geral, e sugestões para melhorar o acesso das mulheres migrantes. Explorou-se a relação do acesso a esses serviços com o processo migratório e o papel das organizações sociais. Resultados: Identificou-se a falta de informações sobre direitos em SSR como a principal barreira para o acesso à IVG. Outras barreiras identificadas foram: atitude em relação à IVG, excesso de burocracia para obter atenção médica, dificuldades para inclusão no sistema de seguridade social, falta de capacitação e atenção em SSR e xenofobia nos hospitais. As entrevistadas declararam desconhecer o enquadramento jurídico na Colômbia e os trâmites para obter atenção ao aborto seguro. Conclusões: Apesar dos esforços institucionais e de cooperação internacional, as mulheres migrantes venezuelanas em Barranquilla estão em situação de vulnerabilidade por falta de acesso aos serviços de SSR, incluindo a IVG. A implementação de estratégias para atenção integral a migrantes possibilitará a melhoria das condições atuais de saúde e a efetiva fruição dos direitos em SSR.

Site-specific and substrate-specific control of accurate mRNA editing by a helicase complex in trypanosomes.

Trypanosome U-insertion/deletion RNA editing in mitochondrial mRNAs involves guide RNAs (gRNAs) and the auxiliary RNA editing substrate binding complex (RESC) and RNA editing helicase 2 complex (REH2C). RESC and REH2C stably copurify with editing mRNAs but the functional interplay between these complexes remains unclear. Most steady-state mRNAs are partially edited and include misedited "junction" regions that match neither pre-mRNA nor fully edited transcripts. Editing specificity is central to mitochondrial RNA maturation and function, but its basic control mechanisms remain unclear. Here we applied a novel nucleotide-resolution RNA-seq approach to examine ribosomal protein subunit 12 (RPS12) and ATPase subunit 6 (A6) mRNA transcripts. We directly compared transcripts associated with RESC and REH2C to those found in total mitochondrial RNA. RESC-associated transcripts exhibited site-preferential enrichments in total and accurate edits. REH2C loss-of-function induced similar substrate-specific and site-specific editing effects in total and RESC-associated RNA. It decreased total editing primarily at RPS12 5' positions but increased total editing at examined A6 3' positions. REH2C loss-of-function caused site-preferential loss of accurate editing in both transcripts. However, changes in total or accurate edits did not necessarily involve common sites. A few 5' nucleotides of the initiating gRNA (gRNA-1) directed accurate editing in both transcripts. However, in RPS12, two conserved 3'-terminal adenines in gRNA-1 could direct a noncanonical 2U-insertion that causes major pausing in 3'-5' progression. In A6, a noncanonical sequence element that depends on REH2C in a region normally targeted by the 3' half of gRNA-1 may hinder early editing progression. Overall, we defined transcript-specific effects of REH2C loss.

Acute Graft-Versus-Host Disease After Orthotopic Liver Transplantation: Predicting This Rare Complication Using Machine Learning.

Acute graft-versus-host disease (GVHD) is a rare complication after orthotopic liver transplantation (OLT) that carries high mortality. We hypothesized that machine-learning algorithms to predict rare events would identify patients at high risk for developing GVHD. To develop a predictive model, we retrospectively evaluated the clinical features of 1938 donor-recipient pairs at the time they underwent OLT at our center; 19 (1.0%) of these recipients developed GVHD. This population was divided into training (70%) and test (30%) sets. A total of 7 machine-learning classification algorithms were built based on the training data set to identify patients at high risk for GVHD. The C5.0, heterogeneous ensemble, and generalized gradient boosting machine (GGBM) algorithms predicted that 21% to 28% of the recipients in the test data set were at high risk for developing GVHD, with an area under the receiver operating characteristic curve (AUROC) of 0.83 to 0.86. The 7 algorithms were then evaluated in a validation data set of 75 more recent donor-recipient pairs who underwent OLT at our center; 2 of these recipients developed GVHD. The logistic regression, heterogeneous ensemble, and GGBM algorithms predicted that 9% to 11% of the validation recipients were at high risk for developing GVHD, with an AUROC of 0.93 to 0.96 that included the 2 recipients who developed GVHD. In conclusion, we present a practical model that can identify patients at high risk for GVHD who may warrant additional monitoring with peripheral blood chimerism testing.

Apixaban Dosing Patterns Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation Receiving Dialysis: A Retrospective Cohort Study.

BACKGROUND & OBJECTIVES: Comparison of clinical outcomes across anticoagulation regimens using different apixaban dosing or warfarin is not well-defined in patients with nonvalvular atrial fibrillation (AF) who are receiving dialysis. This study compared these outcomes in a US national cohort of patients with kidney failure receiving maintenance dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Patients receiving dialysis represented in the US Renal Data System database 2013-2018 who had AF and were treated with apixaban or warfarin. EXPOSURE: First prescribed treatment with apixaban dosed according to the label, apixaban dosed below the label, or warfarin. OUTCOME: Ischemic stroke/systemic embolism, major bleeding, and all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models with inverse probability of treatment weighting. Analyses simulating an intention-to-treat (ITT) approach as well as those incorporating censoring at drug switch or discontinuation (CAS) were also implemented. Inverse probability of censoring weighting was used to account for possible informative censoring. RESULTS: Among 17,156 individuals, there was no difference in risk of stroke/systemic embolism among the label-concordant apixaban, below-label apixaban, and warfarin treatment groups. Both label-concordant (HR, 0.67 [95% CI, 0.55-0.81]) and below-label (HR, 0.68 [95% CI, 0.55-0.84]) apixaban dosing were associated with a lower risk of major bleeding compared with warfarin in ITT analyses. Compared with label-concordant apixaban, below-label apixaban was not associated with a lower bleeding risk (HR, 1.02 [95% CI, 0.78-1.34]). In the ITT analysis of mortality, label-concordant apixaban dosing was associated with a lower risk versus warfarin (HR, 0.85 [95% CI, 0.78-0.92]) while there was no significant difference in mortality between below-label dosing of apixaban and warfarin (HR, 0.97 [95% CI, 0.89-1.05]). Overall, results were similar for the CAS analyses. LIMITATIONS: Study limited to US Medicare beneficiaries; reliance on administrative claims to ascertain outcomes of AF, stroke, and bleeding; likely residual confounding. CONCLUSIONS: Among patients with nonvalvular AF undergoing dialysis, warfarin is associated with an increased risk of bleeding compared with apixaban. The risk of bleeding with below-label apixaban was not detectably less than with label-concordant dosing. Label-concordant apixaban dosing is associated with a mortality benefit compared to warfarin. Label-concordant dosing, rather than reduced-label dosing, may offer the most favorable benefit-risk trade-off for dialysis patients with nonvalvular AF.

Association of Donor and Recipient Cytomegalovirus Serostatus on Graft and Patient Survival in Liver Transplant Recipients.

Among solid organ transplant recipients, donor cytomegalovirus (CMV) seropositive (D+) and recipient seronegative (R-) status are associated with an increased risk of graft loss and mortality after kidney or lung transplantation. Whether a similar relationship exists among liver transplant recipients (LTR) is unknown. We assessed graft loss and mortality among adult LTRs from January 1, 2010, to March 14, 2020, in the Organ Procurement and Transplantation Network database. We used multivariable mixed Cox proportional hazards regression to analyze the association of donor and recipient CMV serostatus group with graft loss and mortality, with donor seronegative (D-) and recipient seronegative (R-) as the reference group. Among 54,078 LTRs, the proportion of D-R-, D- and recipient seropositive (R+), D+R-, and D+R+ was 13.4%, 22.5%, 22%, and 42%, respectively. By unadjusted Kaplan-Meier survival curve estimates, survival by the end of follow-up was 73.3%, 73.5%, 70.1%, and 69.7%, among the D-R-, D-R+, D+R-, and D+R+ groups, respectively. By multivariable Cox regression, the CMV D+R- serogroup, but not other serogroups, was independently associated with increased risks of graft loss (adjusted hazard ratio [aHR], 1.13; 95% confidence interval [CI], 1.05-1.22) and mortality (aHR, 1.13; 95% CI, 1.05-1.22). The magnitude of the association of the CMV D+R- serostatus group with mortality was similar when the Cox regression analysis was restricted to the first year after transplant and beyond the first year after transplant: aHR, 1.13 (95% CI, 1.01-1.27) and aHR, 1.13 (95% CI, 1.02-1.25), respectively. Even in an era of CMV preventive strategies, CMV D+R- serogroup status remains independently associated with increased graft loss and mortality in adult LTRs. Factors in addition to direct CMV-associated short-term mortality are likely, and studies to define the underlying mechanism(s) are warranted.

CKD Progression in Medicare Beneficiaries With Nonvalvular Atrial Fibrillation Treated With Apixaban Versus Warfarin.

RATIONALE & OBJECTIVE: Comparing kidney disease progression among patients treated with direct oral anticoagulants (DOACs) versus warfarin has not been well studied. We hypothesized that apixaban would be associated with lower risks of progression of chronic kidney disease (CKD) and progression to incident kidney failure than warfarin in patients with atrial fibrillation (AF). STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Medicare recipients with stage 3, 4, or 5 CKD and incident AF who received a new prescription for apixaban or warfarin from 2013 through 2017. EXPOSURE: Apixaban or warfarin. OUTCOMES: Progression to incident kidney failure or, separately, to a more advanced stage of CKD. ANALYTICAL APPROACH: Marginal structural cause-specific proportional hazards models with inverse probability weighting to estimate marginal hazard ratios (HRs) for each outcome. HRs compared apixaban to warfarin in intention-to-treat and censored-at-drug-switch analyses. RESULTS: 12,816 individuals met inclusion criteria (50.3% received apixaban; 49.7% received warfarin). After weighting, the mean age of the cohort was 80 ± 7 years, 51% were women, and 88% were White. Approximately 84% had stage 3, 15% had stage 4, and 1% had stage 5 CKD. In the intention-to-treat analysis, apixaban, relative to warfarin, was associated with an HR of developing incident kidney failure of 0.98 (95% confidence interval [CI], 0.79-1.22) and of CKD stage progression of 0.90 (95% CI, 0.82-0.99). Corresponding HRs for censored-at-drug-switch analyses were 0.81 (95% CI, 0.56-1.17) and 0.81 (95% CI, 0.70-0.92). Results were similar for a series of subgroup and sensitivity analyses. LIMITATIONS: CKD was defined based on diagnosis codes from claims; findings may not be generalizable to non-Medicare CKD populations. CONCLUSIONS: Apixaban, compared with warfarin, was associated with lower risk of CKD stage progression, but not with incident kidney failure.

Do funding sources influence long-term patient survival in pediatric liver transplantation?

BACKGROUND: Socioeconomic status has been associated with inferior outcomes after multiple surgical procedures, but has not been well studied with respect to pediatric liver transplantation. This study evaluated the impact of insurance status (as a proxy for socioeconomic status) on patient and allograft survival in pediatric first-time liver transplant recipients. METHODS: Our retrospective analysis of the UNOS data base from January 2002 through September 2017 revealed 6997 pediatric patients undergoing first-time isolated liver transplantation. A mixed Cox proportional hazards model adjusted for donor, recipient, and program characteristics determined the RR of insurance status on allograft and patient survival. All results were considered significant at P < .05. All statistical results were obtained using R version 3.5.1 and coxme version 2.2-10. RESULTS: Medicaid status had a significant negative impact on long-term survival after controlling for multiple covariates. Pediatric patients undergoing first-time isolated liver transplantation with Medicaid insurance had a RR of 1.42 [confidence interval: 1.18-1.60] of post-transplant death. CONCLUSION: Pediatric patients undergoing first-time isolated liver transplantation have multiple risk factors that may impact long-term survival. Having Medicaid insurance almost doubles the chances of dying post-liver transplant. This patient population may require more global support post-transplant to improve long-term survival.

Carotid petrous segment aneurysm presenting as hypoglossal nerve palsy.

Aneurysm in the petrous segment of the internal carotid artery is extremely rare, and symptoms are usually derived from compression of neighbor structures such as nerve palsies. Clinical symptoms can be nonspecific and imaging findings are complex, making the diagnosis of this kind of aneurysms extremely challenging. CT angiography is the best diagnostic tool, and treatment options include surgical and endovascular approaches, the latest being preferred. We report an extremely rare case of an aneurysm in the petrous apex presenting with hypoglossal nerve palsy. We document the aneurysm through CT and confirm it using angiography. We also describe the satisfactory management of this rare case. To the best of our knowledge this an extremely rare aneurism presenting with hypoglossal nerve palsy, in which successful interventional management was achieved through a specific and prompt diagnosis.

Antiviral activity of hexapeptides derived from conserved regions of bacterial proteases against HCV NS3 protease.

The main cause of hepatitis C is hepatitis C virus or HCV and for the cure of hepatitis C, NS3/4A protease has been found an important and emerging target. A number of HCV NS3/4A protease inhibitors have been discovered which have shown subsequent reduction in reducing the viral load leading to this infection however they are still undergoing clinical trials for improvement. Bacterial proteases are of great pharmaceutical importance and have a key role in various biological processes and in life cycle of several pathogens. The current study was planned to explore hexapeptides derived from conserved regions of bacterial proteases for their potential in blocking the NS3 protease activity of HCV which would finally inhibit HCV multiplication. For this, a novel protease gene nprB was isolated from a thermophilic bacterium Streptomyces thermovulgaris and bioinformatics analyses were performed. PCR amplification and sequencing of nprB gene indicated an open reading frame of 178 aa (20191.18 Dalton).The peptide GGVHIN was the top ranked with minimum S-score of -17.21) followed by hexapeptides VDAHAN, GVGREA, GALNES and VHINSS with their S-scores of -14.73, -13.78, -10.72 and -10.70, respectively. A phylogram was also reconstructed to reveal evolutionary relationships of nprB with its various homologs. The provided data will serve as a background to further reveal pharmaceutical and biotechnological importance of this novel protease gene from S. thermovulgaris in future.

Accessibility of substituted cysteines in TM2 and TM10 transmembrane segments in the Plasmodium falciparum equilibrative nucleoside transporter PfENT1.

Infection with Plasmodium species parasites causes malaria. Plasmodium parasites are purine auxotrophic. They import purines via an equilibrative nucleoside transporter (ENT). In P. falciparum, the most virulent species, the equilibrative nucleoside transporter 1 (PfENT1) represents the primary purine uptake pathway. This transporter is a potential target for the development of antimalarial drugs. In the absence of a high-resolution structure for either PfENT1 or a homologous ENT, we used the substituted cysteine accessibility method (SCAM) to investigate the membrane-spanning domain structure of PfENT1 to identify potential inhibitor-binding sites. We previously used SCAM to identify water-accessible residues that line the permeation pathway in transmembrane segment 11 (TM11). TM2 and TM10 lie adjacent to TM11 in an ab initio model of a homologous Leishmania donovani nucleoside transporter. To identify TM2 and TM10 residues in PfENT1 that are at least transiently on the water-accessible transporter surface, we assayed the reactivity of single cysteine-substitution mutants with three methanethiosulfonate (MTS) derivatives. Cysteines substituted for 12 of 14 TM2 segment residues reacted with MTS-ethyl-ammonium-biotin (MTSEA-biotin). At eight positions, MTSEA-biotin inhibited transport, and at four positions substrate transport was potentiated. On an α helical wheel projection of TM2, the four positions where potentiation occurred were located in a cluster on one side of the helix. In contrast, although MTSEA-biotin inhibited 9 of 10 TM10 cysteine-substituted mutants, the reactive residues did not form a pattern consistent with either an α helix or ß sheet. These results may help identify the binding site(s) of PfENT1 inhibitors.

Direct-Acting Oral Anticoagulants Versus Warfarin in Medicare Patients With Chronic Kidney Disease and Atrial Fibrillation.

BACKGROUND AND PURPOSE: The comparative effectiveness of direct-acting oral anticoagulants, compared with warfarin, for risks of stroke/systemic embolism, major bleeding, or death have not been studied in Medicare beneficiaries with atrial fibrillation and nondialysis-dependent chronic kidney disease. METHODS: Medicare data from 2011 to 2017 were used to identify patients with stages 3, 4, or 5 chronic kidney disease and new atrial fibrillation who received a new prescription for warfarin, apixaban, rivaroxaban, or dabigatran. We estimated marginal hazard ratios with 95% CIs for the association of each direct-acting oral anticoagulant, compared with warfarin, for the outcomes of interest using inverse-probability-of-treatment weighted Cox proportional hazards models in as-treated and intention-to-treat analyses. RESULTS: A total of 22 739 individuals met criteria (46.3% warfarin, 29.6% apixaban, 17.2% rivaroxaban, 6.9% dabigatran). Across the groups of anticoagulant users, mean age was 78.4 to 79.0 years; 50.3% to 51.4% were women, and 80.3% to 82.8% had stage 3 chronic kidney disease. In the as-treated analysis, for stroke/systemic embolism, hazard ratios, all compared with warfarin, were 0.70 (0.51-0.96) for apixaban, 0.80 (0.54-1.17) for rivaroxaban, and 1.15 (0.69-1.94) for dabigatran. For major bleeding, analogous hazard ratios were 0.47 (0.37-0.59) for apixaban, 1.05 (0.85-1.30) for rivaroxaban, and 0.95 (0.70-1.31) for dabigatran. There was no difference in the risk of all-cause mortality between the direct-acting oral anticoagulants and warfarin. Results of the intention-to-treat analysis were similar. CONCLUSIONS: Apixaban, compared with warfarin, was associated with decreased risk of stroke/systemic embolism and major bleeding; risks for both outcomes with rivaroxaban and dabigatran did not differ from risks with warfarin.