Influence of dengue virus serotypes on the abundance of Aedes aegypti insect-specific viruses (ISVs).

A comprehensive understanding of the virome in mosquito vectors is crucial for assessing the potential transmission of viral agents, designing effective vector control strategies, and advancing our knowledge of insect-specific viruses (ISVs). In this study, we utilized Oxford Nanopore Technologies metagenomics to characterize the virome of Aedes aegypti mosquitoes collected in various regions of Colombia, a country hyperendemic for dengue virus (DENV). Analyses were conducted on groups of insects with previous natural DENV infection (DENV-1 and DENV-2 serotypes), as well as mosquito samples that tested negative for virus infection (DENV-negative). Our findings indicate that the Ae. aegypti virome exhibits a similar viral composition at the ISV family and species levels in both DENV-positive and DENV-negative samples across all study sites. However, differences were observed in the relative abundance of viral families such as Phenuiviridae, Partitiviridae, Flaviviridae, Rhabdoviridae, Picornaviridae, Bromoviridae, and Virgaviridae, depending on the serotype of DENV-1 and DENV-2. In addition, ISVs are frequently found in the core virome of Ae. aegypti, such as Phasi Charoen-like phasivirus (PCLV), which was the most prevalent and showed variable abundance in relation to the presence of specific DENV serotypes. Phylogenetic analyses of the L, M, and S segments of the PCLV genome are associated with sequences from different regions of the world but show close clustering with sequences from Brazil and Guadeloupe, indicating a shared evolutionary relationship. The profiling of the Ae. aegypti virome in Colombia presented here improves our understanding of viral diversity within mosquito vectors and provides information that opens the way to possible connections between ISVs and arboviruses. Future studies aimed at deepening our understanding of the mechanisms underlying the interactions between ISVs and DENV serotypes in Ae. aegypti could provide valuable information for the design of effective vector-borne viral disease control and prevention strategies.IMPORTANCEIn this study, we employed a metagenomic approach to characterize the virome of Aedes aegypti mosquitoes, with and without natural DENV infection, in several regions of Colombia. Our findings indicate that the mosquito virome is predominantly composed of insect-specific viruses (ISVs) and that infection with different DENV serotypes (DENV-1 and DENV-2) could lead to alterations in the relative abundance of viral families and species constituting the core virome in Aedes spp. The study also sheds light on the identification of the genome and evolutionary relationships of the Phasi Charoen-like phasivirus in Ae. aegypti in Colombia, a widespread ISV in areas with high DENV incidence.

Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS).

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).

The Impact of Mental Health on Patient Outcomes in Peripheral Arterial Disease and Critical Limb Threatening Ischemia and Potential Avenues to Treatment.

The physical consequences of peripheral artery disease (PAD) are well established; however, the impact of comorbid mental health disorders such as depression and anxiety are not well understood. The impact of psychological stress is not only associated with worse perioperative morbidity and mortality but also with a physiologic cascade that accelerates plaque formation. Increasing screening to identify and subsequently treat comorbid mental health disorders is an integral next step in improving outcomes in PAD management. Failure to adequately address social and psychological impact on PAD patients will further widen the gap in disparities faced by high-risk and disenfranchised populations. Integration of mental health professionals, addiction specialists, and community navigators into multidisciplinary care teams can bolster support for PAD patients and improve outcomes.

Denim industry wastewater treatment by a heterogeneous solar-Fenton process catalyzed by Fe supported on recycled polyethylene terephthalate (PET) by ultrasonic modification.

The textile industry is an important economic sector; however, its wastewater generates a great impact on the environment. A heterogeneous solar Fenton (HSF) process was evaluated for denim wastewater treatment. The catalyst was obtained through ultrasonic modification of recycled polyethylene terephthalate (PET) with Fe nanoparticles (PET/NPs- Fe3O4). The SFH process was optimized using surface response methodology with a face-centered central composite design considering the effects of the hydraulic retention time (10, 25, and 40 min), hydrogen peroxide dosage (500, 1000, and 1500 mg/L), and mass of the packed catalyst (4, 6 and 8 g) on the color, COD, and turbidity removal efficiencies. The operating conditions for maximum COD removal were H2O2 541.7 mg/L, HRT 33.9 min, and PET/NPs- Fe3O4 dose 7.9 g with solar radiation. The removal of 91.2% COD, 86.2% color, 90.4% turbidity, and 81.9% TOC was obtained at 14.2 kJ/L QUva. PET modification yielded 1.6 mg Fe/g PET, and the modification method does not allow Fe leaching. The effluent obtained from the SFH process complies with the maximum permissible limits in Mexican legislation in terms of COD, TOC, turbidity, and color and allows the reuse of PET.

Influence of biomass burning on ozone levels in the Megalopolis of Central Mexico during the COVID-19 lockdown.

The massive reductions in anthropogenic emissions resulting from the COVID-19 lockdown provided a unique opportunity to evaluate the effect of mitigation measures aiming to abate air pollution. In Mexico, the total lockdown period took place during the dry-hot season when biomass burning activity is enhanced. Here, we investigate the role of biomass burning emissions on regional ozone levels in the Megalopolis of Central Mexico. The studied period covers the lockdown phases 2 and 3, and the first month of the New Normal. We applied a factor separation technique and process analysis to estimate the pure and synergistic contributions of emission reductions under lockdown and that from biomass burning to daily ozone maximum concentrations in 7 metropolitan areas of different states in the Megalopolis. The results revealed that biomass burning plumes likely masked the effect of massive reductions from mobile emissions, impacted the PBL development during phase 3 and favored transition and mixed NOx-limited and VOC-limited regional regimes. This contributed to increased ozone production in the middle to lower PBL by changing the regional background levels which potentially could bias high ozone production efficiency estimations. Given the Megalopolis contribution to economic and societal development at national scale, our study suggests that ozone mitigation measures during the dry-hot season targeting mainly mobile emissions will likely be offset by biomass burning plumes. A regional and synergic policy aiming to control biomass burning would help to reduce the occurrence of high ozone levels in Central Mexico with the co-benefit of tackling short-lived climate pollutants.

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

E6/E7 from Beta-2-HPVs 122, 38b, and 107 possess transforming properties in a fibroblast model in vitro.

Beta-2 Human papillomaviruses 38b, 107, and 122 have been frequently found in cervical cancer samples in western Mexico. Because their E6/E7 genes functions are not fully elucidated, we deepen into their transformation capabilities. To achieve this goal, primary human fibroblasts (FB) were transduced with E6/E7 genotype-specific viral particles. Additionally, E6/E7 from HPVs 16 and 18 were included as controls. All E6/E7-cell models increased their lifespan; however, it is important to highlight that FB-E6/E7-122 showed growth as accelerated as FB-E6/E7-16 and 18. Furthermore, both FB-E6/E7-38b and 122 exhibited abilities to migrate, and FB-E6/E7-122 presented high invasive capacity. On the other hand, ΔNp73 expression was found in all cell models, except for FB-pLVX (empty-vector). Finally, RNAseq found differentially expressed genes enriched in signaling pathways related to cell cycle, epithelial-mesenchymal transition, and cancer, among others. This study shows for the first time, the great transformative potential that genotypes of the Beta-2 also possess, especially HPV122. These Beta-2 HPVs can modulate some of the genes that are well known to be regulated by Alpha-HPVs, however, they also possess alternative strategies to modulate diverse signaling pathways. These data support the idea that Beta-2 HPVs should play an important role in co-infections with Alpha-HPV during carcinogenesis.

Preoperative Depression is Associated with Worse Outcomes after The Lower Extremity Revascularization.

OBJECTIVE: This retrospective study sought to describe the association between preoperative diagnosis of depression and major adverse events after infrainguinal bypass surgery or peripheral vascular intervention (PVI). METHODS: We retrospectively analyzed a consecutive series of all patients undergoing PVI and/or infrainguinal bypass surgery at a single tertiary institution between 2010 and 2019. Propensity matching and Cox regression analysis were conducted to examine the impact of comorbid depression on the incidence of major adverse events (MAEs), defined as re-intervention, major amputation, or death, within 2 years of surgery. RESULTS: Of all patients (n = 512) undergoing intervention at our institution, 166 (32.4%) suffered an MAE and 169 (33.0%) patients had a preoperative diagnosis of depression. After propensity score matching, univariate (HR, 1.7; 95% CI, 1.1-2.7) and multivariable hazard analyses (aHR, 1.50; [1.1-2.2]) demonstrate that there is a statistically significant relationship between the diagnosis of depression and increased MAE. CONCLUSION: Over one-third of our lower extremity revascularization patients were noted to have a preoperative diagnosis of depression. After intervention, these patients had worse outcomes compared to patients without depression; this finding was more evident in patients who underwent PVI mainly due to high overall mortality rate. Prospective studies are necessary to better understand this association and to ascertain if early intervention can improve post-procedure vascular outcomes.

Splicing Characterization and Isoform Switch Events in Human Keratinocytes Carrying Oncogenes from High-Risk HPV-16 and Low-Risk HPV-84.

Infection of epithelial cells with high-risk HPV (HR-HPV) types, followed by expression of virus oncogenic proteins (E5, E6, and E7), leads to genomic imbalance, suppression of tumor inhibitors, and induction of oncogenes. Low-risk HPV (LR-HPV) may slow the rate at which cervical cancer spreads to an invasive stage since co-infection with LR-HPV is linked to a decreased risk of future invasive cancer than infection with HR-HPV alone. We then propose that cancer-progressing changes may be distinguished through identifying the functional differences between LR-HPV and HR-HPV. Lentiviral strategies were followed to establish HaCaT cells with constitutive expression of HPV oncogenes. RNAseq experiments were designed to analyze the transcriptome modulations caused by each of the E5, E6, and E7 oncogenes of HPV-16 and HPV-84 in HaCaT cells. We identified enhanced RNA degradation, spliceosome, and RNA polymerase pathways related to mRNA processing. ATTS (alternative transcription termination site) was discovered to be more prevalent in cells with HPV-16E5 than HPV-84E5. In HPV-16E6-infected cells, ATTS gain was significantly higher than ATTS loss. Cells with HPV-16E7 had more isoforms with intron retention (IR) than those with HPV-84E7. We identified switches in ADAM10, CLSPN, and RNPS1 that led to greater expression of the coding isoforms in HR-HPV. The results of this work highlight differences between LR-HPV and HR-HPV in mRNA processing. Moreover, crucial cervical cancer-related switch events were detected.

Pentoxifylline Inhibits TNF-α/TGF-ß1-Induced Epithelial-Mesenchymal Transition via Suppressing the NF-κB Pathway and SERPINE1 Expression in CaSki Cells.

Cervical cancer (CC) is one of the most common and deadly types of female cancer worldwide. Late diagnosis in CC increases the risk of tumor cells spreading to distant organs (metastasis). The epithelial-mesenchymal transition (EMT) is a fundamental process of cancer metastasis. Inflammation can lead to tumor progression, EMT induction, and metastasis. The inflammatory microenvironment is a potent inducer of EMT; inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α) and Transforming growth factor-beta (TGF-ß1) activate transcriptional factors such as STAT3, Snail, Smad, and the Nuclear Factor kappa light-chain-enhancer of activated beta cells (NF-κΒ), which drive EMT. Anti-inflammatory compounds may be an option in the disruption of EMT. PenToXifylline (PTX) possesses potent anti-inflammatory effects by inhibiting NF-κB activity. In addition, PTX exerts an anti-fibrotic effect by decreasing Smad2/3/4. We hypothesize that PTX could exert anti-EMT effects. CaSki human cervical tumor cells were exposed to TNF-α 10 ng/mL and TGF-ß1 alone or in combination for 5 days. Our results revealed that TNF-α and TGF-ß1 induced N-cadherin and Vimentin, confirming the induction of EMT. Furthermore, the combination of cytokines synergized the expression of mesenchymal proteins, enhanced IκBα and p65 phosphorylation, and upregulated Serpin family E member 1 (SERPINE1) mRNA. PTX pretreatment prior to the addition of TNF-α and TGF-ß1 significantly reduced N-cadherin and Vimentin levels. To our knowledge, this is the first time that this effect of PTX has been reported. Additionally, PTX reduced the phosphorylation of IκB-α and p65 and significantly decreased SERPINE1 expression, cell proliferation, migration, and invasion. In conclusion, PTX may counteract EMT in cervical cancer cells by decreasing the NF-κB and SERPINE1.

Pan American League of Associations for Rheumatology Guidelines for the Treatment of Takayasu Arteritis.

OBJECTIVE: To develop the first evidence-based Pan American League of Associations for Rheumatology (PANLAR) guidelines for the treatment of Takayasu arteritis (TAK). METHODS: A panel of vasculitis experts developed a series of clinically meaningful questions addressing the treatment of TAK patients in the PICO (population/intervention/comparator/outcome) format. A systematic literature review was performed by a team of methodologists. The evidence quality was assessed according to the GRADE (Grading of Recommendations/Assessment/Development/Evaluation) methodology. The panel of vasculitis experts voted each PICO question and made recommendations, which required ≥70% agreement among the voting members. RESULTS: Eleven recommendations were developed. Oral glucocorticoids are conditionally recommended for newly diagnosed and relapsing TAK patients. The addition of nontargeted synthetic immunosuppressants (e.g., methotrexate, leflunomide, azathioprine, or mycophenolate mofetil) is recommended for patients with newly diagnosed or relapsing disease that is not organ- or life-threatening. For organ- or life-threatening disease, we conditionally recommend tumor necrosis factor inhibitors (e.g., infliximab or adalimumab) or tocilizumab with consideration for short courses of cyclophosphamide as an alternative in case of restricted access to biologics. For patients relapsing despite nontargeted synthetic immunosuppressants, we conditionally recommend to switch from one nontargeted synthetic immunosuppressant to another or to add tumor necrosis factor inhibitors or tocilizumab. We conditionally recommend low-dose aspirin for patients with involvement of cranial or coronary arteries to prevent ischemic complications. We strongly recommend performing surgical vascular interventions during periods of remission whenever possible. CONCLUSION: The first PANLAR treatment guidelines for TAK provide evidence-based guidance for the treatment of TAK patients in Latin American countries.

Outcomes of Infrainguinal Bypass in Patients with Cannabis vs Opioid Use Disorder.

BACKGROUND: Marijuana and opioids are commonly used illicit drugs in the United States and their use continues to rise. Cannabis use disorder (CUD) and Opioid use disorder (OUD) are associated with adverse effects on public health and postoperative outcomes. However, their impact on vascular surgery, specifically infrainguinal bypass repair (IIB). is not well described in the literature. Therefore, our study aimed to assess perioperative outcomes in patients with CUD and OUD who underwent IIB. METHODS: A retrospective analysis of the National Inpatient Sample database for the years 2005 to 2018 was performed. Using the International Classification of Diseases Clinical Modification, Ninth and Tenth revisions, patients who were diagnosed with peripheral artery disease and underwent IIB repair.were identified. Our primary outcome was the comparison of rates of in-hospital complications between the groups, and the secondary outcomes included analysis of total hospital charges and length of stay. A 1:1 propensity score matching (PSM) CUD and OUD patients to their control groups without the disease was conducted using the nearest-neighbor method. The matching was based on select patient demographics and comorbidities included in our analyses. RESULTS: A total of 190,794 patients were identified: 972 patients with CUD and 682 patients with OUD. In the matched cohorts, patients with a diagnosis of CUD had a higher incidence of in-hospital cardiac complications (adjusted Odds Ratio [aOR], 1.76; 95% Confidence Interval [CI], 0.99-3.12) and acute kidney injury (AKI) (aOR, 1.51; CI, 1.09-2.08). Additionally, total hospital charges and mean length of stay were higher in the CUD group (P < 0.001). Those with OUD had a higher incidence of postoperative respiratory complications (aOR, 1.92; CI, 1.23-2.99), sepsis (aOR, 2.39; CI, 1.32-4.34), infection (aOR, 3.55; CI, 1.16-10.84), AKI (aOR, 2.11; CI,1.47-3.04), major amputations (aOR, 1.69; CI, 1.07-2.69), along with higher total charges and mean length of stay (P < 0.001). CONCLUSIONS: Both CUD and OUD have increased incidence of postoperative complications following IIB. The OUD group had generally worse outcomes compared to patients with CUD. Both were associated with a substantial increase in total hospital charges and length of hospital stay. A further prospective study is warranted to provide better insight on the effects of substance use disorders on the procedure's short- and long-term outcomes.

Humeral offset as a predictor of outcomes after reverse shoulder arthroplasty.

INTRODUCTION: The Grammont-style reverse shoulder arthroplasty (RSA) relies on medialization and distalization of the shoulder center of rotation. Lateralized designs have recently gained popularity. The amount of lateralization, however, remains a controversial topic. The purpose of this study was to correlate the change in humeral offset (HO) with outcomes and complications following RSA. We hypothesized that a lateralized HO following RSA would be associated with improved range of motion (ROM), better patient-reported outcomes (PROs), and fewer complications. MATERIALS AND METHODS: A consecutive series of 104 patients (109 shoulders) was retrospectively evaluated. All patients underwent primary RSA by 2 shoulder and elbow fellowship-trained orthopedic surgeons at 2 different centers. Inclusion criteria was a primary RSA with at least 1-year follow-up. All patients had the HO measured on a preoperative and a postoperative Grashey radiograph, and the change in HO was calculated (ΔHO = PostHO-PreHO). A negative value was defined as a medialized HO and a positive value as a lateralized HO. ROM and primary outcomes, including forward elevation (FE), external rotation (ER), internal rotation (IR), Subjective Shoulder Value (SSV), and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score, were collected. Complications and revisions were also reported. RESULTS: The mean age was 72 years with a mean follow-up of 22.3 months. The average FE (92° vs. 148°), ER (34° vs. 44°), SSV (35% vs. 87%), and ASES score (37.2 vs. 81.2) increased significantly (all P < .01) compared with preoperative values. The HO was medialized postoperatively in 63 shoulders and lateralized in 46 shoulders. No statistically significant differences in the mean values for postoperative FE (147° vs. 146°, P = .892), ER (43° vs. 45°, P = .582), IR (L3 vs. L3, P = .852), SSV (88% vs. 85%, P = .476), and ASES score (81.3 vs. 81.1, P = .961) were found between the groups. However, there was significantly more improvement in ER in the lateralized HO cohort than the medialized cohort (16° vs. 7°, P = .033). Six shoulders, 5 medialized and 1 lateralized HO, demonstrated scapular notching and remained asymptomatic. Five shoulders, 4 medialized and 1 lateralized HO, experienced at least 1 instability incident, and 2 shoulders with medialized HO had an acromion/scapular spine fracture. Overall, 2 shoulders with medialized HO underwent revision surgery because of instability. CONCLUSIONS: Although RSA provides significant improvement in ROM and PROs regardless of postoperative HO, restoring baseline HO or lateralization beyond baseline may be favorable for improving ER and decreasing complications following RSA.

Novel technique of development of human derived acellular dermal matrix.

Reconstructive surgery techniques have evolved exponentially in last decades. From regional flaps to free tissue transfer, tissue movilization has become the gold standart treatment in many reconstructive procedures. Main disadvantage from these techniques lies in the possibility of sequels in donor zone. Furthermore, raising comorbidities in general population and growing indications for reconstructive surgery in elder people, have triggered the development of new biomaterials which can offer support in the reconstruction while elicit donor zone morbidity. Advances in tissue decellularization techniques have brought numerous matrices which have shown effectivity in many reconstructive procedures. Use of acellular dermal matrices may become an eligible solution for many reconstructive procedures. From breast reconstruction assisted by matrices to complex wound coverage passing throught tendon repair techniques, acellular dermal matrices have shown effectiveness in last studies. Local production of this biomaterial leads to cost minimization derived from harvesting and manufacturing matrices in our centre and avoid out-of-stock and storage issues. Current original protocol proposed by our group include all steps from harvesting samples from cadaveric donors till matrix storage after decellularization proccess. The result is a high valued biomaterial in terms of biocompatibility and security profile available.

Multitarget Action of Xanthones from Garcinia mangostana against α-Amylase, α-Glucosidase and Pancreatic Lipase.

Digestive enzymes such α-amylase (AA), α-glucosidase (AG) and pancreatic lipase (PL), play an important role in the metabolism of carbohydrates and lipids, being attractive therapeutic targets for the treatment of type 2 diabetes and obesity. Garcinia mangostana is an interesting species because there have been identified xanthones with the potential to inhibit these enzymes. In this study, the multitarget inhibitory potential of xanthones from G. mangostana against AA, AG and PL was assessed. The methodology included the isolation and identification of bioactive xanthones, the synthesis of some derivatives and a molecular docking study. The chemical study allowed the isolation of five xanthones (1-5). Six derivatives (6-11) were synthesized from the major compound, highlighting the proposal of a new solvent-free methodology with microwave irradiation for obtaining aromatic compounds with tetrahydropyran cycle. Compounds with multitarget activity correspond to 2, 4, 5, 6 and 9, highlighting 6 with IC50 values of 33.3 µM on AA, 69.2 µM on AG and 164.4 µM on PL. Enzymatic kinetics and molecular docking studies showed that the bioactive xanthones are mainly competitive inhibitors on AA, mixed inhibitors on AG and non-competitive inhibitors on PL. The molecular coupling study established that the presence of methoxy, hydroxyl and carbonyl groups are important in the activity and interaction of polyfunctional xanthones, highlighting their importance depending on the mode of inhibition.

Severe infections in patients with ANCA-associated vasculitis treated with rituximab.

OBJECTIVES: Rituximab (RTX) is an anti-CD20 antibody that selectively depletes B cells and has emerged as a therapy for ANCA-associated vasculitis (AAV) during the past decade. This study sought to quantify and determine potential risk factors for severe infections in AAV patients treated with RTX at rheumatology clinics in Mexico City, Mexico and Lund, Sweden. METHODS: The study consisted of a retrospective case-record review (2005-15) with standardized data collection related to the occurrence of severe infection in 46 patients with AAV in Mexico City (n = 20) and Lund (n = 26) treated with RTX during their disease course. Median duration of follow-up from first RTX dose to death or end of study was 26 months. RESULTS: Eleven (24%) patients suffered a total of 18 severe infections (infection rate of 11.5/100 patient-years). Thirteen of the 18 infections (72%) occurred within the first year of treatment. Risk factors for severe infection were older age at RTX initiation and absence of ENT involvement at diagnosis. In multivariate analyses, age at RTX infusion was the only independent factor predicting severe infection. Four patients (9%) died during follow-up, all as a result of infection. CONCLUSION: Severe infections are common following RTX treatment, and mortality due to infection is a major concern. Most severe infections occur within the first year of RTX treatment. The negative correlation of ENT involvement with severe infection might reflect granulomatosis with polyangiitis phenotype heterogeneity. Older age at time of RTX treatment independently predicts severe infections.

A systematic review of the quality of cardiovascular surgery studies that extracted data from the MAUDE database.

OBJECTIVE: To investigate opportunities and limitations of using the Manufacturer and User Facility Device Experience (MAUDE) database for cardiovascular surgery research, we analyzed the quality of studies having ever used MAUDE, in the field of cardiovascular surgery. METHODS: We systematically searched the Cochrane Library, PubMed, EMBASE, and Google Scholar for randomized and nonrandomized studies, from inception to July 2019. Two authors evaluated the quality of the retrieved observational studies, according to the National Institutes of Health quality assessment tool for either case series or cross-sectional studies. These tools quantify the quality of case series and cohorts/cross-sectional studies, respectively, with nine and 14 queries. RESULTS: Fifty-eight studies were included in the final qualitative review. Of 58 identified studies, 32 were case series, 8 were abstracts of case series, and 13 were reviews or case discussion with an included series from MAUDE. Also, five articles were cross-sectional studies. Of the 32 formal case series, 26 (81%) were found to have poor quality. The most common reasons for a poor quality designation included a lack of consecutive participants, undetermined comparability of participants, and undetermined follow-up adequacy. Only one out of five cross-sectional studies had fair quality; four others were evaluated as poor quality studies. CONCLUSIONS: Cardiovascular surgery studies using the MAUDE database, whether case series or cross-sectional design, are mostly of poor quality. Their low quality is partly caused by poor study design, but mainly by intrinsic limitations to the MAUDE database: cases recruited are not consecutive; patient characteristics are not detailed enough to allow a meaningful comparison of patient characteristics between different patient entries; outcome measures are unclear; there is a limited follow-up; and time-to-event data are lacking. We conclude that the quality of cardiovascular surgery publications that rely on data from MAUDE could be improved if investigators were to extract all relevant data points from MAUDE entries, then apply standard quality assessment tools in compiling and reporting the data. MAUDE might be improved if it used medical case report standards during the process of reporting and indexing adverse events. To calculate the incidence rate of any adverse event, all event-free cases, as well as all adverse events in patients using a device, are required. Neither of these two variables is available in the MAUDE at the time of writing.

Influence of the crystal packing in singlet fission: one step beyond the gas phase approximation.

Singlet fission (SF), a multiexciton generation process, has been proposed as an alternative to enhance the performance of solar cells. The gas phase dimer model has shown its utility to study this process, but it does not always cover all the physics and the effect of the surrounding atoms has to be included in such cases. In this contribution, we explore the influence of crystal packing on the electronic couplings, and on the so-called exciton descriptors and electron-hole correlation plots. We have studied three tetracene dimers extracted from the crystal structure, as well as several dimers and trimers of the α and ß polymorphs of 1,3-diphenylisobenzofuran (DPBF). These polymorphs show different SF yields. Our results highlight that the character of the excited states of tetracene depends on both the mutual disposition of molecules and inclusion of the environment. The latter does however not change significantly the interpretation of the SF mechanism in the studied systems. For DPBF, we establish how the excited state analysis is able to pinpoint differences between the polymorphs. We observe strongly bound correlated excitons in the ß polymorph which might hinder the formation of the 1TT state and, consequently, explain its low SF yield.

Use of real-world evidence for oncology clinical decision making in emerging economies.

Real-world evidence (RWE) can provide insights into patient profiles, disease detection, treatment choice, dosing strategies, treatment sequencing, adverse event management and financial toxicity associated with oncology treatment. However, the full potential of RWE is untapped in emerging economies due to structural and behavioral factors. Structural barriers include lack of regulatory engagement, real-world data availability, quality and integrity. Behavioral barriers include entrenched healthcare professional behaviors that impede rapid RWE understanding and adoption. These barriers can be addressed with close collaboration of healthcare stakeholders; of whom, regulators need to be at the forefront given their ability to facilitate use of RWE in healthcare policy and legislation.

Lay abstract Traditionally, randomized clinical trials have been used to provide insights on new medical therapies and continue to remain the gold standard for approval. The-increasing availability of patient level data in the real-world, it is now possible to generate evidence regarding the usage and potential benefits or risks of a medical therapy derived from analysis of real-world data. This evidence is collectively referred to real-world evidence (RWE). randomized clinical trials and RWE are complementary and the area of Oncology especially benefits from RWE to guide clinical decision making across the patient journey. Key benefits include cancer screening and diagnosis, optimal treatment choices (including personalized medicine) and disease management such as dosing and treatment of side effects. In recent times, RWE generation in oncology has been prolific in the USA and western Europe. With expansive biopharmaceutical investments into infrastructure harnessing patient-level data and greater local regulatory guidance, oncology patients in emerging economies may now also have the opportunity to benefit from clinical decision making informed by RWE.

International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis.

An international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of EGPA patients. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms, purpura, polyneuropathy, unexplained heart, gastrointestinal or kidney disease, and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic work­up for EGPA. Patients with MPO-ANCA associated EGPA have more frequently vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations than patients with ANCA negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having "vasculitic" or "eosinophilic" EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.