Senescent glia link mitochondrial dysfunction and lipid accumulation.

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.

Outcomes and Health Care Utilization After Early Hospital Dismissal in Kidney Transplantation: An Analysis of 1001 Consecutive Cases.

OBJECTIVE: To understand whether reduced lengths of stay after kidney transplantation were associated with excess health care utilization in the first 90 days or long-term graft and patient survival outcomes. BACKGROUND: Reducing length of stay after kidney transplant has an unknown effect on post-transplant health care utilization. We studied this association in a cohort of 1001 consecutive kidney transplants. METHODS: We retrospectively reviewed 2011-2015 data from a prospectively-maintained kidney transplant database from a single center. RESULTS: A total of 1001 patients underwent kidney transplant, and were dismissed from the hospital in 3 groups: Early [≤2 days] (19.8%), Normal [3-7 days] (79.4%) and Late [>7 days] (3.8%). 34.8% of patients had living donor transplants (Early 51%, Normal 31.4%, Late 18.4%, P < 0.001). Early patients had lower delayed graft function rates (Early 19.2%, Normal 32%, Late73.7%, P = 0.001). By the hospital dismissal group, there were no differences in readmissions or emergency room visits at 30 or 90 days. Glomerular filtration rate at 12 months and rates of biopsy-proven acute rejection were also similar between groups. The timing of hospital dismissal was not associated with the risk-adjusted likelihood of readmission. Early and Normal patients had similar graft and patient survival. Late dismissal patients, who had higher rates of cardiovascular complications, had significantly higher late mortality versus Normal dismissal patients in unadjusted and risk-adjusted models. CONCLUSION: Dismissing patients from the hospital 2 days after kidney transplant is safe, feasible, and improves value. It is not associated with excess health care utilization or worse short or long-term transplant outcomes.

Single-port laparoscopic appendicectomy versus conventional three-port approach for acute appendicitis: A systematic review, meta-analysis and trial sequential analysis of randomised controlled trials.

AIMS: The aim of this systematic review and meta-analysis is to compare outcomes of single-port laparoscopic appendicectomy (SPLA) and conventional three-port laparoscopic appendicectomy (CLA) in the management of acute appendicitis. METHODS: A comprehensive systematic review of randomised controlled trials (RCTs) with subsequent meta-analysis and trial sequential analysis of outcomes were conducted. Post-operative pain at 12-h, cosmesis, need for an additional port(s), operative time, port-site hernia, ileus, surgical site infection (SSI), intra-abdominal collection, length of hospital stay (LOS), readmission, and reoperation were the evaluated outcome parameters. RESULTS: Sixteen RCTs with total number of 2017 patients who underwent SPLA (n = 1009) or CLA (n = 1008) were included. SPLA was associated with a significantly higher cosmetic score (MD 1.11, P= 0.03) but significantly longer operative time (MD 7.08, P = 0.00001) compared to CLA. However, the difference was not significant between SPLA and CLA in the post-operative pain score at 12-h (MD -0.13, P = 0.69), need for additional port(s) (RR0.03, P = 0.07), port-site hernia (RD: 0.00, P = 0.68), ileus (RR 0.74, P = 0.51), SSI (RR 1.38, P = 0.28), post-operative intra-abdominal collection (RR 0.00, P = 0.62), LOS (MD -2.41, P = 0.16), readmission to the hospital (RR 0.45, P = 0.22), and return to theatre (RR 0.00, P = 0.49). Trial sequential analysis demonstrated that the meta-analysis is conclusive for most of the outcomes, except LOS and intra-abdominal collection. CONCLUSION: Although SPLA is associated with a slightly longer operative time, its efficacy and safety are comparable to CLA in management of uncomplicated appendicitis. Moreover, it offers improved post-operative cosmesis. The available evidence is conclusive, and further trials may not be required.

Single-port laparoscopic appendicectomy versus conventional three-port approach for acute appendicitis in children: a systematic review and meta-analysis.

AIM: To evaluate comparative outcomes of single-port laparoscopic appendicectomy (SPLA) and conventional three-port laparoscopic appendicectomy (CLA) in the management of acute appendicitis in children. METHODS: A comprehensive systematic review of randomised controlled trials (RCTs) with subsequent meta-analysis of outcomes were conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards. Operative time, surgical site infection, intra-abdominal collection, incisional hernia, length of hospital stay (LOS), additional port/s and conversion to open were the evaluated outcome parameters. RESULTS: Four RCTs reporting a total number of 520 patients who underwent SPLA (n = 260) or CLA (n = 260) were included. There was no difference between SPLA and CLA group in post-operative collection (risk difference (RD) - 0.00, P = 0.94), surgical site infection (RD 0.02, P = 0.25), incisional hernia (RD 0.00 P = 1), LOS (mean difference (MD) 0.73 P = 0.93), need for additional port/s (RD 0.04, P = 0.24) and conversion to open (RD 0.00, P = 1). However, there was a significantly longer operative time in the SPLA group (MD 9.80, P = 0.00001). The certainty of the evidence was judged to be moderate for all outcomes. CONCLUSIONS: SPLA and CLA seem to have comparable efficacy and safety in children with acute appendicitis although the former may be associated with longer procedure time. Future high-quality RCTs with adequate sample sizes are required to provide stronger evidence in favour of an intervention.

Clinical Outcomes of Portosystemic Shunts on the Outcome of Liver Transplantation.

Spontaneous portosystemic shunts (SPSSs) have been associated with worse clinical outcomes in the pre-liver transplantation (LT) setting, but little is known about their post-LT impacts. Our aim was to compare LT candidates with and without SPSSs and assess the impact of SPSSs on patient mortality and graft survival in the post-LT setting. Patients 18 years or older with abdominal imaging done prior to LT were included. Exclusion criteria were the presence of pre-LT surgical shunts, LT indications other than cirrhosis, and combined solid organ transplantations. SPSSs were classified as absent, small, or large according to their maximum diameter (8 mm). Multiple variables that could influence the post-LT course were extracted for analysis. Patient and graft survival were estimated using the Kaplan-Meier method and were compared between groups using a log-rank test. The project received institutional review board approval. We extracted data from 326 patients. After comparing patients without SPSS or with small or large SPSSs, no statistical difference was found for overall patient survival: no SPSS (n = 8/63), reference; small SPSS (n = 18/150), hazard ratio (HR), 1.05 (95% confidence interval [CI], 0.45-2.46); and large SPSS (n = 6/113), HR, 0.60 (95% CI, 0.20-1.78); P = 0.20. Also, no difference was found for graft survival: no SPSS (n = 11/63), reference; small SPSS (n = 21/150), HR, 0.80 (95% CI, 0.38-1.70); large SPSS (n = 11/113), HR, 0.59 (95% CI, 0.25-1.40); P = 0.48. Similarly, no statistical significance was found for these variables when comparing if the graft used was procured from a donation after circulatory death donor versus a donation after brain death donor. In conclusion, the previously described association between SPSSs and worse clinical outcomes in pre-LT patients seems not to persist once patients undergo LT. This study suggests that no steps to correct SPSS intraoperatively are necessary.

New synthesis of 6″-[18 F]fluoromaltotriose for positron emission tomography imaging of bacterial infection.

6″-[18 F]fluoromaltotriose is a positron emission tomography tracer that can differentiate between bacterial infection and inflammation in vivo. Bacteria-specific uptake of 6″-[18 F]fluoromaltotriose is attributed to the targeting of maltodextrin transporter in bacteria that is absent in mammalian cells. Herein, we report a new synthesis of 6″-[18 F]fluoromaltotriose as a key step for its clinical translation. In comparison with the previously reported synthesis, the new synthesis features unambiguous assignment of the fluorine-18 position on the maltotriose unit. The new method utilizes direct fluorination of 2″,3″,4″-tri-O-acetyl-6″-O-trifyl-α-D-glucopyranosyl-(1-4)-O-2',3',6'-tri-O-acetyl-α-D-glucopyranosyl-(1-4)-1,2,3,6-tetra-O-acetyl-D-glucopyranose followed by basic hydrolysis. Radiolabeling of the new maltotriose triflate precursor proceeds using a single HPLC purification step, which results in shorter reaction time in comparison with the previously reported synthesis. Successful synthesis of 6″-[18 F]fluoromaltotriose has been achieved in 3.5 ± 0.3% radiochemical yield (decay corrected, n = 7) and radiochemical purity above 95%. The efficient radiosynthesis of 6″-[18 F]fluoromaltotriose would be critical in advancing this positron emission tomography tracer into clinical trials for imaging bacterial infections.

Does sites of recurrence impact survival in secondary cytoreduction surgery for recurrent epithelial ovarian cancer?

Outcomes of secondary cytoreduction surgery (SCS) were evaluated for morbidity, progression free survival (PFS) and overall survival (OS) and factors influencing results were explored. Retrospective analysis of all cases of SCS for epithelial ovarian cancer (EOC) was performed from October 2010 to December 2017. 62 patients were prospectively identified as candidates for SCS and 57 underwent SCS. 20(35%) patients required bowel resection/s, 24(42%) had nodal resections and 11(19%) had extensive upper abdominal surgery. 51(89%) achieved complete cytoreduction. After a median follow-up of 30 months (range 9-95 months), median PFS was 32 months (CI 17-76 months) and median OS has not reached. Seventeen patients have died and 32 have progressed. Three patients had Clavien-Dindo grade-3 and two had grade-4 morbidity. Patients who had multi-site recurrence had shorter median PFS (p = 0.04) and patients who required bowel resections had lower median OS (p = 0.009) compared to rest of the cohort.IMPACT STATEMENTWhat is already known on this subject? Retrospective studies have confirmed survival advantage for recurrence in epithelial ovarian cancer and recommend SCS for carefully selected patients. This finding is being evaluated in randomised control trials currently.What do the results of this study add? This study presents excellent results for survival outcomes after SCS and highlights importance of careful selection of patients with a goal to achieve complete cytoreduction. In addition, for the first time in literature, this study also explores various factors that may influence results and finds that there are no differences in survival outcomes whether these patients had early stage or advanced stage disease earlier. Patients who have multisite recurrence tend to have shorter PFS but no difference were noted for overall survival. Patients who have recurrence in bowels necessitating resection/s have a shorter median OS compared to rest of cohorts, however, still achieving a good survival time.What are the implications of these findings for clinical practice and/or further research? These findings will raise awareness for the clinicians and patients while discussing surgical outcomes and would set an achievable standard to improve cancer services. The pattern of recurrence and associated outcomes also point towards difference in biological nature of recurrent disease and could provide an opportunity for scientists to study the biological makeup of these recurrent tumours.

A novel synthesis of 6''-[18 F]-fluoromaltotriose as a PET tracer for imaging bacterial infection.

The aim of this study was to develop a positron emission tomography (PET) tracer to visualize and monitor therapeutic response to bacterial infections. In our continued efforts to find maltose based PET tracers that can image bacterial infections, we have designed and prepared 6''-[18 F]fluoromaltotriose as a second generation PET imaging tracer targeting the maltodextrin transporter of bacteria. We have developed methods to synthesize 6''-deoxy-6''-[18 F]fluoro-α-D-glucopyranosyl-(1-4)-O-α-D-glucopyranosyl-(1-4)-O-D-glucopyranose (6''-[18 F]-fluoromaltotriose) as a bacterial infection PET imaging agent. 6''-[18 F]fluoromaltotriose was prepared from precursor, 2'',3'',4''-tri-O-acetyl-6''-O-nosyl-α-D-glucopyranosyl-(1-4)-O-2',3',6'-tri-O-acetyl-α-D-glucopyranosyl-(1-4)-1,2,3,6-tetra-O-acetyl-D-glucopyranose (per-O-acetyl-6''-O-nosyl-maltotriose 4). This method utilizes the reaction between precursor 4 and anhydrous [18 F]KF/Kryptofix 2.2.2 in dimethylformamide (DMF) at 85°C for 10 minutes to yield per-O-acetyl-6''-deoxy-6-'' [18 F]-fluoromaltotriose (7). Successive acidic and basic hydrolysis of the acetyl protecting groups in 7 produced 6''-[18 F]fluoromaltotriose (8). Also, cold 6''- [19 F]fluoromaltotriose was prepared from per-O-acetyl-6''-hydroxymaltotriose via a diethylaminosulfur trifluoride reaction followed by a basic hydrolysis. A successful synthesis of 6''-[18 F]-fluoromaltotriose has been accomplished in 8 ± 1.2% radiochemical yield (decay corrected). Total synthesis time was 120 minutes. Serum stability of 6''-[18 F]fluoromaltotriose at 37°C indicated that 6''-[18 F]-fluoromaltotriose remained intact up to 2 hours. In conclusion, we have successfully synthesized 6''-[18 F]-fluoromaltotriose via direct fluorination of an appropriate precursor of a protected maltotriose.

Development and Validation of an Immuno-PET Tracer as a Companion Diagnostic Agent for Antibody-Drug Conjugate Therapy to Target the CA6 Epitope.

PURPOSE: To develop and compare three copper 64 ((64)Cu)-labeled antibody fragments derived from a CA6-targeting antibody (huDS6) as immuno-positron emission tomography (immuno-PET)-based companion diagnostic agents for an antibody-drug conjugate by using huDS6. MATERIALS AND METHODS: Three antibody fragments derived from huDS6 were produced, purified, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and evaluated in the following ways: (a) the affinity of the fragments and the DOTA conjugates was measured via flow cytometry, (b) the stability of the labeled fragments was determined ex vivo in human serum over 24 hours, and (c) comparison of the in vivo imaging potential of the fragments was evaluated in mice bearing subcutaneous CA6-positive and CA6-negative xenografts by using serial PET imaging and biodistribution. Isotype controls with antilysozyme and anti-DM4 B-Fabs and blocking experiments with an excess of either B-Fab or huDS6 were used to determine the extent of the antibody fragment (64)Cu-DOTA-B-Fab binding specificity. Immunoreactivity and tracer kinetics were evaluated by using cellular uptake and 48-hour imaging experiments, respectively. Statistical analyses were performed by using t tests, one-way analysis of variance, and Wilcoxon and Mann-Whitney tests. RESULTS: The antibody fragment (64)Cu-DOTA-B-Fab was more than 95% stable after 24 hours in human serum, had an immunoreactivity of more than 70%, and allowed differentiation between CA6-positive and CA6-negative tumors in vivo as early as 6 hours after injection, with a 1.7-fold uptake ratio between tumors. Isotype and blocking studies experiments showed tracer-specific uptake in antigen-positive tumors, despite some nonspecific uptake in both tumor models. CONCLUSION: Three antibody fragments were produced and examined as potential companion diagnostic agents. (64)Cu-DOTA-B-Fab is a stable and effective immuno-PET tracer for CA6 imaging in vivo.

Hammondia hammondi harbors functional orthologs of the host-modulating effectors GRA15 and ROP16 but is distinguished from Toxoplasma gondii by a unique transcriptional profile.

Toxoplasma gondii and its nearest extant relative, Hammondia hammondi, are phenotypically distinct despite their remarkable similarity in gene content, synteny, and functionality. To begin to identify genetic differences that might drive distinct infection phenotypes of T. gondii and H. hammondi, in the present study we (i) determined whether two known host-interacting proteins, dense granule protein 15 (GRA15) and rhoptry protein 16 (ROP16), were functionally conserved in H. hammondi and (ii) performed the first comparative transcriptional analysis of H. hammondi and T. gondii sporulated oocysts. We found that GRA15 and ROP16 from H. hammondi (HhGRA15 and HhROP16) modulate the host NF-κB and STAT6 pathways, respectively, when expressed heterologously in T. gondii. We also found the transcriptomes of H. hammondi and T. gondii to be highly distinct. Consistent with the spontaneous conversion of H. hammondi tachyzoites into bradyzoites both in vitro and in vivo, H. hammondi high-abundance transcripts are enriched for genes that are of greater abundance in T. gondii bradyzoites. We also identified genes that are of high transcript abundance in H. hammondi but are poorly expressed in multiple T. gondii life stages, suggesting that these genes are uniquely expressed in H. hammondi. Taken together, these data confirm the functional conservation of known T. gondii virulence effectors in H. hammondi and point to transcriptional differences as a potential source of the phenotypic differences between these species.

Surgical management of SLAP lesions: Which technique has better surgical outcomes?

Background: The gold-standard surgical management for superior labral anterior to posterior (SLAP) lesions is unclear. This meta-analysis compares the outcomes of different surgical SLAP lesion management techniques including labral repair, long head of biceps (LHB) tenodesis and LHB tenotomy with consideration to clinical scores, return to sports, re-operation, range-of-motion and patient satisfaction. Methods: PRISMA guidelines were adhered. Web of Science, PubMed, Cochrane Central, Science direct and EMBASE were searched using relevant keywords. Eligible studies were screened, data extracted and synthesised using Review Manager (Version 5.4.1). Bayesian network meta-analysis (NMA) was conducted. Randomised control and clinical trials regarding SLAP lesion management in patients over 18 years old were included. Studies were excluded if patients had concomitant massive tears of the rotator cuff, Bankart lesions or instability of the shoulder. Results: Patient satisfaction with LHB tenodesis was superior to superior labral repair. No difference was demonstrated with respect to ASES score, pain VAS score, return to sports and pre-injury activities, reoperation rate or range-of-motion. LHB tenodesis and LHB tenotomy show no difference in ASES score or post operative deformity in management of SLAP lesions. Discussion: High-quality, standardised randomised control studies between the different surgical techniques is warranted.

Early and 1-year mortality of native geriatric distal femur fractures: A systematic review and time-to-event meta-analysis.

Purpose: Distal femur fractures (DFF) account for 6% of all femoral fractures and predominate in females. The current 1-year mortality of DFF is currently reported to be between 10 and 38%, a wide margin, and confounded by multiple factors including age, high energy mechanisms, pathological and periprosthetic fractures. The purpose of this study was to assess and determine all-cause mortality following geriatric native distal femur fractures at 30 days, six months and one year. Methods: - The databases Cochrane CENTRAL, MEDLINE, EMBASE and NHS NICE Healthcare Databases Advanced Search Interface were searched in accordance with PRISMA guidelines. Original research articles relevant to mortality outcomes in native geriatric distal femur fractures following low energy trauma were included. A time-to-event data meta-analysis model was used to estimate pooled 30-day, six month and one-year mortality. A random effects meta-regression model was performed to assess potential sources of heterogeneity when studies reported on factors affecting the mortality observed in patients with geriatric distal femur fractures. Results: - Thirteen studies were included in the meta-analysis with a mean age of 79.6 years. Eight studies reported the 30-day mortality of distal femur fractures in patients as a pooled estimate of 8.14%. Pooled estimate for 6-month mortality reported was 19.5% and the one-year mortality reported by ten studies was 26.10%. Time-to-event modelling showed that risk of mortality at one year in elderly patients with distal femur fractures was significantly higher HR = 4.31 (p < 0.001). When evaluating prognostic predictors, age and Type C fracture were predictive of highest mortality rates. Conclusions: - This study is the first meta-analysis to evaluate the early and long-term mortality observed in elderly patients presenting with native distal femoral fractures. Through our results we have shown the quantifiable impact patient age and fracture configuration has on one-year mortality in this patient cohort.

Surgical management of cubital tunnel syndrome: A systematic review and meta-analysis of randomised trials.

Background: Cubital tunnel syndrome (CUTS) is a common upper limb compression neuropathy with significant consequences when left untreated. Surgical decompression remains gold-standard treatment for moderate to severe disease, however the optimal operative technique remains unclear. This network meta-analysis (NMA) of Level I and II randomised prospective studies aims to discern superiority between open in-situ, endoscopic and anterior transposition (subcutaneous or submuscular techniques) with respect to the primary outcome of response-to-treatment and secondary outcomes which include complications, post-operative chronic pain VAS scale, return to work and re-operation. Methods: This NMA adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. PubMed, Web of Science, Cochrane Central, Science direct and Embase were searched. The MESH database was further searched with the terms 'cubital tunnel' to improve sensitivity of the search. Data pertaining to the primary and secondary outcomes were pooled for NMA. Results: Following abstract and full-text screening, 10 randomised prospective trials were included. There was no statistical difference in the response-to-treatment between the four studied techniques. Endoscopic decompression conferred a significantly higher complication rate compared to open decompression (Odds Ratio [OR], 4.21; 95% CI, 1.22-14.59). Endoscopic decompression had a statistically significant lower risk of post-operative chronic pain compared to open in-situ decompression (OR, 0.03, 95% CI, 0.00-0.32). There were no differences between techniques with respect to return to work or re-operation rates. Conclusion: Response-to-treatment was similar between the four operative techniques for CUTS. Endoscopic decompression was found to be more hazardous when compared to open-in situ decompression but conferred significantly less post-operative chronic pain. There was significant heterogeneity in reported outcomes between the included articles. The authors suggest conducting more high-quality research with standardised outcome reporting to facilitate comparison. Level of evidence ii: Systematic Review and Meta-analysis of Randomised Prospective Trials- Therapeutic study.

Radiological and Long-Term Functional Outcomes of Displaced Distal Clavicle Fractures.

OBJECTIVES: To investigate radiological and long-term functional outcomes in modified Neer 2a, 2b, and 5 distal clavicle fractures. DESIGN: Retrospective cohort study. SETTING: A single university teaching hospital. PATIENTS/PARTICIPANTS: One hundred fifteen patients sustaining displaced distal clavicle fractures between January 01, 2010 and December 12, 2017. INTERVENTION: Operative versus nonoperative management. MAIN OUTCOME MEASUREMENTS: Radiographs were reviewed for fracture management and union. A customised questionnaire consisting of QuickDASH (Disabilities of the Arm, Shoulder and Hand), work, sports/performing arts, global satisfaction, and complication modules was used to determine functional outcome. RESULTS: One hundred fifteen patients were included [mean age of 49 (18-89) years]. Thirty-three (29%) underwent early fixation (<6 weeks from injury) and were younger (37 vs. 53 years, P < 0.0001). Radiographs were available for 96 patients. Nonunion rate was 55% (53/96), and majority had undergone initial nonoperative management (49 vs. 4, P < 0.00001). Eleven patients with symptomatic nonunion were deemed appropriate for delayed fixation with all cases uniting. Of the operatively managed patients, 27% (12/44) underwent metalwork removal. There were no differences in functional outcome between operative versus nonoperative and union versus nonunion patient groups at a mean follow-up of 79 months ( P > 0.05). CONCLUSION: Functional outcome and patient satisfaction at long-term follow-up were similar regardless of operative fixation or radiological union. Nonunion in displaced distal clavicle fractures seemed to cause minimal functional deficit in most elderly sedentary individuals, or the outcome measures were not sensitive enough to capture these differences. An individualized approach should be adopted, with less active, comorbid, and elderly patients counseled regarding the minimal functional improvement of surgery and risk of reoperation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Aspirin as a thromboprophylaxis agent after revision knee arthroplasty: A retrospective analysis.

Introduction: Total knee arthroplasty is a common and effective procedure. Although complication rates are low, certain complications such as venous thromboembolism are potentially serious. The optimal prophylactic agent and dosage after revision knee arthroplasty remains unclear. The main objective of this work was to study the efficacy and safety of aspirin as a thromboprophylaxis agent following revision knee arthroplasties. Patients and methods: A retrospective review of patients undergoing revision knee arthroplasty between 2013 and 2020at a University Teaching Hospital was undertaken. The primary outcome was the development of a symptomatic thromboembolic event requiring treatment within 90 days post-surgery. The secondary outcomes were adverse events associated with aspirin therapy: surgical site infection rate; incidence of major bleeding; readmission rate and mortality within 90 days post-surgery. Results: 490 patients were included. 374 (76.3%) received prophylactic aspirin (150 mg once daily for 28 days) and 75 (15.3%) patients received dalteparin for 28 days due to contraindication to aspirin use. Those already receiving other thromboprophylaxis agents for pre-existing comorbidities continued these after relevant medical consultation. The overall rates of venous thromboembolism and symptomatic DVT after aspirin prophylaxis were 0.6% (3/490) and 0.8% (3/374), respectively. VTE incidence did not significantly differ between those administered aspirin and other agents. No patient experienced major bleeding within 90 postoperative days. Only 2 of 490 (0.4%) patients had wound infection requiring readmission; neither received prophylactic aspirin. Conclusion: Extended out-of-hospital thromboembolic prophylaxis with aspirin may be at least as effective as other agents in patients undergoing revision knee arthroplasty. Aspirin is safe, effective, and cheap compared with other agents.

Epidemiology and Diagnosis of Post-Thrombotic Syndrome: Qualitative Synthesis with a Systematic Review.

Background: Post-thrombotic syndrome (PTS) is a common and debilitating sequela of lower limb deep vein thrombosis (DVT). There is significant heterogeneity in reported PTS incidence due to lack of standardised diagnostic criteria. This review aimed to develop diagnostic criteria for PTS and subsequently refine the reported incidence and severity. Methods: PRISMA principles were followed; however, the review was not registered. The Cochrane CENTRAL database, MEDLINE, Embase, the NHS NICE Healthcare Databases Advanced Search interface, and trial registers including isrctn.com and clinicaltrials.gov were searched for studies addressing areas of interest (PTS definition, epidemiology, assessment). An experienced Clinical Librarian undertook the systematic searches, and two independent reviewers agreed on the relevance of the papers. Conflicts were resolved through panel review. Evidence quality was assessed using a modified Coleman scoring system and weighted according to their relevance to the aforementioned areas of interest. Results: A total of 339 abstracts were retrieved. A total of 33 full-text papers were included in this review. Following qualitative analysis, four criteria were proposed to define PTS: (1) a proven thrombotic event on radiological assessment; (2) a minimum 24-month follow-up period after an index DVT; (3) assessment with a validated score; and (4) evidence of progression of venous insufficiency from baseline. Four papers conformed to our PTS definition criteria, and the incidence of mild to moderate PTS ranged from 7 to 36%. On reviewing the studies which utilised the recommended Villalta scale, PTS incidence narrowed further to 23-36%. Incidence and severity reached a plateau at 24 months. Conclusions: Four diagnostic criteria were developed from qualitative synthesis. When these criteria were applied to the literature, the range of reported PTS incidence narrowed. These four criteria may standardise PTS diagnosis in future studies, facilitating the pooling of data for meta-analysis and synthesis of higher levels of evidence.

A focused small-molecule screen identifies 14 compounds with distinct effects on Toxoplasma gondii.

Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role of Toxoplasma-secreted kinases in the interaction of Toxoplasma with its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-Toxoplasma drugs and define new pathways important for parasite survival. We selected a small (n = 527) but diverse set of putative kinase inhibitors and screened them for effects on the growth of Toxoplasma in vitro. We identified and validated 14 noncytotoxic compounds, all of which had 50% effective concentrations in the nanomolar to micromolar range. We further characterized eight of these compounds, four inhibitors and four enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appeared to target the parasite, and interestingly, two of the enhancers appeared to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model, where one compound proved potent. Overall, these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite.

Insights gained from symptom evaluation of esophageal motility disorders: a review of 4,215 patients.

BACKGROUND/AIMS: Achalasia (Ach), diffuse esophageal spasm (DES), nutcracker esophagus (NE), and nonspecific motility disorder (NSMD) are described primary esophageal body motility disorders; however, their clinical symptom correlation is poorly understood. The aim of this study is to examine the association between a patient's presenting symptoms and their manometric diagnosis. METHODS: Manometric findings and reported symptoms of all patients undergoing esophageal manometry at the Creighton University Medical Center were prospectively entered in a database. Twenty-four-year data from 1984 through 2008 were accessed and analyzed. RESULTS: Of the 4,215 patients, 130 (3.1%) had Ach, 192 (4.6%) had DES, 290 (6.9%) had NE, 508 (12.1%) had NSMD, and 3,095 (73.4%) had normal esophageal body motility. There was significant symptom overlap between the groups. Ach and DES had a similar symptom distribution, with dysphagia being the predominant symptom. Patients with NE, normal body motility, and NSMD presented predominantly with reflux symptoms. There was an increasing prevalence of esophageal dysmotility (DES and NSMD) with age, and women were found to be more likely to have NE than men. CONCLUSION: In an individual, reported symptoms do not correlate with their manometric diagnosis in a predictable fashion, and a thorough physiological assessment should be obtained to understand and diagnose the disease process. Esophageal motility deteriorates with age.

Loss of miR-34 in Drosophila dysregulates protein translation and protein turnover in the aging brain.

Aging is a risk factor for neurodegenerative disease, but precise mechanisms that influence this relationship are still under investigation. Work in Drosophila melanogaster identified the microRNA miR-34 as a modifier of aging and neurodegeneration in the brain. MiR-34 mutants present aspects of early aging, including reduced lifespan, neurodegeneration, and a buildup of the repressive histone mark H3K27me3. To better understand how miR-34 regulated pathways contribute to age-associated phenotypes in the brain, here we transcriptionally profiled the miR-34 mutant brain. This identified that genes associated with translation are dysregulated in the miR-34 mutant. The brains of these animals show increased translation activity, accumulation of protein aggregation markers, and altered autophagy activity. To determine if altered H3K27me3 was responsible for this proteostasis dysregulation, we studied the effects of increased H3K27me3 by mutating the histone demethylase Utx. Reduced Utx activity enhanced neurodegeneration and mimicked the protein accumulation seen in miR-34 mutant brains. However, unlike the miR-34 mutant, Utx mutant brains did not show similar altered autophagy or translation activity, suggesting that additional miR-34-targeted pathways are involved. Transcriptional analysis of predicted miR-34 targets identified Lst8, a subunit of Tor Complex 1 (TORC1), as a potential target. We confirmed that miR-34 regulates the 3' UTR of Lst8 and identified several additional predicted miR-34 targets that may be critical for maintaining proteostasis and brain health. Together, these results present novel understanding of the brain and the role of the conserved miRNA miR-34 in impacting proteostasis in the brain with age.

Intervention to Improve Compliance With National Guidelines on Venous Thromboembolism Chemoprophylaxis for Patients With Operatively Managed Ankle Fractures.

Background: Trauma and subsequent immobilization of the lower limb increase the risk of venous thromboembolism (VTE). Our aim was to evaluate compliance with national guidance on operatively managed ankle fractures and VTE chemoprophylaxis before and after implementation of a change in practice. Methods: We conducted an initial single-center audit of patients undergoing ankle fracture fixation. The primary outcome was quality of operation note documentation, and the secondary outcome was whether VTE chemoprophylaxis was prescribed on discharge. All stakeholders were educated on audit findings, new guidelines were synthesized, and the practice was re-audited. Results: A total of 137 patients were included in the initial audit, and 49 patients were included in the loop closure. The first audit highlighted that chemoprophylaxis prescription on discharge was significantly higher when both the agent and treatment duration were clearly stipulated in the operation note compared to when either treatment duration or both agent and treatment duration were omitted (97.2% vs 51.8% and 32.4%, respectively, P<0.001). Following our intervention, operation note documentation of agent and treatment duration improved from 29% to 90% (P<0.001). VTE chemoprophylaxis on discharge significantly improved from 57% to 98% (P<0.001). Conclusion: Our closed-loop audit identified suboptimal operation note documentation as the root cause of VTE noncompliance. The operation note is an important clinical interface between the operating theater and ward staff. We addressed these deficiencies with a basic intervention.