A decade's experience with retrograde open mesenteric stenting for acute mesenteric ischemia.

OBJECTIVE: Retrograde open mesenteric stenting (ROMS) is an alternative to mesenteric bypass in patients with acute mesenteric ischemia (AMI) with variable reported 30-day mortality rates. Large studies evaluating patient outcomes following ROMS are scarce. Our study aims to assess the results of this approach among patients presenting with AMI. METHODS: We reviewed all the patients with AMI who were treated with ROMS (2011-2022). Patient demographics, presentation, operative details, and outcomes were analyzed. Primary end points were in-hospital, 30-day, and 1-year mortality. Kaplan-Meier estimate for 1-year mortality and primary patency loss were generated. Secondary end points included postoperative 30-day complications. RESULTS: Between 2011 and 2022, ROMS was attempted on a total of 42 patients. The median age was 70 ± 15 years and the majority of patients were female. Pain out of proportion to the physical examination was the most common presenting symptom (n = 18, 42.9%) followed by peritonitis (n = 14, 33.4%). All patients underwent preoperative intravenous contrast computed tomography imaging. In situ thrombosis was identified as the etiology of AMI in 36 patients (85.7%). Technical success was achieved in 40 patients (95.2%). Conventional, non-hybrid operating rooms were used for the majority of cases. Revascularization of all 40 patients involved angioplasty and stenting of superior mesenteric artery. A single stent was placed in 35 patients (87.5%) and the reminder had more than one stent. Eighty percent of patients required bowel resection. A second-look laparotomy was required in 34 patients (85.0%). The mean operative time, including both the general surgery and vascular surgery portions of the index procedure, was 192 ± 57 minutes. Sepsis was the most common complication observed within 30 days, occurring in 8 patients (20.0%). In terms of mortality, 13 patients (32.5%) died during their index hospitalization, and 9 died (22.5%) within 30 days. On Kaplan-Meier analysis, the 1-year overall patient survival rate was 58.6%, and the primary patency rate for stents was 51.4%. CONCLUSIONS: ROMS has an excellent technical success rate in management of AMI with lower than traditionally reported mortality rates for AMI. The dual benefits of rapid revascularization and bowel evaluation should make this surgical modality an alternative approach for treatment of AMI.

Enhancement of Antibody-Dependent Cellular Cytotoxicity and Phagocytosis in Anti-HIV-1 Human-Bovine Chimeric Broadly Neutralizing Antibodies.

No prophylactic vaccine has provided robust protection against human immunodeficiency virus type 1 (HIV-1). Vaccine-induced broadly neutralizing antibodies (bNAbs) have not been achieved in humans and most animals; however, cows vaccinated with HIV-1 envelope trimers produce bNAbs with unusually long third heavy complementarity-determining regions (CDRH3s). Alongside neutralization, Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP), may be critical for in vivo bNAb antiviral activity. Here, we aimed to augment the Fc-dependent effector functions of a chimeric human-bovine bNAb, NC-Cow1, which binds the CD4 binding site (CD4bs) and exhibits broader and more potent neutralization than most human CD4bs bNAbs by using an exceptionally long 60-amino acid (aa) CDRH3. The bovine variable region of NC-Cow1 was paired with a human IgG1 Fc region mutated to create the following three variants: G236R/L328R (GRLR) that abrogates Fc-gamma receptor (FcγR) binding, and two variants that enhance binding, namely, G236A/S239D/I332E (GASDIE) and G236A/S239D/A330L/I332E (GASDALIE). Both GASDIE and GASDALIE improved binding to human FcγRIIA and FcγRIIIA, enhanced human natural killer (NK) cell activation, and mediated higher levels of ADCC and ADP activity than the wild-type human IgG1 Fc. GASDALIE mediated higher phagocytic activity than GASDIE. As expected, GRLR eliminated binding to FcγRs and did not mediate ADCC or ADP. We demonstrated that mutations in the human Fc region of bovine chimeric antibodies with ultralong CDRH3s could enhance antibody effector functions while maintaining envelope binding and neutralization. This study will have significant implications in the development of multifunctional anti-HIV antibodies, which may be important to prevent HIV-1 transmission in an antibody-based topical microbicide. IMPORTANCE Despite successful antiviral chemotherapy, human immunodeficiency virus (HIV) is still a lifelong persistent virus, and no vaccine yet prevents HIV transmission. Topical microbicides offer an important alternative method to prevent sexual transmission of HIV-1. With the production of highly potent anti-HIV-1 broadly neutralizing antibodies (bNAbs) and multifunctional antibodies, monoclonal antibodies are now important prophylactic agents. Recently discovered anti-HIV-1 bovine bNAbs (with higher potency and breadth than most human bNAbs) could be novel candidates as potent topical microbicides. Our study is significant as it demonstrates the compatibility of combining bovine-derived neutralization with human-derived antibody-effector functions. This study is a new approach to antibody engineering that strengthens the feasibility of using high-potency bovine variable region bNAbs with augmented Fc function and promotes them as a strong candidate for antibody-mediated therapies.

Female Gender is a Predictor of Lower Iliac Vein Stenting Patency Rates.

BACKGROUND: Iliac venous stenting (IVS) for thrombotic and nonthrombotic venous disease is increasingly used as evidence of the safety, efficacy and durability of these interventions increases. Female gender has been implicated as a predictor of failure in arterial endovascular interventions. We hypothesize that female gender could be predictive of patency rates of iliac vein stenting. METHODS: Consecutive patients who underwent IVS for thrombotic or nonthrombotic venous disease at our institution from 2007 until 2019 were identified and divided into groups based on gender. Operative notes, venograms, and the electronic health record were then queried to obtain operative details, co-morbid conditions, postoperative outcomes and stent patency. Study outcome was long term patency rate. The data was analyzed using chi-square, logistic regression, and Kaplan-Meier analysis as appropriate. RESULTS: A total of 200 consecutive patients (231 limbs) were identified in our retrospective analysis, with a mean age of 48.8 ± 17.3, and BMI of 31.6 ± 8.6. Of those, 119 (59.5%) patients, (131 [56.8%] limbs) were female. Comparisons between the gender groups revealed no difference in age, BMI, or preoperative comorbidities. There was no difference in type of venous disease between male (85% thrombotic, 15% nonthrombotic) and female (84% thrombotic, 16% nonthrombotic), P= 0.830. The male cohort was more likely to present with leg ulceration (17% vs. 4.6%, P = 0.002), and the female cohort was more likely to present with leg edema (98.5% vs. 93.0%, P= 0.03). The male cohort had a higher rate of caval (48% vs. 33.6%, P= 0.027) and infrainguinal stent extension. (11% vs. 6.9%, P= 0.02). Females had a higher rate of left sided stenting (80.9% vs. 66/0%, P= 0.010). There was no difference in the median stent diameter used between the cohorts. Primary patency at 5 years was significantly higher for the male cohort (94.1% vs. 74.4%, P= 0.01) On adjusted multivariable cox regression female gender was a predictor of loss of primary patency within 5 years (HR, 4.04; P= 0.007). CONCLUSIONS: In this single center retrospective analysis of IVS, male patients were found to have better primary stent patency compared to female.

Tat IRES modulator of tat mRNA (TIM-TAM): a conserved RNA structure that controls Tat expression and acts as a switch for HIV productive and latent infection.

Tat protein is essential to fully activate HIV transcription and processing of viral mRNA, and therefore determines virus expression in productive replication and the establishment and maintenance of latent infection. Here, we used thermodynamic and structure analyses to define a highly conserved sequence-structure in tat mRNA that functions as Tat IRES modulator of tat mRNA (TIM-TAM). By impeding cap-dependent ribosome progression during authentic spliced tat mRNA translation, TIM-TAM stable structure impacts on timing and level of Tat protein hence controlling HIV production and infectivity along with promoting latency. TIM-TAM also adopts a conformation that mediates Tat internal ribosome entry site (IRES)-dependent translation during the early phases of infection before provirus integration. Our results document the critical role of TIM-TAM in Tat expression to facilitate virus reactivation from latency, with implications for HIV treatment and drug development.

Is lateral ankle sprain of the child and adolescent a myth or a reality? A systematic review of the literature.

BACKGROUND: Ankle trauma in children and adolescents is the most common orthopedic injury encountered in pediatric trauma. It has long been recognized that a lateral ankle injury in this population is often a Salter and Harris type I fracture of the distal fibula (SH1). The purpose of this study is to confirm the existence of a lateral ankle sprain and to report the incidence of each pathology of the lateral ankle compartment: SH1 fracture, ATFL injury, and osteochondral avulsions. METHODS: A systematic review of the literature is done using the database provided by PubMed and Embase. All articles reporting the incidence of imaging modality-confirmed lateral ankle injury (SH1, ATFL injury, osteochondral avulsion) in children and adolescents were included. Exclusion criteria were the following: case reports or articles with less than ten subjects, unspecified imaging modality and articles unrelated to lateral ankle lesions. Thus, 237 titles and abstracts were selected, 25 were analyzed thoroughly, and 11 articles were included for final analysis. RESULTS: SH1 fractures were found in 0-57.5% of the cases in all series and 0-3% in the most recent series. A diagnosis of an ATFL injury was found in 3.2-80% and an osteochondral avulsion of the distal fibula in 6-28.1%. The most recent series report 76-80% and 62% for ATFL injury and osteochondral avulsion respectively. CONCLUSIONS: There is a non-negligible incidence of ATFL sprains and fibular tip avulsions in patients with a suspected SH1 fracture of the distal fibula. According to recent evidence and MRI examinations, the most common injuries of the pediatric ankle are ATFL sprain and osteochondral avulsions. This should be taken into consideration in daily practice when ordering radiological examination and deciding on treatment modalities.

Utilization and Outcomes of Radial Artery Access for Lower Extremity Endovascular Intervention.

INTRODUCTION: Radial artery access has become popular for cardiac interventions, but its role in lower extremity interventions is not well defined. We aimed to describe current utilization and outcomes of transradial access for lower extremity interventions. METHODS: Peripheral vascular intervention (PVI) from 2016-2020 where transradial access was employed in the Vascular Quality Initiative (VQI) registry were studied. Cases before 2016 were excluded as documentation of transradial access was not possible in earlier years. PVIs involving radial artery access were evaluated with regard to access guidance, access-site complications, target vessels treated and the technical success of these interventions. RESULTS: Of 167,098 PVIs, 1,096 (0.66%) involved radial access. Utilization varied significantly by region (P < 0.01). The left radial artery was used in 66.9% of cases. Ultrasound-guided access was documented in 72.7% of cases. There were no significant differences in age, body mass index, or sex between the transradial group and other PVIs. In 450 procedures, a second access site was utilized, most commonly a retrograde femoral access (60.0%) or retrograde pedal access (16.7%). The largest sheath was 6-Fr in 78.0%. Interventions documenting radial-only access more commonly treated the aortoiliac segment (49.4% vs. 29.5%, P < 0.001) and less commonly treated the tibial segments (7.1% vs. 32.1%, P < 0.001). Technical success was 94.0%, with inability to cross the lesion (3.1%) and residual stenosis after treatment (2.2%) being most common. There were access-site complications in 2.9%, with hematoma (2.4%) being most common. DISCUSSION: Radial access is associated with high technical success rates and low access-site complication rates. Advances in device profile and shaft length may overcome shortcomings of transradial access and lead to further utilization of this access site.

Functional properties and sequence variation of HTLV-1 p13.

Human T cell leukemia virus type-1 (HTLV-1) was the first retrovirus found to cause cancer in humans, but the mechanisms that drive the development of leukemia and other diseases associated with HTLV-1 infection remain to be fully understood. This review describes the functional properties of p13, an 87-amino acid protein coded by HTLV-1 open reading frame II (orf-II). p13 is mainly localized in the inner membrane of the mitochondria, where it induces potassium (K+) influx and reactive oxygen species (ROS) production, which can trigger either proliferation or apoptosis, depending on the ROS setpoint of the cell. Recent evidence indicates that p13 may influence the cell's innate immune response to viral infection and the infected cell phenotype. Association of the HTLV-1 transcriptional activator, Tax, with p13 increases p13's stability, leads to its partial co-localization with Tax in nuclear speckles, and reduces the ability of Tax to interact with the transcription cofactor CBP/p300. Comparison of p13 sequences isolated from HTLV-1-infected individuals revealed a small number of amino acid variations in the domains controlling the subcellular localization of the protein. Disruptive mutations of p13 were found in samples obtained from asymptomatic patients with low proviral load. p13 sequences of HTLV-1 subtype C isolates from indigenous Australian patients showed a high degree of identity among each other, with all samples containing a pattern of 5 amino acids that distinguished them from other subtypes. Further characterization of p13's functional properties and sequence variants may lead to a deeper understanding of the impact of p13 as a contributor to the clinical manifestations of HTLV-1 infection.

Nationwide trends in drug-coated balloon and drug-eluting stent utilization in the femoropopliteal arteries.

OBJECTIVE: Drug-coated balloons (DCB) and drug-eluting stents (DES) have significantly altered treatment paradigms for femoropopliteal lesions. We aimed to describe changes in practice patterns as a result of the infusion of these technologies into the treatment of peripheral arterial disease. METHODS: We queried the Vascular Quality Initiative registry from 2010 to 2017 for all peripheral vascular interventions involving the superficial femoral artery and/or the popliteal artery. Cases were divided into a PRE and a POST era with a cutoff of September 2016, when specific device identity was first recorded in Vascular Quality Initiative. For each artery, a primary treatment was identified as either plain balloon angioplasty, atherectomy, DCB, bare-metal stent, or DES. The relative distribution of primary treatments between the PRE and POST eras was evaluated, as were lesion characteristics associated with DCB and DES use and regional variability in the adoption of these new technologies. RESULTS: Of 210,666 arteries in the dataset, 91,864 femoropopliteal arteries (across 74,842 procedures in 55,437 patients) were included. Each artery received 1.5 ± 0.6 treatments. Primary treatment use changed from 40% balloon angioplasty, 45% stenting, and 15% atherectomy in the PRE era to 22% plain balloon angioplasty, 26% bare-metal stent, 8% atherectomy, 37% DCB, and 8% DES in the POST era (P < .001). Forty-three percent of arteries received a drug-containing device as a primary or adjunctive therapy and 1.3% received both a DCB and DES in the POST era. DCB use as the primary treatment was highest in lesions with length 10.0 to 19.9 cm (42%), TransAtlantic InterSociety A, B, or C lesions (38%), and lesions with mild to no calcification (38%). DES use was highest in lesions with a length of 20 cm or more (12%), TransAtlantic InterSociety D lesions (13%), and lesions with moderate to severe calcification (9%). The range of use across 18 regions was 125 to 40% for DCB and 1% to 14% for DES. Regional variability was greater for DES (SD 4% vs mean 8%) than for DCB (SD 7% vs mean 29%). CONCLUSIONS: There has been a rapid dissemination of DCB and DES technology in the femoropopliteal vessels, with nearly one-half of arteries receiving a drug-containing therapy in modern practice. DCBs are most used in medium length, minimally calcified lesions and DESs are most used in longer, more heavily calcified lesions. There is significant regional variability in adoption, especially with DES.

Influence of Physical Activity Level on Composite Indices of Femoral Neck Strength in a Group of Young Overweight Men.

The aim of the present study was to explore the influence of physical activity level on composite indices of femoral neck strength (compression strength index [CSI], bending strength index, and impact strength index) in a group of young overweight men. To do so, we compared composite indices of femoral neck strength in active overweight men and insufficiently active overweight men. They were divided into 2 groups based on their physical activity level: 70 active overweight men (engaging in more than 150 minutes of physical activity per week; 8.7 ± 4.8 h/wk) and 26 insufficiently active overweight men (engaging in less than 150 minutes of physical activity per week; 1.2 ± 0.7 h/wk). Height (m) and weight (kg) were measured, and body mass index (kg/m2) was calculated. Bone mineral density was measured by dual-energy X-ray absorptiometry at whole body, lumbar spine, total hip, and femoral neck. Body weight, lean mass, fat mass, and body mass index were not significantly different between the 2 groups. CSI, bending strength index, and impact strength index were significantly higher in active overweight men compared to insufficiently active overweight men. After adjustment for age, physical activity (h/wk) and lean mass, only CSI remained higher in active overweight men compared to insufficiently active overweight men. This study suggests that, in young overweight men, being active (engaging in more than 150 minutes of physical activity per week) is associated with greater composite indices of femoral neck strength. To our knowledge, this is the first study that finds a significant difference regarding composite indices of femoral neck strength between 2 groups of young overweight men with different levels of physical activity.

Does the induced membrane have antibacterial properties? An experimental rat model of a chronic infected nonunion.

INTRODUCTION: The Masquelet procedure proved its efficiency in treating infected nonunion filling bony gaps up to 25 cm. Yet the use of local antibiotics is still questionable in the daily practice with lack of evidence regarding its usefulness in controlling infection. An experimental rat model is put in place to study the antibacterial properties of the induced membrane produced during the first stage of Masquelet. METHOD: Twenty-three-month-old wistar male rats are inoculated with a 0.5 mL solution of 10^8 CFU/mL MRSA over a critical fracture done on the right femur. Six weeks later, remaining 11 rats exhibiting signs of a chronic infection with a sinus tract and oozing pus along with radiological nonunion are used for a first stage Masquelet procedure. They are randomly divided into two groups with six rats having no local antibiotic in the cement mixture and five rats having 3 g of vancomycin mixed with gentamycin loaded cement. Six weeks later (twelve weeks from baseline), all eleven rats are euthanized and blood samples for C-reactive protein are withdrawn. The induced membrane is identified and resected along with bone fragments and sent for cultures and pathology. RESULTS: MRSA is isolated in the cultures of all six rats in the first group where no local antibiotic was added. Altered polymorphonuclears with abscess and pus are noted on four of six pathology samples. However in the second group where local antibiotics were added, three out of five rats exhibited eradication of MRSA (p = 0.034) and all samples did not exhibit clear infection signs on pathology. A pyo-epithelioid over a foreign body reaction is seen predominantly in this group demonstrating a regenerative process. DISCUSSION: The induced membrane does not have antimicrobial properties capable of overcoming an infected nonunion on its own. When local antibiotics were added during the first stage of the Masquelet procedure, new bone formation occurred indicating the need to control an infection in order for bone union to occur. CONCLUSION: Local antibiotics use in adjunction to extensive debridement is advisable during the first stage of a Masquelet procedure for an infected nonunion.

Impact of Hepatitis B Virus Coinfection on Human T-Lymphotropic Virus Type 1 Clonality in an Indigenous Population of Central Australia.

The prevalence of human T-cell lymphotropic virus type 1 (HTLV-1) and hepatitis B virus (HBV) coinfection is high in certain Indigenous Australian populations, but its impact on HTLV-1 has not been described. We compared 2 groups of Indigenous adults infected with HTLV-1, either alone or coinfected with HBV. The 2 groups had a similar HTLV-1 proviral load, but there was a significant increase in clonal expansion of HTLV-1-infected lymphocytes in coinfected asymptomatic individuals. The degree of clonal expansion was correlated with the titer of HBV surface antigen. We conclude that HTLV-1/HBV coinfection may predispose to HTLV-1-associated malignant disease.

Role of HTLV-1 orf-I encoded proteins in viral transmission and persistence.

The human T cell leukemia virus type 1 (HTVL-1), first reported in 1980 by Robert Gallo's group, is the etiologic agent of both cancer and inflammatory diseases. Despite approximately 40 years of investigation, the prognosis for afflicted patients remains poor with no effective treatments. The virus persists in the infected host by evading the host immune response and inducing proliferation of infected CD4+ T-cells. Here, we will review the role that viral orf-I protein products play in altering intracellular signaling, protein expression and cell-cell communication in order to escape immune recognition and promote T-cell proliferation. We will also review studies of orf-I mutations found in infected patients and their potential impact on viral load, transmission and persistence. Finally, we will compare the orf-I gene in HTLV-1 subtypes as well as related STLV-1.

p30 protein: a critical regulator of HTLV-1 viral latency and host immunity.

The extraordinarily high prevalence of HTLV-1 subtype C (HTLV-1C) in some isolated indigenous communities in Oceania and the severity of the health conditions associated with the virus impress the great need for basic and translational research to prevent and treat HTLV-1 infection. The genome of the virus's most common subtype, HTLV-1A, encodes structural, enzymatic, and regulatory proteins that contribute to viral persistence and pathogenesis. Among these is the p30 protein encoded by the doubly spliced Tax-orf II mRNA, a nuclear/nucleolar protein with both transcriptional and post-transcriptional activity. The p30 protein inhibits the productive replication cycle via nuclear retention of the mRNA that encodes for both the viral transcriptional trans-activator Tax, and the Rex proteins that regulate the transport of incompletely spliced viral mRNA to the cytoplasm. In myeloid cells, p30 inhibits the PU-1 transcription factor that regulates interferon expression and is a critical mediator of innate and adaptive immunity. Furthermore, p30 alters gene expression, cell cycle progression, and DNA damage responses in T-cells, raising the hypothesis that p30 may directly contribute to T cell transformation. By fine-tuning viral expression while also inhibiting host innate responses, p30 is likely essential for viral infection and persistence. This concept is supported by the finding that macaques, a natural host for the closely genetically related simian T-cell leukemia virus 1 (STLV-1), exposed to an HTLV-1 knockout for p30 expression by a single point mutation do not became infected unless reversion and selection of the wild type HTLV-1 genotype occurs. All together, these data suggest that inhibition of p30 may help to curb and eventually eradicate viral infection by exposing infected cells to an effective host immune response.

Multiplex Droplet Digital PCR Assay for Quantification of Human T-Cell Leukemia Virus Type 1 Subtype c DNA Proviral Load and T Cells from Blood and Respiratory Exudates Sampled in a Remote Setting.

During human T-cell leukemia virus type 1 (HTLV-1) infection, the frequency of cells harboring an integrated copy of viral cDNA, the proviral load (PVL), is the main risk factor for progression of HTLV-1-associated diseases. Accurate quantification of provirus by droplet digital PCR (ddPCR) is a powerful diagnostic tool with emerging uses for monitoring viral expression. Current ddPCR techniques quantify HTLV-1 PVL in terms of whole genomic cellular material, while the main targets of HTLV-1 infection are CD4+ and CD8+ T cells. Our understanding of HTLV-1 proliferation and the amount of viral burden present in different compartments is limited. Recently a sensitive ddPCR assay was applied to quantifying T cells by measuring loss of germ line T-cell receptor genes as method of distinguishing non-T-cell from recombined T-cell DNA. In this study, we demonstrated and validated novel applications of the duplex ddPCR assay to quantify T cells from various sources of human genomic DNA (gDNA) extracted from frozen material (peripheral blood mononuclear cells [PBMCs], bronchoalveolar lavage fluid, and induced sputum) from a cohort of remote Indigenous Australians and then compared the T-cell measurements by ddPCR to the prevailing standard method of flow cytometry. The HTLV-1 subtype c (HTLV-1c) PVL was then calculated in terms of extracted T-cell gDNA from various compartments. Because HTLV-1c preferentially infects CD4+ T cells, and the amount of viral burden correlates with HTLV-1c disease pathogenesis, application of this ddPCR assay to accurately measure HTLV-1c-infected T cells can be of greater importance for clinical diagnostics and prognostics as well as monitoring therapeutic applications.

Occult type I or III endoleaks are a common cause of failure of type II endoleak treatment after endovascular aortic repair.

OBJECTIVE: Most type II endoleaks have a benign natural history, but 6% to 8% are associated with sac enlargement and respond poorly to treatment. Our aim was to evaluate whether these enlargements are associated with delayed or occult type I and III endoleaks. METHODS: Patients with interventions for endoleak after endovascular aortic repair from 2000 to 2016 were reviewed retrospectively. Patient demographics, comorbidities, endoleak type, secondary procedures, aortic sac growth (≥5 mm), and mortality were collected. Successful treatment was defined as endoleak resolution with no further aortic sac growth. Secondary procedures, ruptures, endograft explant, and death were captured. RESULTS: There were 130 patients diagnosed with a primary type II endoleak after endovascular aortic repair at a median of 1.3 months (interquartile range, 1.0-13.3 months). One hundred eighteen had their initial treatment for a primary type II. Twelve of the 130 were initially stable and observed, but were treated for a delayed type I or III endoleak. The 130 patients underwent 279 procedures for endoleaks (mean of 2.2 ± 1.3) over 6.9 ± 3.8 years of follow-up. Of the 118 patients treated for primary type II endoleaks, 26 (22.0%) later required interventions for delayed type I and III endoleaks. The mean time to intervention for a delayed type I or III endoleak was 5.4 ± 2.8 years. Overall, there were 16 type IA, 11 type IB, 2 type III, 7 combined type IA/IB, and 2 type IA/III delayed endoleaks. The odds of harboring a delayed type I or III endoleak was 22.0% before the first attempt at type II endoleak treatment, 35.1% before the second, 44.8% before the third, and 66.6% before the fourth attempts. Rapid aortic sac growth of ≥5 mm/y before initial endoleak treatment was associated with increased risk for delayed type I or III endoleak (47.8 vs 14.1%; P = .003). Patients with delayed type I or III endoleaks had a lower successful treatment rate (8.3% vs 52.3%; P = .001) than those with only type II endoleaks. Late rupture was increased with delayed type I or III endoleak (P = .002), whereas mortality (P = .96) and aortic-related mortality (P = .46) were similar. Graft explant (P = .06) trended toward an increase with a delayed type I or III endoleak, but was not statistically significant. CONCLUSIONS: Failed attempts treating type II endoleaks and/or a rapid aortic sac growth of 5 mm/y or greater should raise the suspicion of a delayed or occult type I or III endoleak. Occult endoleaks are associated with decreased chance of endoleak resolution.

Editor's Choice - Comparison of Outcomes After Open Surgical and Endovascular Lower Extremity Revascularisation Among End Stage Renal Disease Patients on Dialysis.

OBJECTIVES: End stage renal disease (ESRD) patients with peripheral arterial disease (PAD) are at high risk of complications following open surgical revascularisation (OSR). Endovascular revascularisation (ER) is an option, but its role is unclear. This study sought to characterise the outcomes of ER and OSR in ESRD patients treated for claudication or critical limb ischaemia (CLI). METHODS: The United States Renal Data System was used to investigate outcomes after lower extremity ER and OSR from 2005 to 2011. Primary outcomes were mortality, amputation, and peri-procedural myocardial infarction (MI). Kaplan-Meier (K-M) estimates were generated for mortality and amputation, logistic regression models for 30 day predictors, and proportional hazards models for long-term predictors. RESULTS: A total of 20,347 patients underwent OSR and ER (20.3% OSR, 79.7% ER). CLI was the indication in 80.8% of ER and 88.4% of OSR. The unadjusted major amputation rate at 30 days was higher after ER compared with OSR (8.8% vs. 6.4%, p < .001). Conversely, the unadjusted mortality rate at 30 days was lower after ER compared with OSR (8.0% vs. 10.5%, p < .001). Multivariable logistic regression models adjusting for medical covariables and CLI versus claudication status demonstrated increased 30 day mortality risk with OSR compared with ER (OR 2.00, 95% CI 1.43-1.79, p < .001), MI (OR 1.38, 1.23-1.54, p < .001), and the combined endpoint of mortality and major amputation (OR 1.57, 1.16-2.12, p = .004), but lower odds of 30 day major amputation alone (OR 0.67, 0.58-0.77, p < .001). Proportional hazards models demonstrated increased long-term mortality risk with OSR compared with ER (HR 1.05, 1.00-1.09, p = .037), without a difference in major amputation (HR 0.99, 0.93-1.05, p = NS). CONCLUSIONS: In this retrospective analysis of an administrative database, ESRD patients suffer from high mortality and amputation rates following lower extremity revascularisation. Compared with ER, OSR is associated with higher mortality. OSR has better 30 day limb salvage, although long-term outcomes are similar.

HIV latency reversing agents act through Tat post translational modifications.

BACKGROUND: Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing. RESULTS: Here we show that various lysine and arginine mutations reduce the capacity of Tat to induce both transcription and mRNA splicing. The lysine 28 and lysine 50 residues of Tat, or the acetylation and methylation modifications of these basic amino acids, were essential for Tat transcriptional control, and also for the proviral expression effects elicited by histone deacetylase inhibitors (HDACi) or the bromodomain inhibitor JQ1. We also found that JQ1 was the only LRA tested that could induce HIV mRNA splicing in the absence of Tat, or rescue splicing for Tat lysine mutants in a BRD4-dependent manner. CONCLUSIONS: Our data provide evidence that Tat activities in both co-transcriptional RNA processing together with transcriptional initiation and processivity are crucial during reactivation of latent HIV infection. The HDACi and JQ1 LRAs act with Tat to increase transcription, but JQ1 also enables post-transcriptional mRNA splicing. Tat residues K28 and K50, or their modifications through acetylation or methylation, are critical for LRAs that function in conjunction with Tat.

Physical Performance Variables and Bone Mineral Density in a Group of Young Overweight and Obese Men.

The aim of this study was to explore the relationships between performances obtained in different physical tests and bone parameters (bone mineral density [BMD], bone mineral content, hip geometry indices, and trabecular bone score [TBS]) in a group of young Lebanese overweight and obese adult men. Fifty-two overweight and/or obese (body mass index > 25 kg/m2) young men whose ages range from 18 to 35 yr participated in this study. Weight and height were measured, and body mass index was calculated. Body composition, BMD, cross-sectional area and section modulus (Z) of the femoral neck (FN), and TBS were measured by dual-energy X-ray absorptiometry. Maximum oxygen consumption (VO2 max, in liter per minute) was determined by direct measurement while exercising on a medical treadmill. One-repetition-maximum half-squat and maximum power (P max) of the lower limbs were measured using validated exercises. Lean mass was a positive determinant of whole-body bone mineral content (r = 0.71, p < 0.001), FN cross-sectional area (r = 0.51, p < 0.001), and FN Z (r = 0.58, p < 0.001). VO2 max (in liter per minute) was a positive determinant of whole-body BMD (r = 0.47, p < 0.001), total hip BMD (r = 0.43, p < 0.01), and FN BMD (r = 0.42, p < 0.01). VO2 max (in milliliter per minute per kilogram) was a positive determinant of TBS (r = 0.30, p < 0.05). One repetition maximum was a positive determinant of L1-L4 BMD (r = 0.33, p < 0.05). This study suggests that VO2 max (in liter per minute) is a positive determinant of BMD, and VO2 max (in milliliter per minute per kilogram) is a positive determinant of TBS in overweight and obese men.

The Molecular Biology of HIV Latency.

HIV remains incurable due to the existence of a reservoir of cells that harbor intact integrated genomes of the virus in the absence of viral replication. This population of infected cells remains invisible to the immune system and is not targeted by the drugs used in the current antiretroviral therapies (cART). Reversal of latency by the use of inhibitors of chromatin-remodeling enzymes has been studied extensively in an attempt to purge this reservoir of latent HIV but has thus far not shown any success in clinical trials. The full complexity of latent HIV infection has still not been appreciated, and the gaps in knowledge prevent development of adequate small-molecule compounds that can effectively perturb this reservoir. In this review, we will examine the role of epigenetic silencing of HIV transcription, posttranscriptional regulation, and mRNA processing in promoting HIV-1 latency.

High mortality rates after both open surgical and endovascular thoracic aortic interventions in patients with end-stage renal disease.

BACKGROUND: Morbidity and mortality have improved with the evolution of endovascular techniques (thoracic endovascular aortic repair [TEVAR]) for thoracic aortic disease, but results after aortic intervention in patients with end-stage renal disease (ESRD) remain unclear. The objective of this study was to evaluate outcomes of open and endovascular descending thoracic aortic repair in dialysis-dependent patients. METHODS: We identified 352 patients with ESRD on dialysis undergoing open repair (n = 136) or TEVAR (n = 216) of the thoracic aorta from 2005 to 2008 using the United States Renal Data System database. Acute presentation was defined as ruptured aneurysm, dissection, or traumatic injury; all other interventions were considered elective. End points were 30-day mortality, overall survival, rates of perioperative complications, and procedural trends over time. Between-group comparisons and survival analysis used standard statistical methods. Logistic regression and Cox regression were performed using multivariate analysis. RESULTS: TEVAR subjects were older than those undergoing open repair (68.2 ± 11.5 vs 60.8 ± 13.2 years; P < .001); no other demographics differed. There were 303 patients who had thoracic or thoracoabdominal aneurysms; 47 (13.4%) were ruptured on presentation. There were 44 patients (12.5%) who had aortic dissection and 5 (1.4%) with aortic trauma. Overall 30-day mortality was 21.3% (n = 75), and it was greater for open repair (n = 41 [30.1%]) than for TEVAR (n = 34 [15.7%]; P = .002). Elective 30-day mortality for open repair (n = 27 [29.3%]) was also greater than for TEVAR (n = 24 [14.3%]; P = .005). Those with acute presentation trended toward higher mortality for open repair (n = 14 [31.8%] vs n = 10 [15.7%]; P = .17). Respiratory failure was higher for open repair (n = 69 [50.7%] vs n = 56 [25.9%]; P < .001); postoperative stroke was higher with TEVAR (n = 21 [9.7%] vs n < 10 [<7%]; P = .02). Estimated 1-year survival was 50% and did not differ between groups (44% for open repair, 53% for TEVAR). In multivariate analysis, TEVAR decreased odds of 30-day mortality compared with open repair (odds ratio, 0.41; 95% confidence interval, 0.24-0.71) but failed to demonstrate long-term survival advantage. CONCLUSIONS: In ESRD patients, TEVAR provides short-term mortality benefits compared with open repair, but long-term mortality remains high regardless of treatment modality. Elective intervention for thoracic aortic disease in this population remains high risk and should be approached with caution.