Health Literacy and Health Care System Confidence as Determinants of Attitudes to Vaccines in France: Representative Cross-Sectional Study.

BACKGROUND: Health literacy involves individuals' knowledge, personal skills, and confidence to take action to evaluate and appraise health-related information and improve their health or that of their community. OBJECTIVE: This study aimed to analyze the association between health literacy and attitude toward vaccines, adjusted with other factors. METHODS: We used the SLAVACO Wave 3, a survey conducted in December 2021 among a sample of 2022 individuals, representative of the French adult population. We investigated factors associated with the attitude toward vaccines using respondents' different sociodemographic data, health literacy levels, and the health care system confidence levels using a multinomial logistic regression analysis. RESULTS: Among the participants, 440.4 (21.8%) were classified as "distrustful of vaccines in general," 729.2 (36.1%) were "selectively hesitant," and 852.4 (42.2%) were "nonhesitant." In our model, the level of health literacy was not statistically different between the "distrustful of vaccines in general" and the "selectively hesitant" (P=.48), but it was associated with being a "nonhesitant" (adjusted odds ratio [aOR] 1.86, 95% CI 1.25-2.76). The confidence in the health care system was a strong predictor for a "nonhesitant" attitude toward vaccines (aOR 12.4, 95% CI 7.97-19.2). We found a positive correlation of 0.34 (P<.001) between health literacy and confidence in the health care system, but the interaction term between health literacy and health care system confidence was not significant in our model. CONCLUSIONS: Health literacy was associated with a "nonhesitant" attitude toward vaccines. The findings demonstrated that health literacy and confidence in the health care system are modestly correlated. Therefore, to tackle the subject of vaccine hesitancy, the main focus should be on increasing the population's confidence and on increasing their health literacy levels or providing vaccine information addressing the needs of less literate citizens.

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 endpoints were in-hospital, 30-day and 1-year mortality. Kaplan-Meier estimate for 1-year mortality and primary patency loss were generated. Secondary endpoints 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 exam was the most common presenting symptom (n=18 ,42.9%) followed by peritonitis (n= 14, 33.4%). All patients had pre-operative IV contrast computed tomography imaging. In-situ thrombosis was identified as the etiology of AMI in 36 (85.7%) patients. Technical success was achieved in 40 (95.2%) patients. Conventional, non-hybrid operating rooms were utilized for the majority of cases. Revascularization of all 40 patients involved angioplasty and stenting of superior mesenteric artery (SMA): A single stent was placed in 35 (87.5%) patients and the reminder had more than one stent. 80% of patients required bowel resection. A second-look laparotomy was required in 34 (85.0%) patients. 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 (20.0%) patients. In terms of mortality, 13 (32.5%) patients died during their index hospitalization, while 9 (22.5%) died 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%. CONCLUSION: ROMS has 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.

The "HAT-TRICK" technique: A modification of soft tissue grafting using volume stable collagen matrix and cross-linked hyaluronic acid. Part A: The pontic site.

Vertical soft tissue augmentation between implants can be clinically challenging and burdensome for patients when employing conventional techniques. Recently, with the introduction of xenogenic collagen matrices, the principle of single-site surgery has become more common. However, some issues persist regarding graft stability and tissue integration. In the present technical note, the authors introduce the "HAT-TRICK" technique to address these observed difficulties. As the name suggests, this technique is believed to provide improved stability, volumetric gain, and histological integration of the implanted matrix by shaping it appropriately resembling a hat over the crest with apical bevels, stabilized with fixation pins and infused with cross-linked hyaluronic acid (xHya). A two-month observation of a bi-maxillary case is presented with detailed description of the technique and digitalized comparison methods for an easier explanation of the introduced technique.

A New Concept of Horizontal Bone Augmentation Using Collagen Bovine Bone Blocks Without Membrane at Implant Placement: A Preliminary Study.

Purpose: A buccal bone thickness (BBT) of at least 1.8-2 mm is necessary to ensure long-term implant stability, and a bone grafting procedure is commonly needed to restore this BBT. This study aims to prove the effectiveness of a novel bone augmentation technique in which minero-organic bone substitutes are solely used to restore adequate BBT, excluding the need for coverage membranes. Methods: Fifty partially edentulous patients having a residual bone width ranging between 5 and 6 mm were enrolled in this study. The horizontal buccal defects were grafted simultaneously at implant placement. Minero-organic collagen bovine bone blocks (CBBB) were placed on the outer side of the buccal bone wall, and adapted to the defect morphology through slow compressive movements. The grafted sites were not covered with any type of membrane nor stabilized with fixation pins. Cone-beam computed tomography scans were obtained pre-operatively, immediately post-surgery, and four months later. Scans were superimposed on the ITK-Snap software to measure the amount of bone gain and assess the percentage of CBBB resorption. Measurements were effectuated at four different levels apically to crestal level. Results: Radiographic findings showed BBT increase and CBBB resorption in all cases, four months post-grafting. A mean horizontal bone gain of 1.39 mm was calculated at a crestal level. Conclusion: Based on these findings, it appears that this novel and user-friendly bone grafting technique can achieve positive outcomes from both clinical and radiographic perspectives.

Clinical and radiographic assessment of cross-linked hyaluronic acid addition in demineralized bovine bone based alveolar ridge preservation: A human randomized split-mouth pilot study.

PURPOSE: To investigate clinically and radiographically at 4 months post-operatively the outcomes of mixing demineralized bovine bone material (DBBM) with cross-linked hyaluronic acid in alveolar ridge preservation. MATERIAL AND METHODS: Seven patients presenting bilateral hopeless teeth (14 teeth) were enrolled in the study, the test site contained demineralized bovine bone material (DBBM) mixed with cross-linked hyaluronic acid (xHyA) while the control site contained only DBBM. 4 months post-operatively prior to implant placement a Cone beam computed tomography (CBCT) scan was recorded and compared to the initial scan to assess the volumetric and linear bone resorption that occurred in both sites. Clinically, sites that needed further bone grafting at the implant placement stage were recorded. Differences in volumetric and linear bone resorption between both groups were assessed using Wilcoxon signed rank test. McNemar test was also used to evaluate difference in bone grafting need between both groups. RESULTS: All sites healed uneventfully, volumetric and linear resorption differences between the baseline and 4 months post-operatively were obtained for each site. The mean volumetric and linear bone resorption were respectively 36.56 ± 1.69%, 1.42 ± 0.16 mm in the controls sites and 26.96 ± 1.83%; 0.73 ± 0.052 mm in the tests sites. The values were significantly higher among controls sites (P=0.018). No significant differences were observed in the need for bone grafting between both groups. CONCLUSION: Cross-linked hyaluronic acid (xHyA) appears to limit the post-extractional alveolar bone resorption when mixed with DBBM.

Return to Sport After Revision ACL Reconstruction: A Comparative Cohort Study of Outcomes After Single- Versus Multiple-Revision Surgeries.

Background: The return-to-sport rate at 2 years after multiple-revision anterior cruciate ligament (ACL) reconstructions has not been evaluated. Hypothesis: It was hypothesized that patients who undergo multiple-revision ACL reconstructions would have a lower return-to-sport rate at 2 years after surgery than those who undergo a single-revision reconstruction. Furthermore, it was hypothesized that the multiple-revision group would have lower functional scores. Study Design: Cohort study; Level of evidence, 3. Methods: A single-center cohort study in patients who underwent revision ACL reconstruction was begun in 2012. This study included 2 groups: Patients who underwent a single revision, and those who underwent multiple revisions. The main evaluation criterion was the return to sport at the 2-year follow-up. The secondary criteria were the International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm, and ACL-Return to Sport after Injury (ACL-RSI) functional knee scores at the 1- and 2-year follow-ups. Results: A total of 322 patients (single-revision group: n = 302; multiple-revision group: n = 20) were included. A significant difference in the percentage of patients who stopped all sports activity was found between the 2 groups at 2 years (single-revision group: 19.4%; multiple-revision group: 50%). The return-to-sport rate at the same or lower level of performance was higher in the single-revision group as well (17% vs 14.3% for return at the same level; 45.6% vs 14.3% for return at a lower level; P = .03). At the 2-year follow-up, the functional scores of the single-revision group were significantly higher those than in the multiple-revision group: IKDC (77.7 ± 13.82 vs 64.79 ± 15.22; P < .001), KOOS (72.66 ± 17.63 vs 52.5 ± 15.64; P < .001), Lysholm (84.05 ± 11.88 vs 72.5 ± 13.49; P < .001), and ACL-RSI (52.34 ± 21.83 vs 46.43 ± 14.8; P = .0036). Conclusion: Only a small percentage of patients returned to the same level of sport after single- revision and multiple-revision ACL reconstruction, yet significantly more in the former. More patients who underwent multiple revisions gave up their sport. Functional scores were higher for single-revision than multiple-revision surgeries.

Detection of Chimeric Cellular: HIV mRNAs Generated Through Aberrant Splicing in HIV-1 Latently Infected Resting CD4+ T Cells.

Latent HIV-1 provirus in infected individuals on suppressive therapy does not always remain transcriptionally silent. Both HIV-1 LTR and human gene promoter derived transcriptional events can contribute HIV-1 sequences to the mRNA produced in the cell. In addition, chimeric cellular:HIV mRNA can arise through readthrough transcription and aberrant splicing. Using target enrichment coupled to the Illumina Mi-Seq and PacBio RS II platforms, we show that 3' LTR activation is frequent in latently infected cells from both the CCL19-induced primary cell model of HIV-1 latency as well as ex vivo samples. In both systems of latent HIV-1 infection, we detected several chimeric species that were generated via activation of a cryptic splice donor site in the 5' LTR of HIV-1. Aberrant splicing involving the major HIV-1 splice donor sites, SD1 and SD4 disrupts post-transcriptional processing of the gene in which HIV-1 is integrated. In the primary cell model of HIV-1 latency, Tat-encoding sequences are incorporated into the chimeric mRNA transcripts through the use of SD4. Our study unravels clues to the characteristics of HIV-1 integrants that promote formation of chimeric cellular:HIV mRNA and improves the understanding of the HIV-1 RNA footprint in latently infected cells.

A modified vaccinia Ankara vaccine expressing spike and nucleocapsid protects rhesus macaques against SARS-CoV-2 Delta infection.

SARS-CoV-2 vaccines should induce broadly cross-reactive humoral and T cell responses to protect against emerging variants of concern (VOCs). Here, we inactivated the furin cleavage site (FCS) of spike expressed by a modified vaccinia Ankara (MVA) virus vaccine (MVA/SdFCS) and found that FCS inactivation markedly increased spike binding to human ACE2. After vaccination of mice, the MVA/SdFCS vaccine induced eightfold higher neutralizing antibodies compared with MVA/S, which expressed spike without FCS inactivation, and protected against the Beta variant. We next added nucleocapsid to the MVA/SdFCS vaccine (MVA/SdFCS-N) and tested its immunogenicity and efficacy via intramuscular (IM), buccal (BU), or sublingual (SL) routes in rhesus macaques. IM vaccination induced spike-specific IgG in serum and mucosae (nose, throat, lung, and rectum) that neutralized the homologous (WA-1/2020) and heterologous VOCs, including Delta, with minimal loss (<2-fold) of activity. IM vaccination also induced both spike- and nucleocapsid-specific CD4 and CD8 T cell responses in the blood. In contrast, the SL and BU vaccinations induced less spike-specific IgG in secretions and lower levels of polyfunctional IgG in serum compared with IM vaccination. After challenge with the SARS-CoV-2 Delta variant, the IM route induced robust protection, the BU route induced moderate protection, and the SL route induced no protection. Vaccine-induced neutralizing and non-neutralizing antibody effector functions positively correlated with protection, but only the effector functions correlated with early protection. Thus, IM vaccination with MVA/SdFCS-N vaccine elicited cross-reactive antibody and T cell responses, protecting against heterologous SARS-CoV-2 VOC more effectively than other routes of vaccination.

A primer on skeletal dysplasias.

Skeletal dysplasia encompasses a heterogeneous group of over 400 genetic disorders. They are individually rare, but collectively rather common with an approximate incidence of 1/5000. Thus, radiologists occasionally encounter skeletal dysplasias in their daily practices, and the topic is commonly brought up in radiology board examinations across the world. However, many radiologists and trainees struggle with this issue because of the lack of proper resources. The radiological diagnosis of skeletal dysplasias primarily rests on pattern recognition-a method that is often called the "Aunt Minnie" approach. Most skeletal dysplasias have an identifiable pattern of skeletal changes composed of unique findings and even pathognomonic findings. Thus, skeletal dysplasias are the best example to which the Aunt Minnie approach is readily applicable.

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.

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.

Protective efficacy of the anti-HIV broadly neutralizing antibody PGT121 in the context of semen exposure.

BACKGROUND: HIV-1 infections occur following viral exposure at anogenital mucosal surfaces in the presence of semen. Semen contains immunosuppressive and pro-inflammatory factors. Semen from HIV-1-infected donors contains anti-HIV-1 antibodies. We assessed if passively infused anti-HIV-1 neutralizing antibody conferred protection from rectal SHIVSF162P3 challenge at semen exposed mucosae. METHODS: We pooled seminal plasma from HIV-1-infected donors. The pool was screened by ELISA for antibodies against HIV-1SF162 gp140. The ability of seminal plasma to inhibit macaque NK cells from responding to direct and antibody-dependent stimulation was assessed. The ability of seminal plasma to inhibit macaque granulocytes from mediating oxidative burst was also assessed. To demonstrate viral infectivity in the presence of seminal plasma, macaques (n = 4) were rectally challenged with SHIVSF162P3 following exposure to 2.5 mL of seminal plasma. To evaluate if anti-HIV-1 neutralizing antibody confers protection against rectal SHIV challenge at semen exposed mucosae, eight macaques were intravenously infused with PGT121, either wild type (n = 4) or the Fc receptor binding deficient LALA variant (n = 4), and rectally challenged with SHIVSF162P3 following exposure to 2.5 mL of seminal plasma. FINDINGS: Anti-HIV-1SF162 gp140 antibodies were detected in seminal plasma. Seminal plasma inhibited direct and antibody-dependent NK cell activation and granulocyte oxidative burst in vitro. Rectal SHIVSF162P3 challenge of control macaques following seminal plasma exposure resulted in infection of all animals. All macaques infused with wild type or LALA PGT121 and challenged with SHIVSF162P3 following seminal plasma exposure were protected. INTERPRETATION: PGT121 conferred protection against rectal SHIVSF162P3 challenge at semen exposed mucosae. Future research should investigate if semen alters protection conferred by antibodies more dependent on non-neutralizing functions. FUNDING: This work was supported by a grant from the Australian National Health and Medical Research Council (APP1124680).

Potential Utility of Natural Killer Cells for Eliminating Cells Harboring Reactivated Latent HIV-1 Following the Removal of CD8+ T Cell-Mediated Pro-Latency Effect(s).

An impediment to curing HIV-1 infection is the persistence of latently infected cells in ART-treated people living with HIV (PLWH). A key strategy for curing HIV-1 infection is to activate transcription and translation of latent virus using latency reversing agents (LRAs) and eliminate cells harboring reactivated virus via viral cytopathic effect or immune clearance. In this review, we provide an overview of available LRAs and their use in clinical trials. Furthermore, we describe recent data suggesting that CD8+ T cells promote HIV-1 latency in the context of ART, even in the presence of LRAs, which might at least partially explain the clinical inefficiency of previous "shock and kill" trials. Here, we propose a novel cure strategy called "unlock, shock, disarm, and kill". The general premise of this strategy is to shut down the pro-latency function(s) of CD8+ T cells, use LRAs to reverse HIV-1 latency, counteract anti-apoptotic molecules, and engage natural killer (NK) cells to mediate the killing of cells harboring reactivated latent HIV-1.

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.

The RNA-Binding Proteins SRP14 and HMGB3 Control HIV-1 Tat mRNA Processing and Translation During HIV-1 Latency.

HIV-1 Tat protein is essential for virus production. RNA-binding proteins that facilitate Tat production may be absent or downregulated in resting CD4+ T-cells, the main reservoir of latent HIV in people with HIV (PWH) on antiretroviral therapy (ART). In this study, we examined the role of Tat RNA-binding proteins on the expression of Tat and control of latent and productive infection. Affinity purification coupled with mass spectrometry analysis was used to detect binding partners of MS2-tagged tat mRNA in a T cell-line model of HIV latency. The effect of knockdown and overexpression of the proteins of interest on Tat transactivation and translation was assessed by luciferase-based reporter assays and infections with a dual color HIV reporter virus. Out of the 243 interactions identified, knockdown of SRP14 (Signal Recognition Particle 14) negatively affected tat mRNA processing and translation as well as Tat-mediated transactivation, which led to an increase in latent infection. On the other hand, knockdown of HMGB3 (High Mobility Group Box 3) resulted in an increase in Tat transactivation and translation as well as an increase in productive infection. Footprinting experiments revealed that SRP14 and HMGB3 proteins bind to TIM-TAM, a conserved RNA sequence-structure in tat mRNA that functions as a Tat IRES modulator of tat mRNA. Overexpression of SRP14 in resting CD4+ T-cells from patients on ART was sufficient to reverse HIV-1 latency and induce virus production. The role of SRP14 and HMGB3 proteins in controlling HIV Tat expression during latency will be further assessed as potential drug targets.

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.

Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency.

BACKGROUND: One strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed. METHODS: We quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat. FINDINGS: In total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA. INTERPRETATION: Following administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal. FUNDING: NHMRC, NIH DARE collaboratory.

Human T-cell lymphotropic virus type-1: a lifelong persistent infection, yet never truly silent.

Human T-cell lymphotropic virus type-1 (HTLV-1) has a large global burden and in some key communities, such as Indigenous Australians living in remote areas, greater than 45% of people are infected. Despite HTLV-1 causing serious malignancy and myelopathic paraparesis, and a significant association with a range of inflammatory comorbidities and secondary infections that shorten lifespan, few biomedical interventions are available. HTLV-1 starkly contrasts with other blood-borne sexually transmitted viral infections, such as, HIV, hepatitis B virus, and hepatitis C virus, with no antiviral treatments that reduce virus-infected cells, no rapid diagnostics or biomarker assays suitable for use in remote settings, and no effective vaccine. We review how the replication strategies and molecular properties of HTLV-1 establish a long-term stealthy viral pathogenesis through a fine-tuned balance of persistence, immune cell dysfunction, and proliferation of proviral infected cells that collectively present robust barriers to treatment and prevention. An understanding of the nature of the HTLV-1 provirus and opposing actions of viral-coded negative-sense HBZ and positive-sense regulatory proteins Tax, p12 and its cleaved product p8, and p30, is needed to improve the biomedical tools for preventing transmission and improving the long-term health of people with this lifelong infection.

Risk factors for acute kidney injury after pharmacomechanical thrombolysis for acute deep vein thrombosis.

BACKGROUND: Pharmacomechanical thrombolysis (PMT) is an established treatment for selected patients with acute deep vein thrombosis (DVT). Despite significant clinical success, hemolysis can lead to acute kidney injury (AKI) with unknown longer term implications. Our aim was to characterize the rate of AKI after PMT and identify those patients at the greatest risk. METHODS: A retrospective medical record review of patients with acute DVT who had undergone PMT in our institution from 2007 to 2018 was performed. The baseline demographics, comorbidities, preoperative clinical characteristics, procedural details, postoperative hospital course, and follow-up data were reviewed. The primary outcome was postoperative AKI (≥1.5 times preoperative creatinine), and longer term renal impairment. Logistic regression modeling was used to identify associated factors. RESULTS: A total of 137 patients (mean age, 47 ± 16.6 years; 49.6% male) who had undergone PMT for treatment of acute DVT were identified (85.4% AngioJet system; Boston Scientific Corp, Marlborough, Mass). Of the 137 patients, 30 (21.9%) had developed AKI in the periprocedural period, 1 of whom had required hemodialysis in the perioperative period. The patients who had developed AKI had had significantly greater rates of preoperative coronary artery disease (23.1% vs 4.7%; P = .002), diabetes mellitus (19.2% vs 6.6%; P = .045), dyslipidemia (42.3% vs 17.9%; P = .008), and hypertension (53.6% vs 29.3%; P = .018). No significant difference was found in preoperative creatinine (0.99 vs 0.92 mg/dL; P = .65) or glomerular filtration rate (GFR; 96.9 vs 91.8 mL/min; P = .52) between the two groups. Multivariate analysis demonstrated bilateral DVT (odds ratio [OR], 4.35; 95% confidence interval [CI], 1.47-12.86; P = .008), single-session PMT (OR, 3.05; 95% CI, 1.02-9.11; P = .046), and female sex (OR, 2.85; 95% CI, 1.01-8.04; P = .048) were significant predictors of AKI. Of the 30 patients, 10 had had normal renal function at discharge and 15 and 25 patients had had normal renal function at the first and subsequent clinical follow-up visits, respectively. The remaining five patients (3.6%) had progressed to moderate (GFR, <60 mL/min) or severe (GFR, <30 mL/min) renal insufficiency, with one requiring long-term hemodialysis. CONCLUSIONS: The use of PMT for treatment of acute DVT conferred a risk of AKI that will progress to chronic renal failure in a small fraction of affected patients. Patients with bilateral extensive DVTs have a greater risk of AKI; thus, longer priming with a thrombolytic drip before PMT should be preferred for this population.

One-by-one immediate dental implants: A papillae preservation concept for adjacent implants in a compromised periodontal case.

In an immediate implant placement and provisionalization strategy, the esthetic results of multiple adjacent implants can be obtained even with compromised periodontium by implementing the "one-by-one" protocol. Staged extractions of multiple adjacent teeth to maintain soft tissue architecture are a key feature of the technique described.