HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.

The use of a PETTICOAT concept with an addition of a bare metal stent distal to the proximal thoracic endograft offers positive aortic remodeling in the thoracoabdominal aorta at 6 months.

The presence of 2 distinct populations of somatic or germline cells within a single individual harboring different genotypes is termed mosaicism. Recent reports suggest that parental mosaicism is involved in the heritability of type 1 Timothy syndrome (TS1), an extremely rare and life-threatening multisystem disorder characterized by severe QT interval prolongation, syndactyly, and several other complications. Although full TS1 is caused by a single missense mutation in the CACNA1C-encoded cardiac calcium channel, mosaic TS1 parents can display isolated syndactyly without additional phenotypic manifestations. A newborn boy presented with syndactyly at birth. The presence of syndactyly in his mother led to a diagnosis of benign familial syndactyly. However, at 9 months of age, during his first syndactyly-corrective surgery, intraoperative electrocardiograms revealed extreme QT prolongation and 2:1 atrioventricular block. A comprehensive cardiac evaluation was performed, and both mother and child were tested genetically, confirming a clinical suspicion of TS1. Only the patient tested positive for the TS1 mutation; however, more extensive molecular testing revealed a limited presence of the mutation in maternally-derived DNA. This case illustrates the potential of parental mosaicism to confound the diagnosis of potentially life-threatening genetic diseases, such as TS1. Here, a mother with a partial TS1 phenotype and genetically confirmed mosaicism transmitted the TS1-causative mutation to her son, resulting in fully expressive TS1. Thus, a shared partial phenotype should not be dismissed as a benign or insignificant finding, but should be evaluated further to rule out the possibility of parental mosaicism concealing a potentially fatal heritable disease.

This study shows that mortality in TS patients is due to multifactorial mechanisms, which include ventricular arrhythmias, pulseless electrical activity, and hypoglycemia. A simple nomenclature for ongoing studies of TS and related syndromes is described. A worldwide prospective registry is needed for continued exploration of this syndrome.

Propensity score matching yielded 116 pairs of non-hemiarch patients versus 116 hemiarch patients. Within the propensity score-matched cohort, there were no differences in postoperative stroke (1.7% versus 3.4%; p = 0.41), new postoperative dialysis (6.0% versus 5.2%; p = 0.78), postoperative renal insufficiency (27.6% versus 19.8%; p = 0.16), 30-day mortality (2.6% versus 3.4%; p = 0.701), or 1-year mortality (4.3% versus 4.3%; p = 1.00) CONCLUSIONS: Hemiarch replacement using DHCA with RCP does not increase the risk of operative complications compared with a normothermic, clamped-distal aortic anastomosis, and therefore its use should not be limited when planning complex multiprocedural reconstructions during elective ascending thoracic aortic replacement with concomitant cardiac surgery.

Acute type A aortic dissection (TAAD) is a complex disease associated with extremely high morbidity and mortality for which we advocate a coordinated, protocol-driven system of care delivery that begins at patient diagnosis and continues throughout and beyond aortic reconstruction. Essential components of TAAD repair include prompt restoration of true lumen blood flow with obliteration of the false lumen flow, resection of the primary tear sites, restoration of valvular competency, and elimination of any organ malperfusion. This article focuses specifically on extent of repair of the aortic arch and explains our protocols regarding cannulation location and technique, cerebral and distal organ protection strategy, management of the brachiocephalic vessels, and extent of distal aortic reconstruction. We describe an operative strategy for TAAD repair that includes (1) continuous neurocerebral monitoring in all cases, (2) uninterrupted antegrade and/or retrograde cerebral perfusion (depending upon extent of arch repair) during open arch reconstruction, (3) aortic arch replacement technique with or without brachiocephalic vessel replacement using a custom trifurcate graft, and (4) descending aortic stabilization with or without the use of an elephant or frozen elephant trunk (distal stent graft). Our protocol for extent of aortic arch and brachiocephalic reconstruction has been standardized and is predicated on distinct pathoanatomic findings and/or cerebral malperfusion that are outlined. Operative Techniques in Thoracic and Cardiovasculary Surgery 24:82À102

Background: The aim of this study is to evaluate the source of infectious complications following contemporary left ventricular assist device (LVAD) implantation and to determine the impact of infections on patient outcomes.Methods: All patients who underwent centrifugal LVAD implantation between 2014 and 2020 at a single center were retrospectively reviewed. Postimplant infections were categorized as VAD-specific, VAD-related, or non-VAD according to previously published definitions. Postoperative survival and freedom from readmission were assessed using Kaplan-Meier analysis. Univariable and multivariable analyses were performed to determine the risk factors for postoperative infectious complications.Results: A total of 212 patients underwent centrifugal LVAD implantation (70 HeartMate 3, 142 HeartWare HVAD) during the study period. One hundred and two patients (48.1%) developed an infection, including 34 VAD-specific, 11 VAD-related, and 57 non-VAD. Staphylococcus species were the most common source of postoperative infection (n = 57, 33.7%). In multivariable analysis, diabetes significantly impacted overall postoperative infection rate. At 12 and 24 months, respectively, Kaplan-Meier survival was 81.1% and 61.6% in the infection group and 83.4% and 78.1% in the noninfection group (p = 0.006). Within the total cohort, 12-and 24-month freedom from infection were 46.2% and 31.9%, respectively. Patients with infectious complication had significantly lower rate of transplantation (16.4% vs. 43.6%; p < 0.001), increased overall mortality (46.3% vs. 17.3%, p < 0.001), and increased rates of noncardiac readmission (58.2% vs. 37.3%, p = 0.007). Conclusions: Infections are common following contemporary LVAD implantation and are most commonly non-VAD related. Patients with postoperative infectious complications have significantly reduced rates of transplantation, survival, and freedom from noncardiac readmission.

No abstract