Relationships between neighborhood disadvantage and cardiovascular findings at autopsy in subjects with sudden death.

BACKGROUND: Neighborhood disadvantage is associated with a higher risk of sudden cardiac death. However, autopsy findings have never been investigated in this context. Here, we sought to explore associations between neighborhood disadvantage and cardiovascular findings at autopsy in cases of sudden death in the State of Maryland. METHODS: State of Maryland investigation reports from 2,278 subjects within the CVPath Sudden Death Registry were screened for street addresses and 9-digit zip codes. Area deprivation index (ADI), used as metric for neighborhood disadvantage, was available for 1,464 subjects; 650 of whom self-identified as Black and 814 as White. The primary study outcome measurements were causes of death and gross and histopathologic findings of the heart. RESULTS: Subjects from most disadvantaged neighborhoods (i.e., ADI ≥ 8; n = 607) died at younger age compared with subjects from less disadvantaged neighborhoods (i.e., ADI ≤ 7; n = 857; 46.07 ± 14.10 vs 47.78 ± 13.86 years; P = 0.02) and were more likely Black or women. They were less likely to die from cardiac causes of death (61.8% vs 67.7%; P = 0.02) and had less severe atherosclerotic plaque features, including plaque burden, calcification, intraplaque hemorrhage, and thin-cap fibroatheromas. In addition, subjects from most disadvantaged neighborhoods had lower frequencies of plaque rupture (18.8% vs 25.1%, P = 0.004). However, these associations were omitted after adjustment for traditional risk factors and race. CONCLUSION: Neighborhood disadvantage did not associate with cause of death or coronary histopathology after adjustment for cardiovascular risk factors and race, implying that social determinants of health other than neighborhood disadvantage play a more prominent role in sudden cardiac death.

The identification of a novel lead class for phosphodiesterase 2 inhibition by fragment-based drug design.

We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Ki = 22.4 µM), exhibited good binding efficiencies (LBE = 0.49, LLE = 4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.

Translational value of preclinical models for renal denervation: a histological comparison of human versus porcine renal nerve anatomy.

BACKGROUND: Preclinical models have provided key insights into the response of local tissues to radiofrequency (RF) renal denervation (RDN) that is unobtainable from human studies. However, the anatomic translatability of these models to the procedure in humans is incompletely understood.  Aims: We aimed to compare the renal arterial anatomy in normotensive pigs treated with RF-RDN to that of human cadavers to evaluate the suitability of normotensive pigs for determining the safety of RF-RDN. METHODS: Histopathologic analyses were performed on RF-treated renal arteries in a porcine model and untreated control renal arteries. Similar analyses were performed on untreated renal arteries from human cadavers.  Results: In both human and porcine renal arteries, the median number of nerves was lower in the more distal sections (the numbers in the proximal, middle, distal, 1st bifurcation, and 2nd bifurcation sections were 65, 58, 47, 22.5, and 14.7 in humans, respectively, and 39, 26, 29, 16.5, and 9.3 in the porcine models, respectively). Renal nerves were common in the regions between arteries and adjacent veins, but only 3% and 13% of the renal nerves in humans and pigs, respectively, were located behind the renal vein. The semiquantitative score of RF-induced renal arterial nerve necrosis was significantly greater at 7 days than 28 days (0.98 vs 0.75; p=0.01), and injury to surrounding organs was rarely observed. CONCLUSIONS: The distribution of nerve tissue and the relative distribution of extravascular anatomic structures along the renal artery was similar between humans and pigs, which validates the translational value of the normotensive porcine model for RDN.

Analysis of cellularity in H&E-stained rat bone marrow tissue via deep learning.

Our objective was to develop an automated deep-learning-based method to evaluate cellularity in rat bone marrow hematoxylin and eosin whole slide images for preclinical safety assessment. We trained a shallow CNN for segmenting marrow, 2 Mask R-CNN models for segmenting megakaryocytes (MKCs), and small hematopoietic cells (SHCs), and a SegNet model for segmenting red blood cells. We incorporated the models into a pipeline that identifies and counts MKCs and SHCs in rat bone marrow. We compared cell segmentation and counts that our method generated to those that pathologists generated on 10 slides with a range of cell depletion levels from 10 studies. For SHCs, we compared cell counts that our method generated to counts generated by Cellpose and Stardist. The median Dice and object Dice scores for MKCs using our method vs pathologist consensus and the inter- and intra-pathologist variation were comparable, with overlapping first-third quartile ranges. For SHCs, the median scores were close, with first-third quartile ranges partially overlapping intra-pathologist variation. For SHCs, in comparison to Cellpose and Stardist, counts from our method were closer to pathologist counts, with a smaller 95% limits of agreement range. The performance of the bone marrow analysis pipeline supports its incorporation into routine use as an aid for hematotoxicity assessment by pathologists. The pipeline could help expedite hematotoxicity assessment in preclinical studies and consequently could expedite drug development. The method may enable meta-analysis of rat bone marrow characteristics from future and historical whole slide images and may generate new biological insights from cross-study comparisons.

Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1.

Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1-infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase-p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1+ cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4+ T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.

Efficacy of allograft fascia lata in tympanic membrane repair.

We conducted a retrospective study to determine the efficacy of allograft fascia lata in both primary and revision tympanic membrane surgery (myringoplasty). Our patient population included 64 patients-31 men and 33 women, aged 19 to 98 years (mean: 49.5)-who had undergone tympanic membrane surgery with allograft fascia lata. Patients were grouped according to whether they had undergone primary surgery (n = 47) or revision surgery (n = 17). Data were compiled at preoperative and immediate postoperative visits, as well as at 3, 6, 9, and 12 months postoperatively. Residual perforations were defined as those present for less than 6 weeks postoperatively, and recurrent perforations were defined as those that occurred more than 6 weeks postoperatively. A residual perforation was found in only 1 patient (1.6%), a primary surgery patient. Recurrent perforations were found in 8 of the 64 patients (12.5%), including 5 in the primary group (10.6%) and 3 in the revision group (17.6%). We conclude that allograft fascia lata is a comparable alternative to other graft materials for performing myringoplasty.