Faculty Bibliography

Arrhythmogenic cardiomyopathy (ACM) is a familial disease, with approximately 60% of patients displaying a pathogenic variant. The majority of genes linked to ACM code for components of the desmosomes: plakophilin-2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2), plakoglobin (JUP) and desmoplakin (DSP). Genetic variants involving the desmosomes are known to cause dysfunction of cell-to-cell adhesions and intercellular gap junctions. In turn, this may result in failure to mechanically hold together the cardiomyocytes, fibrofatty myocardial replacement, cardiac conduction delay and ventricular arrhythmias. It is becoming clearer that pathogenic variants in desmosomal genes such as PKP2 are not only responsible for a mechanical dysfunction of the intercalated disc (ID), but are also the cause of various pro-arrhythmic mechanisms. In this review, we discuss in detail the different molecular interactions associated with desmosomal pathogenic variants, and their contribution to various ACM phenotypes.

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [¹⁸F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [¹⁸F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [¹⁸F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

Ire1 is an endoplasmic reticulum (ER) transmembrane RNase that cleaves substrate mRNAs to help cells adapt to ER stress. Because there are cell types with physiological ER stress, loss of Ire1 results in metabolic and developmental defects in diverse organisms. In Drosophila, Ire1 mutants show developmental defects at early larval stages and in pupal eye photoreceptor differentiation. These Drosophila studies relied on a single Ire1 loss of function allele with a Piggybac insertion in the coding sequence. Here, we report that an Ire1 allele with a specific impairment in the RNase domain, H890A, unmasks previously unrecognized Ire1 phenotypes in Drosophila eye pigmentation. Specifically, we found that the adult eye pigmentation is altered, and the pigment granules are compromised in Ire1^H890A homozygous mosaic eyes. Furthermore, the Ire1^H890A mutant eyes had dramatically reduced Rhodopsin-1 protein levels. Drosophila eye pigment granules are most notably associated with late endosome/lysosomal defects. Our results indicate that the loss of Ire1, which would impair ER homeostasis, also results in altered adult eye pigmentation.

BACKGROUND:The association between isotretinoin and psychiatric disturbance, including depression and suicidal behavior, is controversial. OBJECTIVE:To investigate whether acne patients prescribed isotretinoin or antibiotics were more likely to have psychiatric disorders and/or engage in suicidal behavior. METHODS:Retrospective cohort study identified acne patients prescribed isotretinoin or oral antibiotics in the IBM® MarketScan® Databases of commercial US insurance claims data from 2011-2017 who were also diagnosed with psychiatric disorders or suicidal behavior. RESULTS:A total of 72,555 patients were included. Compared to acne patients prescribed isotretinoin, patients in the general population were 1.47 times more likely to be diagnosed with suicidal ideation or attempt (adjusted OR 1.47; 1.27, 1.70, p <.0001). However, the general population (adjusted OR 0.87; 0.84, 0.89, p<0.0001) and acne patients prescribed antibiotics (adjusted OR 0.88; 0.85, 0.91, p<0.0001) were less likely to have a psychiatric diagnosis compared to acne patients prescribed isotretinoin. The prevalence of suicidal behavior during isotretinoin treatment was lower (0.10%) (p=0.082), than during the year prior to (0.22%) and during the year after isotretinoin treatment (0.34%), (p = 0.004). LIMITATIONS/CONCLUSIONS:Study excludes individuals with public or no insurance and relies on physician coding accuracy. CONCLUSIONS:Compared to the general population, acne patients prescribed isotretinoin were less likely to engage in suicidal behavior. Further exploration is warranted into the slight increase in suicidal behavior seen in isotretinoin patients one year after therapy.

BACKGROUND:Staged implant-based breast reconstruction is the most common reconstructive modality following mastectomy. Postoperative implant infections can have a significant impact on adjuvant oncologic care and reconstructive outcome. Here, we investigate the impact of β-lactam antibiotics (i.e., bactericidal) compared to alternative antibiotic agents on postoperative outcomes for implant-based breast reconstruction. METHODS:A retrospective analysis of patients who underwent immediate sub-pectoral tissue expander placement with an inferior acellular dermal matrix (ADM) sling at a single institution between May 2008 and July 2018 was performed. Patient demographics, comorbidities, and complication rates were retrieved. The impact of antibiotic regimen on postoperative outcomes, including infection rate and reconstructive failure, was investigated. RESULTS:, respectively, who underwent 542 immediate breast reconstructions were included in the study. The use of a β-lactam antibiotic was protective against postoperative infection (odds ratio [OR] = 0.467, p = .046), infection requiring operative management (OR = 0.313, p = .022), and reconstructive failure (OR = 0.365, p = .028). Extended, that is, post-discharge, prophylaxis was not associated with any clinical benefit. CONCLUSION/CONCLUSIONS:The use of β-lactam antibiotics for pre-/peri-operative prophylaxis is superior to alternative antibiotics with a bacteriostatic mechanism of action regarding rates of postoperative infection and reconstructive failure following immediate tissue expander-based breast reconstruction. Extended, that is, post-discharge, prophylaxis does not appear to be indicated, regardless of the antibiotic chosen.

BACKGROUND:Limited research has addressed the obesity-COVID-19 severity association in paediatric patients. OBJECTIVE:To determine whether obesity is an independent risk factor for COVID-19 severity in paediatric patients and whether age modifies this association. METHODS:SARS-CoV-2-positive patients at NYU Langone Health from 1 March 2020 to 3 January 2021 aged 0-21 years with available anthropometric measurements: weight, length/height and/or body mass index (BMI). Modified log-Poisson models were utilized for the analysis. Main outcomes were 1) hospitalization and 2) critical illness (intensive care unit [ICU] admission). RESULTS:One hundred and fifteen of four hundred and ninety-four (23.3%) patients had obesity. Obesity was an independent risk factor for critical illness (adjusted risk ratio [ARR] 2.02, 95% CI 1.17 to 3.48). This association was modified by age, with obesity related to a greater risk for critical illness in adolescents (13-21 years) [ARR 3.09, 95% CI 1.48 to 6.47], but not in children (0-12 years). Obesity was not an independent risk factor for hospitalization for any age. CONCLUSION/CONCLUSIONS:Obesity was an independent risk factor for critical illness in paediatric patients, and this association was modified by age, with obesity related to a greater risk for critical illness in adolescents, but not in children. These findings are crucial for patient risk stratification and care.

The field of cardio-oncology has emerged in response to the increased risk of cardiovascular disease (CVD) in patients with cancer. However, recent studies suggest a more complicated CVD-cancer relationship, wherein development of CVD, either prior to or following a cancer diagnosis, can also lead to increased risk of cancer and worse outcomes for patients. In this review, we describe the current evidence base, across epidemiological as well as preclinical studies, which supports the emerging concept of 'reverse-cardio oncology', or CVD-induced acceleration of cancer pathogenesis.

Hand injuries often result in significant functional impairments and are rarely completely restored. The spontaneous regeneration of injured appendages, which occurs in salamanders and newts, for example, has been reported in human fingertips after distal amputation, but this type of regeneration is rare in mammals and is incompletely understood. Here, we study fingertip regeneration by amputating murine digit tips, either distally to initiate regeneration, or proximally, causing fibrosis. Using an unbiased microarray analysis, we found that digit tip regeneration is significantly associated with hair follicle differentiation, Wnt, and sonic hedgehog (SHH) signaling pathways. Viral over-expression and genetic knockouts showed the functional significance of these pathways during regeneration. Using transgenic reporter mice, we demonstrated that, while both canonical Wnt and HH signaling were limited to epidermal tissues, downstream hedgehog signaling (through Gli) occurred in mesenchymal tissues. These findings reveal a mechanism for epidermal/mesenchyme interactions, governed by canonical hedgehog signaling, during digit regeneration. Further research into these pathways could lead to improved therapeutic outcomes after hand injuries in humans.

Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.