Faculty Bibliography

Background Obesity is a global epidemic. The prevalence of obesity has significantly increased in recent decades and is expected to impact a large portion of the US population. Hypertension continues to be one of the most common complications associated with obesity, and the overlap between these two conditions has been growing over time. However, mortality trends in patients with obesity and hypertension have not been investigated in the literature. Objectives This study aimed to investigate mortality trends, stratified by sex, race, age groups, and geographic distribution, in the US population between 1999 and 2020. Methods Death certificates from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) were examined and analyzed between 1999 and 2020 for patients with obesity and hypertension as the contributing causes of death. The age-adjusted mortality rates (AAMRs) and annual percent changes (APCs) per 100000 people were calculated by sex, race, age group, and geographic region. Results Among individuals aged ≥15, a total of 294854 deaths occurred in individuals with obesity and hypertension between 1999 and 2020. The overall AAMR increased from 1.08 in 1999 to 12.14 in 2020. The AAMR has steadily increased since 1999, with a sudden spike occurring between 2018 and 2020 during the COVID-19 pandemic. This trend has been observed across nearly all variables analyzed in our study. Our results exhibited a 28% increase in mortality related to obesity and hypertension during the early years of the COVID-19 pandemic. During the study period, men had a higher overall AAMR than women (men, 5.92; women, 4.32). Mortality was highest among the 55-74-year-old age group, followed by the 75-plus-year-old, 35-54-year-old, and finally 15-34-year-old age groups, which displayed the lowest AAMR (AAMR: 55-74, 11.76; 75+, 10.83; 35-54, 4.73; and 15-34, 0.54). Among the races, non-Hispanic (NH) Blacks had the highest overall AAMR (9.81), followed by NH American Indians or Alaskan Natives (6.01), NH Whites (4.64), Hispanics (4.08), and NH Asians or Pacific Islanders (1.17). However, NH Whites showed the highest average APC (AAPC) (11.44), indicating a possible future shift in mortality. By geographic region, the Southern United States had the highest AAMR, followed by the Western, Midwestern, and Northeastern regions. Non-metropolitan areas had consistently higher obesity- and hypertension-related AAMRs (5.63 overall) compared to metropolitan areas (4.99 overall). Conclusion In our retrospective analysis of death certificate data from 1999 to 2020, we found that age-adjusted mortality rates among individuals with both obesity and hypertension consistently displayed an increasing trend across all demographic groups. The overall rising AAMRs, compounded by the disproportionately high average annual percent changes among White individuals and those aged 15-34, raise serious concerns for the healthcare system. These findings have significant implications for public health policy. Focused interventions are essential to curb the upward trajectory of mortality in this population, as early intervention can greatly help tackle the dual burden of obesity and hypertension, which are largely preventable.

Myeloproliferative neoplasms (MPNs) are a spectrum of clonal hematologic malignancies, characterized by an acquired somatic mutation in hematopoietic stem cells (HSC). Consequent constitutive activation of the JAK/STAT signaling pathway ultimately leads to HSC clonal expansion, a heightened inflammatory state, and aberrant trafficking of the malignant stem cells to sites of extramedullary hematopoiesis. While polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are distinct disease entities, each with their own diagnostic criteria, risk stratification, and molecular profiles, they share a common pathogenesis and exist on a spectrum, with overlapping clinical features, propensity for thrombohemorrhagic events, and risk for transformation to acute leukemia. Interferon alpha (IFN-α) has both anti-proliferative and immunomodulatory effects on MPN HSCs, and therefore is an effective treatment modality for PV, ET, and MF. In this review, we discuss the rationale for IFN-α use in MPNs, examine the evidence supporting its use, and convey practical considerations.

Idasanutlin is a small molecule inhibitor that restores p53 activity, triggering apoptosis. Two trials (phase 1/2) of idasanutlin therapy in polycythemia vera patients that were intolerant or refractory to hydroxyurea resulted in substantial clinical and molecular responses. Here the long term outcomes of these patients are reported.

Mitochondria are critical cellular powerhouses that produce adenosine triphosphate to maintain the structure and integrity of the cell. Mitochondria generate 90% of the energy of a cell. Chronic inflammation causes damage to mitochondria. When enough mitochondria are dysfunctional, the involved organ will suffer. Mitochondria become dysfunctional in the setting of chronic inflammation. Under noninflammatory conditions, the body generates new mitochondria (mitochondrial biogenesis) and removes old and damaged mitochondria via mitophagy. When mitochondria are damaged, they "spontaneously" leak out reactive oxygen species, mitochondrial DNA, and damage-associated molecular patterns, generating erroneous innate immune responses. Autophagy is a recycling and housekeeping process that removes dysfunctional components, organelles, and proteins, promoting the recovery and maintenance of cell health. Mitophagy is a specific variant of this process that removes dysfunctional mitochondria from the cell. Mitophagy declines with age, allowing dysfunctional mitochondria to accumulate, and chronic inflammation leads to cardiovascular disease (CVD). In CVD, impairment of both autophagy and mitophagy leads to more chronic inflammation, characterized by hyperactivation of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a key component of the immune system. Once activated, it triggers inflammation, leading to excessive cytokine activity, proinflammatory macrophage polarization, pyroptosis, and increased immune cell infiltration into cardiac and vascular tissues. Pyroptosis is a form of inflammatory cell death triggered by programmed cues; however, in autoimmunity and cancer, when overactivated, this process can become detrimental. Adequate regulation of these events reduces oxidative stress, inflammatory cascades, fibrosis, and maladaptive remodeling, thereby improving overall cardiovascular health. Targeted therapeutic enhancement of autophagy and mitophagy represents a promising strategy to modulate immune-driven pathology and improve outcomes in cardiovascular conditions. We will review the mechanisms of how this inflammation causes CVD.

INTRODUCTION/UNASSIGNED:negative myeloproliferative neoplasm (MPN) driven by recurrent acquired somatic mutations in hematopoietic stem cells and characterized by progressive bone marrow fibrosis, cytopenias, and extramedullary hematopoiesis. Janus kinase inhibitors (JAKi) improve splenomegaly and MF symptom burden but without achieving molecular remission or clear disease course modification. Novel therapies targeting epigenetic dysregulation through bromodomain and extra-terminal domain (BET) proteins have emerged as a key therapeutic approach, aimed at reducing pro-inflammatory and oncogenic transcription to deepen clinical responses in combination with JAKi therapy. AREAS COVERED/UNASSIGNED:This review summarizes the biology, preclinical data, and emerging clinical data in the development of novel BET inhibitor (BETi). Trials assessing the efficacy of pelabresib, ABBV-744, INCB057643, BMS-986158, and OPN-2853 are detailed herein. EXPERT OPINION/UNASSIGNED:BET protein inhibition is a promising therapeutic target complementing JAK inhibition by co-targeting inflammatory pathways, fibrosis, and clonal proliferation. Pelabresib is a pan-BETi furthest in development demonstrating clinical benefit with ongoing trials. Research into novel pan-and selective-BETis both as monotherapy and in combination with JAKis or other mechanism-based therapies is ongoing. Whether BETi therapy in MF will ultimately deliver substantial anti-clonal activity to modify disease biology and meaningfully impact clinical outcomes is yet to be determined.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by progressive cytopenias, splenomegaly, and constitutional symptoms. The hallmark of MF pathophysiology is constitutive activation of JAK/STAT signaling, which, in the majority of cases, is associated with an acquired mutation in one of three driver mutations, JAK2, CALR, or MPL. Our growing understanding of the molecular biology of MPNs has resulted in regulatory approval of four JAK inhibitors (JAKi), which have demonstrated efficacy in improving symptom burden and reducing spleen size. Despite clear benefits of JAKi therapy, including evidence of improved survival, these therapeutic interventions have not established an ability to modify disease in terms of resolution of bone marrow fibrosis or molecular remissions. Therefore, recent emphasis has been on the development of novel therapies with informed targets outside of the JAK/STAT signaling pathway. Moreover, combination approaches utilizing JAK and non-JAK targeting agents underscore the potential for disease modification along with deeper and more durable clinical responses. Emerging combination strategies and their clinical development will be reviewed here, including investigations that pair JAKi therapy with BCL-2 family inhibitors, BET inhibitors, restored p53 cell death signals, telomerase inhibitors, PIM1 kinase inhibitors, and mutant CALR targeted therapies. While several combination clinical trials suggest improved spleen and symptom responses and the possibility of disease modification, toxicity profiles and optimal sequencing remain areas of active investigation.

BACKGROUND:Parents in the United Kingdom seeking an assessment for attention-deficit/hyperactivity disorder (ADHD) for their child experience a significant wait before receiving an appointment with Child and Adolescent Mental Health Services (CAMHS), yet little has been written on how parents experience this period. Through qualitative interviews, we sought to understand how the period of waiting from being accepted onto a service waitlist and receiving a diagnostic assessment impacts parents and their children. METHOD:The study was nested within a large randomised controlled trial. We conducted semi-structured interviews with 41 parents of children aged 5-11 years. 30% of parents had waited between 18 and 24 months on a CAMHS waitlist, with 10% waiting more than 2 years. Reflexive thematic analysis was used to analyse data. RESULTS:At the point of the interview, around 50% of children were still waiting for an initial assessment. Six themes reflecting parents' uncertainty around the assessment process, lack of communication from services, the importance of receiving a diagnosis, difficulty accessing support and the negative impact of waiting on mental health and education, as well as recommendations to improve communication between services and families, emerged. CONCLUSION:Parents recognised the pressures on services to offer timely support; however, their well-being could be substantially improved by more clarity around wait times, as well as more effective signposting and support from services concerning the assessment process. This may help alleviate some of the stressors associated with their child's assessment journey, such as feeling responsible for their child's difficulties and the burden of supporting their educational needs. PATIENT AND PUBLIC CONTRIBUTION:This study was nested within the OPTIMA trial, where PPI panel members provided ongoing support in various aspects of the study, including advising on participant communication, study design and data analysis. All PPI members have lived experience of having a neurodivergent child. For this study, the PPI co-produced the interview schedule and took part in transcript analysis using a thematic framework approach. To acknowledge their contributions, members of the PPI panel are included as co-authors.

BACKGROUND:Coronary microvascular dysfunction (CMD) is a mechanism of ischemia with nonobstructive coronary arteries (INOCA) diagnosed by invasive coronary function testing (CFT). It is unknown whether CMD reflects a systemic microcirculatory disorder. Sidestream darkfield (SDF) microscopy permits noninvasive imaging of red blood cells (RBCs) in the sublingual microcirculation. OBJECTIVES/OBJECTIVE:We sought to evaluate whether SDF microscopy identifies sublingual microvascular abnormalities in patients with INOCA due to CMD. METHODS:Adults with INOCA underwent CFT for CMD, defined by abnormal coronary flow reserve <2.5 or index of microcirculatory resistance ≥25. Sublingual SDF microscopy was performed to determine the endothelial glycocalyx perfused boundary region (PBR), RBC filling percentage (%RBC), and perfused microvascular density (PMVD). RESULTS:A total of 135 participants with INOCA (mean age 59.3 ± 12.1 years, 80% female) underwent CFT and sublingual SDF microscopy. CMD was present in 63 participants (46.7%). The median PBR was 1.96 (IQR: 0.4), median %RBC was 72.6 (IQR: 8.0), and median PMVD was 406 (IQR: 141). No differences in sublingual PBR, %RBC, and PMVD were observed by CMD status. No correlations between sublingual parameters and continuous measures of coronary flow reserve or index of microcirculatory resistance were observed. CONCLUSIONS:Noninvasive SDF microscopy did not identify sublingual microvascular abnormalities in INOCA patients with CMD.

OBJECTIVES/OBJECTIVE:The COVID-19 pandemic highlighted an urgent need to more efficiently identify patients at highest risk for developing respiratory failure. We investigated whether plasma levels of lung injury biomarkers are associated with progression to respiratory failure among adults hospitalized with COVID-19 pneumonia without respiratory failure at admission. DESIGN/METHODS:This was a nested case-control study of COVID-19 patients enrolled in the Accelerating COVID-19 Therapeutic Interventions and Vaccines-3 (ACTIV-3)/Therapeutics for Inpatients with COVID-19 (TICO) platform trial who were on less than 20 L/min supplemental oxygen at enrollment. We compared baseline measurements of lung injury biomarkers between participants who progressed to respiratory failure or died by study day 10 (cases) and matched controls who did not progress to respiratory failure or death. Cases and controls were matched 1:1 on age, baseline oxygen requirement, immunomodulator use, and study arm. SETTING/METHODS:Hospitals enrolling in the ACTIV-3/TICO trials. PATIENTS/METHODS:Four hundred five cases and 405 matched controls. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Baseline levels of plasma interleukin (IL)-6, IL-8, IL-18, tumor necrosis factor receptor, angiopoietin-2, soluble receptor for advanced glycation end-products (sRAGE), C-reactive protein (CRP), and surfactant protein D (SPD) were compared between cases and controls using matched logistic regression. Forward variable selection was used to identify biomarkers that were independently associated with progression to respiratory failure or death in a multivariate model. All lung injury biomarkers with the exception of SPD were significantly associated with progression to respiratory failure or death, with sRAGE demonstrating the highest odds ratio (OR) for each doubling of biomarker level (OR, 1.85; 95% CI, 1.61-2.12). In multivariate regression analysis, sRAGE, IL-6, and CRP were independently associated with progression, with sRAGE as the biomarker with the strongest association. CONCLUSIONS:Baseline levels of plasma lung injury biomarkers are significantly associated with progression to respiratory failure or death among hospitalized COVID-19 patients without respiratory failure at admission. These findings support the potential utility of measuring lung injury biomarkers in patients hospitalized without respiratory failure and should be tested in more heterogeneous patient groups including non-COVID-19 cohorts.

PURPOSE/UNASSIGNED:To examine the correlation between hydroxychloroquine levels with real body weight and ideal body weight dose and identify patient characteristics at risk for subtherapeutic or supratherapeutic dosing. METHODS/UNASSIGNED:A retrospective chart review of 181 patients with lupus (429 unique hydroxychloroquine whole blood levels) was performed. Hydroxychloroquine levels <100 (indicating medication noncompliance) were excluded (n = 26). Summary statistics, linear regression of hydroxychloroquine level and real body weight/ideal body weight, and odds ratios (ORs) for factors associated with supratherapeutic (>2000 ng/mL) or subtherapeutic (<750 ng/mL) hydroxychloroquine levels were calculated. RESULTS/UNASSIGNED:, respectively. CONCLUSIONS/UNASSIGNED:All dosing schedules show variability in hydroxychloroquine levels. Ideal body weight may correlate more strongly with hydroxychloroquine level than real body weight. Under real body weight-based guidelines, obesity may increase the risk for supratherapeutic hydroxychloroquine levels, and low weight may increase the risk for subtherapeutic levels.