Hermansky-Pudlak syndrome (HPS) is a genetic disorder associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. Unifying mechanisms of AT2 cell dysfunction in genetic and sporadic fibrotic lung diseases remain unknown. Incorporating AT2 cell lineage tracing in HPS mice, we observed a progressive decline in AT2 cell numbers with aging and aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. HPS AT2 cell proliferation was impaired ex vivo and in vivo , suggesting an intrinsic progenitor defect. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and cellular senescence. Through lineage tracing and organoid modeling, we demonstrated that HPS AT2 cells were primed to persist in a Krt8 + reprogrammed transitional state, mediated by p53 activity. These findings suggest that pulmonary fibrosis in HPS may be driven by AT2 cell progenitor dysfunction in the setting of p53-mediated senescence, highlighting a novel potential therapeutic target in HPS and suggesting unifying mechanisms underlying HPS and other forms of pulmonary fibrosis.

Intraoperative molecular imaging (IMI) uses cancer-targeted fluorescent probe to locate nodules. Pafolacianine is a Food and Drug Administration-approved fluorescent probe for lung cancer. However, it has a 8-12% false negative rate for localization. Our goal is to define preoperative predictors of tumour localization by IMI. We performed a retrospective review of patients who underwent IMI using pafolacianine for lung lesions from June 2015 to August 2019. Candidate predictors including sex, age, body mass index, smoking history, tumour size, distance of tumour from surface, use of neoadjuvant therapy and positron emission tomography avidity were included. The outcome was fluorescence in vivo and comprehensively included those who were true or false positives negatives. Multiple imputation was used to handle the missing data. The final model was evaluated using the area under the receiver operating characteristic curve. Three hundred nine patients were included in our study. The mean age was 64 (standard deviation 13) and 68% had a smoking history. The mean distance of the tumours from the pleural surface was 0.4 cm (standard deviation 0.6). Smoking in pack-years and distance from pleura had an odds ratio of 0.99 [95% confidence interval: 0.98-0.99; P = 0.03] and 0.46 [95% confidence interval: 0.27-0.78; P = 0.004], respectively. The final model had an area under the receiver operating characteristic curve of 0.68 and was used to create a nomogram that gives a probability of fluorescence in vivo. Primary tumours that are deeper from the pleural surface, especially in patients with a higher pack-years, are associated with a decreased likelihood of intraoperative localization. We identified a nomogram to predict the likelihood of tumour localization with IMI with pafolacianine.

Individuals with multiple sclerosis (MS) may experience a variety of visible and invisible symptoms and, as they age, comorbidities related and unrelated to their MS. This can result in a complex medication regimen that includes disease-modifying therapies, symptom management drugs, and prescriptions for other comorbid disorders. We reviewed the existing literature to discover how to optimally integrate neurology clinical pharmacists into the MS care team and how clinical pharmacists can directly support both providers and patients through their expertise in pharmacology and medication management. With approaches founded on a shared decision-making process alongside neurology providers, patients, and care partners, clinical pharmacists can help meet the complex challenges of MS care in a variety of ways. Especially within MS clinics, they are well positioned to enhance current neurology practices given their extensive training in comprehensive medication management and their ability to identify nuances in medication management to promote pharmacovigilance and patient-centered care. Neurology clinical pharmacists bring multifaceted medication management and patient counseling and education skills to the MS care team and can support the shared decision-making process by serving as an accessible resource for patients and clinicians. By building trusted partnerships between neurology providers and clinical pharmacists, MS care teams can achieve effective and efficient patient care. Future research should compare clinical and patient-reported outcomes between patients receiving standard care and those receiving multidisciplinary, pharmacist-integrated care.

Real-world clinical data, outside of clinical trials and expert centers, on adverse events related to the use of SyncCardia total artificial heart (TAH) remain limited. We aim to analyze adverse events related to the use of SynCardia TAH reported to the Food and Drug Administration (FDA)'s Manufacturers and User Defined Experience (MAUDE) database. We reviewed the FDA's MAUDE database for any adverse events involving the use of SynCardia TAH from 1/01/2012 to 9/30/2020. All the events were independently reviewed by three physicians. A total of 1,512 adverse events were identified in 453 "injury and death" reports in the MAUDE database. The most common adverse events reported were infection (20.2%) and device malfunction (20.1%). These were followed by bleeding events (16.5%), respiratory failure (10.1%), cerebrovascular accident (CVA)/other neurological dysfunction (8.7%), renal dysfunction (7.5%), hepatic dysfunction (2.2%), thromboembolic events (1.8%), pericardial effusion (1.8%), and hemolysis (1%). Death was reported in 49.4% of all the reported cases (n=224/453). The most common cause of death was multiorgan failure (n=73, 32.6%), followed by CVA/other non-specific neurological dysfunction (n=44, 19.7%), sepsis (n=24, 10.7%), withdrawal of support (n=20, 8.9%), device malfunction (n=11, 4.9%), bleeding (n=7, 3.1%), respiratory failure (n=7, 3.1%), gastrointestinal disorder (n=6, 2.7%), and cardiomyopathy (n=3, 1.3%). Infection was the most common adverse event following the implantation of TAH. Most of the deaths reported were due to multiorgan failure. Early recognition and management of any possible adverse events after the TAH implantation are essential to improve the procedural outcome and patient survival.

Prior studies showed that neighborhood deprivation increases the risk of lethal prostate cancer. However, the role of neighborhood gentrification in prostate cancer development and outcome remains poorly understood. We examined the relationships of gentrification with prostate cancer and serum proteome-defined inflammation and immune function in a diverse cohort. The case-control study included 769 cases [405 African American (AA), 364 European American (EA) men] and 1023 controls (479 AA and 544 EA), with 219 all-cause and 59 prostate cancer-specific deaths among cases. Geocodes were linked to a neighborhood gentrification index (NGI) derived from US Census data. Cox and logistic regression, and MANOVA, were used to determine associations between NGI, as continuous or quintiles (Q), and outcomes. Adjusting for individual socioeconomic status (SES), continuous NGI was positively associated with prostate cancer among all men (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.01-1.14). AA and low-income men experienced the highest odds of prostate cancer when residing in tracts with moderate gentrification, whereas EA men experienced reduced odds of regional/metastatic cancer with increased gentrification in SES-adjusted analyses. Continuous NGI also associated with mortality among men presenting with localized disease and low-income men in SES-adjusted Cox regression analyses. NGI was not associated with serum proteome-defined chemotaxis, inflammation, and tumor immunity suppression. Findings show that neighborhood gentrification associates with prostate cancer and mortality in this diverse population albeit associations were heterogenous within subgroups. The observations suggest that changing neighborhood socioeconomic environments may affect prostate cancer risk and outcome, likely through multifactorial mechanisms.

Abstract Background Understanding the impact of family life stressors on maternal health is crucial, particularly in highly industrialized areas. This study assessed the validity of an Italian-language version of the Crisis in Family Systems-Revised (CRISYS-R) survey in Northern and Southern Italian cohorts. Methods Mothers (n = 252) completed an Italian version of CRISYS-R, translated from English using the forward-backward method. At least 14 days after initial survey completion, a random subset of mothers (n = 44) retook CRISYS-R. Information about family demographics, socioeconomic status, and maternal health were collected by self-report on structured surveys. Statistical analyses were performed in R. Results Test-retest analysis yielded a Pearson coefficient of 0.714 (Brescia: 0.845, Taranto: 0.726). Cronbach’s alpha coefficient for internal consistency was 0.765 (Brescia: 0.718, Taranto: 0.784). In multivariable regression, the total number of stressors reported on the initial CRISYS-R test was positively associated with: poor maternal mental health (p < 0.001), poor maternal physical health (p < 0.01), and residence in the Southern rather than Northern Italy (p = 0.02). Univariate correlations yielded similar results, plus a negative correlation between annual family income and total life stressors (p < 0.05). Conclusions Statistical analyses support the validity and reliability of an Italian-language CRISYS-R in industrialized areas, while highlighting relationships between family stressors and maternal mental and physical health. This survey instrument has the potential to inform public health policies and interventions serving families in Italian-speaking areas with high burdens of industrial pollution.

AbstractLymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites.

Abstract In the Neuro Intensive Care Unit (Neuro-ICU), patients with Disorders of Consciousness (DoC) often experience sensory deprivation. DoC, resulting from brain damage, encompasses varying degrees of wakefulness and awareness, ranging from coma to vegetative state and minimally conscious state. Research highlights a concerning trend in the Neuro-ICU, where older adults with DoC are more susceptible to mortality compared to their younger counterparts. This study emphasizes the indispensable role of nurses in effectively managing DoC within the Neuro-ICU, particularly through the thoughtful application of sensory stimulation interventions. Sensory stimulation is a promising approach that engages patients’ various senses—touch, sight, sound, and smell, aiming to awaken awareness and cognitive responses in DoC patients. By fostering neural activity, sensory stimulation holds the potential to contribute to their recovery. Importantly, these techniques can be customized to each patient’s specific condition and responses, and nurses, due to their continuous patient interactions, are uniquely positioned to administer these interventions at the bedside. Recognizing this vital role, evidence-based strategies are proposed, encompassing thorough literature analysis, assessment of nurses’ attitudes, and exploration of potential interventions within the Neuro-ICU setting. This research highlights the significant impact nursing can have on elevating patient outcomes. It demonstrates how evidence-based interventions like sensory stimulation can be seamlessly woven into patient care, providing a valuable and holistic approach for individuals grappling with the intricate challenges presented by DoC.

Abstract Disorders of consciousness (DoC) following brain injury are challenging for families, who often decide about end-of-life care without a clear understanding of a patient’s recovery. This has special significance for older and geriatric populations, as they often rely on caregivers, proxies, and family members in making health and life decisions, and now face the added severity of decisions surrounding continuing treatment. In improving neuroprognostication, we hope to decrease this burden in aging-related decision-making. Functional magnetic resonance imaging (fMRI) has proved helpful in identifying brain activity in DoC with implications for recovery of consciousness, function, and quality of life. This project seeks to develop and implement a standardized fMRI protocol to best induce signals of consciousness in participants and predict the likelihood of neurologic recovery. From there, we will measure how the protocol contributes to an accurate outcome prediction following a DoC as compared to standard methods. The study will be conducted in the intensive care unit(s) of the Hospital of the University of Pennsylvania; we anticipate having an initial analysis of results by Fall of 2023. The study will be enrolling and conducting fMRI’s with the device over one year under a randomized control trial. This study emphasizes improvements in the practice of neuroprognostication after stroke, anoxic brain injury following cardiac arrest, and other related conditions. The literature on these particular forms of traumatic brain injury and neuroprognostication remains limited, which is of disservice to older and geriatric populations who suffer these events at higher rates.