Treatment of Sulfur Mustard Corneal Injury by Augmenting the DNA Damage Response (DDR): A Novel Approach.

Sulfur mustard (SM) is a highly reactive organic chemical has been used as a chemical warfare agent and terrorist threat since World War I. The cornea is highly sensitive to SM toxicity and exposure to low vapor doses can cause incapacitating acute injuries. Exposure to higher doses can elicit persistent secondary keratopathies that cause reduced quality of life and impaired or lost vision. Despite a century of research, there are no specific treatments for acute or persistent ocular SM injuries. SM cytotoxicity emerges, in part, through DNA alkylation and double-strand breaks (DSBs). Because DSBs can naturally be repaired by DNA damage response pathways with low efficiency, we hypothesized that enhancing the homologous recombination pathway could pose a novel approach to mitigate SM injury. Here, we demonstrate that a dilithium salt of adenosine diphosphoribose (INV-102) increases protein levels of p53 and Sirtuin 6, upregulates transcription of BRCA1/2, enhances γH2AX focus formation, and promotes assembly of repair complexes at DSBs. Based on in vitro evidence showing INV-102 enhancement of DNA damage response through both p53-dependent and p53-independent pathways, we next tested INV-102 in a rabbit preclinical model of corneal injury. In vivo studies demonstrate a marked reduction in the incidence and severity of secondary keratopathies in INV-102-treated eyes compared with vehicle-treated eyes when treatment was started 24 hours after SM vapor exposure. These results suggest DNA repair mechanisms are a viable therapeutic target for SM injury and suggest topical treatment with INV-102 is a promising approach for SM as well as other conditions associated with DSBs. SIGNIFICANCE STATEMENT: Sulfur mustard gas corneal injury currently has no therapeutic treatment. This study aims to show the therapeutic potential of activating the body's natural DNA damage response to activate tissue repair.

Coordination of MAPK and p53 dynamics in the cellular responses to DNA damage and oxidative stress.

In response to different cellular stresses, the transcription factor p53 undergoes different dynamics. p53 dynamics, in turn, control cell fate. However, distinct stresses can generate the same p53 dynamics but different cell fate outcomes, suggesting integration of dynamic information from other pathways is important for cell fate regulation. To determine how MAPK activities affect p53-mediated responses to DNA breaks and oxidative stress, we simultaneously tracked p53 and either ERK, JNK, or p38 activities in single cells. While p53 dynamics were comparable between the stresses, cell fate outcomes were distinct. Combining MAPK dynamics with p53 dynamics was important for distinguishing between the stresses and for generating temporal ordering of cell fate pathways. Furthermore, cross-talk between MAPKs and p53 controlled the balance between proliferation and cell death. These findings provide insight into how cells integrate signaling pathways with distinct temporal patterns of activity to encode stress specificity and drive different cell fate decisions.

Dual-Sensing Piezoresponsive Foam for Dynamic and Static Loading.

Polymeric foams, embedded with nano-scale conductive particles, have previously been shown to display quasi-piezoelectric (QPE) properties; i.e., they produce a voltage in response to rapid deformation. This behavior has been utilized to sense impact and vibration in foam components, such as in sports padding and vibration-isolating pads. However, a detailed characterization of the sensing behavior has not been undertaken. Furthermore, the potential for sensing quasi-static deformation in the same material has not been explored. This paper provides new insights into these self-sensing foams by characterizing voltage response vs frequency of deformation. The correlation between temperature and voltage response is also quantified. Furthermore, a new sensing functionality is observed, in the form of a piezoresistive response to quasi-static deformation. The piezoresistive characteristics are quantified for both in-plane and through-thickness resistance configurations. The new functionality greatly enhances the potential applications for the foam, for example, as insoles that can characterize ground reaction force and pressure during dynamic and/or quasi-static circumstances, or as seat cushioning that can sense pressure and impact.

Association Between Nonsurgical Weight Loss From Body Mass Index >40 to Body Mass Index <40 and Complications and Readmissions Following Total Hip Arthroplasty.

BACKGROUND: Elevated body mass index (BMI) is a risk factor for adverse outcomes following total hip arthroplasty (THA). It is unknown if preoperative weight loss to a BMI <40 kg/m2 is associated with reduced risk of adverse outcomes. METHODS: We retrospectively reviewed elective, primary THA performed at an academic center from 2015 to 2019. Patients were split into groups based on their BMI trajectory prior to THA: BMI consistently <40 ("BMI <40"); BMI >40 at the time of surgery ("BMI >40"); and BMI >40 within 2 years preoperatively, but <40 at the time of surgery ("Weight Loss"). Length of stay (LOS), 30-day readmissions, and complications as defined by Centers for Medicare and Medicaid Services were compared between groups using parsimonious regression models and Fisher's exact testing. Adjusted analyses controlled for sex, age, and American Society of Anesthesiologists class. RESULTS: In total, 1589 patients were included (BMI <40: 1387, BMI >40: 96, Weight Loss: 106). The rate of complications in each group was 3.5%, 6.3%, and 8.5% and the rate of 30-day readmissions was 3.0%, 4.2%, and 7.5%, respectively. Compared to the BMI <40 group, the weight loss group had a significantly higher risk of 30-day readmission (odds ratio [OR] 2.70, 95% confidence interval [CI] 1.19-6.17, P = .02), higher risk of any complication (OR 2.47, 95% CI 1.09-5.59, P = .03), higher risk of mechanical complications (OR 3.07, 95% CI 1.14-8.25, P = .03), and longer median LOS (16% increase, P = .002). The BMI >40 group had increased median LOS (10% increase, P = .03), but no difference in readmission or complications (P > .05) compared to BMI <40. CONCLUSION: Weight loss from BMI >40 to BMI <40 prior to THA was associated with increased risk of readmission and complications compared to BMI <40, whereas BMI >40 was not. LEVEL OF EVIDENCE: Level III - Retrospective Cohort Study.

Do In-Hospital Rothman Index Scores Predict Postdischarge Adverse Events and Discharge Location After Total Knee Arthroplasty?

BACKGROUND: There have been efforts to reduce adverse events and unplanned readmissions after total joint arthroplasty. The Rothman Index (RI) is a real-time, composite measure of medical acuity for hospitalized patients. We aimed to examine the association among in-hospital RI scores and complications, readmissions, and discharge location after total knee arthroplasty (TKA). We hypothesized that RI scores could be used to predict the outcomes of interest. METHODS: This is a retrospective study of an institutional database of elective, primary TKA from July 2018 until December 2019. Complications and readmissions were defined per Centers for Medicare and Medicaid Services. Analysis included multivariate regression, computation of the area under the curve (AUC), and the Youden Index to set RI thresholds. RESULTS: The study cohort's (n = 957) complications (2.4%), readmissions (3.6%), and nonhome discharge (13.7%) were reported. All RI metrics (minimum, maximum, last, mean, range, 25th%, and 75th%) were significantly associated with increased odds of readmission and home discharge (all P < .05). RI scores were not significantly associated with complications. The optimal RI thresholds for increased risk of readmission were last ≤ 71 (AUC = 0.65), mean ≤ 67 (AUC = 0.66), or maximum ≤ 80 (AUC = 0.63). The optimal RI thresholds for increased risk of home discharge were minimum ≥ 53 (AUC = 0.65), mean ≥ 69 (AUC = 0.65), or maximum ≥ 81 (AUC = 0.60). CONCLUSION: RI values may be used to predict readmission or home discharge after TKA.

Ancient Roots of Today's Emerging Renaissance in Psychedelic Medicine.

An international ban on psychedelics initiated by the United Nations' Convention on Psychotropic Substances in 1971 restricted the clinical use of these ancient psychoactive substances. Yet, in an era marked by rising mental health concerns and a growing "Deaths of Despair" epidemic (i.e., excess mortality and morbidity from suicide, drug overdose, and alcoholism), the structured psychedelic use that has long been a part of ritual healing experiences for human societies is slowly regaining credibility in Western medicine for its potential to treat various mental health conditions. We use a historical lens to examine the use of psychedelic therapies over time, translate ancient lessons to contemporary clinical and research practice, and interrogate the practical and ethical questions researchers must grapple with before they can enter mainstream medicine. Given the COVID-19 pandemic and its contributions to the global mental health burden, we also reflect on how psychedelic therapy might serve as a tool for medicine in the aftermath of collective trauma. Ultimately, it is argued that a "psychedelic renaissance" anchored in the lessons of antiquity can potentially help shift healthcare systems-and perhaps the broader society-towards practices that are more humane, attentive to underlying causes of distress, and supportive of human flourishing.

Transmission Dynamics of Clostridioides difficile in 2 High-Acuity Hospital Units.

BACKGROUND: The key epidemiological drivers of Clostridioides difficile transmission are not well understood. We estimated epidemiological parameters to characterize variation in C. difficile transmission, while accounting for the imperfect nature of surveillance tests. METHODS: We conducted a retrospective analysis of C. difficile surveillance tests for patients admitted to a bone marrow transplant (BMT) unit or a solid tumor unit (STU) in a 565-bed tertiary hospital. We constructed a transmission model for estimating key parameters, including admission prevalence, transmission rate, and duration of colonization to understand the potential variation in C. difficile dynamics between these 2 units. RESULTS: A combined 2425 patients had 5491 admissions into 1 of the 2 units. A total of 3559 surveillance tests were collected from 1394 patients, with 11% of the surveillance tests being positive for C. difficile. We estimate that the transmission rate in the BMT unit was nearly 3-fold higher at 0.29 acquisitions per percentage colonized per 1000 days, compared to our estimate in the STU (0.10). Our model suggests that 20% of individuals admitted into either the STU or BMT unit were colonized with C. difficile at the time of admission. In contrast, the percentage of surveillance tests that were positive within 1 day of admission to either unit for C. difficile was 13.4%, with 15.4% in the STU and 11.6% in the BMT unit. CONCLUSIONS: Although prevalence was similar between the units, there were important differences in the rates of transmission and clearance. Influential factors may include antimicrobial exposure or other patient-care factors.

Progress and challenges in understanding the regulation and function of p53 dynamics.

The dynamics of p53 expression provide a mechanism to increase differentiation between cellular stresses and specificity in appropriate responses. Here, we review recent advances in our understanding of the molecular mechanisms regulating p53 dynamics and the functions of the dynamics in the regulation of p53-dependent cell stress responses. We also compare dynamic encoding in the p53 system with that found in other important cell signaling systems, many of which can interact with the p53 network. Finally, we highlight some of the current challenges in understanding dynamic cell signaling within a larger cellular network context.

Validity of claims-based algorithms to identify neurodevelopmental disorders in children.

PURPOSE: To validate healthcare claim-based algorithms for neurodevelopmental disorders (NDD) in children using medical records as the reference. METHODS: Using a clinical data warehouse of patients receiving outpatient or inpatient care at two hospitals in Boston, we identified children (≤14 years between 2010 and 2014) with at least one of the following NDDs according to claims-based algorithms: autism spectrum disorder/pervasive developmental disorder (ASD), attention deficit disorder/other hyperkinetic syndromes of childhood (ADHD), learning disability, speech/language disorder, developmental coordination disorder (DCD), intellectual disability, and behavioral disorder. Fifty cases per outcome were randomly sampled and their medical records were independently reviewed by two physicians to adjudicate the outcome presence. Positive predictive values (PPVs) and 95% confidence intervals (CIs) were calculated. RESULTS: PPVs were 94% (95% CI, 83%-99%) for ASD, 88% (76%-95%) for ADHD, 98% (89%-100%) for learning disability, 98% (89%-100%) for speech/language disorder, 82% (69%-91%) for intellectual disability, and 92% (81%-98%) for behavioral disorder. A total of 19 of the 50 algorithm-based cases of DCD were confirmed as severe coordination disorders with functional impairment, with a PPV of 38% (25%-53%). Among the 31 false-positive cases of DCD were 7 children with coordination deficits that did not persist throughout childhood, 7 with visual-motor integration deficits, 12 with coordination issues due to an underlying medical condition and 5 with ADHD and at least one other severe NDD. CONCLUSIONS: PPVs were generally high (range: 82%-98%), suggesting that claims-based algorithms can be used to study NDDs. For DCD, additional criteria are needed to improve the classification of true cases.

Glycemic relapse in a collaborative primary care-based type 2 diabetes management program.

OBJECTIVES: The purpose of this study is to evaluate the incidence of glycemic relapse in patients who attained their glycosylated hemoglobin (A1C) goal through a health system-wide collaborative primary care-based pharmacist- and Certified Diabetes Care and Education Specialist (CDCES)-led type 2 diabetes (T2D) management program and to identify relapse risk factors. METHODS: This retrospective cohort study examined patients with T2D in the diabetes management program with a baseline A1C of at least 9% who attained their A1C goal. The primary outcome was incidence of glycemic relapse. Time to relapse was estimated using Kaplan-Meier curve, and a cox proportional hazards model was fitted to identify the risk factors for glycemic relapse. RESULTS: Three hundred sixty-two patients were followed-up for a median of 10.5 (interquartile range 12.1) months after program completion; 38 patients (10.5%) experienced a glycemic relapse. Kaplan-Meier analysis estimated a 12-month relapse rate of 8.3%. The presence of a medication adherence barrier, presence of a higher number of chronic medications at baseline, presence of a baseline body mass index (BMI) of 30-39.9, and use of insulin at program completion increased risk for glycemic relapse in a univariate model. In multivariate regression, baseline BMI of 30-39.9 remained statistically significant. Older age at baseline was associated with a statistically significantly decreased relapse risk in both models. CONCLUSION: This study highlights a low incidence of glycemic relapse for patients with T2D who reach their A1C goal through a collaborative primary care-based pharmacist- and CDCES-led T2D management program. The presence of risk factors for glycemic relapse may indicate a need for ongoing intensive care despite achieving A1C goal.

Repurposing Waste Streams: Lessons on Integrating Hospital Food Waste into a Community Garden.

There have been increasing efforts in recent decades to divert institutional food waste into composting programs. As major producers of food waste who must increasingly demonstrate community benefit, hospitals have an incentive to develop such programs. In this article, we explain the emerging opportunity to link hospitals' food services to local community gardens in order to implement robust composting programs. We describe a partnership model at our hospital in central Pennsylvania, share preliminary outcomes establishing feasibility, and offer guidance for future efforts. We also demonstrate that the integration of medical students in such efforts can foster systems thinking in the development of programs to manage hospital waste streams in more ecologically-friendly ways.

Propranolol Decreases Proliferation of Endothelial Cells Transformed by Kaposi's Sarcoma-Associated Herpesvirus and Induces Lytic Viral Gene Expression.

Kaposi's sarcoma (KS) is common in Africa, but economic constraints hinder successful treatment in most patients. Propranolol, a generic ß-adrenergic antagonist, decreased proliferation of KS-associated herpesvirus (KSHV)-infected cells. Downregulation of cyclin A2 and cyclin-dependent kinase 1 (CDK1) recapitulated this phenotype. Additionally, propranolol induced lytic gene expression in association with downregulation of CDK6. Thus, propranolol has diverse effects on KSHV-infected cells, and this generic drug has potential as a therapeutic agent for KS.

Investigation of nasal CO2 receptor transduction mechanisms in wild-type and GC-D knockout mice.

The main olfactory system of mice contains a small subset of olfactory sensory neurons (OSNs) that are stimulated by CO2. The objective of this study was to record olfactory receptor responses to a range of CO2 concentrations to further elucidate steps in the proposed CO2 transduction pathway in mice. Electro-olfactograms (EOGs) were recorded before and after inhibiting specific steps in the CO2 transduction pathway with topically applied inhibitors. Inhibition of extracellular carbonic anhydrase (CA) did not significantly affect EOG responses to CO2 but did decrease EOG responses to several control odorants. Inhibition of intracellular CA or cyclic nucleotide-gated channels attenuated EOG responses to CO2, confirming the role of these components in CO2 sensing in mice. We also show that, like canonical OSNs, CO2-sensitive OSNs depend on Ca²âº-activated Cl⁻ channels for depolarization of receptor neurons. Lastly, we found that guanylyl cyclase-D knockout mice were still able to respond to CO2, indicating that other pathways may exist for the detection of low concentrations of nasal CO2. We discuss these findings as they relate to previous studies on CO2-sensitive OSNs in mice and other animals.

Deubiquitinating enzyme A20 negatively regulates NF-κB signaling in skeletal muscle in mdx mice.

Duchenne muscular dystrophy (DMD) is caused by the lack of a functional dystrophin protein that results in muscle fiber membrane disruption and, ultimately, degeneration. Regeneration of muscle fibers fails progressively, and muscle tissue is replaced with connective tissue. As a result, DMD causes progressive limb muscle weakness and cardiac and respiratory failure. The absence of dystrophin from muscle fibers triggers the chronic activation of the nuclear factor of kappa B (NF-κB). Chronic activation of NF-κB in muscle leads to infiltration of macrophages, up-regulation of the ubiquitin-proteosome system, and down-regulation of the helix-loop-helix muscle regulatory factor, MyoD. These processes, triggered by NF-κB activation, promote muscle degeneration and failure of muscle regeneration. A20 (TNFAIP3) is a critical negative regulator of NF-κB. In this study, we characterize the role of A20 in regulating NF-κB activation in skeletal muscle, identifying a novel role in muscle regeneration. A20 is highly expressed in regenerating muscle fibers, and knockdown of A20 impairs muscle differentiation in vitro, which suggests that A20 expression is critically important for regeneration of dystrophic muscle tissue. Furthermore, down-regulation of the classic pathway of NF-κB activation is associated with up-regulation of the alternate pathway in regenerating muscle fibers, suggesting a mechanism by which A20 promotes muscle regeneration. These results demonstrate the important role of A20 in muscle fiber repair and suggest the potential of A20 as a therapeutic target to ameliorate the pathology and clinical symptoms of DMD.

Association Between COVID-19 and Delirium Development in the General Medical Units at an Academic Medical Center.

INTRODUCTION: Evidence suggests that inpatients who develop delirium experience worse outcomes. Although there is reason to believe that COVID-positive patients may be at a higher risk for developing delirium, little is known about the association between COVID-19 and delirium among hospitalized patients outside the intensive care unit (ICU). This study aimed to examine (1) the independent association between COVID-19 infection and the development of delirium among all non-ICU patients and (2) the risk factors associated with developing delirium among patients admitted with COVID-19, with a special focus on presenting symptoms. METHODS: Using electronic health record (EHR) data of adults admitted to any general medical unit at a large academic medical center from July 2020 through February 2021, we used a cross-sectional multivariable logistic regression to estimate the associations, while adjusting for patients' sociodemographic, clinical characteristics, delirium-free length of stay, as well as time fixed effects. RESULTS: Multivariable regression estimates applied to 20 509 patients hospitalized during the study period indicate that COVID-19-positive patients had 72% higher relative risk (odds ratio 1.72; 95% CI, 1.31 - 2.26; P < 0.001) of developing delirium than the COVID-19-negative patients. However, among the subset of patients admitted with COVID-19, having any COVID-19-specific symptoms was not associated with elevated odds of developing delirium compared to those who were asymptomatic, after controlling for potential confounders. CONCLUSIONS: COVID-19 positivity was associated with higher odds of developing delirium among patients during their non-ICU hospitalization. These findings may be helpful in targeting the use of delirium prevention strategies among non-ICU patients.

Efficacy of a Digital Intervention to Increase Annual Wellness Visit Scheduling Amid COVID-19 Backlog.

BACKGROUND: The Medicare Annual Wellness Visit is a preventive visit that is largely underutilized, a problem further compounded by the COVID-19 pandemic. METHODS: We implemented a digital outreach intervention to improve Annual Wellness Visit scheduling in our health system. Using a bulk outreach functionality in the electronic medical record, we sent a message to patients due for an Annual Wellness Visit and analyzed the efficacy of this message on scheduling rates while also assessing its impact by race. RESULTS: Patients who read the message were 40% more likely to schedule an Annual Wellness Visit (OR 1.42; 95% CI, 1.34 - 1.50) compared to those who did not read the message. DISCUSSION: After this intervention, Annual Wellness Visit scheduling rates increased by 50% for White patients and 325% for Black patients versus prepandemic rates in 2019.

Effect of Implementing a Commercial Electronic Early Warning System on Outcomes of Hospitalized Patients.

Despite the widespread adoption of early warning systems (EWSs), it is uncertain if their implementation improves patient outcomes. The authors report a pre-post quasi-experimental evaluation of a commercially available EWS on patient outcomes at a 700-bed academic medical center. The EWS risk scores were visible in the electronic medical record by bedside clinicians. The EWS risk scores were also monitored remotely 24/7 by critical care trained nurses who actively contacted bedside nurses when a patient's risk levels increased. The primary outcome was inpatient mortality. Secondary outcomes were rapid response team calls and activation of cardiopulmonary arrest (code-4) response teams. The study team conducted a regression discontinuity analysis adjusting for age, gender, insurance, severity of illness, risk of mortality, and hospital occupancy at admission. The analysis included 53,229 hospitalizations. Adjusted analysis showed no significant change in inpatient mortality, rapid response team call, or code-4 activations after implementing the EWS. This study confirms the continued uncertainty in the effectiveness of EWSs and the need for further rigorous examinations of EWSs.

A phase 2 study of pegylated interferon α-2b (PEG-Intron(®)) in children with diffuse intrinsic pontine glioma.

BACKGROUND: Interferon-α is a cytokine that has demonstrated activity in patients with supratentorial gliomas, but its ideal dose and schedule of administration is unknown. Studies suggest that low-dose, continuous exposure is more efficacious than intermittent, high doses. The authors performed a phase 2 study of recombinant interferon α-2b with monomethoxy polyethylene glycol (PEG-Intron(®)) in children with diffuse intrinsic pontine glioma (DIPG), a population with dismal survival despite decades of clinical investigation. The primary objective was to compare 2-year survival with a historic cohort that received radiation therapy alone. METHODS: Patients received weekly subcutaneous PEG-Intron(®) at a dose of 0.3 µg/kg beginning 2 to 10 weeks after the completion of radiation therapy until they developed disease progression. Patients were evaluated clinically and radiographically at regular intervals. Serum and urine were assayed for biomarkers before each cycle. Quality-of-life (QOL) evaluations were administered at baseline and before every other cycle of therapy to the parents of patients ages 6 to 18 years. RESULTS: Thirty-two patients (median age, 5.3 years; range, 1.8-14.8 years) were enrolled and received a median of 7 cycles of therapy (range, from 1 cycle to ≥70 cycles). PEG-Intron(®) was well tolerated, and no decrease in QOL scores was noted in the subset of patients tested. The 2-year survival rate was 14%, which was not significantly improved compared with the historic cohort. However, the median time to progression was 7.8 months, which compared favorably with recent trials reporting a time to progression of 5 months in a similar population. CONCLUSIONS: Although low-dose PEG-Intron(®) therapy did not significantly improve 2-year survival in children with DIPG compared with an historic control population, it did delay the time to progression.