Clinical outcomes in hospitalized plasma and platelet transfusion recipients prior to and following widespread blood donor SARS-CoV-2 infection and vaccination.

BACKGROUND: The safety of transfusion of SARS-CoV-2 antibodies in high plasma volume blood components to recipients without COVID-19 is not established. We assessed whether transfusion of plasma or platelet products during periods of increasing prevalence of blood donor SARS-CoV-2 infection and vaccination was associated with changes in outcomes in hospitalized patients without COVID-19. METHODS: We conducted a retrospective cohort study of hospitalized adults who received plasma or platelet transfusions at 21 hospitals during pre-COVID-19 (3/1/2018-2/29/2020), COVID-19 pre-vaccine (3/1/2020-2/28/2021), and COVID-19 post-vaccine (3/1/2021-8/31/2022) study periods. We used multivariable logistic regression with generalized estimating equations to adjust for demographics and comorbidities to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 21,750 hospitalizations of 18,584 transfusion recipients without COVID-19, there were 697 post-transfusion thrombotic events, and oxygen requirements were increased in 1751 hospitalizations. Intensive care unit length of stay (n = 11,683) was 3 days (interquartile range 1-5), hospital mortality occurred in 3223 (14.8%), and 30-day rehospitalization in 4144 (23.7%). Comparing the pre-COVID, pre-vaccine and post-vaccine study periods, there were no trends in thromboses (OR 0.9 [95% CI 0.8, 1.1]; p = .22) or oxygen requirements (OR 1.0 [95% CI 0.9, 1.1]; p = .41). In parallel, there were no trends across study periods for ICU length of stay (p = .83), adjusted hospital mortality (OR 1.0 [95% CI 0.9-1.0]; p = .36), or 30-day rehospitalization (p = .29). DISCUSSION: Transfusion of plasma and platelet blood components collected during the pre-vaccine and post-vaccine periods of the COVID-19 pandemic was not associated with increased adverse outcomes in transfusion recipients without COVID-19.

Targeting OXPHOS and the electron transport chain in cancer; Molecular and therapeutic implications.

Oxidative phosphorylation (OXPHOS) takes place in mitochondria and is the process whereby cells use carbon fuels and oxygen to generate ATP. Formerly OXPHOS was thought to be reduced in tumours and that glycolysis was the critical pathway for generation of ATP but it is now clear that OXPHOS, at least in many tumour types, plays a critical role in delivering the bioenergetic and macromolecular anabolic requirements of cancer cells. There is now great interest in targeting the OXPHOS and the electron transport chain for cancer therapy and in this review article we describe current therapeutic approaches and challenges.

Automated Identification of Adults at Risk for In-Hospital Clinical Deterioration.

BACKGROUND: Hospitalized adults whose condition deteriorates while they are in wards (outside the intensive care unit [ICU]) have considerable morbidity and mortality. Early identification of patients at risk for clinical deterioration has relied on manually calculated scores. Outcomes after an automated detection of impending clinical deterioration have not been widely reported. METHODS: On the basis of a validated model that uses information from electronic medical records to identify hospitalized patients at high risk for clinical deterioration (which permits automated, real-time risk-score calculation), we developed an intervention program involving remote monitoring by nurses who reviewed records of patients who had been identified as being at high risk; results of this monitoring were then communicated to rapid-response teams at hospitals. We compared outcomes (including the primary outcome, mortality within 30 days after an alert) among hospitalized patients (excluding those in the ICU) whose condition reached the alert threshold at hospitals where the system was operational (intervention sites, where alerts led to a clinical response) with outcomes among patients at hospitals where the system had not yet been deployed (comparison sites, where a patient's condition would have triggered a clinical response after an alert had the system been operational). Multivariate analyses adjusted for demographic characteristics, severity of illness, and burden of coexisting conditions. RESULTS: The program was deployed in a staggered fashion at 19 hospitals between August 1, 2016, and February 28, 2019. We identified 548,838 non-ICU hospitalizations involving 326,816 patients. A total of 43,949 hospitalizations (involving 35,669 patients) involved a patient whose condition reached the alert threshold; 15,487 hospitalizations were included in the intervention cohort, and 28,462 hospitalizations in the comparison cohort. Mortality within 30 days after an alert was lower in the intervention cohort than in the comparison cohort (adjusted relative risk, 0.84, 95% confidence interval, 0.78 to 0.90; P<0.001). CONCLUSIONS: The use of an automated predictive model to identify high-risk patients for whom interventions by rapid-response teams could be implemented was associated with decreased mortality. (Funded by the Gordon and Betty Moore Foundation and others.).

Safety and Outcomes With Combination Therapy With Sarilumab and Baricitinib for Severe COVID-19 Respiratory Infection in Cancer Patients.

OBJECTIVES: This study aims to describe the clinical outcomes of combination therapy with sarilumab and baricitinib for severe novel Coronavirus-19 (COVID-19) infection in cancer patients. With this study, we aim to evaluate the role of expanded immunotherapy for severely ill patients with COVID-19 respiratory infections with limited options. The secondary objective is to assess the safety of combination therapy with sarilumab and baricitinib for severe COVID-19 infection. METHODS: This was a retrospective cohort study of patients admitted to Moffitt Cancer Center with COVID-19 infection between January 2020 and April 2022. Our research received a waiver to sign consent by the patients according to our institutional IRB because it was free of any risk for the patients and respected the patient's privacy. Following the Institutional IRB approval and relevant Equator guidelines, we collected information on patients with severe COVID-19 infection and received sarilumab and baricitinib. We evaluated the survival rate and safety of combination therapy. All the patient's information was de-identified to protect their information according to Health Insurance Portability and Accountability Act (HIPAA). RESULTS: Four patients were included in the data analysis. Two survived, and two of them died (Table 1). All the patients that survived were previously vaccinated. Among the two patients who died, one was vaccinated, and the other was unvaccinated. All the patients tolerated the combination therapy well, and none of the patients who survived developed secondary infections or COVID-19-associated complications beyond 12 months of discharge. CONCLUSION: Our study explores the potential safe combination use of different immune modulators targeting multiple pathways of the inflammatory cascade for severe and refractory COVID-19 respiratory infections in high-risk oncology patients. The small number of patients in our observational study was a limitation. A larger sample of patients will be needed to conclude more precisely the efficacy of the combination therapy of sarilumab and baricitinib for refractory cases of severe COVID-19 respiratory infection. Moreover, exploring other cytokine release signaling pathway targets may be the key to significantly reducing inflammation and further pulmonary fibrosis with chronic unbearable respiratory sequela.

ExPeCT: a randomised trial examining the impact of exercise on quality of life in men with metastatic prostate cancer.

PURPOSE: All patients living with cancer, including those with metastatic cancer, are encouraged to be physically active. This paper examines the secondary endpoints of an aerobic exercise intervention for men with metastatic prostate cancer. METHODS: ExPeCT (Exercise, Prostate Cancer and Circulating Tumour Cells), was a multi-centre randomised control trial with a 6-month aerobic exercise intervention arm or a standard care control arm. Exercise adherence data was collected via heart rate monitors. Quality of life (FACT-P) and physical activity (self-administered questionnaire) assessments were completed at baseline, at 3 months and at 6 months. RESULTS: A total of 61 patients were included (69.4 ± 7.3 yr, body mass index 29.2 ± 5.8 kg/m2). The median time since diagnosis was 34 months (IQR 7-54). A total of 35 (55%) of participants had > 1 region affected by metastatic disease. No adverse events were reported by participants. There was no effect of exercise on quality of life (Cohen's d = - 0.082). Overall adherence to the supervised sessions was 83% (329 out of 396 possible sessions attended by participants). Overall adherence to the non-supervised home exercise sessions was 72% (months 1-3) and 67% (months 3-6). Modelling results for overall physical activity scores showed no significant main effect for the group (p-value = 0.25) or for time (p-value = 0.24). CONCLUSION: In a group of patients with a high burden of metastatic prostate cancer, a 6-month aerobic exercise intervention did not lead to change in quality of life. Further exercise studies examining the role of exercise for people living with metastatic prostate cancer are needed. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov (NCT02453139) on May 25th 2015.

Adults hospitalized with breakthrough COVID-19 have lower mortality than matched unvaccinated adults.

BACKGROUND: Coronavirus disease 2019 (COVID-19) breakthrough infections are common. OBJECTIVE: Evaluate in-hospital mortality of patients with COVID-19 by vaccination status using retrospective cohort study. METHODS: We generated propensity scores for receipt of full vaccination in adults requiring supplemental oxygen hospitalized at Kaiser Permanente Northern California (1 April 2021 to 30 November 2021) with positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction tests. Optimal matching of fully vaccinated/unvaccinated patients was performed comparing in-hospital mortality. RESULTS: Of 7305 patients, 1463 (20.0%) were full, 138 (1.9%) were partial, and 5704 (78.1%) were unvaccinated. Fully vaccinated were older than partial or unvaccinated (71.0, 63.0, and 54.0 years, respectively, p < 0.001) with more comorbidities (Comorbidity Point Scores 33.0, 22.0, and 10.0, p < 0.001) and immunosuppressant (11.5%, 8.7%, and 3.0%, p < 0.001) or chemotherapy exposure (2.8%, 0.7%, and 0.4%, p < 0.001). Fewer fully vaccinated patients died compared to matched unvaccinated (9.0% vs. 16.3%, p < 0.0001). CONCLUSION: Fully vaccinated patients are less likely to die compared to matched unvaccinated patients.

Unsupervised probabilistic models for sequential Electronic Health Records.

We develop an unsupervised probabilistic model for heterogeneous Electronic Health Record (EHR) data. Utilizing a mixture model formulation, our approach directly models sequences of arbitrary length, such as medications and laboratory results. This allows for subgrouping and incorporation of the dynamics underlying heterogeneous data types. The model consists of a layered set of latent variables that encode underlying structure in the data. These variables represent subject subgroups at the top layer, and unobserved states for sequences in the second layer. We train this model on episodic data from subjects receiving medical care in the Kaiser Permanente Northern California integrated healthcare delivery system. The resulting properties of the trained model generate novel insight from these complex and multifaceted data. In addition, we show how the model can be used to analyze sequences that contribute to assessment of mortality likelihood.

COVID-19 in Immunocompromised Cancer Patients: A Case Series and Review of the Literature.

The global pandemic of the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented newfound challenges to the oncology community regarding management of disease progression in immunocompromised and cancer patients. Further, the large influx of COVID-19 patients has overwhelmed healthcare facilities, limited access to intensive care unit beds and ventilators, and canceled elective surgeries causing disruptions to the cancer care continuum and re-organization of oncological care. While it is known that the potential threat of infection is greatest in elderly patients (>60 years of age) and patients with underlying comorbidities, there is still insufficient data to determine the risk of COVID-19 in cancer patients. Given the immunosuppressive status in cancer patients arising from chemotherapy and other comorbidities, management of COVID-19 in this patient population carries a unique set of challenges. We report three cases of COVID-19 in immunocompromised cancer patients and discuss the challenges in preventing, diagnosing, and treating this vulnerable group.

Preventing the Spread: A Comprehensive Cancer Center's Journey to Prevent the Spread of Coronavirus Disease (Covid-19) During the 2020 Pandemic.

BACKGROUND: On March 11, 2020, the World Health Organization (WHO) declared Coronavirus Disease (COVID-19) a pandemic. Hospitals around the world began to implement infection prevention and control (IPC) measures to stop further spread and prevent infections within their facilities. Healthcare organizations were challenged to develop response plans, procure personal protective equipment (PPE) that was in limited supply while continuing to provide quality, safe care. METHODS: As a comprehensive cancer center with immunocompromised patients, our efforts began immediately. Preventative measures were established and, as of September 2020, over 14,000 patients have been tested within the facility. From March 2020 through September 2020, only one case of hospital acquired (HA) COVID-19 was identified among our patients. Two cases of suspected community acquired (SCA) cases were also identified. Following the Centers for Disease Control (CDC) guidance, IPC measures were implemented within the facility as information science about the virus developed. This article addresses the IPC measures taken, such as enhancing isolation precautions, implementing screening protocols, disinfecting and reusing N95 respirators, by the center throughout the pandemic as well as the challenges that arouse with a new and emerging infectious disease. CONCLUSIONS: The infection control measures implemented at our comprehensive cancer center during the COVID-19 pandemic allowed our center to continue to provide world class cancer care with minimal COVID-19 infection transmission among patients and team members.

Nonstationary multivariate Gaussian processes for electronic health records.

Advances in the modeling and analysis of electronic health records (EHR) have the potential to improve patient risk stratification, leading to better patient outcomes. The modeling of complex temporal relations across the multiple clinical variables inherent in EHR data is largely unexplored. Existing approaches to modeling EHR data often lack the flexibility to handle time-varying correlations across multiple clinical variables, or they are too complex for clinical interpretation. Therefore, we propose a novel nonstationary multivariate Gaussian process model for EHR data to address the aforementioned drawbacks of existing methodologies. Our proposed model is able to capture time-varying scale, correlation and smoothness across multiple clinical variables. We also provide details on two inference approaches: Maximum a posteriori and Hamilton Monte Carlo. Our model is validated on synthetic data and then we demonstrate its effectiveness on EHR data from Kaiser Permanente Division of Research (KPDOR). Finally, we use the KPDOR EHR data to investigate the relationships between a clinical patient risk metric and the latent processes of our proposed model and demonstrate statistically significant correlations between these entities.

The Impact of Pharmacy-specific Predictors on the Performance of 30-Day Readmission Risk Prediction Models.

RESEARCH OBJECTIVE: Pharmacists are an expensive and limited resource in the hospital and outpatient setting. A pharmacist can spend up to 25% of their day planning. Time spent planning is time not spent delivering an intervention. A readmission risk adjustment model has potential to be used as a universal outcome-based prioritization tool to help pharmacists plan their interventions more efficiently. Pharmacy-specific predictors have not been used in the constructs of current readmission risk models. We assessed the impact of adding pharmacy-specific predictors on performance of readmission risk prediction models. STUDY DESIGN: We used an observational retrospective cohort study design to assess whether pharmacy-specific predictors such as an aggregate pharmacy score and drug classes would improve the prediction of 30-day readmission. A model of age, sex, length of stay, and admission category predictors was used as the reference model. We added predictor variables in sequential models to evaluate the incremental effect of additional predictors on the performance of the reference. We used logistic regression to regress the outcomes on predictors in our derivation dataset. We derived and internally validated our models through a 50:50 split validation of our dataset. POPULATION STUDIED: Our study population (n=350,810) was of adult admissions at hospitals in a large integrated health care delivery system. PRINCIPAL FINDINGS: Individually, the aggregate pharmacy score and drug classes caused a nearly identical but moderate increase in model performance over the reference. As a single predictor, the comorbidity burden score caused the greatest increase in model performance when added to the reference. Adding the severity of illness score, comorbidity burden score and the aggregate pharmacy score to the reference caused a cumulative increase in model performance with good discrimination (c statistic, 0.712; Nagelkerke R, 0.112). The best performing model included all predictors: severity of illness score, comorbidity burden score, aggregate pharmacy score, diagnosis groupings, and drug subgroups. CONCLUSIONS: Adding the aggregate pharmacy score to the reference model significantly increased the c statistic but was out-performed by the comorbidity burden score model in predicting readmission. The need for a universal prioritization tool for pharmacists may therefore be potentially met with the comorbidity burden score model. However, the aggregate pharmacy score and drug class models still out-performed current Medicare readmission risk adjustment models. IMPLICATIONS FOR POLICY OR PRACTICE: Pharmacists have a great role in preventing readmission, and therefore can potentially use one of our models: comorbidity burden score model, aggregate pharmacy score model, drug class model or complex model (a combination of all 5 major predictors) to prioritize their interventions while exceeding Medicare performance measures on readmission. The choice of model to use should be based on the availability of these predictors in the health care system.

Secreted factors from metastatic prostate cancer cells stimulate mesenchymal stem cell transition to a pro-tumourigenic 'activated' state that enhances prostate cancer cell migration.

Mesenchymal stem cells (MSCs) are a heterogeneous population of multipotent cells that are capable of differentiating into osteocytes, chondrocytes and adipocytes. Recently, MSCs have been found to home to the tumour site and engraft in the tumour stroma. However, it is not yet known whether they have a tumour promoting or suppressive function. We investigated the interaction between prostate cancer cell lines 22Rv1, DU145 and PC3, and bone marrow-derived MSCs. MSCs were 'educated' for extended periods in prostate cancer cell conditioned media and PC3-educated MSCs were found to be the most responsive with a secretory profile rich in pro-inflammatory cytokines. PC3-educated MSCs secreted increased osteopontin (OPN), interleukin-8 (IL-8) and fibroblast growth factor-2 (FGF-2) and decreased soluble fms-like tyrosine kinase-1 (sFlt-1) compared to untreated MSCs. PC3-educated MSCs showed a reduced migration and proliferation capacity that was dependent on exposure to PC3-conditioned medium. Vimentin and α-smooth muscle actin (αSMA) expression was decreased in PC3-educated MSCs compared to untreated MSCs. PC3 and DU145 education of healthy donor and prostate cancer patient-derived MSCs led to a reduced proportion of FAP+ αSMA+ cells contrary to characteristics commonly associated with cancer associated fibroblasts (CAFs). The migration of PC3 cells was increased toward both PC3-educated and DU145-educated MSCs compared to untreated MSCs, while DU145 migration was only enhanced toward patient-derived MSCs. In summary, MSCs developed an altered phenotype in response to prostate cancer conditioned medium which resulted in increased secretion of pro-inflammatory cytokines, modified functional activity and the chemoattraction of prostate cancer cells.

Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice.

Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR-dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.

Bile duct ligation-induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell-deficient KitW-sh mice.

Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL), increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC-deficient (KitW-sh ) mice. Wild-type (WT) and KitW-sh mice were subjected to sham or BDL for up to 7 days and KitW-sh mice were injected with cultured mast cells or 1× phosphate-buffered saline (PBS) before collecting serum, liver, and cholangiocytes. Liver damage was assessed by hematoxylin and eosin and alanine aminotransferase levels. IBDM was detected by cytokeratin-19 expression and proliferation by Ki-67 immunohistochemistry (IHC). Fibrosis was detected by IHC, hydroxyproline content, and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and transforming growth factor-beta 1 (TGF-ß1) expression/secretion were evaluated. Histidine decarboxylase (HDC) and histamine receptor (HR) expression were detected by qPCR and HA secretion by enzymatic immunoassay. To evaluate vascular cells, von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF)-C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and alpha-smooth muscle actin levels were measured. BDL-induced liver damage was reduced in BDL KitW-sh mice, whereas injection of MCs did not mimic BDL-induced damage. In BDL KitW-sh mice, IBDM, proliferation, HSC activation/fibrosis, and TGF-ß1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL KitW-sh mice. vWF and VEGF-C expression decreased in BDL KitW-sh mice. In KitW-sh mice injected with MCs, IBDM, proliferation, fibrosis, and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or KitW-sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL KitW-sh mice. CONCLUSION: MCs promote hyperplasia, fibrosis, and vascular cell activation. Knockout of MCs decreases BDL-induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies. (Hepatology 2017;65:1991-2004).

Malignancy Trends in HIV-Infected Patients Over the Past 10 Years in a Single-Center Retrospective Observational Study in the United States.

The introduction of antiretroviral therapy (ART) in 1995 had a dramatic impact on the morbidity and mortality of the HIV population, and subsequently, the natural history of cancer has changed. The purpose of our study was to review the prevalence of AIDS-defining malignancies and non-AIDS defining cancers (NADC), taking into consideration racial and gender variations. After the institutional review board approval, the study was conducted as a retrospective chart review of 279 HIV-infected patients who were treated at the Moffitt Cancer Center between January 1, 2000 and December 31, 2010. The demographic characteristics included gender, ethnicity, race, presence or absence of ART, and the type of malignancy reviewed. Of 233 men, 78 (33.5%) had AIDS-defining malignancies. AIDS-related non-Hodgkin lymphoma (NHL) was detected in 49 (21%) patients and Kaposi sarcoma (KS) in 29 (12%) patients. Two-thirds of male patients had NADC, with anal cancer being the most prevalent (8.5%), followed by Hodgkin lymphoma (6%). AIDS-related NHL was also the predominant malignancy for women with a prevalence of 19.5% followed by invasive cervical cancer (ICC) and breast cancer, both with a similar prevalence of 11%. Kaposi sarcoma and anal cancer were equally detected in 2% of women. The prevalence rates of AIDS-defining malignancies among those of white race were 34%, ranging from 21% for NHL to 13% for KS and 1.5% for ICC. Twenty-one (7.7%) patients had anal cancer. AIDS-defining malignancies were found in 36% of patients of black race and 60% had NHL. Non-AIDS-related NHL was the second most common malignancy, followed by breast cancer and anal cancer with a similar prevalence of 6.5%. Of 279 patients, 53% were taking ART; 39.4% were not taking ART; and in 7.5% of the patients, it was unknown if they were taking ART. In the ART era, our study found NADC to be more prevalent than AIDS-defining malignancies with 60% versus 40%, respectively. Non-Hodgkin lymphoma remained the most common AIDS-related malignancy in both genders. Among the patients with NADC, anal cancer was the predominant malignancy. The increasing incidence of some of the NADC is expected as this population is living longer with chronic exposure of viral replication of virus with oncogenic potential such as Human papillomavirus (HPV), Hepatitis B virus (HBV), Epstein-Barr virus (EBV), and Human herpesvirus 8 (HHV-8). Early ART initiation, aggressive vaccination, and judicious cancer screening are the cornerstone of cancer prevention of this growing population.

Flexible, cluster-based analysis of the electronic medical record of sepsis with composite mixture models.

The widespread adoption of electronic medical records (EMRs) in healthcare has provided vast new amounts of data for statistical machine learning researchers in their efforts to model and predict patient health status, potentially enabling novel advances in treatment. In the case of sepsis, a debilitating, dysregulated host response to infection, extracting subtle, uncataloged clinical phenotypes from the EMR with statistical machine learning methods has the potential to impact patient diagnosis and treatment early in the course of their hospitalization. However, there are significant barriers that must be overcome to extract these insights from EMR data. First, EMR datasets consist of both static and dynamic observations of discrete and continuous-valued variables, many of which may be missing, precluding the application of standard multivariate analysis techniques. Second, clinical populations observed via EMRs and relevant to the study and management of conditions like sepsis are often heterogeneous; properly accounting for this heterogeneity is critical. Here, we describe an unsupervised, probabilistic framework called a composite mixture model that can simultaneously accommodate the wide variety of observations frequently observed in EMR datasets, characterize heterogeneous clinical populations, and handle missing observations. We demonstrate the efficacy of our approach on a large-scale sepsis cohort, developing novel techniques built on our model-based clusters to track patient mortality risk over time and identify physiological trends and distinct subgroups of the dataset associated with elevated risk of mortality during hospitalization.

The Timing of Early Antibiotics and Hospital Mortality in Sepsis.

RATIONALE: Prior sepsis studies evaluating antibiotic timing have shown mixed results. OBJECTIVES: To evaluate the association between antibiotic timing and mortality among patients with sepsis receiving antibiotics within 6 hours of emergency department registration. METHODS: Retrospective study of 35,000 randomly selected inpatients with sepsis treated at 21 emergency departments between 2010 and 2013 in Northern California. The primary exposure was antibiotics given within 6 hours of emergency department registration. The primary outcome was adjusted in-hospital mortality. We used detailed physiologic data to quantify severity of illness within 1 hour of registration and logistic regression to estimate the odds of hospital mortality based on antibiotic timing and patient factors. MEASUREMENTS AND MAIN RESULTS: The median time to antibiotic administration was 2.1 hours (interquartile range, 1.4-3.1 h). The adjusted odds ratio for hospital mortality based on each hour of delay in antibiotics after registration was 1.09 (95% confidence interval [CI], 1.05-1.13) for each elapsed hour between registration and antibiotic administration. The increase in absolute mortality associated with an hour's delay in antibiotic administration was 0.3% (95% CI, 0.01-0.6%; P = 0.04) for sepsis, 0.4% (95% CI, 0.1-0.8%; P = 0.02) for severe sepsis, and 1.8% (95% CI, 0.8-3.0%; P = 0.001) for shock. CONCLUSIONS: In a large, contemporary, and multicenter sample of patients with sepsis in the emergency department, hourly delays in antibiotic administration were associated with increased odds of hospital mortality even among patients who received antibiotics within 6 hours. The odds increased within each sepsis severity strata, and the increased odds of mortality were greatest in septic shock.

Risk Adjustment for Hospital Characteristics Reduces Unexplained Hospital Variation in Pressure Injury Risk.

BACKGROUND: Research investigating risk factors for hospital-acquired pressure injury (HAPI) has primarily focused on the characteristics of patients and nursing staff. Limited data are available on the association of hospital characteristics with HAPI. OBJECTIVE: We aimed to quantify the association of hospital characteristics with HAPI and their effect on residual hospital variation in HAPI risk. METHODS: We employed a retrospective cohort study design with split validation using hierarchical survival analysis. This study extends the analysis "Hospital-Acquired Pressure Injury (HAPI): Risk Adjusted Comparisons in an Integrated Healthcare Delivery System" by Rondinelli et al. (2018) to include hospital-level factors. We analyzed 1,661 HAPI episodes among 728,266 adult hospitalization episodes across 35 California Kaiser Permanente hospitals, an integrated healthcare delivery system between January 1, 2013, and June 30, 2015. RESULTS: After adjusting for patient-level and hospital-level variables, 2 out of 12 candidate hospital variables were statistically significant predictors of HAPI. The hazard for HAPI decreased by 4.8% for every 0.1% increase in a hospital's mean mortality ([6.3%, 2.6%], p < .001), whereas every 1% increase in a hospital's proportion of patients with a history of diabetes increased HAPI hazard by 5% ([-0.04%, 10.0%], p = .072). Addition of these hierarchical variables decreased unexplained hospital variation of HAPI risk by 35%. DISCUSSION: We found hospitals with higher patient mortality had lower HAPI risk. Higher patient mortality may decrease the pool of patients who live to HAPI occurrence. Such hospitals may also provide more resources (specialty staff) to care for frail patient populations. Future research should aim to combine hospital data sets to overcome power limitations at the hospital level and should investigate additional measures of structure and process related to HAPI care.

Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin.

Giant axonal neuropathy (GAN) is a progressive neurodegenerative disease caused by autosomal recessive mutations in the GAN gene resulting in a loss of a ubiquitously expressed protein, gigaxonin. Gene replacement therapy is a promising strategy for treatment of the disease; however, the effectiveness and safety of gigaxonin reintroduction have not been tested in human GAN nerve cells. Here we report the derivation of induced pluripotent stem cells (iPSCs) from three GAN patients with different GAN mutations. Motor neurons differentiated from GAN iPSCs exhibit accumulation of neurofilament (NF-L) and peripherin (PRPH) protein and formation of PRPH aggregates, the key pathological phenotypes observed in patients. Introduction of gigaxonin either using a lentiviral vector or as a stable transgene resulted in normalization of NEFL and PRPH levels in GAN neurons and disappearance of PRPH aggregates. Importantly, overexpression of gigaxonin had no adverse effect on survival of GAN neurons, supporting the feasibility of gene replacement therapy. Our findings demonstrate that GAN iPSCs provide a novel model for studying human GAN neuropathologies and for the development and testing of new therapies in relevant cell types.

Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats.

Melatonin is a hormone produced by the pineal gland with increased circulating levels shown to inhibit biliary hyperplasia and fibrosis during cholestatic liver injury. Melatonin also has the capability to suppress the release of hypothalamic gonadotropin-releasing hormone (GnRH), a hormone that promotes cholangiocyte proliferation when serum levels are elevated. However, the interplay and contribution of neural melatonin and GnRH to cholangiocyte proliferation and fibrosis in bile duct-ligated (BDL) rats have not been investigated. To test this, cranial levels of melatonin were increased by implanting osmotic minipumps that performed an intracerebroventricular (ICV) infusion of melatonin or saline for 7 days starting at the time of BDL. Hypothalamic GnRH mRNA and cholangiocyte secretion of GnRH and melatonin were assessed. Cholangiocyte proliferation and fibrosis were measured. Primary human hepatic stellate cells (HSCs) were treated with cholangiocyte supernatants, GnRH, or the GnRH receptor antagonist cetrorelix acetate, and cell proliferation and fibrosis gene expression were assessed. Melatonin infusion reduced hypothalamic GnRH mRNA expression and led to decreased GnRH and increased melatonin secretion from cholangiocytes. Infusion of melatonin was found to reduce hepatic injury, cholangiocyte proliferation, and fibrosis during BDL-induced liver injury. HSCs supplemented with BDL cholangiocyte supernatant had increased proliferation, and this increase was reversed when HSCs were supplemented with supernatants from melatonin-infused rats. GnRH stimulated fibrosis gene expression in HSCs, and this was reversed by cetrorelix acetate cotreatment. Increasing bioavailability of melatonin in the brain may improve outcomes during cholestatic liver disease.NEW & NOTEWORTHY We have previously demonstrated that GnRH is expressed in cholangiocytes and promotes their proliferation during cholestasis. In addition, dark therapy, which increases melatonin, reduced cholangiocyte proliferation and fibrosis during cholestasis. This study expands these findings by investigating neural GnRH regulation by melatonin during BDL-induced cholestasis by infusing melatonin into the brain. Melatonin infusion reduced cholangiocyte proliferation and fibrosis, and these effects are due to GNRH receptor 1-dependent paracrine signaling between cholangiocytes and hepatic stellate cells.