Artificial intelligence for dementia drug discovery and trials optimization.

Drug discovery and clinical trial design for dementia have historically been challenging. In part these challenges have arisen from patient heterogeneity, length of disease course, and the tractability of a target for the brain. Applying big data analytics and machine learning tools for drug discovery and utilizing them to inform successful clinical trial design has the potential to accelerate progress. Opportunities arise at multiple stages in the therapy pipeline and the growing availability of large medical data sets opens possibilities for big data analyses to answer key questions in clinical and therapeutic challenges. However, before this goal is reached, several challenges need to be overcome and only a multi-disciplinary approach can promote data-driven decision-making to its full potential. Herein we review the current state of machine learning applications to clinical trial design and drug discovery, while presenting opportunities and recommendations that can break down the barriers to implementation.

Artificial intelligence for dementia-Applied models and digital health.

INTRODUCTION: The use of applied modeling in dementia risk prediction, diagnosis, and prognostics will have substantial public health benefits, particularly as "deep phenotyping" cohorts with multi-omics health data become available. METHODS: This narrative review synthesizes understanding of applied models and digital health technologies, in terms of dementia risk prediction, diagnostic discrimination, prognosis, and progression. Machine learning approaches show evidence of improved predictive power compared to standard clinical risk scores in predicting dementia, and the potential to decompose large numbers of variables into relatively few critical predictors. RESULTS: This review focuses on key areas of emerging promise including: emphasis on easier, more transparent data sharing and cohort access; integration of high-throughput biomarker and electronic health record data into modeling; and progressing beyond the primary prediction of dementia to secondary outcomes, for example, treatment response and physical health. DISCUSSION: Such approaches will benefit also from improvements in remote data measurement, whether cognitive (e.g., online), or naturalistic (e.g., watch-based accelerometry).

Artificial intelligence for diagnostic and prognostic neuroimaging in dementia: A systematic review.

INTRODUCTION: Artificial intelligence (AI) and neuroimaging offer new opportunities for diagnosis and prognosis of dementia. METHODS: We systematically reviewed studies reporting AI for neuroimaging in diagnosis and/or prognosis of cognitive neurodegenerative diseases. RESULTS: A total of 255 studies were identified. Most studies relied on the Alzheimer's Disease Neuroimaging Initiative dataset. Algorithmic classifiers were the most commonly used AI method (48%) and discriminative models performed best for differentiating Alzheimer's disease from controls. The accuracy of algorithms varied with the patient cohort, imaging modalities, and stratifiers used. Few studies performed validation in an independent cohort. DISCUSSION: The literature has several methodological limitations including lack of sufficient algorithm development descriptions and standard definitions. We make recommendations to improve model validation including addressing key clinical questions, providing sufficient description of AI methods and validating findings in independent datasets. Collaborative approaches between experts in AI and medicine will help achieve the promising potential of AI tools in practice. HIGHLIGHTS: There has been a rapid expansion in the use of machine learning for diagnosis and prognosis in neurodegenerative disease Most studies (71%) relied on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with no other individual dataset used more than five times There has been a recent rise in the use of more complex discriminative models (e.g., neural networks) that performed better than other classifiers for classification of AD vs healthy controls We make recommendations to address methodological considerations, addressing key clinical questions, and validation We also make recommendations for the field more broadly to standardize outcome measures, address gaps in the literature, and monitor sources of bias.

Simultaneous arsenic and fluoride removal from synthetic and real groundwater by electrocoagulation process: Parametric and cost evaluation.

Co-existence of arsenic and fluoride in groundwater has raised severe health issues to living being. Thus, the present research has been conducted for simultaneous removal of arsenic and fluoride from synthetic groundwater by using electrocoagulation process with aluminum electrode. Effects of initial pH, current density, run time, inter electrode distance and NaCl concentration over percentage removal of arsenic and fluoride as well as operating cost have been studied. The optimum experimental conditions are found to be initial pH: 7, current density: 10 A/m2, run time: 95 min, inter electrode distance: 1 cm, NaCl concentration: 0.71 g/l for removal of 98.51% arsenic (initial concentration: 550 µg/l) and 88.33% fluoride (initial concentration: 12 mg/l). The concentration of arsenic and fluoride in treated water are found to be 8.19 µg/l and 1.4 mg/l, respectively, with an operating cost of 0.357 USD/m3 treated water. Pseudo first and second order kinetic model of individual and simultaneous arsenic and fluoride removal in electrocoagulation have also been studied. Produced sludge characterization studies also confirm the presence of arsenic in As(III) form, and fluoride in sludge. The present electrocoagulation process is able to reduce the arsenic and fluoride concentration of synthetic as well as real groundwater to below 10 µg/l and 1.5 mg/l, respectively, which are maximum contaminant level of these elements in drinking water according to WHO guidelines.

Risk factors for the development of acute lung injury in patients with infectious pneumonia.

INTRODUCTION: Although pneumonia has been identified as the single most common risk factor for acute lung injury (ALI), we have a limited knowledge as to why ALI develops in some patients with pneumonia and not in others. The objective of this study was to determine frequency, risk factors, and outcome of ALI in patients with infectious pneumonia. METHODS: A retrospective cohort study of adult patients with microbiologically positive pneumonia, hospitalized at two Mayo Clinic Rochester hospitals between January 1, 2005, and December 31, 2007. In a subsequent nested case-control analysis, we evaluated the differences in prehospital and intrahospital exposures between patients with and without ALI/acute respiratory distress syndrome (ARDS) matched by specific pathogen, isolation site, gender, and closest age in a 1:1 manner. RESULTS: The study included 596 patients; 365 (61.2%) were men. The median age was 65 (IQR, 53 to 75) years. In total, 171 patients (28.7%) were diagnosed with ALI. The occurrence of ALI was less frequent in bacterial (n = 99 of 412, 24%) compared with viral (n = 19 of 55, 35%), fungal (n = 39 of 95, 41%), and mixed isolates pneumonias (n = 14 of 34, 41%; P = 0.002). After adjusting for baseline severity of illness and comorbidities, patients in whom ALI developed had a markedly increased risk of hospital death (ORadj 9.7; 95% CI, 6.0 to 15.9). In a nested case-control study, presence of shock (OR, 8.9; 95% CI, 2.8 to 45.9), inappropriate initial antimicrobial treatment (OR, 3.2; 95% CI, 1.3 to 8.5), and transfusions (OR, 4.8; 95% CI, 1.5 to 19.6) independently predicted ALI development. CONCLUSIONS: The development of ALI among patients hospitalized with infectious pneumonia varied among pulmonary pathogens and was associated with increased mortality. Inappropriate initial antimicrobial treatment and transfusion predict the development of ALI independent of pathogen.

Severe Bradycardia Leading to Hemodynamic Instability Associated with Remdesivir Use in a Patient with COVID-19 Pneumonia.

Remdesivir (RDV) is an approved treatment for hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There is limited literature on the cardiac adverse effects of RDV. We report a case of a patient who developed hemodynamically unstable bradycardia after the initiation of RDV that resolved after discontinuing RDV.

Long-term survival in patients with tracheostomy and prolonged mechanical ventilation in Olmsted County, Minnesota.

BACKGROUND: An increasing number of patients require prolonged mechanical ventilation (PMV), which is associated with high morbidity and poor long-term survival, but there are few data regarding the incidence and outcome of PMV patients from a community perspective. METHODS: We retrospectively reviewed the electronic medical records of adult Olmsted county, Minnesota, residents admitted to the intensive care units at the 2 Mayo Clinic Rochester hospitals from January 1, 2003, to December 31, 2007, who underwent tracheostomy for PMV. RESULTS: Sixty-five patients, median age 68 years (interquartile range [IQR] 49-80 y), 39 male, underwent tracheostomy for PMV, resulting in an age-adjusted incidence of 13 (95% CI 10-17) per 100,000 patient-years at risk. The median number of days on mechanical ventilation was 24 days (IQR 18-37 d). Forty-six patients (71%) survived to hospital discharge, and 36 (55%) were alive at 1-year follow-up. After adjusting for age and baseline severity of illness, the presence of COPD was independently associated with 1-year mortality (hazard ratio 3.4, 95% CI 1.4-8.2%). CONCLUSIONS: There was a considerable incidence of tracheostomy for PMV. The presence of COPD was an independent predictor of 1-year mortality.

Simultaneous removal of arsenic, fluoride, and manganese from synthetic wastewater by Vetiveria zizanioides.

Main aim of the present research is to explore the potential use of Vetiveria zizanioides L. for phytoremediation of arsenic, fluoride, and manganese simultaneously from synthetic wastewater in a batch scale floating platform unit. Half strength Hoagland's nutrient solution spiked with arsenic, fluoride, and manganese concentrations of 1, 20, and 10 mg/L, respectively has been used. The effects of pH and treatment time on simultaneous removal of arsenic, fluoride, and manganese have been performed. V. zizanioides has exhibited optimum growth at pH 8 and the removal of arsenic and fluoride is observed to be 59.6 and 38.1%, respectively. This plant has successfully removed all of the manganese (99.3%). The uptake of manganese is found to be faster than the arsenic and fluoride. The trend of arsenic, fluoride, and manganese accumulation in various parts of V. zizanioides is found as roots > stems > leaves. Result showed that the use of V. zizanioides would be appropriate to treat arsenic, fluoride, and manganese contaminated wastewater.

Prognostic implications of prior contrast reaction in patients with emergency premedication before undergoing percutaneous coronary intervention.

BACKGROUND: Patients with iodinated contrast material (ICM) adverse reactions are at increased risk for breakthrough reactions. Previous studies suggest that the severity of a prior ICM adverse reaction corresponds to the severity of a repeat reaction. OBJECTIVE: We investigated whether the severity of prior ICM adverse reactions in patients receiving emergency premedication therapy prior to PCI predicts outcomes. METHODS: A retrospective observational study of percutaneous coronary intervention (PCI) encounters between January 1, 2005, and May 30, 2018, was conducted at Geisinger Medical Center. Patients with ICM adverse reactions premedicated with an emergency premedication regimen prior to PCI were included in the study. PCIs were stratified based on the severity of the index ICM adverse reactions; PCIs with a prior severe reaction were compared to PCIs with a prior mild-moderate reaction. RESULTS: We evaluated 604 PCI, of these, 144 (23.8%) had prior severe reactions and 460 (76.2%) had mild-to-moderate reactions. Nine patients had breakthrough reactions, of which seven were of the same or decreased severity in comparison to the index reactions. The overall breakthrough reactions occurred in 1 of 144 patients (0.7%) with an initial severe reaction and in 8 of 460 (1.7%) with an initial mild/moderate reaction (p = 0.69). Outcomes including length of hospital stay and 30-day mortality were similar for PCI with or without severe index ICM reactions. CONCLUSION: Frequency and severity of breakthrough reaction and clinical outcomes in patients treated with emergency premedication regimen prior to PCI were independent of the severity of index ICM reactions.

Ephrin B2/EphB4 pathway in hepatic stellate cells stimulates Erk-dependent VEGF production and sinusoidal endothelial cell recruitment.

Chemotaxis signals between hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC) maintain hepatic vascular homeostasis and integrity and also regulate changes in sinusoidal structure in response to liver injury. Our prior studies have demonstrated that the bidirectional chemotactic signaling molecules EphrinB2 and EphB4 are expressed in HSC. The aim of our present study was to explore whether and how the EphrinB2/EphB4 system in HSC could promote SEC recruitment, which is essential for sinusoidal structure and remodeling. Stimulation of human HSC (hHSC) with chimeric agonists (2 microg/ml) of either EphrinB2 or EphB4 (EphrinB2 Fc or EphB4 Fc, respectively) significantly increased VEGF mRNA levels in hHSC as assessed by quantitative PCR, with respective small interfering RNAs for EphrinB2 and EphB4 inhibiting this increase (P < 0.05, n = 3). EphrinB2 agonist-induced increase in VEGF mRNA levels in hHSC was associated with increased phosphorylation of Erk and was significantly blocked by U0126 (20 microM), an inhibitor of MEK, which is a kinase upstream from Erk (P < 0.05, n = 3). The EphB4 agonist also significantly increased human VEGF promoter activity (P < 0.05, n = 3) as assessed by promoter reporter luciferase assay in transfected LX2-HSC. This was associated with upregulation of the vasculoprotective transcription factor, Kruppel-like factor 2 (KLF2). In Boyden chamber assays, conditioned media from hHSC stimulated with agonists of EphrinB2 or EphB4 increased SEC chemotaxis in a VEGF-dependent manner, compared with control groups that included basal media with agonists of EphrinB2, EphB4, or HSC-conditioned media from HSC in absence of agonist stimulation (P < 0.05, n = 3). EphB4 expression was detected in situ within liver sinusoidal vessels of rats after carbon tetrachloride-induced liver injury. In summary, activation of the EphrinB2/EphB4 signaling pathway in HSC promotes chemotaxis of SEC through a pathway that involves Erk, KLF2, and VEGF. These studies identify EphrinB2 or EphB4 as a key intermediary that links HSC signal transduction pathways with angiogenesis and sinusoidal remodeling.

Towards the prevention of acute lung injury: a population based cohort study protocol.

BACKGROUND: Acute lung injury (ALI) is an example of a critical care syndrome with limited treatment options once the condition is fully established. Despite improved understanding of pathophysiology of ALI, the clinical impact has been limited to improvements in supportive treatment. On the other hand, little has been done on the prevention of ALI. Olmsted County, MN, geographically isolated from other urban areas offers the opportunity to study clinical pathogenesis of ALI in a search for potential prevention targets. METHODS/DESIGN: In this population-based observational cohort study, the investigators identify patients at high risk of ALI using the prediction model applied within the first six hours of hospital admission. Using a validated system-wide electronic surveillance, Olmsted County patients at risk are followed until ALI, death or hospital discharge. Detailed in-hospital (second hit) exposures and meaningful short and long term outcomes (quality-adjusted survival) are compared between ALI cases and high risk controls matched by age, gender and probability of developing ALI. Time sensitive biospecimens are collected for collaborative research studies. Nested case control comparison of 500 patients who developed ALI with 500 matched controls will provide an adequate power to determine significant differences in common hospital exposures and outcomes between the two groups. DISCUSSION: This population-based observational cohort study will identify patients at high risk early in the course of disease, the burden of ALI in the community, and the potential targets for future prevention trials.

Evaluation of Anticoagulation Practice With New-Onset Atrial Fibrillation in Patients with Sepsis and Septic Shock in Medical Intensive Care Unit: A Retrospective Observational Cohort Study.

Objective To investigate the anticoagulation practice in patients presenting with new-onset atrial fibrillation (NOAF) during sepsis and septic shock with one-year follow-up since discharge and to evaluate factors associated with the development of NOAF. Methods A retrospective observational cohort study was conducted using chart review in patients diagnosed with sepsis and septic shock.  Results There was a total of 1132 patients diagnosed with sepsis and septic shock over a one-year period. Thirty-two patients were found to have NOAF in the setting of sepsis. Of this, eight (25%) patients were anticoagulated with warfarin and 14 (44%) patients were not anticoagulated during discharge. At one-year follow-up post-discharge, nine (29%) patients continued on warfarin and 16 (52%) patients remained not anticoagulated. Conclusion We found that the majority of patients who developed NOAF did not get anticoagulated at the time of discharge. A similar trend followed after one year of follow-up. Since proper treatment guidelines are not in place, these patients are at high risk for recurrent atrial fibrillation, stroke, transient ischemic attack, and death.

Pyrolysis of wood sawdust: Effects of process parameters on products yield and characterization of products.

The aim of present research was to study the pyrolysis of wood sawdust in a semi batch reactor and explored the influence of pyrolysis process parameters on the products yield. Pyrolysis process parameters such as temperature, heating rate, nitrogen (N2) flow rate and particle size of wood sawdust were varied as 350-650 °C, 10 and 50 °C/min, 50-200 cm3/min and <0.25 to >1.7 mm, respectively. The maximum bio-oil yield was found as 44.16 wt% at temperature of 500 °C, heating rate of 50 °C/min and nitrogen flow rate of 100 cm3/min for particle size range of 0.6 < dp < 1 mm. The composition and characteristics of bio-oil and bio-char were determined. Different methods such as ultimate analysis, Fourier transformed infrared spectroscopy (FTIR), Gas chromatography-mass spectroscopy (GC-MS), and Nuclear magnetic resonance spectroscopy (1H NMR) were used to characterize bio-oil. Boiling point range of bio-oil was found in between 63 and 360 °C. Bio-char and original biomass were analyzed by physicochemical, thermogravimetric as well as analytical methods using sophisticated instruments such as Field emission scanning electron microscope (FESEM), and X-ray diffractometer (XRD).

The efficacy of self-disinfecting bedrail covers in an intensive care unit.

BACKGROUND: Hospital surfaces are considered important vectors in the spread of nosocomial pathogens. This study evaluated microbial counts on novel antimicrobial bedrail covers over a 2-week period in a critical care environment. METHODS: Disposable bedrail covers (Aionx Inc, Hershey, PA) made of a copper and silver polymer and capable of conducting an imperceptible surface potential, were installed in a case-control manner on a series of occupied intensive care unit beds. Seventeen bedrails were covered with the study bedrail surface, and 17 were left uncovered. Two hundred seventy-two microbial surface cultures were obtained from both study and control bedrails and analyzed for microbial growth by bacterial enumeration and speciation. RESULTS: The bedrails covered with the study surface demonstrated >80% average decrease in colony forming units across the study period of 15 days. CONCLUSIONS: These novel, detachable bedrail covers successfully demonstrated significant bacterial count reduction in an intensive care unit setting. This may have implications for acquisition of hospital-acquired infections.

Palytoxin-induced acute respiratory failure.

Palytoxin is one of the most potent toxins known to mankind and poses a high risk to humans through ingestion, inhalation and dermal routes [1,2]. Although the exact mechanism of action is unknown it is postulated that palytoxin binds to the Na+/K + ATPase pump resulting in K+ efflux, Ca2+ influx and membrane depolarization leading to widespread secondary pharmacological actions [2]. Palytoxin is highly toxic and can affect multiple organs causing severe symptoms including death. Palytoxin poisoning is mainly developed after ingesting seafood. We are reporting a case of suspected inhalational palytoxin poisoning in a healthy healthcare provider from who developed severe respiratory distress within 12 hours of exposure to vapors. We have highlighted diagnostic clues and clinical features in the patients' history that may help intensivists to diagnose a case of ARDS secondary to palytoxin poisoning.

Sequential episodes of ethylene glycol poisoning in the same person.

Ethylene glycol is a common alcohol found in many household products such as household hard surface cleaner, paints, varnish, auto glass cleaner and antifreeze. While extremely toxic and often fatal on ingestion, few cases with early presentation by the patient have resulted in death; thus, rapid diagnosis is paramount to effectively treating ethylene glycol poisoning. In this study, we compare two sequential cases of ethylene glycol poisoning in a single individual, which resulted in strikingly different outcomes.

Acute eosinophilic pneumonia following recent cigarette smoking.

In this report we describe the case of an 18 year old female who presented with fever, shortness of breath, and chest pain. Chest X-ray revealed diffuse bilateral infiltrates and eosinophilia was reported from her broncholaveolar lavage (BAL) fluid. She started smoking 3 weeks prior to the onset of symptoms and based on her clinical presentation, BAL findings and dramatic improvement, acute eosinophilic pneumonia (AEP) was diagnosed.

Preliminary noise reduction efforts in a medical intensive care unit.

Noise is a significant contributor to sleep disruption in the intensive care unit (ICU) that may result in increased patient morbidity such as delirium and prolonged length of stay in ICU. We conducted a pre-post intervention study in a 24-bed tertiary care academic medical ICU to reduce the mean noise levels. Baseline dosimeter recordings of ICU noise levels demonstrated a mean noise level of 54.2 A-weighted decibels (dBA) and peak noise levels of 109.9 dBA, well above the Environmental Protection Agency's recommended levels. There were 1735 episodes of "defects" (maximum noise levels > 60 dBA). Following implementation of multipronged interventions, although the mean noise levels did not change significantly between pre- and post-intervention (54.2 vs 53.8 dBA; p = 0.96), there was a significant reduction in the number of "defects" post-intervention (1735 vs 1289, p ≤ 0.000), and the providers felt that the patients were sleeping longer in the ICU post-intervention.