bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety Summary of the Selective Cytopheretic Device: A Review of Safety Data Across Multiple Clinical Trials in ICU Patients With Acute Kidney Injury and Multiple Organ Failure
Authors: Humes H. David , Goldstein Stuart L. , Yessayan Lenar T. , Catanzaro David A. , Scribe Emily C. , Iyer Sai Prasad N. , Chung Kevin K.
Published: October 2023

OBJECTIVES:

Acute kidney injury (AKI) requiring continuous kidney replacement therapy is a significant complication in ICU patients with mortality rates exceeding 50%. A dysregulated immune response can lead to systemic inflammation caused by hyperactivity of pro-inflammatory neutrophils and monocytes leading to tissue damage. The selective cytopheretic device (SCD) is an investigational medical device in a new class of cell-directed extracorporeal therapies distinct from cytokine adsorbers or filters, as it targets activated leukocytes. These leukocytes are the cellular sources driving this hyperinflammatory process. The objective of this report is to summarize the safety experience from clinical studies of the SCD in ICU patients with AKI or acute respiratory distress syndrome (ARDS) and multiple organ dysfunction (MOD).

DATA SOURCES AND STUDY SELECTION:

The studies included in this report represent all relevant trials of the SCD conducted in patients with AKI or ARDS and MOD. Adverse event data, clinical laboratory data and mortality rates were described and summarized in this report.

DATA EXTRACTION AND DATA SYNTHESIS:

Five clinical studies were included in this report, including four adult studies of AKI and/or ARDS and one pediatric AKI study, which involved 151 patients treated with the SCD in an ICU setting. Over 800 SCD sessions were deployed with an estimated 19,000 exposure hours with no device-related infections or attributable serious adverse events. Furthermore, there were no safety signals of leukopenia, thrombocytopenia, or other indications of immunodepletion or immunosuppression.

CONCLUSIONS:

The SCD has shown to be a promising extracorporeal therapy with promising clinical results and a favorable safety profile. These studies support that the SCD can be added as a therapeutic intervention in critically ill AKI patient populations with multiple organ failure without adding additional safety risks.
Delirium During Critical Illness and Subsequent Change of Treatment in Patients With Cancer: A Mediation Analysis*
Authors: Vizzacchi Bárbara A. , Dettino Aldo L. A. , Besen Bruno A. M. P. , Caruso Pedro , Nassar Antonio P.
Published: October 2023

OBJECTIVES:

To assess whether delirium during ICU stay is associated with subsequent change in treatment of cancer after discharge.

DESIGN:

Retrospective cohort study.

SETTING:

A 50-bed ICU in a dedicated cancer center.

PATIENTS:

Patients greater than or equal to 18 years old with a previous proposal of cancer treatment (chemotherapy, target therapy, hormone therapy, immunotherapy, radiotherapy, oncologic surgery, and bone marrow transplantation).

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We considered delirium present if Confusion Assessment Method for the ICU was positive. We assessed the association between delirium and modification of the treatment after discharge. We also performed a mediation analysis to assess both the direct and indirect (i.e., mediated by the development of functional dependence after discharge) of delirium on modification of cancer treatment and whether the modification of cancer treatment was associated with mortality at 1 year. We included 1,134 patients, of whom, 189 (16.7%) had delirium. Delirium was associated with the change in cancer treatment (adjusted odds ratio [OR], 3.80; 95% CI, 2.72–5.35). The association between delirium in ICU and change of treatment was both direct and mediated by the development of functional dependence after discharge. The proportion of the total effect of delirium on change of treatment mediated by the development of functional dependence after discharge was 33.0% (95% CI, 21.7–46.0%). Change in treatment was associated with increased mortality at 1 year (adjusted OR, 2.68; 95% CI, 2.01–3.60).

CONCLUSIONS:

Patients who had delirium during ICU stay had a higher rate of modification of cancer treatment after discharge. The effect of delirium on change in cancer treatment was only partially mediated by the development of functional dependence after discharge. Change in cancer treatment was associated with increased 1-year mortality.
Introducing DEPDOSE, a Tool to Calculate Dose Coefficients to Members of the Public for Radioactive Aerosols
Authors: Klumpp John , Bertelli Luiz , Eckerman Keith , Nelson Matthew , Wedell Liam , Deshler Mina , Brambilla Sara , Brown Michael
Published: October 2023

This paper presents DEPDOSE, an open-source computer application that combines the KDEP respiratory tract deposition fractions for inhaled aerosols with DC_PAK committed equivalent dose coefficients for a unit deposition in each region of the respiratory tract. DEPDOSE allows the user to rapidly produce tables of dose coefficients for workers and members of the public inhaling precisely defined, user-specified aerosols using the ICRP Publication 60 methodology. Combined with a plume dispersion modeling system, such as the Quick Urban & Industrial Complex (QUIC) Dispersion Modeling System, this makes it possible to predict radiation doses downstream from an accidental or intentional release of radioactive materials. For this work, a radioactive plume was calculated to members of the public downstream from a dirty bomb in Chicago. DEPDOSE is published under an open source license, and can be downloaded at https://github.com/lanl/DEPDOSE.
Risk Factors and Frequency of Examinations for Detecting Visual Field Deterioration in Patients with Newly Diagnosed Exfoliation Glaucoma in Sweden
Authors: Ayala Marcelo
Published: October 2023

Précis:

The study identified risk factors for exfoliation glaucoma and recommended re-evaluating target intraocular pressure (IOP) after 5 visual fields to slow disease progression.

Purpose:

This study aimed to establish risk factors for exfoliation glaucoma and determine the earliest time points for estimating disease progression.

Patients:

A total of 96 patients with newly diagnosed exfoliation glaucoma were included. Included patients were required to perform at least 7 visual field tests within a 3-year period (±3 months). All patients were treated at inclusion.

Methods:

This was a nonrandomized, prospective cohort study. The predictors measured included IOP, mean deviation (MD), and visual field index (VFI). Progression was assessed using the rate of progression based on MD, VFI, and “Guided Progression Analysis.” Linear or logistic regression models were developed based on the variables studied. An analysis of variance was used to establish the earliest time point. At the earliest time point, the models were retested. The area under the receiver operating characteristic curve was calculated.

Results:

The general rate of progression of the cohort was −3.84 (±2.61) dB for the MD values and 9.66 (±6.25) % for the VFI values over 3 years. The IOP, MD, and VFI values at diagnosis were predictors of progression for both linear and logistic regression. Analysis of variance and post hoc Tukey test showed significant values at 24 months for MD and VFI. The area under the curve at 24 months showed significant values for MD and VFI.

Conclusions:

The predictors studied (IOP, MD, and VFI) showed moderate accuracy at baseline but excellent predictive capacity at 24 months postdiagnosis. Re-evaluating the target IOP at 24 months can effectively slow down disease progression.
Omidenepag Isopropyl in Latanoprost Low/Nonresponders With Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 3, Nonrandomized, Two-Phase, Open-Label Study
Authors: Panarelli Joseph F. , Bowden Eileen C. , Tepedino Michael E. , Odani-Kawabata Noriko , Pei Zifan , McLaurin Eugene B. , Ropo Auli
Published: October 2023

Précis:

This study demonstrates the efficacy and safety of once-daily 0.002% omidenepag isopropyl (OMDI) in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT) who do not respond or respond poorly to latanoprost.

Purpose:

The purpose of this study was to evaluate the intraocular pressure (IOP)-lowering efficacy and safety of OMDI in latanoprost low/nonresponders with POAG or OHT.

Materials and Methods:

Phase 3, nonrandomized, 2-phase, open-label, multicenter study (NCT03697811) in the United States. Key inclusion criteria included individuals aged 18 years or above, POAG or OHT diagnosis in both eyes, IOP ≥22 mm Hg in ≥1 eye, and ≤34 mm Hg in both eyes at all time points. Overall, 107 patients were enrolled; 104 completed treatment. Included a screening period (≤35-day washout period and 8-week latanoprost run-in period) and a 3-month treatment period comprising one drop of OMDI 0.002% once daily in both eyes. The primary study endpoint was changed from baseline in the mean diurnal (MD) IOP at month 3. Safety endpoints included incidence of adverse events, serious adverse events, and adverse drug reactions.

Results:

At baseline (visit 4), 75 (70.1%) patients had POAG, 32 (29.9%) had OHT, and 68 (63.6%) had prior use of prostaglandin/prostaglandin analogs (37.4% of whom used latanoprost). The mean (SD) baseline MD IOP was 23.34 mm Hg (2.12). The mean (SD) 3-month (visit 7) MD IOP change from baseline (following latanoprost run-in period and OMDI treatment period) was an additional decrease of 2.96 mm Hg (2.83) (P<0.0001). No significant safety issues were reported during OMDI treatment.

Conclusions:

These data demonstrate OMDI efficacy and safety in latanoprost low/nonresponders with POAG or OHT, suggesting OMDI is a treatment option in the patient population in this study.
Microscopic analysis of preinsertion cutting modalities on custom, flexible iris prostheses
Authors: Snyder Michael E. , Leone Adam R. , Werner Liliana , Bundogji Nour , Hawn Vivian
Published: October 2023

Purpose:

To determine the induced edge effects of different clinically used device postmanufacture modification styles and modalities on custom iris implants.

Settings:

An academically affiliated multispecialty private practice group and an academic medical center.

Design:

Laboratory study.

Methods:

Sample custom iris prostheses were cut using patterns, blades, and surgical instruments described in the literature. The cut edges were evaluated with slitlamp microscopy, light microscopy, and scanning electron microscopy.

Results:

Disposable blades yielded smoother cuts than scissors. Trephine blade brand significantly affected the cut surface smoothness of the silicone matrix. Meshwork-embedded prostheses had some irregular sharp edges where the mesh fibers were cut with all modalities, although these were worse with scissors and one tested trephine brand compared with the other. Pseudoiridectomies and scissor cuts created sharp points and corners in the device periphery.

Conclusions:

Postmanufacture modifications of iris implants should be minimized. The cut margins of the fiber-free implants have fewer sharp edges and may be preferable for sulcus placement. In-the-bag device placement may mitigate clinical impact of sharp edges and corners. These practices may help to minimize inflammatory sequelae postimplantation.
Stress at Work and Well-being Before and During the COVID-19 Pandemic
Authors: Galliker Sibylle , Igic Ivana , Semmer Norbert K. , Elfering Achim
Published: October 2023

Objective

The aim of the study is to analyze the development of conditions at work and health-related variables (notably exhaustion) in Switzerland longitudinally before and during the COVID-19 pandemic.

Methods

Questionnaire data were collected from a population-based sample of 1,553 employees in February 2020 and 1 year later. Health and well-being associated with (a) working conditions in general and (b) COVID-19–specific predictors such as worries about being infected and conditions for working at home were analyzed using analysis of (co)variance and multiple regression.

Results

Conditions at work and well-being were stable overall, even indicating slight improvements, notably for men compared with women. Both an index representing stressors and resources at work in general (Job Stress Index) and a COVID-19–related demand index showed consistent effects on health and the effect of COVID-19–related demands was stronger if the Job Stress Index deteriorated than when it improved.
Outcomes of a Vial-Sparing Antithrombin III Protocol in Pediatric Extracorporeal Membrane Oxygenation
Authors: Young McKenzie R. , Hovey Sara W. , Hollis Taemyn K. , Simpson Mindy L. , Bak Erica , Kalinowski Valerie , Jacobson Jessica L.
Published: October 2023

Exogenous antithrombin III (AT3) may be administered to pediatric patients supported by extracorporeal membrane oxygenation (ECMO) to achieve a greater systemic response to heparin. Antithrombin III administration and dosing practices vary between ECMO centers. This study compared the outcomes of two different AT3 replacement protocols used by a single pediatric ECMO center for 47 patients between December 2013 and August 2021. In May 2016, a weight-based continuous infusion protocol (WBP) was transitioned to a vial-sparing protocol (VSP) as a cost-saving measure. No difference was observed in the percentage of heparin monitoring levels within goal range, with a median of 56.5% therapeutic levels on the WBP compared with a median of 60.7% on the VSP (p = 0.170). No significant differences were observed in amount of exogenous blood products administered, number of hemorrhagic or thrombotic events, number of mechanical failures, or number of circuit changes required. The VSP resulted in fewer AT3 dispenses (p < 0.001) and units dispensed (p = 0.005), resulting in a significant median cost reduction from $15,610.62 on the WBP to $7,765.56 on the VSP (p = 0.005). A vial-sparing AT3 replacement protocol resulted in significant cost savings with similar efficacy and safety outcomes.
The Acceptability, Feasibility, and Preliminary Effectiveness of a Courier HIV-Treatment Delivery and SMS Support Intervention for Young People Living With HIV in South Africa
Authors: Giovenco Danielle , Pettifor Audrey , Qayiya Yamkela , Jones Jeb , Bekker Linda-Gail
Published: October 2023

Background:

Young people living with HIV (YPLWH) experience poorer rates of virological suppression compared with adults. Differentiated service delivery models for YPLWH are urgently needed to address this disparity.

Setting:

Participants were recruited from an HIV treatment clinic near Cape Town, South Africa.

Methods:

We conducted a longitudinal pilot study to examine the acceptability, feasibility, and preliminary effectiveness of a courier ART delivery and SMS support intervention to retain YPLWH (13–24 years) in care during COVID-19. YPLWH had the option to enroll in the courier service and were randomized 1:1 to receive adherence support via a weekly SMS. Modified Poisson regression was used to estimate the preliminary effectiveness of the courier intervention on viral suppression (HIV-1 RNA <200 copies/mL) at months 3 and 6.

Results:

Among 215 participants, 82% elected to enroll in the courier ART service at baseline, 41% reported receiving a delivery in the past 3 months at month 3, and 49% reported receiving a delivery in the past 3 months at month 6. Among those who received a delivery, most (91%–100%) rated the intervention as acceptable. Participants who reported receiving a delivery in the past 3 months at month 3 were 1.26 (95% CI: 1.05, 1.54) times as likely to have a suppressed viral load at month 3 and 1.21 (0.99, 1.48) times as likely at month 6, controlling for potential confounders.

Conclusions:

Findings reveal high uptake and acceptability of a courier ART delivery intervention among YPLWH and promising evidence for its effectiveness in increasing the probability of viral suppression. A fully powered trial is warranted.
Navigating Food and Drug Administration Mandated Breast Implant Patient Literature
Authors: Boyd Louisa C. , Kareh Aurora M. , Rodby Katherine A.
Published: October 2023

Objectives

In October 2021, the US Food and Drug Administration mandated patient decision checklists and new labeling for breast implants with the goal of improving the informed decision-making process for patients considering breast implantation. Given growing concerns over breast implant–associated anaplastic large cell lymphoma, breast implant–associated squamous cell carcinoma, and breast implant illness, patients should be able to easily review these resources to make a fully informed decision when considering surgery. This study seeks to elucidate the accessibility, and therefore the utility of the newly mandated literature for the average breast implant patient.

Methods

Patient decision checklists and breast implant boxed warnings were obtained from the most used breast implant manufacturers in the United States—Allergan, Mentor, and Sientra. Readability analysis of all Food and Drug Administration required documents was performed using the Flesch Reading Ease Score, Flesch Kincaid Grade Level, Gunning-Fog Index, Coleman-Liau Index, Simplified Measure of Gobbledygook, and Automated Readability Index.

Results

The overall readability of all Allergan, Mentor, and Sientra patient materials correlates with a college reading level. Documents from all 3 implant manufacturers were of a statistically significantly higher reading level than that recommended by the American Medical Association and US Department of Health and Human Services. No materials were found to be at or below the recommended sixth-grade level.

Conclusions

The newly mandated breast implant patient decision guides are written at a college reading level. These materials should be simplified to improve health literacy shared decision making.
A Retrospective Review of Laser Therapy for Treatment of Hidradenitis Suppurativa
Authors: Fortoul Marla C. , Macias Martinez Brian , Ventura Rodriguez Darisel , Dallara Marissa , Stelnicki Eric J. , Kamel George
Published: October 2023

Purpose

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful and foul-smelling cystic nodules and sinus tracts in the apocrine gland-bearing regions. The treatment options include topical, intralesional, systemic, and surgical modalities. Currently, the most novel therapy is laser therapy to provide localized treatment without systemic adverse effects. However, data regarding patient outcomes after laser treatment are limited because of the low prevalence of this disease. This study aimed to evaluate the efficacy of laser therapy as a treatment modality for patients with HS.

Methods

A retrospective review cohort analysis of patients with HS undergoing laser treatment between 2016 and 2021 was conducted. Patient demographics, lesion location(s), Hurley stage, age of onset and diagnosis, treatment length, type, outcomes, and complications were analyzed.

Results

Ninety-four patients met the inclusion criteria; on average, patients were treated with 5.8 laser sessions for 14.8 months with no complications and minor blood loss. Hidradenitis suppurativa progression commonly starts during puberty, with a median onset of 13.8 years and diagnosis of HS at 16.2 years. All patients (n = 94) showed an improvement in HS disease severity: 59.6% completed treatment, 12.0% are currently undergoing treatment, and 26.0% were lost to follow-up.

Conclusions

Laser therapy is an effective and safe therapy for HS leading to improved quality of life and should be considered in the treatment and management of HS.
Facial Masculinization Surgery
Authors: Hoffman Alexandra F. , Laspro Matteo , Verzella Alexandra N. , Tran David L. , Rodriguez Eduardo D.
Published: October 2023

Introduction

Facial masculinization surgery (FMS) is increasingly popular among cisgender and transgender men. The benefits of FMS are focused on facial identity and have been proven to decrease gender dysphoria in this population. Previous research showed increasing interest in gender affirmation surgery and facial feminization surgery, but the prevalence of FMS has not been explored. It is difficult to find these data based on surgical records alone because institutions do not have standardized methods of reporting and lack publications in the field. Our study aimed to analyze public interest in FMS by using worldwide Google Trends to quantify these trends.

Methods

A worldwide Google Trends search was completed from January 1, 2008, to December 31, 2022, for terms focused on FMS. Then, search terms were analyzed for nonfacial masculinization procedures and were aggregated. Lastly, a PubMed search was conducted for the terms “transgender” and “facial masculinization” from January 1, 2008, to December 31st, 2022, to compare publication rates.

Results

Our data showed an increasing interest in FMS through Google search trends since the year 2008. A similar trend was demonstrated for non-FMS gender-affirming terms. PubMed analysis showed “transgender” medicine publishing rates were approximately 39.65 times greater than “facial masculinization” publishing rates, although “facial masculinization” medicine did produce a positive trend over the study period of approximately 4 publications per year. The medical literature on transgender surgeries rapidly outpaces publications specifically focusing on FMS.

Conclusion

Our study showed increasing interest in gender affirmation surgery over time, particularly FMS. These increasing trends should encourage greater scientific exploration of FMS and research to properly quantify and assess surgical outcomes in this special population. Additional educational interventions for both the general public and medical providers, to increase awareness of unique challenges that impact this community and highlight changes in health care coverage over time, should be created to keep pace with increasing patient demand and address the physical, systemic, and psychosocial issues faced by people who identify as transgender.
Ventilator-associated pneumonia due to Aeromonas hydrophila: A rare case report
Authors: Srivastava Amit , Tripathy Sarvodaya , Gutte Shreyas , Sahu Chinmoy , Gurjar Mohan , Patel Sangram Singh
Published: October 2023

Introduction.

Aeromonas hydrophila

is an opportunistic pathogen that can cause various infections, including pneumonia, in immunocompromised individuals. This case report presents a rare occurrence of ventilator-associated pneumonia (VAP) caused by

Aeromonas hydrophila

in an apparently non-immunocompromised patient.

Case presentation. The patient exhibited signs and symptoms of VAP and was successfully treated with intravenous ciprofloxacin. The discussion highlights the characteristics of

Aeromonas

species, its virulence factors, risk factors for infection, and antibiotic profile.

Conclusion. It emphasizes the need for awareness and suspicion of

Aeromonas

as a potential cause of VAP in ICU settings, as well as the importance of early detection and appropriate treatment for improved outcomes.
Lelliottia amnigena recovered from the lung of a harbour porpoise, and comparative analyses with Lelliottia spp.
Authors: Negus David , Foster Geoffrey , Hoyles Lesley
Published: October 2023

Strain M1325/93/1 (= GFKo1) of Lelliottia amnigena was isolated from the lung of a harbour porpoise in 1993. The genome sequence and antimicrobial resistance profile (genomic, phenotypic) of the strain were generated, with the genomic data compared with those from closely related bacteria. We demonstrate the recently described chromosomally-encoded AmpC β-lactamase blaLAQ is a core gene of L. amnigena, and suggest new variants of this class of lactamase are encoded by other members of the genus Lelliottia. Although presence of blaLAQ is ubiquitous across the currently sequenced members of L. amnigena, we highlight that strain GFKo1 is sensitive to ampicillin and cephalosporins. These data suggest blaLAQ may act as a useful genetic marker for identification of L. amnigena strains, but its presence may not correlate with expected phenotypic resistances. Further studies are required to determine the regulatory mechanisms of blaLAQ in L. amnigena.
XAV-19 a Glyco-Humanized polyclonal antibody targeting SARS-CoV-2 accelerates the recovery of mild to moderate COVID-19 patients and keeps its neutralizing activity against Omicron and its subvariants
Authors: Poulakou Garyfallia , Royer Pierre-Joseph , Evgeniev Nikolai , Evanno Gwénaëlle , Shneiker Françoise , Vanhove Bernard , Duvaux Odile , Marot Stéphane , Calvez Vincent
Published: October 2023

Background

XAV-19 is a glyco-humanized swine polyclonal antibody targeting SARS-CoV-2. The safety and clinical efficacy of XAV-19 was investigated in patients with a WHO score of 2 to 4 in the WHO 7-point ordinal scale. The activity of XAV-19 against Omicron and its subvariants was assessedin vitro.

Methods

A phase II/III, multicentric randomized double-blind placebo-controlled, clinical trial was conducted to evaluate the safety and clinical efficacy of XAV-19 in inpatients with COVID-19 requiring or not oxygen therapy and outpatients not requiring oxygen (EUROXAV trial,NCT04928430). Most patients were not vaccinated. The primary endpoint was the proportion of patients with an aggravation of COVID-19 within 8 days after treatment. Binding and neutralization of Omicron or its subvariants by XAV-19 was investigated by ELISA or with a whole virus neutralization assay.

Results

Patients received either 150mg of XAV-19 (N=139) or placebo (N=140). Low enrolment forced the premature trial termination. XAV-19 was well tolerated. No difference in the primary endpoint, nor in the proportion with an improvement at day 8 (secondary endpoint) was observed between the 2 groups. For patients not requiring oxygen therapy, XAV-19 reduced the time to improvement significantly (7 daysvs14 days p=0.0159). Neutralizing activity against Omicron and BA.2, BA2.12.1, BA.4/5 and BQ1.1 subvariants was shown in vitro.

Conclusions

XAV-19 did not reduce the aggravation in COVID-19 patients. While it did not bring any benefit to patients requiring oxygen, it reduced the time to improvement for patients not requiring oxygen (WHO score 2 or 3). These preliminary clinical data might indicate a therapeutic potential for patients with mild to moderate COVID-19 requiring supplementation with anti-SARS-CoV-2 neutralizing antibodies.
Insights into Drug Cardiotoxicity from Biological and Chemical Data: The First Public Classifiers for FDA DICTrank
Authors: Seal Srijit , Spjuth Ola , Hosseini-Gerami Layla , García-Ortegón Miguel , Singh Shantanu , Bender Andreas , Carpenter Anne E.
Published: October 2023

Drug-induced cardiotoxicity (DICT) is a major concern in drug development, accounting for 10-14% of postmarket withdrawals. In this study, we explored the capabilities of various chemical and biological data to predict cardiotoxicity, using the recently released Drug-Induced Cardiotoxicity Rank (DICTrank) dataset from the United States FDA. We analyzed a diverse set of data sources, including physicochemical properties, annotated mechanisms of action (MOA), Cell Painting, Gene Expression, and more, to identify indications of cardiotoxicity. We found that such data, including protein targets, especially those related to ion channels (such as hERG), physicochemical properties (such as electrotopological state) as well as peak concentration in plasma offer strong predictive ability as well as valuable insights into DICT. We also found compounds annotated with particular mechanisms of action, such as cyclooxygenase inhibition, could distinguish between most-concern and no-concern DICT compounds. Cell Painting features related to ER stress discern the most-concern cardiotoxic compounds from non-toxic compounds. While models based on physicochemical properties currently provide substantial predictive accuracy (AUCPR = 0.93), this study also underscores the potential benefits of incorporating more comprehensive biological data in future DICT predictive models. With the availability of - omics data in the future, using biological data promises enhanced predictability and delivers deeper mechanistic insights, paving the way for safer therapeutic drug development. All models and data used in this study are publicly released athttps://broad.io/DICTrank_Predictor
Comparison of the effectiveness of different normalization methods for metagenomic cross-study phenotype prediction under heterogeneity
Authors: Wang Beibei , Sun Fengzhu , Luan Yihui
Published: October 2023

The human microbiome, comprising microorganisms residing within and on the human body, plays a crucial role in various physiological processes and has been linked to numerous diseases. To analyze microbiome data, it is essential to account for inherent heterogeneity and variability across samples. Normalization methods have been proposed to mitigate these variations and enhance comparability. However, the performance of these methods in predicting binary phenotypes remains understudied. This study systematically evaluates different normalization methods in microbiome data analysis and their impact on disease prediction. Our findings highlight the strengths and limitations of scaling, compositional data analysis, transformation, and batch correction methods. Scaling methods like TMM and RLE show consistent performance, while compositional data analysis methods exhibit mixed results. Transformation methods, such as Blom and NPN, demonstrate promise in capturing complex associations. Batch correction methods, including BMC and Limma, consistently outperform other approaches. However, the influence of normalization methods is constrained by population effects, disease effects, and batch effects. These results provide insights for selecting appropriate normalization approaches in microbiome research, improving predictive models, and advancing personalized medicine. Future research should explore larger and more diverse datasets and develop tailored normalization strategies for microbiome data analysis.
A procedure for solid phase extractions using metal oxide coated silica column in lipidomics
Authors: Takeda Hiroaki , Takeuchi Manami , Hasegawa Mayu , Miyamoto Junki , Tsugawa Hiroshi
Published: October 2023

Lipid enrichment is indispensable for enhancing the coverage of targeted molecules in mass spectrometry (MS)-based lipidomics studies. In this study, we developed a simple stepwise fractionation method using a titanium- and zirconium-dioxide-coated solid-phase extraction (SPE) silica column that separates neutral lipids, phospholipids, and other lipids, including fatty acids (FAs) and glycolipids. Chloroform was used to dissolve the lipids, and neutral lipids, including steryl esters and di- and triacylglycerols, were collected in the loading fraction. Second, methanol with formic acid (99:1, v/v) was used to retrieve FAs, ceramides, and glycolipids, including glycosylated ceramides and glycosylated diacylglycerols, by competing for affinity with the Lewis acid sites on the metal oxide surface. Finally, phospholipids strongly retained via chemoaffinity interactions were eluted using a solution containing 5% ammonia and high water content (45:50 v/v, 2-propanol:water), which canceled the electrostatic and chelating interactions with the SPE column. High average reproducibility of <10% and coverage of ∼100% compared to those of the non-SPE samples were demonstrated by untargeted lipidomics of human plasma and mouse brain, testis, and feces. The advantage of our procedure was showcased by characterizing minor lipid subclasses, including dihexosylceramides containing very long-chain polyunsaturated FA in the testis, mono- and digalactosyl monoacylglycerols in feces, and acetylated and glycolylated derivatives of gangliosides in the brain that were not detected using conventional solvent extraction methods. Likewise, the value of our method in biology is maximized during glycolipidome profiling in the absence of neutral lipids and phospholipids that cover more than 80% of the chromatographic peaks.

Table of Contents artwork
Development of a novel healthcare discrimination measure: PreDict
Authors: Oladele Carol R. , Gonzalez-Colaso Rosana , Schulze Arian , Rizzo Tara ,   The PreDict Writing Group, Nunez-Smith Marcella
Published: October 2023

Introduction

Patient reported quality of care measures are widely recognized tools for healthcare system performance assessment. Yet, there are few existing patient reported quality of care measures regarding health equity, and none to specifically collect patient experiences of discrimination in health care.

Objective

To develop an item pool to measure patient experiences of healthcare discrimination-the Patient-Reported Experiences of Discrimination in Care Tool (PreDict).

Methods

Utilizing a multistage, exploratory sequential mixed methods study design, we conducted qualitative interviews (n=73) and expert panel consensus analysis to develop items to capture patient experiences of discrimination. This process plus systematic literature review identified extant items and informedde novoitems for inclusion in the item pool. Items were developed in English and Spanish and were not represented by extant items. Following identification of the initial item pool (n=125), candidate items underwent cognitive interview testing with English (n=113) and Spanish (n=70) speaking participants to evaluate items for clarity and comprehensiveness. English and Spanish items were also evaluated by a bilingual expert panel to recommend pool items for inpatient field testing.

Results

One hundred and three items underwent cognitive interview testing and fifty-nine items were retained. Lack of clarity was the most cited factor for removal or revision of items. Expert panel review resulted in the removal of one additional item and the revision of seven items.

Fifty-eight candidate items were retained for inclusion in field testing and future analyses using item response theory modeling.

Conclusion

PreDict fills an important gap in measurement of discrimination, which is known to influence patient health outcomes. Development and testing to date demonstrate evidence of validity in characterizing the complex phenomenon of healthcare discrimination.
Identification and development of Tetra-ARMS PCR-based screening test for a genetic variant of OLA1 (Tyr254Cys) in the human failing heart
Authors: Dubey Praveen K , Dubey Shubham , Singh Sarojini , Bhat Purnima Devaki , Pogwizd Steven , Krishnamurthy Prasanna
Published: October 2023

Obg-like ATPase 1 (OLA1) protein has GTP and ATP hydrolyzing activities and is important for cellular growth and survival. The human OLA1 gene maps on chromosome 2, at the locus 1q31, close to the Titin (TTN) gene, which is associated with familial dilated cardiomyopathy (DCM). In this study, we found that expression of OLA1 was significantly downregulated in human failing heart tissue (HF) as compared to in non-failing heart tissues (NF). Moreover, using the Sanger sequencing method, we characterized the human OLA1 gene and screened genetic mutations in patients with heart-failing and non-failing. Among failing and non-failing heart patients, we found a total of 15 mutations, including two transversions, one substitution, one indel, and eleven transition mutations in theOLA1gene. All the mutations were intronic except for a non-synonymous mutation, 5144A>G, resulting in 254Tyr>Cys in exon 8 of theOLA1gene. Furthermore, haplotype analysis of these mutations revealed that these single nucleotide polymorphisms (SNPs) are linked to each other, resulting in disease-specific haplotypes. Additionally, to screen for the 254Tyr>Cys point mutation, we developed a cost-effective, rapid genetic screening PCR test that can differentiate between homozygous (AA and GG) and heterozygous (A/G) genotypes. Our results show that this test can be used as a genetic screening tool for human cardiomyopathy. These findings have important implications for the diagnosis and treatment of cardiomyopathy.

Abstract Figure
Regional quantification of cardiac metabolism with hyperpolarized [1 -13C]-pyruvate MRI evaluated in an oral glucose challenge
Authors: Larson Peder E. Z. , Tang Shuyu , Liu Xiaoxi , Sinha Avantika , Dwork Nicholas , Sivalokanathan Sanjay , Liu Jing , Bok Robert , Ordovas Karen G. , Slater James , Gordon Jeremy W. , Abraham M. Roselle
Published: October 2023

Background

The heart has metabolic flexibility, which is influenced by fed/fasting states, and pathologies such as myocardial ischemia and hypertrophic cardiomyopathy (HCM). Hyperpolarized (HP)13C-pyruvate MRI is a promising new tool for non-invasive quantification of myocardial glycolytic and Krebs cycle flux. However, human studies of HP13C-MRI have yet to demonstrate regional quantification of metabolism, which is important in regional ischemia and HCM patients with asymmetric septal/apical hypertrophy.

Methods

We developed and applied methods for whole-heart imaging of13C-pyruvate,13C-lactate and13C-bicarbonate, following intravenous administration of [1-13C]-pyruvate. The image acquisition used an autonomous scanning method including bolus tracking, real-time magnetic field calibrations and metabolite-specific imaging. For quantification of metabolism, we evaluated13C metabolite images, ratio metrics, and pharmacokinetic modeling to provide measurements of myocardial lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) mediated metabolic conversion in 5 healthy volunteers (fasting & 30 min following oral glucose load).

Results

We demonstrate whole heart coverage for dynamic measurement of pyruvate-to-lactate conversion via LDH and pyruvate-to-bicarbonate conversion via PDH at a resolution of 6×6×21 mm3(13C-pyruvate) and 12×12×21 mm3(13C-lactate,13C-bicarbonate).13C-pyruvate and13C-lactate were detected simultaneously in the RV blood pool, immediately after intravenous injection, reflecting LDH activity in blood. In healthy volunteers, myocardial13C-pyruvate-SNR,13C-lactate-SNR,13C-bicarbonate-SNR,13C-lactate/pyruvate ratio,13C-pyruvate-to-lactate conversion rate, kPL, and13C-pyruvate-to-bicarbonate conversion rate, kPB, all had statistically significant increases following oral glucose challenge. kPB, reflecting PDH activity and pyruvate entering the Krebs Cycle, had the highest correlation with blood glucose levels and was statistically significant.

Conclusions

We demonstrate first-in-human regional quantifications of cardiac metabolism by HP13C-pyruvate MRI that aims to reflect LDH and PDH activity.
Efficient Drug Delivering of a Photodynamic Therapy Agent into Cellular Membranes Rationalized by Molecular Dynamics
Authors: Koca-Findik Basak , Yakavets Ilya , Lassalle Henri-Pierre , Catak saron , MONARI Antonio
Published: October 2023

Photodynamic Therapy (PDT) represents a most attractive therapeutic strategy to reduce side effects of chemotherapy and improve the global quality of life of patients. Yet, many PDT drugs suffer from a poor bioavailability and cellular intake, and thus, drug delivery strategy should be implemented. In this letter we report the behavior of a temoporfin-based PDT drug, commercialized under the name of Foscan, complexed by two beta-cyclodextrin units in presence of a lipid bilayer. Our all atom simulations have shown the internalization of the complex and its spontaneous dissociation inside the lipid bilayer. The factors favoring penetration and dissociation have also been analyzed, together with the membrane perturbation due to the interaction with the cyclodextrin complex. Our results confirm the suitability of the encapsulation strategy for PDT, and rationalize the experimental results concerning its efficacy.
A 2-Hydroxybutyrate- mediated feedback loop regulates muscular fatigue
Authors: Wadsworth Brennan J , Leiwe Marina , Minogue Eleanor A , Cunha Pedro P , Engman Viktor , Brombach Carolin , Asvestis Christos , Sah-Teli Shiv K , Marklund Emilia , Koivunen Peppi , Ruas Jorge L , Rundqvist Helene , Lanner Johanna T , Johnson Randall S
Published: October 2023

The metabolite 2-hydroxybutyrate (2HB) is produced by skeletal muscle acutely during exercise and persists for several hours in the blood post-exertion. We show here that 2HB directly inhibits branched- chain aminotransferase enzymes, and that this inhibition in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity bothin vitroandin vivo, with the latter mimicking the effects of exercise training on whole body metabolism. Thus, we show here that 2-HB production by skeletal muscle represents a novel mechanism for the modification of metabolism by exercise.
Simulated complexes formed from a set of postsynaptic proteins suggest a localised effect of a hypomorphic Shank mutation
Authors: Miski Marcell , Weber Áron , Fekete-Molnár Krisztina , Keömley-Horváth Bence Márk , Csikász-Nagy Attila , Gáspári Zoltán
Published: October 2023

The postsynaptic density is an elaborate protein network beneath the postsynaptic membrane built up from the same major proteins but differing between synapses in exact composition and organization. Mutations perturbing generally occurring protein:protein interactions in this network can lead to specific effects, and the translation of biochemical effects to the system level can be especially challenging. In this work we use systems biology-based modeling of protein complex distributions in a set of major postsynaptic proteins including either a wild-type or a hypomorphic PDZ mutant Shank protein. Our results suggest that the effect of such mutations is heavily dependent on the overall availability of the protein components of the whole network. We simulated protein complex formation based on experimental data of various cell types with diverse protein abundances. The simulations revealed that mutations interfering with a single protein interaction can lead to protein complex changes only in specific cell types and in specific complexes. Although our system is currently far from a comprehensive description of the PSD, the results suggest a way to interpret specific mutations within a complex framework.

Graphical Abstract

Highlights

Effect of mutations affecting protein:protein interactions can be modeled in context

Changes in emerging protein complexes upon mutations are dependent on the availability of the individual proteins

Our model provides conceptual explanation of confided phenotypic effects of a mutation
Genome dilution by cell growth drives starvation-like proteome remodeling in mammalian and yeast cells
Authors: Lanz Michael C. , Zhang Shuyuan , Swaffer Matthew P. , Ziv Inbal , Götz Luisa Hernández , McCarty Frank , Jarosz Daniel F. , Elias Joshua E. , Skotheim Jan M.
Published: October 2023

Cell size is tightly controlled in healthy tissues and single-celled organisms, but it remains unclear how size influences cell physiology. Increasing cell size was recently shown to remodel the proteomes of cultured human cells, demonstrating that large and small cells of the same type can be biochemically different. Here, we corroborate these results in mouse hepatocytes and extend our analysis using yeast. We find that size-dependent proteome changes are highly conserved and mostly independent of metabolic state. As eukaryotic cells grow larger, the dilution of the genome elicits a starvation-like proteome phenotype, suggesting that growth in large cells is limited by the genome in a manner analogous to a limiting nutrient. We also find that this phenomenon explains many proteomic changes ascribed to yeast aging. Overall, our data suggest that genome concentration is a universal determinant of proteome content in growing cells.
TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade
Authors: Xiong Yan , Sharma Jaiprakash , Young Meggie N. , Xiong Wen , Jazayeri Ali , Poncha Karl F. , Ilagan Ma. Xenia G. , Wang Qing , Zheng Hui , Young Nicolas L. , Sardiello Marco
Published: October 2023

Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy that plays a key role in the regulation of cellular clearance pathways. TFEB is regulated via a complex array of post-translational modifications (PTMs), but the exact molecular mechanism that regulates TFEB stability has remained elusive. Here, we show that TFEB levels are critically regulated by a defined phosphorylation-ubiquitination cascade. A human kinome screen identifies IKK (inhibitor of κB kinase) as a TFEB modifier, and a combination of phosphorylation assays, mass spectrometry analyses, and site-specific mutagenesis unveils a previously unrecognized TFEB phospho-degron (423SPFPSLS429) as the target of IKK. We show that IKK-mediated phosphorylation of TFEB triggers ubiquitination of adjacent lysine residues (K430 and K431) by the E3 ligase β-TrCP2 (β-Transducin repeat-containing protein 2), thereby tagging TFEB for degradation. Modified TFEB constructs that abolish these PTMs show much increased stability and expression levels but remain equally sensitive to autophagy- or stress- related stimuli while maintaining the capability to promote the expression of TFEB target genes and the clearance of Alzheimer’s associated tau in a cellular model of disease. Our results therefore uncover an IKK/β-TrCP2 phosphorylation-ubiquitination cascade as a major mechanism that governs TFEB stability independently of other TFEB regulators.
Liver regeneration by a population of midzone-located mesenchymal-hepatocyte hybrid cells
Authors: Yu Guo , Zhang Shaoyang , Romo Ana , Biswas Soma , Li Baojie , Li Jing
Published: October 2023

Regenerative medicine relies on deep understanding of the mechanisms of organ repair and regeneration. The liver, an organ with critical metabolic functions carried out by hepatocytes located in zones 1-3 of liver lobules, has the capacity to fully regenerate itself, which is mainly attributable to midzone hepatocytes. Yet, how differentiated midzone hepatocytes execute transzone regeneration and quickly recover most of the liver mass remains a myth. Here, we uncover a mesenchymal-hepatocyte population (13.7% of total hepatocytes) that are derived from Twist2-lineage EpCAM+progenitors, midzone-located, highly polyploidy, and equipped with great mitogenic and migratory capabilities to the detriment of metabolism. They regenerate about 50% of new hepatocytes and repopulate zones 1 and 3 in liver regeneration. Mechanistically, expansion of these cells is negatively controlled by Notch1 signaling. This study has thus uncovered a hepatocyte subpopulation with great proliferation potential and important mechanisms of liver regeneration.