bluuebunny/crossref_metadata_2025 huggingface dataset:
Major Publications in the Critical Care Pharmacotherapy Literature: 2023
Authors: Murray Brian , Athale Janhavi , Balk Robert A. , Behal Michael L. , Brown Judah E. , Chanas Tyler , Dumitru Roxana , Gifford Dalton C. , Hohlfelder Benjamin , Jones Honey M. , Makic Mary Beth F. , Rausen Michelle S. , Sacco Alicia J. , Sines Benjamin J. , Gurnani Payal K.
Published: October 2024

OBJECTIVES:

We aimed to summarize the most significant and impactful publications describing the pharmacotherapeutic care of critically ill patients in 2023.

DATA SOURCES:

PubMed/MEDLINE and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update.

STUDY SELECTION:

Randomized controlled trials and prospective studies of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2023, and December 31, 2023, were eligible for inclusion in this article.

DATA EXTRACTION:

Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included. An a priori defined three-round modified Delphi process was employed to achieve consensus on the most impactful publications based on the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature.

DATA SYNTHESIS:

The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update returned a total of 1202 articles, of which 1164 were excluded. The remaining 38 articles underwent a three-round modified Delphi process. In each round, articles were independently scored based on overall contribution to scientific knowledge and novelty to the literature. Included articles are summarized and their impact discussed. Article topics included hydrocortisone for severe community-acquired pneumonia, inhaled amikacin for prevention of ventilator-associated pneumonia, methylene blue for septic shock, restrictive vs. liberal fluid management for sepsis-induced hypotension, andexanet alfa for major bleeding associated with factor Xa inhibitors, and early administration of four-factor prothrombin complex concentrate in patients with trauma at risk for massive transfusion.

CONCLUSIONS:

This review provides a summary and perspective on the potential impact of the most relevant articles in 2023 describing advances in the pharmacotherapeutic care of critically ill patients.
International incidence of melanoma in heart transplant recipients: a meta-analysis
Authors: Campillo Paola , Kesler Alice , Ramírez Camila A. , Ramírez Carlos J. , Daher Jean Carlo , Grimm Mason , Sabina Michael , Bizanti Anas
Published: October 2024

The incidence of heart transplants in the USA has increased by 85.8% since 2011, resulting in a growing population of recipients requiring long-term immunosuppressive therapy. While essential for preventing organ rejection, this therapy significantly increases melanoma risk. This meta-analysis investigates the incidence and risk factors of melanoma in heart transplant recipients. A systematic review and meta-analysis were conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, including observational studies reporting melanoma incidence in heart transplant recipients. Relative risk (RR) was synthesized from standardized incidence ratios, hazard ratios, incidence rate ratios, and standardized mortality ratios. The meta-analysis incorporated 10 studies, including 22 415 heart transplant recipients. The pooled RR was 2.21 (95% confidence interval: 1.32–3.71; P = 0.003), indicating a significantly elevated melanoma risk. This study highlights the critical need for preventive dermatological strategies in heart transplant recipients and calls for further research into the impact of different immunosuppressive regimens on melanoma risk. Despite limitations, these findings offer valuable insights for optimizing long-term patient care.
De Novo Natural Language Processing Algorithm Accurately Identifies Myxofibrosarcoma From Pathology Reports
Authors: Lindsay Sarah E. , Madison Cecelia J. , Ramsey Duncan C. , Doung Yee-Cheen , Gundle Kenneth R.
Published: October 2024

Background

Available codes in the ICD-10 do not accurately reflect soft tissue sarcoma diagnoses, and this can result in an underrepresentation of soft tissue sarcoma in databases. The National VA Database provides a unique opportunity for soft tissue sarcoma investigation because of the availability of all clinical results and pathology reports. In the setting of soft tissue sarcoma, natural language processing (NLP) has the potential to be applied to clinical documents such as pathology reports to identify soft tissue sarcoma independent of ICD codes, allowing sarcoma researchers to build more comprehensive databases capable of answering a myriad of research questions.

Questions/purposes

(1) What proportion of patients with myxofibrosarcoma within the National VA Database would be missed by searching only by soft tissue sarcoma ICD codes? (2) Is a de novo NLP algorithm capable of analyzing pathology reports to accurately identify patients with myxofibrosarcoma?

Methods

All pathology reports (10.7 million) in the national VA corporate data warehouse were identified from 2003 to 2022. Using the word-search functionality, reports from 403 veterans were found to contain the term “myxofibrosarcoma.” The resulting pathology reports were manually reviewed to develop a gold-standard cohort that contained only those veterans with pathologist-confirmed myxofibrosarcoma diagnoses. The cohort had a mean ± SD age of 70 ± 12 years, and 96% (287 of 300) were men. Diagnosis codes were abstracted, and differences in appropriate ICD coding were compared. An NLP algorithm was iteratively refined and tested using confounders, negation, and emphasis terms for myxofibrosarcoma. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the NLP-generated cohorts through comparison with the manually reviewed gold-standard cohorts.

Results

The records of 27% (81 of 300) of myxofibrosarcoma patients within the VA database were missing a sarcoma ICD code. A de novo NLP algorithm more accurately (92% [276 of 300]) identified patients with myxofibrosarcoma compared with ICD codes (73% [219 of 300]) or basic word searches (74% [300 of 403]) (p < 0.001). Three final algorithm models were generated with accuracies ranging from 92% to 100%.

Conclusion

An NLP algorithm can identify patients with myxofibrosarcoma from pathology reports with high accuracy, which is an improvement over ICD-based cohort creation and simple word search. This algorithm is freely available on GitHub (https://github.com/sarcoma-shark/myxofibrosarcoma-shark) and is available to facilitate external validation and improvement through testing in other cohorts.

Level of Evidence

Level II, diagnostic study.
Investigating the Potential Short-term Adverse Effects of the Quadrivalent Human Papillomavirus Vaccine: A Novel Regression Discontinuity Analysis
Authors: Margelyte Ruta , Redaniel Maria Theresa , Walter Scott R. , Pyne Yvette , Merriel Sam , Macleod John , Northstone Kate , Tilling Kate
Published: October 2024

Background:

Human papillomavirus (HPV) vaccination has been offered in over a hundred countries worldwide (including the United Kingdom, since September 2008). Controversy around adverse effects persists, with inconsistent evidence from follow-up of randomized controlled trials and confounding by indication limiting the conclusions drawn from larger-scale observational studies. This study aims to estimate the association between receiving a quadrivalent HPV vaccine and the reporting of short-term adverse effects and to demonstrate the utility of regression discontinuity design for examining side effects in routine data.

Methods:

We applied a novel regression discontinuity approach to a retrospective population-based cohort using primary care data from the UK Clinical Practice Research Datalink linked to hospital and social deprivation data. We examined the new onset of gastrointestinal, neuromuscular, pain, and headache/migraine symptoms using READ and International Classification of Diseases, tenth revision diagnostic codes. For each year between 2012 and 2017, we compared girls in school year 8 (born July/August) who were eligible to receive the vaccine with girls in year 7 (born September/October) who were not eligible.

Results:

Of the 21,853 adolescent girls in the cohort, 10,881 (50%) were eligible for HPV vaccination. There was no evidence of increased new gastrointestinal symptoms (adjusted odds ratio [OR]: 0.99; 95% confidence interval [CI]: 0.85, 1.15), headache/migraine symptoms (OR: 0.84; 95% CI: 0.70, 1.01), or pain symptoms (OR: 1.05; 95% CI: 0.95, 1.16) when comparing those eligible and ineligible for HPV vaccination.

Conclusion:

This study found no evidence that HPV vaccination eligibility is associated with reporting short-term adverse effects among adolescent girls.
Current opinions: updates on the changing landscape in the management of cervical cancer
Authors: Venkat Puja S. , Smick Alexandra H. , Salani Ritu
Published: October 2024

Purpose of review

To review the recent updates in the management of cervical cancer across all stages of the disease.

Recent findings

After decades of minor advances, the landscape in cervical cancer is now rapidly changing. Recent studies have reported across the cervical cancer spectrum and on different therapeutic modalities. First, less radical surgery in the assessment and management of patients with early-stage, low-risk disease has been shown to be a safe option with reduced morbidity. The role of checkpoint inhibitor therapy in combination with chemotherapy and radiation has demonstrated improved survival outcomes, moving immunotherapy to earlier lines of therapy. The options for systemic therapy continue to include checkpoint inhibitors as well as treatment with antibody drug conjugates (ADCs) in the recurrent setting. Additional research continues to focus on targeting biomarkers in this disease.

In this paper, we will review the practice-changing trials impacting early stage, locally advanced, and recurrent cervical cancer patients. Despite advances, the limited survival for these patients continues to highlight the need for access to preventive healthcare (vaccine/cytology) and clinical trials to continue to make advances.
Trigeminal Trophic Syndrome With Herpetic Keratitis
Authors: Santos Matthew C. , Chen Howard C.
Published: October 2024

Purpose:

The aim of this study was to report a rare observation of trigeminal trophic syndrome presenting with concurrent herpetic keratitis.

Methods:

This study was a case report.

Results:

A 42-year-old male with a remote history of a motor vehicle accident, traumatic brain injury, extensive facial reconstructive surgery, and traumatic optic neuropathy presented with left periorbital swelling. He was found to have extensive periorbital and total hypoesthesia in the cranial nerve V1 distribution and partial hypoesthesia in the V2 distribution. Corneal findings were highly suspicious for herpes simplex keratitis or zoster ophthalmicus. The patient was diagnosed with herpetic epithelial and stromal keratitis with periorbital ulceration secondary to Trigeminal trophic syndrome. The patient was treated broad spectrum intravenous antibiotics, intravenous acyclovir, and topical antibiotics. He was treated with topical steroids upon closure of epithelial defect. Upon discharge, the patient’s vision improved from hand-motion to 20/30 at near. The patient was later fit with a custom thermoplastic facial mask to minimize further selfinjurious behavior.

Conclusions:

To our knowledge, this is the first report of trigeminal trophic syndrome presenting with concurrent herpetic keratitis. Successful treatment requires a multidisciplinary approach to provide the patient insight and create protective equipment.
Trends and Factors Affecting Functional Limitations on Activities of Daily Living Performance Among Korean Adults With Disabilities, 2008–2020: A Longitudinal Study
Authors: OH Eunmi , NGUYEN Van Cuong , MOON SeolHwa , CHOI Rina , HONG Gwi-Ryung Son
Published: October 2024

Background

Loss of the ability to perform activities of daily living (ADLs) leads to negative health outcomes such as reduced quality of life, institutionalization, and mortality. In Korea, the proportion of older adults with disabilities is increasing along with rapid population aging. Therefore, providing a comprehensive approach to the prevention and management of ADL limitations in people with disabilities is necessary. This can be accomplished by understanding the trends and factors affecting these limitations over time.

Purpose

This study was developed to examine the longitudinal trend and factors affecting ADL limitations over time among people with disabilities in Korea.

Methods

Data from 346 people with disabilities in the 2008–2020 Korean Welfare Panel Study were used. Bivariate analysis and a Kendall trend test were performed to determine the longitudinal trends for ADL limitations, and multiple logistic regression was used to evaluate whether relevant variables could predict these limitations.

Results

The prevalence of ADL limitations among people with disabilities increased by 16.5% over the 12 years of the study. The highest rate of increase in these limitations over time was found in people with mental disorders (27.8%), those over 65 years of age (27.3%), and those with depression (25.6%). In multiple logistic regression, the odds ratios of the variables were slightly different at each survey wave. However, severe disability and low educational level were consistently found to be associated with ADL limitations over time.

Conclusions

The findings provide evidence of a significant relationship between level of disability and/or educational status and ADL limitations in people with disabilities in Korea. To prevent the development of ADL limitations in people with disabilities, comprehensive identification of longitudinal trends and factors affecting ADL limitations is necessary. Early intervention, including integrated services such as home rehabilitation services to prevent ADL limitations, especially for disabled people with severe disabilities and low educational levels, has the potential to delay ADL limitations.
Implementing a Care-Based Nursing Workforce Model
Authors: Polancich Shea , Dick Tracey , Ledlow Jennifer , White-Williams Connie , Chambers Amanda , Thomas Keri , Poe Terri , Miltner Rebecca
Published: October 2024

Background:

Nursing care delivery models may serve as a significant factor contributing to nurse satisfaction, frequency of missed care, and patient outcomes.

Local problem:

The nursing leadership team at our institution sought to determine if an adaptation of our primary registered nurse (RN) nursing model would enhance satisfaction of bedside nurses and care of patients.

Methods:

An improvement study introducing a care-based delivery model was implemented between January 2023 and January 2024 on a medical-surgical neurology/spinal unit at our organization.

Interventions:

Adoption of a care-based nursing model was supported with the delivery of brief education sessions utilizing in situ simulations for development of competencies in teamwork and delegation.

Results:

During the pilot period, overall satisfaction with job role improved 23%. Six missed nursing care elements and 7 teamwork elements significantly improved.

Conclusions:

A care-based nursing model may improve staff satisfaction and quality of nursing care.
Easily Missed Lung Cancer Associated With Cystic Airspaces
Authors: Wang Kangkang , Huang Hao
Published: October 2024

Lung cancer associated with cystic airspaces represents a distinctive subtype of pulmonary malignancies, characterized by the presence of cystic airspaces within or adjacent to the tumor, as identified through imaging studies. The absence of standardized terminology and limited understanding of these malignancies have led to inconsistent descriptions, often referred to as “cancers arising from lung cysts” or “cancers associated with cystic airspaces.” In this article, we present a case of a 77-year-old woman diagnosed with both typical lung cancer and lung cancer associated with cystic airspaces.
Transient Posterior Layering of 18F-FDG in Distended Bladders
Authors: Wang Kangkang , Li Zhenyu
Published: October 2024

Urine activity layering in the bladder sometimes appears in PET/CT scans, but a comprehensive explanation for this phenomenon is still lacking. Previous studies have not documented the dynamic changes of layering in vivo. We present 2 cases of posterior layering in the urinary bladder on 18F-FDG PET/CT scans, which gradually diminished and ultimately disappeared in delayed phase images. Both patients had normal renal function and no signs of urinary tract infection.
Utility of Lactate Levels in the Diagnosis and Prognosis of Septic Shock
Authors: de Souza Daniela Carla , Jabornisky Roberto , Kissoon Niranjan
Published: October 2024

Early recognition of septic shock and its treatment are key factors for limiting progression to multiple organ dysfunction and death. Lactate, a byproduct of metabolic pathways, is usually elevated in tissue hypoperfusion and shock and is associated with poor prognosis in sepsis. As a biomarker, it may help the clinician in risk stratification, and the identification and treatment of sepsis. In this article, we provide an update on lactate's pathophysiology and role in diagnosis, treatment, and prognosis in children with sepsis and septic shock.
68Ga-DOTA-FAPI-46 PET/CT Imaging for Restaging in a Patient With Metastatic Pheochromocytoma
Authors: Şahin Rahime , Baloğlu Mehmet Can , Ergül Nurhan , Çermik Tevfik Fikret , Arslan Esra
Published: October 2024

Pheochromocytomas (PHEOs) are neural crest-derived tumors originating from the chromaffin cells of the adrenal medulla and were recognized as one of the subtypes of paragangliomas by the World Health Organization in 2022. 68Ga-labeled somatostatin analog (68Ga-DOTA-NOC, 68Ga-DOTA-TOC, and 68Ga-DOTA-TATE) PET imaging has shown significant performance compared with 123MIBG scintigraphy in the diagnosis of paragangliomas. It is now known that fibroblast activation protein (FAP) is overexpressed by various cancer-associated fibroblasts, including PHEOs. We would like to present the findings of 68Ga-DOTA-FAPI-46 PET/CT and 68Ga-DOTA-TATE PET/CT imaging performed for restaging on a 42-year-old man diagnosed with metastatic PHEO.
“Cancer Integrin” αvβ6 Imaging With 68Ga-Trivehexin PET/CT in Assessment of Ovarian Carcinoma
Authors: Singh Parneet , Agrawal Kanhaiyalal , Emerson Ralph , Baranwal Abhinav , Patro P. Sai Sradha , Parida Girish Kumar
Published: October 2024

Peritoneal cancer index is an integral parameter for preoperative assessment of peritoneal disease. Current imaging modalities including 18F-FDG PET/CT, though superior to CT, underestimate the disease extent, mainly due to its high physiological background activity. Novel “cancer integrin” targeting imaging with 68Ga-trivehexin demonstrates limited physiological activity in the abdomen with superior target-to-background ratio than 18F-FDG PET/CT. Thus, we describe the first case demonstrating potential utility of novel “cancer integrin” αvβ6 imaging agent 68Ga-trivehexin for assessment of disease burden in advanced epithelial ovarian cancer.
Increased TSPO, COX-1, and COX-2 Uptake in Bone Marrow Within a Falx Cerebri Ossification
Authors: Yan Xuefeng , Siméon Fabrice G. , Pike Victor W. , Innis Robert B. , Zanotti-Fregonara Paolo
Published: October 2024

Ossification is uncommon, generally asymptomatic, and often incidentally identified in imaging studies. We report on a 54-year-old man who participated as a healthy volunteer in a clinical trial using PET imaging to investigate neuroinflammation. An incidental ossified lesion in the anterior falx cerebri was revealed by MRI. CT scan showed a small hypodense center in the lesion, probably corresponding to bone marrow. The PET scans using 18F-SF51, 11C-PS13, and 11C-MC1 showed increased uptake within this lesion, which was probably related to bone marrow activity within the ossification.
Mandible Fracture Outcome Disparities in the Incarcerated Patient Population
Authors: Lewcun Joseph A. , Ghahrai Naomi , Donnelly Madeline , Luo Annie , Knighton Brooks , Shin Stephanie , Bernabe Rendell , Mountziaris Paschalia
Published: October 2024

Introduction

Inmates represent a vulnerable health care population within the United States, with inconsistent access to surgical specialty care. Facial fractures are common among the incarcerated population, comprising approximately 14% of all traumatic injuries. However, few studies have evaluated facial fracture outcomes in this population. The aim of this study is to identify disparities in mandible fracture outcomes in the incarcerated population.

Methods

A retrospective review of all isolated traumatic mandible fractures at a single academic medical center from 2018 to 2023 was conducted. Mandible fractures were treated by plastic surgery, otolaryngology, or oral and maxillofacial surgery. Outcome measures such as rates of persistent malocclusion, motor deficits, surgical site infection, reoperation, and readmission were compared between inmate and civilian subgroups.

Results

A total of 205 patients (mean age, 33.1 years; 81.5% male) who were treated for isolated traumatic mandible fracture were included. A minority of patients (11.7%; n = 24) were inmates, whereas 88.3% (n = 181) were civilians. The mean time to operative intervention was 10.2 days in the incarcerated group and 4.4 days in the civilian group (P < 0.05). Persistent subjective malocclusion after surgery was noted in 20.8% (n = 5) of incarcerated patients and 7.2% (n = 13) of civilian patients (P < 0.05). There were no significant differences in rates of surgical site infection, reoperation, persistent motor deficits, or readmissions within 30 days.

Conclusions

Incarcerated patients with traumatic mandible fractures have increased time to operative intervention and increased rates of subjective malocclusion postoperatively. Increased time to operative intervention may reflect barriers in access to specialty surgical care, which could adversely affect patient outcomes.
Call to Action
Authors: Lu Amy , Pian-Smith May C. M. , Burden Amanda , Fernandez Gladys L. , Fortner Sally A. , Rege Robert V. , Slakey Douglas P. , Velasco Jose M. , Cooper Jeffrey B. , Steadman Randolph H.
Published: October 2024

Summary Statement

Simulation is underutilized as a tool to improve healthcare quality and safety despite many examples of its effectiveness to identify and remedy quality and safety problems, improve teamwork, and improve various measures of quality and safety that are important to healthcare organizations, eg, patient safety indicators. We urge quality and safety and simulation professionals to collaborate with their counterparts in their organizations to employ simulation in ways that improve the quality and safety of care of their patients. These collaborations could begin through initiating conversations among the quality and safety and simulation professionals, perhaps using this article as a prompt for discussion, identifying one area in need of quality and safety improvement for which simulation can be helpful, and beginning that work.
Erysipelothrix rhusiopathiae-associated bloodstream infection in a patient with systemic lupus erythematosus: a case report and literature review
Authors: Lo Calvin Ka-Fung , Schonhofer Cole , Mina Neil , Masud Shazia , Wong Patrick Ho Pun , Chapman Michael G.
Published: October 2024

Introduction

Systemic human infections caused by Erysipelothrix rhusiopathiae have been increasingly reported especially within immunocompromised hosts and those with significant occupational exposure to livestock and aquatic animals. We report a case of Erysipelothrix rhusiopathiae bacteremia in a patient with systemic lupus erythematosus (SLE) and present a literature review on clinical outcomes and microbiologic diagnosis for this organism.

Case Presentation

A 43-year-old female patient was reporting a 1-month history of intermittent fevers. She recently increased her immunosuppression medication for her underlying SLE on advice of her rheumatologist. The patient sustained a finger laceration from butchering cattle meat two weeks after onset of her initial symptoms, with worsening index finger swelling and increased febrile episodes. Two weeks post-injury, multiple blood cultures were drawn and each isolated Gram-positive bacilli. Given her recurrent intermittent fevers, there was concern for ongoing infection and therefore intravenous vancomycin was started with prompt referral to outpatient parenteral antibiotic therapy clinic. The Gram-positive bacillus was confirmed as Erysipelothrix rhusiopathiae via MALDI-TOF analysis. Given intrinsic resistance to vancomycin, vancomycin was switched to intravenous ceftriaxone as targeted antimicrobial therapy for two weeks. Reassuringly, there was no echocardiographic evidence of infective endocarditis warranting prolonged treatment course. Post-treatment, she remained symptom-free with resolution of joint symptoms and fevers.

Conclusion

Our report illustrates a case of Erysipelothrix rhusiopathiae bacteremia from a immunodeficient host, with prompt microbiologic diagnosis and intervention with appropriate antimicrobial coverage. Literature reflects the rarity of this infection, predilections to specific susceptible hosts and the importance for raising awareness of zoonotic infections.
An investigation of scattered light integrating collector technology for rapid blood culture sensitivity testing
Authors: White L. , Hammond R. , Shorten R. J. , Derrick J. P.
Published: October 2024

Introduction. Sepsis rates are increasing, with Gram-negative organisms representing a large proportion of bloodstream infections. Rapid antibiotic administration, alongside diagnostic investigations, is required for the effective management of these patients.

Gap statement. Current diagnostics take ~48 h for a final report; therefore, rapid diagnostics are required.

Aim. This study investigated a novel antibiotic sensitivity method, the scattered light integrating collector (SLIC), combined with a rapid identification method using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) technology to determine if an accurate identification and susceptibility result can be provided within 4 h of a positive blood culture report.

Methodology. A total of 47 blood cultures containing Gram-negative bacteria from 46 patients were processed using the MALDI-TOF Biotyper Sepsityper for identification directly from the blood and the SLIC instrument for susceptibility testing. All organisms were also tested using the current standard workflow used in the host laboratory. Categorical agreement (CA), major errors (MaEs) and very major errors (VMEs) were determined.

Results. SLIC produced susceptibility results with a 71.9% CA, 30.6% MaE and 17.5% VME. The median difference in time to the final result was 44.14 (43 : 05–45 : 15) h earlier compared to the current method.

Conclusion. We conclude that SLIC was unable to consistently provide sufficiently accurate antibiotic susceptibility results compared to the current standard method.
An Open-Label, Interventional, Prospective, Real-World Evidence Study to Evaluate a Multimodal Wound Matrix in Patients with Refractory Wounds
Authors: Dhillon Yadwinder , Mulder Gerit , Patel Keyur D. , Moya Luis , Boghossian Gerard , Swain David , McLafferty Robert B. , Perez Kelly , Nguyen Jessica , Wilkinson Natalie , Arragon Jessica , Contreras Lilia , Geiger Donna , Cummings Ryan , LaVigne Brenda , Bell Desmond P. , Bakewell Suzanne J.
Published: October 2024

Objective

The objective of this open-label, interventional, prospective clinical study was to evaluate the effectiveness of a multimodal wound matrix (MWM), formulated for the treatment of chronic, non- healing wounds that had failed prior therapies. The overall response rate was the proportion of patients that had greater than 40% reduction in size after 4 weeks of treatment. Secondary objectives included the percentage area reduction (PAR) after 4 and 12 weeks, incidence of ulcers closing, and changes in quality of life.

Approach

An open-label, interventional, prospective cohort, real-world evidence study was conducted at 8 US wound care sites. Criteria included chronic non-healing wounds of multiple etiologies in patients with extensive comorbidities. Results were compared to data from the US Wound Registry.

Results

111 patients entered the screening phase and 63 were treated. 54 wounds were eligible for the dataset that included 18 DFUs, 19 VLUs, 2 pressure injuries, 1 surgical, 1 lower extremity wound, and 12 unclassified etiologies. The objective response rate was 42%. The 4-week PAR was 34%. The 12-week PAR was 66%. 18 wounds closed by week 12.

Innovation

MWM is a formulation technology developed to address the major obstacles that prevent healing. Results were evaluated in a patient population with extensive comorbidities who had failed prior treatments and would be generally excluded from controlled trials.

Conclusion

The results from this study support the contention that the multimodal wound matrix achieves substantial clinical improvement in a complex patient population not enrolled in clinical trials and demonstrates an advancement in wound management.
An analysis of buprenorphine distribution patterns among pharmacies and hospitals in the United States from 2019-2023
Authors: Gikoska Maria , Florio Anna K. , George Andrew , Piper Brian J.
Published: October 2024

Background

Opioid Use Disorder (OUD) is a debilitating condition characterized by the overuse of prescription opioid medications and the development of physical and/or psychological dependence. Consequences of this condition include chronic impairment, distress, and later life-altering health conditions such as overdose, all of which have been highlighted by the prominence of OUD in the United States in recent years. Buprenorphine is a standard OUD treatment and commonly used for pain management. Understanding changes in distribution patterns across the US is vital for continuing to improve outcomes for OUD patients.

Methods

This study analyzed changes in buprenorphine distribution among pharmacies and hospitals from 2019-2023 to determine temporal patterns and identify state level disparities. The Drug Enforcement Administrations’ Automated Reports and Consolidated Ordering System (ARCOS), US Census Bureau Population Estimates databases, and mortality rates (CDC WONDER) were analyzed. Data were corrected for population to identify patterns of buprenorphine distribution in the US from 2021-2022 and 2022-2023 through examining percent changes in milligrams per 100 population at national and state level.

Results

The year-to-year percent change of national buprenorphine distribution from pharmacies has remained positive but changed from 12.2% increase from 2019-2020 to a four percent increase every year from 2020-2023. From 2021-2022, there was a +4.9% increase in total grams of buprenorphine distributed to pharmacies and a 95% CI [-5.1, 14.9], with District of Columbia, South Dakota, and Nebraska outside of the 95% CI. Distribution to hospitals increased by 10.2% [-32.3, 52.7] during 2021-2022, with Hawaii, New Hampshire and Delaware being outside of 95% CI. From 2022-2023, there was an increase of +5.7% and 95% CI [-3.5, 14.9] in pharmacy distribution, with states including Washington, Rhode Island and Kansas remaining outside of the 95% CI. Hospital distribution has decreased from twenty percent between 2019-2020 to eighteen percent between 2022-2023. Changes in mortality data from 2022-2023 showed no associations with trends in buprenorphine distribution for those years.

Conclusion

Following increases in buprenorphine distribution during the COVID pandemic, a consistent increase has continued year-over-year in most states and the country overall by both pharmacies and hospitals. Some states (e.g. Rhode Island, Georgia, Washington D.C.) have not followed this pattern. Notably, Hawaii went from the most negative percent change in hospital distribution to the most positive change in the timeframe analyzed. This may offer opportunities to analyze more specific impacts of the increased buprenorphine distribution on populations and their outcomes associated with OUD.
From Past to Present: Pompe Disease, Pseudodeficiency Alleles, and Diagnostic Challenges
Authors: Giliberto Florencia , Buonfiglio Paula Inés , Capellino Gabriel , Massini Carmen Llames , Dalamón Viviana , Luce Leonela , Carcione Micaela
Published: October 2024

Pompe disease is an autosomal recessive disorder caused byGAAvariants leading to acid alpha-glucosidase deficiency. Diagnosis is challenging due to the variable phenotypic presentation and overlap with other conditions. Traditionally, diagnosis relies on measuring enzyme activity, but next-generation sequencing (NGS) advancements have improved accuracy. However, interpreting variants is complex, especially because pseudodeficiency alleles mimic disease-causing variants. We present two patients harboring the pseudodeficiency allele NM_000152.5(GAA):c.271G>A, p.Asp91Asn, which is confusing due to inaccurate reports and results related to enzymatic activity. The first case was a recently published controversial case of a 700-year-old mummy in which the authors classified the variant as pathogenic. The second patient had symptoms compatible with late-onset Pompe disease and was homozygous for the variant. We aimed to determine the correct variant classification usingGAA:c.271G>A as a model and to achieve a genetic diagnosis of the second patient. This variant was analyzed following international guidelines (ACMG-AMP) and reviewed with the Lysosomal Diseases Variant Curation Expert Panel. The second patient underwent NGS. We demonstrated thatGAA:c.271G>A meets the criterion of being classified as benign for Pompe. Additionally, the second patient carried a heterozygous pathogenicPABPN1variant associated with oculopharyngeal muscular dystrophy, which better explained the clinical features. This underscores the importance of expanding the genetic analysis in the presence of pseudodeficiency alleles that can mask the true cause of the disease and highlights the fact that an accurate diagnosis should adhere to guidelines on variant curation to reduce the risk of misdiagnosis, which could result in inadequate care and risky medical decisions.

Graphical abstract
Impaired semantic control in the logopenic variant of primary progressive aphasia
Authors: Henderson Shalom K. , Ramanan Siddharth , Rouse Matthew A. , Cope Thomas E. , Halai Ajay D. , Patterson Karalyn E. , Rowe James B. , Lambon Ralph Matthew A.
Published: October 2024

We investigated semantic cognition in the logopenic variant of primary progressive aphasia (lvPPA), including (i) the status of verbal and non-verbal semantic performance; and (ii) whether the semantic deficit reflects impaired semantic control. Oura priorihypothesis that individuals with lvPPA would exhibit semantic control impairments was motivated by the anatomical overlap between the temporoparietal atrophy typically associated with lvPPA and lesions associated with post-stroke semantic aphasia (SA) and Wernicke’s aphasia (WA), which cause heteromodal semantic control impairments. We addressed the presence, type (semantic representation and semantic control; verbal and non-verbal), and progression of semantic deficits in lvPPA. Since most people with lvPPA have Alzheimer’s disease (AD) pathology and are part of a broader multidimensional phenotype space encompassing AD subtypes, we compared semantic performance in lvPPA and typical amnestic AD (tAD). Given the differences in lesion and atrophy patterns in SA and WAversussemantic dementia/semantic-variant PPA patients, our second aim was to examine atrophy patterns in people with lvPPA and tAD compared to age-matched controls. Twenty-seven patients participated in the study. People were grouped into those meeting consensus criteria for lvPPA (N = 10) and others who may have previously satisfied definitions of lvPPA but had progressed with multi-domain cognitive impairments (herein referred to as “lvPPA+”; N = 8). People with tAD (N = 9) were relatively preserved across verbal and non-verbal semantic assessments. LvPPA patients were impaired on both verbal and non-verbal semantic tasks and their impairments showed the hallmark characteristics of a semantic control deficit. LvPPA and lvPPA+ patients showed effects of varying semantic control demands, positive cueing effects, and correlated performance between semantic and executive tasks. Whole-brain voxel-based morphometry, comparing each of the patient groups to age-matched controls, revealed significantly reduced grey and white matter in the bilateral hippocampi and lateral temporal regions in tAD patients. The lvPPA group exhibited an asymmetric pattern of reduced grey and white matter intensity in the language-dominant left hemisphere, including a significant portion of the lateral and medial temporal lobe. LvPPA+ patients demonstrated reduced grey and white matter in the left temporal lobe extending subcortically, anteriorly and posteriorly, as well as right temporal involvement. Our findings could aid diagnostic subtyping of PPA by adopting semantic control features and offer improved clinical characterisation of lvPPA in the trajectory of semantic decline.
Autoantibodies in maternal serum predict spontaneous preterm delivery
Authors: Rackaityte Elze , Borges Beltran , Shao Shirley J. , Creery Joseph S. , Kortbawi Hannah M. , Miller Haleigh S. , Mayer Margareta , Kouame Elaine , Mann Sabrina A. , McCarthy Frank , Oltman Scott , Zorn Kelsey C. , Kung Andrew F. , Mitchell Anthea , Rizzuto Gabrielle , Baer Rebecca J. , Mandel-Brehm Caleigh , Ryckman Kelli K. , Gaw Stephanie L. , Hillman Sara L. , Jelliffe-Pawlowski Laura L. , Halkias Joanna , Sobhani Nasim C. , Elias Joshua E. , MacKenzie Tippi C. , DeRisi Joseph L.
Published: October 2024

Complications from preterm birth are the leading cause of global mortality in children under age five1,2. Spontaneous preterm labor is the most common cause of preterm delivery and is associated with a breakdown of maternal-fetal tolerance3–5. However, the current understanding of the role of autoantibodies in this process has been limited to a handful of examples of pathogenic antibodies that occur with pregnancy complications6–14. Here, we employ proteome-wide autoantibody profiling via phage display immunoprecipitation and sequencing (PhIP-seq) to identify autoreactivities associated with imminent preterm delivery in maternal sera across four cohorts of human pregnancy (n=1,023). We find that spontaneous preterm pregnancies exhibit greater proteome-wide autoreactivity, validated by placental proteome immunoprecipitation mass spectrometry analysis using patient sera. Within the preterm birth associated autoreactive signature, we find enrichment for pathways known to be critical for normal pregnancy outcomes, including vascular development, reproductive hormones, and regulators of inflammation. Further analysis of autoreactive targets revealed involvement of the IL1β inflammatory cytokine cascade. IL1β is one of the few inflammatory cytokines sufficient to rapidly induce labor in animals15–24and it is also elevated in preterm human pregnancies25–29. Across these four cohorts, antibodies to cytokine IL1 receptor antagonist (IL1RA), a natural antagonist to IL1β are significantly enriched in roughly 10% of preterm pregnancies and yet are completely absent in term pregnancies. Sera from these patients functionally neutralizes IL1RA activityin vitroand anti-IL1RA induces greater resorption, inflammation, and vascular malperfusion in timed-pregnant micein vivo. These findings suggest utility for serologic diagnostics as one approach to stratify risk of spontaneous preterm delivery in addition to interventional strategies for management of IL1β during pregnancy.
Estimating the seroprevalence of tuberculosis (Mycobacterium bovis) infection in a wild deer population in southwest England
Authors: Jinks Rachel , Hollingdale Alison , Avigad Rachelle , Velarde Juan , Pugsley Chris , de la Rua-Domenech Ricardo , Pritchard Charlotte , Roberts Tony , Clark Julia , Robinson Nick , Maynes Ruth , Withenshaw Susan , Smith Graham
Published: October 2024

Bovine tuberculosis (bTB) is a major disease of cattle that is subject to an eradication strategy in England. To inform control policies and manage the epidemic, all potential sources of infection for cattle must be identified and understood. The causative agent of bTB,Mycobacterium bovis, has a wide host range including several deer species. While transmission between cattle and deer has been implicated in some localised endemic regions, the role of deer in the epidemiology of bTB in England is poorly understood. This paper presents the results of a serological survey to estimate the prevalence ofM. bovisin a large wild deer population in the High bTB Risk Area of southwest England.

Blood samples were collected post-mortem over a 12-month period from wild deer during annual deer management controls in the Exmoor area and tested forM. bovisserum antibodies. Overall, 432 samples were collected and 69 (16.0%) were seropositive. The true seroprevalence in our sample was estimated to be 29.2% (95% CrI 21.1-38.6%), using Bayesian Latent Class Analysis to account for imperfect diagnostic test accuracy. Prevalence did not appear to differ between sexes nor between species, although the sample was predominantly red deer. The lowest prevalence was observed in animals aged under 1-year.

Whilst these results provide valuable insights intoM. bovisseroprevalence in this wild deer population, they should be interpreted alongside other relevant information such as ecology, species-specific epidemiology and disease pathology, deer density and cattle management to inform potential transmission risks between cattle and wild deer.
Nuclear Histone 3 Post-translational Modification Profiling in Whole Cells using Spectral Flow Cytometry Histone H3 modification profiling using spectral flow
Authors: Golden Carly S , Williams Saylor , Blankevoort Sophia , Belkina Anna , Yost H. Joseph , Serrano Maria A
Published: October 2024

Discerning the dynamic nature of nuclear histone 3 post-translational modifications (H3-PTMs) is crucial for understanding gene regulatory mechanisms. Although conventional nuclear H3-PTM flow cytometry protocols currently offer acceptable sensitivity, they typically involve isolating nuclei prior to running the assay, leading to significant sample loss and limited throughput. To address these challenges, we present a high-throughput nuclear H3-PTM spectral flow cytometry protocol conducted directly in whole cells. By performing fixation, permeabilization, and antibody incubations in a 96-well plate format, we eliminate the need for nuclei isolation, thereby preserving sample integrity and increasing throughput. Notably, this protocol allows for the simultaneous assessment of histone PTMs, cytoplasmic proteins, plasma membrane receptors, and cell cycle analysis within the same cell, providing comprehensive insights into the status and functional utility of a cell. This approach not only streamlines experimental procedures but also enhances the efficiency and reproducibility of nuclear flow cytometry assays, allowing for a deeper exploration of epigenetic regulation across diverse biological samples.

Summary Statement

We present a protocol for multi-parameter analysis of cell cycle, histone modifications, and caspase 3 in NPCs, utilizing spectral flow cytometry for improved sensitivity and sample integrity without nuclear enrichment.
Meta2DB: Curated Shotgun Metagenomic Feature Sets and Metadata for Health State Prediction
Authors: Kok Car Reen , Mulakken Nisha J. , Thissen James B. , Martí Jose Manuel , Lee Ryan , Trainer Jacob B. , Goncalves Andre R. , Ranganathan Hiranmayi , Avila-Herrera Aram , Jaing Crystal J. , Be Nicholas A.
Published: October 2024

Meta2DB is a curated metagenomic and metadata database that provides structurally consistent microbiome taxonomy feature count tables for 13,897 samples across 84 studies, 23 disease states, and 34 geographical locations. All samples were uniformly processed using a streamlined metagenomic classification pipeline that employs a reference database indexed to contain all sequences across all kingdoms of life that were present in the NCBI Nucleotide (nt) database retrieved on Jan 04, 2023. This pipeline leverages high-performance computing (HPC) resources at Lawrence Livermore National Laboratory and was used to process 50TB of publicly available raw metagenomic sequence data. Extensive metadata curation was carried out through a combination of manual curation and automated parsing, producing a consistent inter-study metadata table specifically structured to facilitate training of ML models for prediction of human health.
Lipid Droplet Targeting of ABHD5 and PNPLA3 I148M is required to promote liver steatosis
Authors: Teskey Grace , Tiwari Nivedita , Butcko Andrew J , Kumar Amit , Yadav Anu , Huang Yu-ming M , Kelly Christopher V , Granneman James G G , Perfield James W , Mottillo Emilio P
Published: October 2024

The storage and release of triacylglycerol (TAG) in lipid droplets (LDs) is regulated by dynamic protein interactions. α/β hydrolase domain-containing protein 5 (ABHD5; also known as CGI-58) is a membrane/LD bound protein that functions as a co-activator of Patatin Like Phospholipase Domain Containing 2 (PNPLA2; also known as Adipose triglyceride lipase, ATGL) the rate-limiting enzyme for TAG hydrolysis. The dysregulation of TAG hydrolysis is involved in various metabolic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). We previously demonstrated that ABHD5 interacted with PNPLA3, a closely related family member to PNPLA2. Importantly, a common missense variant in PNPLA3 (I148M) is the greatest genetic risk factor for MASLD. PNPLA3 148M functions to sequester ABHD5 and prevent co-activation of PNPLA2, which has implications for initiating MASLD; however, the exact mechanisms involved are not understood. Here we demonstrate that LD targeting of both ABHD5 and PNPLA3 I148M is required for the interaction. Molecular modeling demonstrates important resides in the C-terminus of PNPLA3 for LD binding and fluorescence cross-correlation spectroscopy demonstrates that PNPLA3 I148M greater associates with ABHD5 than WT PNPLA3. Moreover, the C-terminus of PNPLA3 is sufficient for functional targeting of PNPLAs to LD and the interaction with ABHD5. In addition, ABHD5 is a general binding partner of LD-bound PNPLAs. Finally, PNPLA3 I148M targeting to LD is required to promote steatosis in vitro and in the liver. Overall results suggest that PNPLA3 I148M is a gain of function mutation and that the interaction with ABHD5 on LD is required to promote liver steatosis.