bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Quality Dietary Protein: The Key to Healthy Granulation Tissue
Authors: Chu Andy S. , Delmore Barbara , Chiu Ernest S.
Published: October 2024

Wound healing is a complex process, particularly for full-thickness, chronic wounds. The processes of wound healing phases require support in order for wound healing to progress and be successful. Chronic wounds present a particular conundrum because they represent a dysfunction or interruption generally occurring between the inflammatory and proliferative phases. This progress remains delayed until the dysfunction is addressed. Older patients and those who are critically ill are generally most at risk of developing a chronic wound. A nonhealing wound is associated with increased healthcare costs and poor patient outcomes. Thus, it is imperative to promote the wound healing processes, reduce healthcare costs, and foster good patient outcomes.

Providers should address clinical issues when stalling is noted and there is a lack of progression through the phases of wound healing. One important issue to address is nutrition, because of its role in the formation of granulation tissue. Unfortunately, the importance of nutrition and its impact on successful wound healing are often overlooked. The literature is replete with nutrition measures that support wound healing, including the importance of protein; however, these are often not specific to the importance of protein in the formation of granulation tissue during the proliferative stage. In this article, the authors discuss the role of protein in creating healthy granulation tissue in the adult patient with a full-thickness wound.

GENERAL PURPOSE

To review the role of nutrition and high-quality dietary protein intake in creating healthy granulation tissue and optimize wound healing in patients with chronic wounds.

TARGET AUDIENCE

This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and registered nurses with an interest in skin and wound care.

LEARNING OBJECTIVES/OUTCOMES

After participating in this educational activity, the participant will:1. Summarize the structure and composition of proteins. 2. Specify the role of proteins in generating healthy granulation tissue and wound healing. 3. Explain the physiologic pathways involved in the wound healing process. 4. Describe evidence-based interventions to support nutrition in wound healing.
Hearing Screening in Older Adults in Primary Care Clinics: How the Effects of Setting and Provider Encouragement Differ by Patient Sex and Race
Authors: West Jessica S. , Dubno Judy R. , Francis Howard W. , Smith Sherri L.
Published: October 2024

Objectives:

Few studies have examined how patient sex or race influence hearing healthcare, which was our study purpose.

Design:

We performed a secondary analysis using data from a pragmatic clinical trial that examined the effect of provider encouragement (yes/no) or setting (at-home/clinic) for older adults to follow through with routine hearing screening in primary care and the hearing healthcare pathway. Three protocols were compared: at-home screening without provider encouragement, at-home screening with provider encouragement, and in-clinic screening with provider encouragement.

Results:

Poisson regression (n = 627) showed few differences by patient sex but showed that Black patients in the at-home protocols were less likely to schedule or complete a formal diagnostic evaluation after a failed screening compared with Black patients in the clinic setting and White patients in all groups. Black patients, regardless of provider encouragement, were less likely to schedule or complete a diagnostic evaluation compared with White patients.

Conclusions:

Results suggest that in-clinic screenings may increase the use of hearing healthcare for Black patients.
A Biomechanical Analysis of Instrumentation Constructs During Vertebral Column Resection: Stability When You Need It!
Authors: Shaw K. Aaron , Niese Brad , Sucato Daniel J.
Published: October 2024

Study Design:

Biomechanical Testing

Objective:

Investigate the optimal construct for stabilization of the spine during vertebral column resection (VCR).

Summary of Background Data:

VCR is a powerful technique for achieving correction in severe cases of spinal deformity. However, this also creates an unstable spine which requires stable fixation to prevent iatrogenic neurologic injury. It is common practice to place a temporary unilateral rod configuration to achieve this stability during surgery but no study to date has investigated the optimal construct configuration.

Methods:

A unilateral VCR model representing an acute 50° kyphotic deformity with a standardized 30 mm resection was created. Three conditions underwent testing: 1) Rod material and diameter, 2) rod configuration, and 3) number of fixation points. Six unique samples were tested in each group in both flexion-extension. Prior to testing a 10N preload and underwent cyclical testing in flexion/extension. System stiffness was calculated and compared across groups.

Results:

Assessment of rod size and composition using a single screw construct (2 total screws) demonstrated that for Titanium (Ti) rods, increasing rod size significantly increased the construct stiffness (P=0.001). Although Cobalt-chromium (Co-Cr) rods where significantly stiffer than the corresponding sized Ti rods, there was no significant difference between rod diameters for Co-Cr (P=0.98). However, when tested using a dual screw (4 total screws) construct, these constructs were significantly stiffer than the corresponding single screw constructs (P<0.0001). Of the various rod configurations, the dual rod demonstrated the greatest stiffness (34.8±2.1 N/mm; P<0.0001).

Conclusion:

Surgical construct stiffness during a VCR is multifactorial. Larger rod diameter, increased number of fixation points, stiffer rod material, and increased number of rods across the resection site increase the construct stiffness. With minimal points of fixation using Co-Cr rods, increasing rod diameter does not impart greater construct stiffness unless additional fixation points are included.
Association Between Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Outcomes in Patients With Acute Coronary Syndrome Who Have Quit Smoking: Study Design of a Prospective Cohort Study
Authors: Li Jing , Qi Zizhao , Xu Ying , Cao Yinan , Li Yi , Han Yaling
Published: October 2024

Despite quitting smoking, patients with acute coronary syndrome (ACS) still have an increased risk of cardiovascular events. Clonal hematopoiesis of indeterminate potential (CHIP), which may be induced by smoking, has been identified to be associated with the development of coronary artery disease. However, it is unclear whether CHIP has a detrimental effect on the poor prognosis of ACS patients even after smoking cessation. This single-center, prospective cohort study will recruit 1,029 ACS patients undergoing complete percutaneous coronary intervention. The enrolled patients will be categorized into 3 groups based on their smoking status at admission: current smoker, non-smoker, and previous smoker. Previous smokers are defined as patients who have quit smoking for at least 1 year before experiencing the index ACS event. Whole-exome sequencing will be performed to identify the occurrence of CHIP in each patient. The primary endpoint is major adverse cardiovascular and cerebrovascular events, defined as a composite of cardiac death, non-fatal myocardial infarction, ischemia-driven revascularization, hospitalization for heart failure, and ischemic stroke. The association between CHIP and the primary endpoint will be determined by using Cox proportional hazard regression. This study aims to investigate the association among smoking cessation, CHIP, and the prognosis of ACS patients to provide new insights into the impact of CHIP on ACS patients, particularly among those who have quit smoking. The results will be published following the STROBE in a peer-reviewed scientific journal (Trial registration number: NCT04987268).
Selective Clonal Regression After Interferon Therapy in Metastatic Melanoma
Authors: Fernandez-Flores Angel
Published: October 2024

Regression (total or partial) is a common phenomenon in melanoma. From a pathogenic perspective, it is highly complex and only partially understood, involving aspects of both the tumor and the individual. One of the determining factors is the clonal selection of the tumor, wherein some clones within the tumor survive while others perish. This clonal selection can sometimes occur as a selective mechanism after the initiation of a therapeutic intervention. In many of these cases, the effect is detrimental, because the surviving clone is resistant to the applied therapy. However, occasionally, the therapy can successfully select the less harmful clone. We present an example of the latter, where therapy with interferon induced regression of the metastatic-capable melanocytic population, with only the primary tumor melanocytic population persisting. To confirm this, we demonstrated BRAF mutational similarity between the 2 populations, and an additional NRAS mutation in the metastatic population, which was absent in the primary tumor.
Perianal Pulse Granuloma Induced by Plant-Derived Baby Wipes
Authors: Wang Robin H. , Lullo Jenna J. , Dahiya Madhu , Eilers David B.
Published: October 2024

Pulse granulomas are unusual foreign body reactions to exogenous plant material, featuring the presence of hyaline ring structures and granulomatous inflammation. Pulse granulomas have been reported to occur in the oral cavity, gastrointestinal tract, and respiratory tract. Cutaneous pulse granulomas are exceedingly rare. All reported cases have been closely associated with underlying pathology such as chronic inflammatory conditions, trauma, or surgical procedures which likely facilitated implantation of exogenous plant material. We report a novel case of a cutaneous pulse granuloma presenting in the perianal region of an otherwise healthy man. The authors propose that the source of the exogenous plant material is plant-derived baby wipes, which the patient had been using daily to the perianal region.
Strengthening the Multiple-Choice Assessment: Improving Item-Writing Skills of Physician Assistant Educators
Authors: Buterbaugh Abigail
Published: October 2024

Physician assistant (PA) educators are tasked with the challenging privilege of ensuring future PAs are knowledgeable and competent to practice medicine. Most enter academia without formal education in providing education. They learn as they go—a treacherous and steep learning curve. This study provides PA educators literature and skills to bolster the strength and validity of multiple-choice examination items to measure learner progress and identify knowledge gaps. Skills can be improved at the level of the individual educator and program or institution. Approaching item writing and item revision in a stepwise, evidence-based manner can improve the quality of the items, strengthening multiple-choice examinations. This process can yield improved assessments of students' medical knowledge and competence. This study aims to provide the PA educator with techniques to improve their item-writing skills.
Effect of NGN-Style Case Studies on Nursing Students’ Anxiety and Self-Confidence With Clinical Decision-Making
Authors: Ross Jennifer G. , Caputo Thomas , Scheve Ann
Published: October 2024

Background:

The Next Generation National Council Licensing Examination (NCLEX) uses the Clinical Judgment Measurement Model in unfolding case studies to assess graduate nurses’ clinical judgment.

Purpose:

This study explored the impact of Next Generation NCLEX (NGN)-style case studies on baccalaureate nursing students’ self-confidence and anxiety with clinical decision-making.

Methods:

Seventy-six second-year baccalaureate nursing students participated in this 1-group convergent mixed-methods study. Students completed 7 NGN-style case studies during a Nursing Essentials course. Data were collected at the beginning and end of the semester.

Results:

Anxiety with clinical decision-making significantly decreased, and self-confidence with clinical decision-making significantly increased from pretest to posttest. Five qualitative themes derived from open-ended responses: realistic application of theory to practice, critical thinking, feedback, collaboration, and NCLEX preparation.

Conclusions:

This study provides preliminary evidence that formative NGN-style case studies are well received by students and result in positive outcomes. Further research is needed to more fully understand the effects of NGN-style case studies.
Development of a Virtual Pediatric Holistic Comfort Care Clinic
Authors: Braswell April A. , Denning Brittany , O’Brien Coleen E. , Harris Avianne
Published: October 2024

Background:

Guided by the tenets of Kolcaba’s holistic comfort theory, we developed, implemented, and evaluated a simulated online pediatric advanced practice health center. The Pediatric Comfy Care Clinic (PCCC) was created to enhance person-centered diagnostic reasoning and holistic advanced management skills for family nurse practitioner students.

Methods:

Our interprofessional team used a standardized approach to online design and development while integrating essential holistic comfort theory concepts for student engagement and assessment of learning. We explored outcomes of pre- and postclinic quizzes and student reflection data using mixed methods.

Results:

Significant differences (P < .001) were noted in all postpractice quizzes in each affiliated PCCC module with variable student outcomes on graded clinic encounters. Important student perspectives on teaching and learning in the virtual clinic were noted.

Conclusion:

A comfort theory-driven, simulated, and digitally enhanced virtual clinic is feasible and valuable with important implications for holistic advanced practice.
HIV and Viremia Prevalence in Nonmigrating Members of Migrant Households in Southern Uganda: A Cross-Sectional Population-Based Study
Authors: Young Ruth , Ssekasanvu Joseph , Kagaayi Joseph , Ssekubugu Robert , Kigozi Godfrey , Reynolds Steven J. , Nonyane Bareng A. S. , Chang Larry W. , Kennedy Caitlin E. , Paina Ligia , Anglewicz Philip A. , Quinn Thomas C. , Serwadda David , Nalugoda Fred , Grabowski M. K.
Published: October 2024

Introduction:

In Africa, migrants are more likely to be living with HIV and HIV viremic than nonmigrants, but less is known about HIV outcomes among nonmigrants living in households with migrants. We compared HIV outcomes in nonmigrating persons in households with and without migration.

Methods:

We analyzed cross-sectional data collected between August 2016 and May 2018 from nonmigrating participants aged 15–49 years in the Rakai Community Cohort Study in Uganda. Migrant households were classified as those reporting ≥1 member moving into or out of the household since the prior survey. HIV serostatus was determined using a validated testing algorithm, and viremia defined as >1000 copies/mL. Modified Poisson regression was used to estimate prevalence ratios between household migration and HIV outcomes. Analyses were stratified by gender, direction of migration (into/out of household), and relationship between nonmigrants and migrants (eg, spouse).

Results:

There were 14,599 nonmigrants (52% women) and 4415 (30%) lived in a household with ≥1 migrant. Of these, 972 (22%) had migrant spouses, 1102 (25%) migrant children, and 875 (20%) migrant siblings. Overall, HIV prevalence and viremia did not differ between nonmigrants in households with and without migration. However, in stratified analyses, nonmigrant women with migrant spouses were significantly more likely to be HIV seropositive compared with nonmigrant women with nonmigrant spouses [adjusted prevalence ratio: 1.44, 95% confidence interval: 1.21 to 1.71]. Conversely, nonmigrant mothers living with HIV who had migrant children were less likely to be viremic (adjusted prevalence ratio: 0.34, 95% confidence interval: 0.13 to 0.86).

Conclusions:

Nonmigrating women with migrating spouses are more likely be living with HIV, and may benefit from additional HIV support services.
Differences in Utilization of Preventive Services for Primary Care Clinicians Participating in MIPS and ACOs
Authors: Shrestha Mina , Sharma Hari , Mueller Keith J.
Published: October 2024

Background and Objective:

Value-based payment programs link payments to the performance of providers on cost and quality of care to incentivize high-value care. To improve quality and lower costs, the Centers for Medicare and Medicaid Services (CMS) implemented the Quality Payment Program (QPP) for clinicians in 2017. Under the Medicare QPP, most eligible clinicians participate in one of the payment models: (a) Advanced Alternative Payment Models (A-APMs) through eligible APMs like Accountable Care Organizations (ACOs) or (b) the Merit-based Incentive Payment System (MIPS). ACO and MIPS clinicians participating in QPP differ in quality reporting requirements, and these differences are likely to affect the utilization of different quality measures, including preventive services. This study evaluated the differences in the utilization of preventive services by primary care clinicians participating in MIPS and ACOs.

Methods:

We use difference-in-difference regressions to compare preventive services in MIPS versus ACOs. Since preventive services like immunization and certain cancer screening are mandatory reporting measures for ACOs and voluntary measures for MIPS, the treatment group for this study is ACO clinicians and the comparison group is non-ACO MIPS clinicians. We obtained the rates of influenza immunization, pneumonia vaccination, tobacco use cessation intervention, depression screening, colorectal cancer screening, breast cancer screening, and wellness visits per 10 000 Medicare beneficiaries from Medicare Provider Utilization and Payment Public Use File (2012-2018).

Results:

We had 508 144 total observations (ACO = 25.78% and MIPS = 74.22%) from 72 592 unique primary care clinicians. Compared to MIPS clinicians, ACO clinicians had significantly higher rates of pneumonia vaccination (incidence rate ratio [IRR] 1.25; 95% confidence interval [CI], 1.10-1.43) but lower rates of colorectal cancer screening (IRR 0.69; 95% CI, 0.50-0.96). Similarly, clinicians in ACO shared savings-only models had significantly higher rates of pneumonia vaccination (IRR 1.28; 95% CI, 1.11-1.48), depression screening (IRR 1.72; 95% CI, 1.09-2.71), and wellness visits (IRR 1.27; 95% CI, 1.09-1.47) compared to MIPS clinicians. There were no differences between ACO and MIPS clinicians on the utilization of breast cancer screening procedures and tobacco use cessation interventions.

Conclusions:

ACO clinicians may have prioritized relatively low-cost services such as pneumonia vaccination, depression screening, and wellness visits to improve their performance under QPP. Policymakers may need to alter incentives in performance-based payment programs to ensure that clinicians are improving all types of quality measures, including cancer screening.
Paraneoplastic Proliferative Myositis on 18F-FDG PET/CT
Authors: Wakankar Ritwik , Bal Jaspriya , Dougall Pankaj
Published: October 2024

We present a rare and never-before-reported case of paraneoplastic proliferative myositis that was incidentally detected in a 42-year-old man who had been receiving systemic cytotoxic chemotherapy for classic Hodgkin lymphoma. We highlight his 18F-FDG PET/CT findings and its utility in helping to diagnose this condition, avoiding unnecessary surgical resection and the added costs associated with it.
A Rare Case of Tumor-Induced Osteomalacia Due to Mesenchymal Tumor at Foramen Magnum Diagnosed Preoperatively on 68Ga DOTATATE PET/CT
Authors: Mouli Chandra , Lila Anurag , Gondhane Abhay , Malhotra Gaurav , Bandgar Tushar
Published: October 2024

A 42-year-old man, a known case of FGF23-dependent hypophosphatemia, underwent 68Ga- DOTATATE PET-CT, which showed a somatostatin receptor–expressing lesion in the left arch of foramen magnum that was correlated on MRI as a soft tissue lesion measuring 2.2 × 1.3 cm. It was excised and histopathologically confirmed as phosphaturic mesenchymal tumor. Postoperatively, patient improved clinically and recovered from hypophosphatemia completely. A distinct focal uptake in a 68Ga- DOTATATE PET-CT in a patient with tumor-induced osteomalacia needs extensive workup and high degree of suspicion to rule out mesenchymal tumor at nonconventional location as seen in the present case.
Improvement in Health-Related Quality of Life and Symptoms Following Lipedema Liposuction
Authors: Karri Vasu
Published: October 2024

Background

Lipedema is a chronic fat disorder characterized by disproportionate fat deposition in the lower limbs, leading to pain, mobility issues and reduced health related quality of life (HRQoL).

There is growing evidence that liposuction of the excess fat not only reduces soft tissue pain but also improves HRQoL. The published data, however, remain limited, and there are no studies of liposuction in the UK lipedema population. This study aimed to evaluate the effectiveness of liposuction on HRQoL and symptoms in UK lipedema patients using 2 HRQoL instruments and a Lipedema Symptom Scale.

Patient and Methods

Lipedema patients undergoing liposuction between January 2016 and December 2021 completed Short-Form Health Survey (SF-36), World Health Organization Quality-of-Life Assessment (WHOQOL-BREF), and 17-question Lipedema Symptom Scale preoperatively and postoperatively. Paired t test was used to compare the preoperative and postoperative mean scores of the different domains of the SF-36 and WHOQOL-BREF and preoperative and postoperative mean scores for the lipedema symptom scale. Paired t test was also used to compare preoperative and postoperative SF-36 scores to age-matched normative data for the English population to assess the extent of HRQoL improvement relative to the general population.

Results

Seventy-six women were included in the study with a mean age of 46.4 ± 12 years. Mean follow-up (interval between first liposuction surgery and postoperative completion of the instruments) was 25.3 ± 23.2 months. There was significant improvement in all SF-36 and WHOQOL-BREF domains postoperatively (P < 0.001). Compared with age-matched normative data, postoperative SF-36 scores remained lower in physical functioning, social functioning, and general health. Postoperative results also showed a highly significant improvement (P < 0.001) across all 17 items of the Lipedema Symptom Scale.

Conclusion

This longitudinal study indicates liposuction is an effective treatment for improving HRQoL and symptoms in lipedema patients, although it may not completely restore HRQoL to normative levels. Limitations include potential selection bias, sampling bias, and the need for longer follow-up. The findings support liposuction as a first-line treatment for lipedema and could inform decision-making for both patients and policymakers.
Mandibular Condylar Head Regeneration Owing to Remodeling of the Costochondral Graft After Condylectomy for Odontogenic Myxoma
Authors: Seok Hyun
Published: October 2024

Odontogenic myxoma of the mandibular condyle is a rare tumor that requires complete surgical resection because of the tendency for recurrence. The right mandibular condyle was resected to remove the myxoma. The author performed immediate condylar reconstruction using a costochondral graft (CCG), and stable temporomandibular joint (TMJ) function and occlusion were achieved. During follow-up, the grafted CCG healed well, and a favorable bony union with the mandibular ramus was observed. Furthermore, unexpected bony remodeling was observed in the CCG; growth of the cartilaginous part resulted in the formation of a structure similar to the condylar head, and the body of the rib bone thickened similar to the mandibular subcondylar region. In conclusion, the author reported the successful removal of an odontogenic myxoma from the right mandibular condyle via condylectomy, condylar reconstruction using a CCG, and condylar head regeneration owing to CCG remodeling.
Perfusate Biomarkers of DCD Cardiac Graft Quality Identified With Proteomics: Studies in an Isolated Rat Heart Model
Authors: Clavier Alexia , Arnold Maria , Segiser Adrian , Méndez-Carmona Natalia , Wyss Rahel , Heller Manfred , Uldry Anne-Christine , Siepe Matthias , Longnus Sarah
Published: October 2024

Background.

Heart transplantation with donation after circulatory death (DCD) enhances cardiac graft availability, but exposes hearts to potentially damaging conditions, such as warm ischemia. Normothermic machine perfusion (NMP), used for graft transportation, allows biomarker determination in perfusate. Using our isolated, rat heart model of DCD, we evaluated potent.

Methods.

Isolated, perfused adult male Wistar rat hearts (n = 5/group) underwent different warm ischemic durations to simulate DCD, followed by reperfusion to simulate NMP. Perfusate samples were collected after 10 min reperfusion, and proteins were analyzed using mass spectrometry. Cardiac recovery was evaluated after 60 min reperfusion. The relationship between perfusate proteins and cardiac recovery was investigated.

Results.

Cardiac recovery decreased with increasing ischemic duration. Principal component analysis of perfusate proteins demonstrated segregation by ischemic group. Several proteins demonstrated an On-Off pattern, and correlated with key outcome measurements. Other proteins were released by all hearts and were confirmed as predictors of cardiac recovery, for example, heat shock protein 70 and valosin-containing protein (area under the curve [AUC] = 0.962–0.968, respectively; P < 0.05 for all). Additionally, proteins such as glycogen phosphorylase, muscle associated (AUC = 0.9632; P < 0.05) showed potential as novel biomarkers for evaluating cardiac graft quality, unlike lactate release after 10 min of reperfusion (AUC = 0.60).

Conclusions.

Multiple perfusate proteins, such as heat shock protein 70, valosin-containing protein, or glycogen phosphorylase, muscle associated, released during early reperfusion are promising as biomarkers for assessing graft quality during NMP. Perfusate proteins, as biomarkers, offer the possibility of both rapid immune detection and out-of-hospital implementation, and may provide valuable information about graft quality, especially when profiled with serial sampling during NMP.
Exploring Outcomes and Engagement Patterns of Hypertensive Patients: An Observational Analysis of the Withings Remote Patient Monitoring Program
Authors: Letzelter Philomène , Vittrant Benjamin , Tunis Rachel
Published: October 2024

Background

Hypertension is a health issue that affects more than one billion people worldwide and can lead to severe health complications. If untreated, hypertensive crises can occur, which are medical emergencies that require immediate care. Remote Patient Monitoring (RPM) offers a transformative approach to managing hypertension by enabling continuous collection and analysis of blood pressure (BP) data. Our study focuses on Withings’ RPM system and analyzes the outcomes and engagement patterns of patients using RPM for hypertension management.

Methods

The study comprises 1,873 patients over 6 months who followed an RPM program and used Withings Blood Pressure Monitors. Data was analyzed using Python and R. The analysis examines patients’ systolic and diastolic BP over time as well as the frequency of measurements that patients took using the RPM system.

Results

The study reveals that patients who consistently followed the program experienced significant reductions in both systolic and diastolic BP levels. Statistically significant reductions in SBP were observed in users with higher grades of hypertension over six months. The percentage of users experiencing hypertensive crises was reduced from more than 8% to less than 3% over 24 weeks. More frequent engagement with the RPM program was associated with greater BP reductions.

Conclusion

These findings highlight the potential of RPM programs in helping patients manage hypertension and minimize hypertensive crises. Future research should go further to understand factors that impact patient outcomes and engagement patterns to improve the effectiveness of RPM programs.
Mapping intratumoral myeloid-T cell interactomes at single-cell resolution reveals targets for overcoming checkpoint inhibitor resistance
Authors: Bridges Kate , Pizzurro Gabriela A. , Baysoy Alev , Baskaran Janani P. , Xu Ziyan , Mathew Varsha , Tripple Victoria , LaPorte Michael , Park Koonam , Damsky William , Kluger Harriet , Fan Rong , Kaech Susan M. , Bosenberg Marcus W. , Miller-Jensen Kathryn
Published: October 2024

Effective cancer immunotherapies restore anti-tumor immunity by rewiring cell-cell communication. Treatment-induced changes in communication can be inferred from single-cell RNA-sequencing (scRNA-seq) data, but current methods do not effectively manage heterogeneity within cell types. Here we developed a computational approach to efficiently analyze scRNA-seq-derived, single-cell-resolved cell-cell interactomes, which we applied to determine how agonistic CD40 (CD40ag) alters immune cell crosstalk alone, across tumor models, and in combination with immune checkpoint blockade (ICB). Our analyses suggested that CD40ag improves responses to ICB by targeting both immuno-stimulatory and immunosuppressive macrophage subsets communicating with T cells, and we experimentally validated a spatial basis for these subsets with immunofluorescence and spatial transcriptomics. Moreover, treatment with CD40ag and ICB established coordinated myeloid-T cell interaction hubs that are critical for reestablishing antitumor immunity. Our work advances the biological significance of hypotheses generated from scRNA-seq-derived cell-cell interactomes and supports the clinical translation of myeloid-targeted therapies for ICB-resistant tumors.
Molecular basis for the increased membrane fusion activity of the Ebola virus glycoprotein A82V variant from the 2013-2016 epidemic: insights from simulations and experiments
Authors: Durham Natasha D. , Jain Aastha , Howard Angela , Luban Jeremy , Munro James B.
Published: October 2024

During the 2013-2016 Ebola virus epidemic in Western Africa, an A82V mutation emerged in the envelope glycoprotein (GP) that persisted in most circulating isolates. Previous studies demonstrated that A82V increased GP-mediated membrane fusion and altered its dependence on host factors. The mechanistic basis for these observations, in particular the impact of A82V on the conformational changes in GP that are needed for membrane fusion, has not been evaluated in molecular detail. Here, using a combination of molecular dynamics simulations, fluorescence correlation spectroscopy, and a novel single-molecule Förster resonance energy transfer imaging assay, we specify the molecular mechanism by which A82V alters GP conformation to enhance GP-mediated viral entry. In so doing, we identify an allosteric network of interactions that links the receptor-binding site to the fusion loop of GP. Thus, the naturally occurring A82V mutation can tune the conformational dynamics of EBOV GP to enhance fusion loop mobility and subsequent viral fusion and infectivity in human cells.
Influenza vaccine effectiveness against medically attended outpatient illness, United States, 2023–24 season
Authors: Chung Jessie R. , Price Ashley M. , Zimmerman Richard K. , Geffel Krissy Moehling , House Stacey L. , Curley Tara , Wernli Karen J. , Phillips C. Hallie , Martin Emily T. , Vaughn Ivana A. , Murugan Vel , Scotch Matthew , Saade Elie A. , Faryar Kiran A. , Gaglani Manjusha , Ramm Jason D. , Williams Olivia L. , Walter Emmanuel B. , Kirby Marie , Keong Lisa M. , Kondor Rebecca , Ellington Sascha R. , Flannery Brendan ,   US Flu VE Network Investigators
Published: October 2024

Background

The 2023–24 U.S. influenza season was characterized by a predominance of A(H1N1)pdm09 virus circulation with co-circulation of A(H3N2) and B/Victoria viruses. We estimated vaccine effectiveness (VE) in the United States against mild-to-moderate medically attended influenza illness in the 2023–24 season.

Methods

We enrolled outpatients aged ≥8 months with acute respiratory illness in 7 states. Respiratory specimens were tested for influenza type/subtype by reverse-transcriptase polymerase chain reaction (RT-PCR). Influenza VE was estimated with a test-negative design comparing odds of testing positive for influenza among vaccinated versus unvaccinated participants. We estimated VE by virus sub-type/lineage and A(H1N1)pdm09 genetic subclades.

Results

Among 6,589 enrolled patients, 1,770 (27%) tested positive for influenza including 796 A(H1N1)pdm09, 563 B/Victoria, and 323 A(H3N2). Vaccine effectiveness against any influenza illness was 41% (95% Confidence Interval [CI]: 32 to 49): 28% (95% CI: 13 to 40) against influenza A(H1N1)pdm09, 68% (95% CI: 59 to 76) against B/Victoria, and 30% (95% CI: 9 to 47) against A(H3N2). Statistically significant protection against any influenza was found for all age groups except adults aged 50–64 years. Lack of protection in this age group was specific to influenza A-associated illness. We observed differences in VE by birth cohort and A(H1N1)pdm09 virus genetic subclade.

Conclusions

Vaccination reduced outpatient medically attended influenza overall by 41% and provided protection overall against circulating influenza A and B viruses. Serologic studies would help inform differences observed by age groups.

Key Points

Influenza vaccine reduced the risk of outpatient illness due to influenza during the 2023–24 season. Protection varied by age group and influenza virus type.
Sequential transcriptional programs underpin activation of quiescent hippocampal stem cells
Authors: Rigo Piero , Ahmed-de-Prado Sara , Johnston Rebecca L. , Choudhury Chandra , Guillemot François , Harris Lachlan
Published: October 2024

Postnatal neural stem cells are primarily quiescent, which is a cellular state that exists as a continuum from deep to shallow quiescence. The molecular changes that occur along this continuum are beginning to be understood but the transcription factor network governing these changes has not been defined. We show that these transitions are regulated by sequential transcription factor programs. Single-cell transcriptomic analyses of mice with loss- or gain-of-function of the essential activation factorAscl1, reveal that Ascl1 promotes the activation of hippocampal neural stem cells by driving these cells out of deep quiescence, despite its low protein expression. Subsequently, during the transition from deep to shallow quiescence,Ascl1induces the expression ofMycn, which drives progression through shallow states of quiescence towards an active state. Together, these results define the required sequence of transcription factors during hippocampal neural stem cell activation.
Orexinergic projections to substantia innominata mediate arousal and analgesia
Authors: Xiang Xuaner , Wang Fei , Chen Chao , Guan Zhonghui , Zhou Wei
Published: October 2024

Understanding neural circuits involved in anesthesia is crucial for improving its safety and efficacy. Hypothalamic orexin neurons (LHAOX), projecting broadly, are essential in regulating arousal and pain. However, the precise targets remain unclear. Here we investigated the orexin projections to the substantia innominata (SI). Combining optogenetics, fiber photometry, and EEG/EMG allowed us to manipulate orexin activities, while simultaneously recording local ligand release and global cortical activities during anesthesia. Brain slice electrophysiology revealed the synaptic connections in the SI, while RNAscope was employed to examine the distribution of orexin receptors and downstream neuronal types. Presynaptic vesicles were identified in the orexin terminals in the SI, where 49.16% of cells expressed OX2R and 6.8% expressed OX1R. Orexin release in the SI was reversibly suppressed by isoflurane. Optogenetic activation of the LHAOX→SI circuit significantly increased orexin release and promoted arousal from various anesthesia stages, including reanimation during 0.75% isoflurane (p < 0.0001), prolongation of 3% isoflurane induction (p = 0.0033), and acceleration of emergence from 2% isoflurane (p < 0.0001). Furthermore, activating this circuit induced analgesia to both thermal (p = 0.0074) and inflammatory (p = 0.0127) pain. Patch-clamp recordings revealed that optogenetic activation of orexin terminals in the SI elicited excitatory postsynaptic currents, which were blocked by the OX2R antagonist. SI contains more GABAergic (28.17%) and glutamatergic (11.96%) neurons than cholinergic neurons (4.13%), all of which expressed OX2R. Thus, LHAOXneurons innervate SI neurons to regulate both arousal and pain predominantly through OX2R.
Deep generative design of neutralizing nanobodies against SARS-CoV-2 variants
Authors: Huo Liyun , Tian Tian , Xu Yanqin , Qin Qin , Jiang Xinyi , Huang Qiang
Published: October 2024

In recent years, single-domain heavy chain antibodies (nanobodies), with only one-tenth the molecular weight of conventional antibodies, have emerged as important therapeutic proteins in the fight against SARS-CoV-2. However, the rapid mutation of the virus often renders existing nanobodies ineffective, underscoring the need to develop nanobodies that specifically target new variants. Traditional methods for discovering nanobodies are time-consuming and complex, making it difficult to efficiently identify nanobodies that bind to specific epitopes. To address this, we propose a de novo nanobody design method based on a Generative Adversarial Network (GAN). We developed a deep generative model, AiCDR, which consists of three discriminators and one generator. By determining the contribution of these three discriminators to the entire network, we can enhance the discrimination of generated sequences and reduce the similarity of the generated CDR3 sequences with natural peptides and random sequences, thereby ensuring their nature-like properties. These generated CDR3 sequences were then grafted onto humanized nanobody scaffolds, resulting in a structural library of approximately 104nanobodies with natural-like properties. Using computational methods, we screened this library against the Spike (S) protein of the SARS-CoV-2 Omicron variant and identified 10 candidate nanobodies. Functional assays confirmed that two of these nanobodies exhibited neutralizing activity against the S protein. Our study demonstrates the potential of deep learning in nanobody design and offers a novel approach for developing nanobodies that target rapidly evolving viral variants.
Larger models yield better results? Streamlined severity classification of ADHD-related concerns using BERT-based knowledge distillation
Authors: Karim Ahmed Akib Jawad , Asad Kazi Hafiz Md. , Alam Md. Golam Rabiul
Published: October 2024

This work focuses on the efficiency of the knowledge distillation approach in generating a lightweight yet powerful BERT-based model for natural language processing (NLP) applications. After the model creation, we applied the resulting model, LastBERT, to a real-world taskclassifying severity levels of Attention Deficit Hyperactivity Disorder (ADHD)-related concerns from social media text data. Referring to LastBERT, a customized student BERT model, we significantly lowered model parameters from 110 million BERT base to 29 million-resulting in a model approximately 73.64% smaller. On the General Language Understanding Evaluation (GLUE) benchmark, comprising paraphrase identification, sentiment analysis, and text classification, the student model maintained strong performance across many tasks despite this reduction. The model was also used on a real-world ADHD dataset with an accuracy of 85%, F1 score of 85%, precision of 85%, and recall of 85%. When compared to DistilBERT (66 million parameters) and ClinicalBERT (110 million parameters), LastBERT demonstrated comparable performance, with DistilBERT slightly outperforming it at 87%, and ClinicalBERT achieving 86% across the same metrics. These findings highlight the LastBERT model’s capacity to classify degrees of ADHD severity properly, so it offers a useful tool for mental health professionals to assess and comprehend material produced by users on social networking platforms. The study emphasizes the possibilities of knowledge distillation to produce effective models fit for use in resource-limited conditions, hence advancing NLP and mental health diagnosis. Furthermore underlined by the considerable decrease in model size without appreciable performance loss is the lower computational resources needed for training and deployment, hence facilitating greater applicability. Especially using readily available computational tools like Google Colab and Kaggle Notebooks. This study shows the accessibility and usefulness of advanced NLP methods in pragmatic world applications.
The STRIPAK complex is required for radial sorting and laminin receptor expression in Schwann cells
Authors: Weaver Michael R. , Shkoruta Dominika , Pellegatta Marta , Berti Caterina , Palmisano Marilena , Ferguson Scott , Hurley Edward , French Julianne , Patel Shreya , Belin Sophie , Selbach Matthias , Paul Florian Ernst , Sim Fraser , Poitelon Yannick , Feltri M. Laura
Published: October 2024

During peripheral nervous system development, Schwann cells undergo Rac1-dependent cytoskeletal reorganization as they insert cytoplasmic extensions into axon bundles to radially sort, ensheath, and myelinate individual axons. However, our understanding of the direct effectors targeted by Rac1 is limited. Here, we demonstrate that striatin-3 and MOB4 are novel Rac1 interactors. We show that, similar to Rac1-null Schwann cells, Schwann cell specific ablation of striatin-3 causes defects in lamellipodia formation. In addition, conditional Schwann cell knockout of multiple striatin proteins presents a severe delay in radial sorting. Finally, we demonstrate here that deletion of Rac1 or striatin-1/3 in Schwann cells causes defects in Hippo pathway regulation, phosphorylation of the Hippo pathway effectors YAP and TAZ, and expression of genes co-regulated by YAP and TAZ, such as extracellular matrix receptors. In summary, our results indicate that striatin-3 is a novel Rac1 interactor, show that striatin proteins are required for peripheral nervous system development, and reveal a role for Rac1 in regulation of the Hippo pathway in Schwann cells.
A synthetic platform for multiplex screening of cell-cell communication between soil fungi
Authors: Schiesaro Giovanni , Jönsson Mathias , Tenente Ricardo , Sørensen Mathies B. , Wäneskog Marcus , Undabarrena Agustina , Deichmann Marcus , Hoch-Schneider Emma E. , Kandasamy Vijayalakshmi , Frimurer Thomas M. , Clemmensen Line , Jensen Michael K. , Jensen Emil D.
Published: October 2024

Fungi are essential members across ecosystems yet also pose significant risks to crops and human health. To thrive in microbial consortia, a fungal organism must integrate the perception of both inter- and intra-species signals. Here we present a Yeast Mating Platform (YeMaP) to decipher cell-cell communication based on fungal G protein-coupled receptors (GPCRs) and pheromone peptides. We use YeMaP to investigate the influence of abiotic factors on cell-cell communication in multiplex and for high-throughput screening of pheromone sequences to identify peptides with improved potency or antagonism action. Additionally, we demonstrate that the plant pathogenFusarium oxysporumGPCR-pheromone interaction is robust across abiotic conditions, and that it can be disrupted by pheromone supplementation to promote the communication of non-pathogenic fungal GPCRs in consortia. Taken together, YeMaP is a useful tool for deciphering the complexity of fungal GPCR-based cell-cell communication and for guiding the design of future crop pest- and disease-management programs.
Genome-wide antibiotic-CRISPRi profiling identifies LiaR activation as a strategy to resensitize fluoroquinolone-resistantStreptococcus pneumoniae
Authors: Sewgoolam Bevika , Jim Kin Ki , de Bakker Vincent , Bock Florian P. , Gibson Paddy , Veening Jan-Willem
Published: October 2024

Streptococcus pneumoniaeis a human pathogen that has become increasingly resistant to the synthetic fluoroquinolone antibiotics that target bacterial topoisomerases. To identify pathways that are essential under fluoroquinolone stress and thus might represent novel targets to revitalize the use of this class of antibiotics, we performed genome-wide CRISPRi-seq screens to determine antibiotic-gene essentiality signatures. As expected, genes involved in DNA recombination and repair become more important under fluoroquinolone-induced DNA damage, such asrecA, recJ, recF, recO, rexABandruvAB.Surprisingly, we also found that specific downregulation of the gene encoding the histidine kinaseliaScaused fluoroquinolone hypersensitivity. LiaS is part of the LiaFSR (VraTSR) three-component regulatory system involved in cell envelope homeostasis. We show that LiaS keeps the response regulator LiaR inactive, and that deletion ofliaScauses hyperphosphorylation of LiaR and subsequent upregulation of the LiaR regulon. RNA-seq was used to refine the LiaR regulon, highlighting the role of the heat-shock response and the pleiotropic regulator SpxA2 in fluoroquinolone sensitivity. Activating the LiaR-regulon by the cell envelope-targeting antibiotic bacitracin synergized with ciprofloxacin and levofloxacin. This synergistic antibiotic combination restored sensitivity in fluoroquinolone-resistant strainsin vitro. Importantly, bacitracin/levofloxacin combination therapy was also effectivein vivoand improved the treatment of fluoroquinolone-resistantS. pneumoniaeinfection in a zebrafish meningitis model. Together, the approaches and findings presented here provides a starting point for identification and validation of potent combination therapies that could be used in the clinic to treat antibiotic-resistant pneumococcal infections.
Short-term plasticity of EI balance at single neurons can detect pattern transitions
Authors: Asopa Aditya , Bhalla Upinder Singh
Published: October 2024

Sensory input and internal context converge onto the hippocampus as spatio-temporal patterns of activity. Transitions in these input patterns are frequently salient, yet the CA1 pyramidal neurons operate under conditions of divisive normalisation of summed patterned input by excitatory-inhibitory (EI) balance which suppresses most responses. We characterized the role of short-term potentiation (STP) in mediating change detection in the mouse hippocampus CA3-CA1 network using optogenetic patterned stimuli in CA3 while recording from CA1 pyramidal neurons. We parameterized STP and its effect on summation, and developed a multiscale model of network projections onto hundreds of E and I boutons each including stochastic signaling to mediate STP on the postsynaptic neuron. We show that STP modulates EI summation across patterns, and predicted and confirmed that single neurons can detect transitions in input patterns responses. Using the model we show that in feedforward networks, STP coupled with moderate sparsity of input due to input pattern sparsity and connections, strengthens rapid pattern change detection by single neurons.