bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward a More Perfect Union
Authors: Sullivan Louis W.
Published: August 2024

In this essay, the author, Dr. Louis Sullivan, describes his life experiences, having been born in the American South during the period of legal racial segregation. Despite many obstacles, Dr. Sullivan became a physician who founded the predominantly Black Morehouse School of Medicine and served as Secretary of the United States Department of Health and Human Services.

In his efforts to improve the health of people from historically marginalized groups, including Black and Brown people as well as those experiencing poverty, Dr. Sullivan organized the Association of Minority Health Professions Schools. He chaired the Sullivan Commission to evaluate the strategies developed to increase the number of Black physicians in the nation. He supported development of the Office for Women’s Health and led efforts to create the National Institute for Minority Health and Health Disparities, both at the National Institutes of Health. When reflecting on his achievements, Dr. Sullivan cites his many mentors and allies who supported him in his career.

Despite significant, ongoing resistance to current efforts to advance diversity, equity, and inclusion in our society, Dr. Sullivan is optimistic that progress toward this goal will continue to be made. He imparts lessons about persistence and positivity and reflects on several initiatives to advance diversity, equity, and inclusion in the health professions and in our society more broadly.
Staged Management for Distal Femur Fractures: Impacts on Reoperation, Stiffness, and Overall Outcomes
Authors: Yeager Matthew T. , Rutz Robert W. , Roszman Alex , McGwin Gerald , Darnley James E. , Johnson Joseph P. , Spitler Clay A.
Published: August 2024

OBJECTIVES:

To evaluate the outcomes of staged management with external fixation (ex-fix) before definitive fixation of distal femur fractures.

METHODS:

Design:

Retrospective cohort.

Setting:

Single Level I Trauma Center.

Patient Selection Criteria:

Adults treated operatively between 2004 and 2019 for distal femur fractures (OTA/AO 33A/33C) were identified using Current Procedural Terminology codes. Excluded cases were those with screw only fixation, acute distal femur replacement, 33B fracture pattern, no radiographs available, or did not have 6-months of follow-up.

Outcome Measures and Comparisons:

Postoperative complication rates including surgical site infection [SSI], reoperation to promote bone healing, final knee arc of motion <90 degrees, heterotopic ossification formation, and reoperation for stiffness were compared between patients treated with ex-fix before definitive fixation and those not requiring ex-fix.

RESULTS:

A total of 407 patients were included with a mean follow-up of 27 months [median (IQR) of 12 (7.33) months] (range 6–192 months). Most patients were male (52%) with an average age of 48 (range: 18–92) years. Ex-fix was utilized in 150 (37%) cases and 257 (63%) cases underwent primary definitive fixation. There was no difference in SSI rates (P = 0.12), final knee arc of motion <90 degrees (P = 0.51), and reoperation for stiffness (P = 0.41) between the ex-fix and no ex-fix groups. The 150 patients requiring ex-fix spent an average of 4.2 days (SD 3.3) in the ex-fix before definitive fixation. These patients were further analyzed by comparing the duration of time spent in ex-fix, <4 days (n = 82) and ≥4 days (n = 68). Despite longer time spent in ex-fix before definitive fixation, there was again no significant difference in any of the complication and reoperation rates when comparing the 2 groups, including final knee arc of motion <90 degrees (P = 0.63), reoperation for stiffness (P = 1.00), and SSI (P = 0.79).

CONCLUSION:

Ex-fix of distal femur fractures as a means of temporary stabilization before definitive open reduction internal fixation does not increase the risk of complications such as SSI, final knee arc of motion <90 degrees, or reoperations for bone healing or stiffness when compared with single-stage open reduction internal fixation of distal femur fractures.

LEVEL OF EVIDENCE:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Is the Orthopaedic Trauma Association-Open Fracture Classification Better Than the Gustilo-Anderson Classification at Predicting Fracture-Related Infections in the Tibia?
Authors: Khoury Philip , Hazra Nina , DeMartino Anthony , Birungi-Huff Kevina , Slobogean Gerard P. , O'Toole Robert V. , O'Hara Nathan N.
Published: August 2024

OBJECTIVES:

To investigate and compare the predictive ability of the Orthopaedic Trauma Association-Open Fracture Classification (OTA-OFC) and the Gustilo-Anderson classification systems for fracture-related infections (FRI) in patients with open tibia fractures.

METHODS:

Design:

Retrospective cohort study.

Setting:

Academic trauma center.

Patient Selection Criteria:

Patients aged 16 years or older with an operatively treated open tibia fracture (OTA–AO 41, 42, and 43) between 2010 and 2021.

Outcome Measures and Comparisons:

The primary outcome was FRI. The OTA-OFC and the Gustilo-Anderson classifications were compared in their ability to predict FRI.

RESULTS:

Eight hundred ninety patients (mean age, 43 years [range, 17 to 96]; 75% men) with 912 open tibia fractures were included. In total, 142 (16%) had an infection. The OTA-OFC was not significantly better at predicting FRI than the Gustilo-Anderson classification (area under the curve, 0.66 vs. 0.66; P = 0.89). The Gustilo-Anderson classification was a stronger predictor of FRI than any single OTA-OFC domain, explaining 72% of FRI variance. Only the addition of the OTA-OFC wound contamination domain to Gustilo-Anderson significantly increased the variance explained (72% vs. 84%, P = 0.04). Embedded contamination increased the risk of FRI by approximately 10% as the risk of FRI with embedded contamination was 16% for type I or type IIs, 26% for type IIIAs, 45% for type IIIBs, and 46% for type IIICs.

CONCLUSIONS:

The more complex OTA-OFC system was not better than the Gustilo-Anderson classification system in predicting FRIs in patients with open tibia fractures. Adding embedded wound contamination to the Gustilo-Anderson classification system significantly improved its prognostic ability.

LEVEL OF EVIDENCE:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Developmental and Validation of Machine Learning Model for Prediction Complication After Cervical Spine Metastases Surgery
Authors: Santipas Borriwat , Suvithayasiri Siravich , Trathitephun Warayos , Wilartratsami Sirichai , Luksanapruksa Panya
Published: August 2024

Study Design:

This is a retrospective cohort study utilizing machine learning to predict postoperative complications in cervical spine metastases surgery.

Objectives:

The main objective is to develop a machine learning model that accurately predicts complications following cervical spine metastases surgery.

Summary of Background Data:

Cervical spine metastases surgery can enhance quality of life but carries a risk of complications influenced by various factors. Existing scoring systems may not include all predictive factors. Machine learning offers the potential for a more accurate predictive model by analyzing a broader range of variables.

Methods:

Data from January 2012 to December 2020 were retrospectively collected from medical databases. Predictive models were developed using Gradient Boosting, Logistic Regression, and Decision Tree Classifier algorithms. Variables included patient demographics, disease characteristics, and laboratory investigations. SMOTE was used to balance the dataset, and the models were assessed using AUC, F1-score, precision, recall, and SHAP values.

Results:

The study included 72 patients, with a 29.17% postoperative complication rate. The Gradient Boosting model had the best performance with an AUC of 0.94, indicating excellent predictive capability. Albumin level, platelet count, and tumor histology were identified as top predictors of complications.

Conclusions:

The Gradient Boosting machine learning model showed superior performance in predicting postoperative complications in cervical spine metastases surgery. With continuous data updating and model training, machine learning can become a vital tool in clinical decision-making, potentially improving patient outcomes.

Level of Evidence:

Level III.
Real-world evidence on efficacy and toxicity of targeted therapy in older melanoma patients treated in a tertiary-hospital setting
Authors: Stoff Ronen , Markovic Svetomir N. , McWilliams Robert R. , Kottschade Lisa A. , Montane Heather N. , Dimou Anastasios , Dudek Arkadiusz Z. , Tan Winston , Dronca Roxana S. , Seetharam Mahesh , Chen Ruqin , Block Matthew S.
Published: August 2024

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal–Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3–4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness.
Experimental Study of Ultra-Pulsed CO2 Fractional Laser Combined With Recombinant Human Epidermal Growth Factor Gel in the Treatment of Eyelid Keloid
Authors: Qu Yixin , Gao Wuyou , Huang Danping , Li Xingyi , Chen Rongxin , Mao Zhen , Lin Xianchai
Published: August 2024

Objective:

Keloid (KD) and hypertrophic scars are prevalent and result from excessive growth of dermal tissue after skin damage. This review focused on the clinical application of the ultra-pulsed CO2fractional laser combined with recombinant human epidermal growth factor (rHEGF) gel in patients with eyelid KD.

Methods:

Patients (N = 98) with KD who underwent surgery were randomly divided into a study group (ultra-pulsed CO2fractional laser combined with rHEGF gel therapy, N = 49) and a control group (ultra-pulsed CO2fractional laser therapy, N = 49). Besides, 5 cases dropped out of the study, including 2 cases in the study group and 3 cases in the control group. Finally, 47 cases of the study group and 46 cases of the study group were included in the analysis. The clinical baseline data such as sex, age, body mass index, scar area, etiology, Vancouver Scar Scale score, Patient and Observer Scar Assessment Scale score, four-item itch questionnaire score, serum interleukin-6 (IL-6), IL-10, and tumor necrosis factor-α level expression were recorded in the study group (N = 47) and the control group (N = 46).

Results:

There was no significant difference in gender, age, body mass index, scar area, etiology, Vancouver Scar Scale score, Patient and Observer Scar Assessment Scale score, 4-item itch questionnaire score, IL-6, IL-10, and tumor necrosis factor-α levels between the patients treated with ultra-pulse CO2fractional laser + rHEGF gel and those only treated with ultra-pulse CO2fractional laser (p> 0.05). Vancouver Scar Scale scores, Patient and Observer Scar Assessment Scale scores, and four-item itch questionnaire scores of patients with eyelid KD decreased to a greater extent than those treated with ultra-pulsed CO2fractional laser combined with rHEGF gel (p<0.01). Compared with ultra-pulsed CO2fractional laser treatment, ultra-pulsed CO2fractional laser combined with rHEGF gel was more efficacious in treating patients with eyelid KD, with a lower incidence of adverse effects and a 1-year recurrence rate.

Conclusions:

Ultra-pulsed CO2fractional laser combined with rHEGF gel can significantly improve the scar status and scar itching in patients with eyelid KD, with an obvious therapeutic effect, a low incidence of adverse effects, a 1-year recurrence rate, and high safety, which is worthy of popularization and application.
Myxoma: An Unusual Aggressive Orbital Lesion
Authors: Quigley Clare , Tong Jessica Y. , Farshid Gelareh , Bonar Fiona , Selva Dinesh
Published: August 2024

Myxoma is a rare tumor that can be challenging to diagnose, with imaging findings that can be nonspecific. We present a case of a 21-year-old man who presented with a subacute history of right visual deterioration and proptosis. Imaging showed a large right superomedial orbital mass of 43 × 31 × 24 mm, which enhanced heterogeneously and was eroding the adjacent orbital roof and medial wall. An excisional biopsy was performed via a lid crease approach under transorbital endoscopic guidance. We review the clinical, radiological, and histological characteristics of myxoma. In addition, we highlight important associations with genetic syndromes including Carney complex and Mazabraud syndrome.
A Multicenter, Single-Arm, Objective Performance Criteria-Controlled Clinical Study of the Safety and Efficacy of the Double-Lumen Eustachian Tube Balloon Catheter
Authors: Si Yu , Shu Fan , Liu Wei , Jiang Yusong , Xu Yaodong , Ou Yongkang , Yang Haidi , Xiong Hao , Liang Maojin , Deng Cuiping , Lu Zhiyin , Luo Yan , Shen Jun , Zhang Hongzheng , Zhang Zhigang , Chen Suijun
Published: August 2024

Background

To prospectively evaluate the technical efficacy and safety of the double-lumen eustachian tube (ET) balloon catheter in patients with ET dysfunction.

Methods

Patients who were diagnosed with ET dysfunction and needed balloon eustachian tuboplasty (BET) were prospectively enrolled. A double-lumen ET balloon catheter was used to dilate the ET and inject medicine. Efficacy results were assessed by the injection channel patency (ICP) rate, the injection reached the expected site (IRES) rate, and the improvement in eustachian tube function was evaluated by the seven-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7) score. Safety results were assessed in terms of adverse events and device defects.

Results

BET was successfully attempted in 87 patients from April 2022 to August 2022 at two academic medical centers in China (01, 02). The ICP rate was 100%, and the IRES rate was 88.51%. The overall ETDQ-7 score was significantly reduced (p < 0.001) postsurgically at both centers. There were no major complications or device defects.

Conclusion

The double-lumen ET balloon catheter is technically effective and safe for the treatment of ET dysfunction.
Cancer in people with multidrug-resistant HIV
Authors: Clemente Tommaso , Pontillo Domenico , Malagnino Vincenzo , Calza Leonardo , Di Biagio Antonio , Cenderello Giovanni , Lolatto Riccardo , Manzillo Elio , Moioli Maria Cristina , De Socio Giuseppe Vittorio , Castagna Antonella , Spagnuolo Vincenzo ,   the PRESTIGIO Study Group∗
Published: August 2024

Retrospective, cohort analysis including people with HIV and 4-class drug resistance (4DR). The 8-year probability of malignancy after first evidence of 4DR was 12%, with an incidence of 1.6/100 person years of follow-up. Cancer risk tended to increase with higher precancer viremia copy-years adjusted for time [per 1 − log10 copies/ml higher: adjusted hazard ratio (aHR) = 1.35; 95% confidence interval (95% CI) = 0.98–1.85] and male sex-assigned-at-birth (aHR = 2.50; 95% CI = 0.86–7.27). Efforts to achieve long-term undetectability, risk factor control, prevention, and more aggressive cancer screening are needed in this fragile population.
Ectopic Cushing Syndrome Localized by 68Ga-DOTA-LM3 PET/CT
Authors: Bastian Moritz B. , Rosar Florian , Burgard Caroline , Blickle Arne , Ezziddin Samer
Published: August 2024

A 53-year-old woman presented with signs of Cushing syndrome with challenges in diagnosis and localization. A novel somatostatin receptor (SSTR)–targeted PET/CT with 68Ga-DOTA-LM3, an SSTR antagonist, revealed a suspicious focal finding in the pancreatic head, proven to be ectopic Cushing syndrome after surgical resection. This interesting image clearly shows the potential of PET imaging with SSTR antagonists as 68Ga-DOTA-LM3 in the diagnosis of ectopic Cushing syndrome.
Intraoperative Ultrasound in Endoscopic Sagittal Suture Synostosis to Optimize Incision Planning and Avoid Misdiagnosis
Authors: Zipfel Julian , Ferraris Kevin Paul , Thompson Angus , Singhal Ash
Published: August 2024

Endoscopy-assisted craniectomy with lateral osteotomies and postoperative helmet molding therapy is a widely used approach in managing sagittal suture craniosynostosis. Generally, the incisions are placed just posterior to the anterior fontanel and just anterior to the posterior fontanel and lambdoid sutures, and accurate incision placement optimizes the safe separation of the superior sagittal sinus. The authors present their 10 year experience with an ultrasound-assisted approach to identify the lambdoid sutures and precisely place the skin incisions. The authors included all patients in care at their institution between 2010 and 2023 who operated for sagittal suture craniosynostosis with endoscopy-assisted craniectomy with lateral osteotomies and postoperative helmet molding therapy. A retrospective review of clinical parameters, surgical data, as well as outcomes, and imaging studies was performed. One hundred patients were operated during the observation period. The mean age was 3.9 ± 3.5 (range: 2.7–6.4) months. Intraoperative ultrasound was documented in 61% of cases (n = 61). In 100% of cases, the incisions were placed behind the anterior and in front of the posterior fontanel, as planned with ultrasound. In 2 additional cases, intraoperative sonography identified a patent sagittal suture in the operating room. A histopathological review showed suture ossification in 100% of operated cases with available reports. Using this technique of ultrasound-guided identification of the lambdoid suture/posterior fontanel, as well as coronal suture/anterior fontanel, may aid in the adequate placement of skin incisions. Patent sutures can be identified in clinically misdiagnosed patients. This study reaffirms the overall utility of ultrasound in pediatric operative neurosurgery.
Use of Free Anterolateral Thigh Flap and Free Latissimus Dorsi Myocutaneous Flap in Head and Neck Reconstruction: Comparison of Complications and Costs
Authors: Tekfiliz Ismail , Kaya Samet , Yasar Emrah Kagan , Alagöz Murat Sahin
Published: August 2024

Free anterolateral thigh flap (ALT) and latissimus dorsi myocutaneous flap (LDMF) are well-defined flaps frequently used to reconstruct head and neck defects. Our study aimed to compare the advantages and disadvantages of these flaps regarding esthetics, complications, and cost burden. The authors retrospectively evaluated 10 patients who applied to our clinic between January 2016 and December 2021 and required free flap reconstruction for the defect in the head and neck region. The first group consisted of 5 patients with ALT flaps, and the second group had 5 patients with LDMF flaps. The average cost burden of the first group was calculated as 18,373 TL, and the second group’s was 23,362 TL. Our study found that the cost and complication rates were statistically higher in the LDMF flap group, and using an ALT flap was more reasonable due to its advantages.
Delayed Hematoma After Rhinoplasty in Young Adult With Hypertension
Authors: Lee Sae Bin , Min Hyun Jin
Published: August 2024

Rhinoplasty is one of the most commonly performed plastic surgical procedures. It has been reported that the overall incidence of complications is low, and hematoma is the most common complication. Recently, the authors experienced a young patient who developed nasal dorsal bleeding and hematoma formation 2 weeks after undergoing rhinoplasty. He had a history of hypertension and was on medication. Due to severe nasal dorsal swelling caused by bleeding and hematoma, the authors ultimately performed an open approach to control the bleeding and evacuate the hematoma. Herein, the authors report the case of a patient with delayed dorsal bleeding 2 weeks after rhinoplasty. The authors learned a lesson that although the patient was young and healthy, in patients with a history of hypertension, the possibility of delayed operative site bleeding should be considered.
Bridging the Gap Between CKD Management Paradigms in Transplant and Nontransplant Settings: Published Evidence, Challenges, and Perspectives
Authors: Dufour Inès , Van Regemorter Elliott , Kanaan Nada , Buemi Antoine , Darius Tom , Mourad Michel , Goffin Eric , Jadoul Michel , Devresse Arnaud , Gillion Valentine
Published: August 2024

Kidney transplantation (KT) is the best treatment for patients with kidney failure, associated with improved survival and quality of life compared with maintenance dialysis. However, despite constant improvements in the assessment and management of the alloimmune response, KT patients frequently demonstrate a reduced estimated glomerular filtration rate. Therefore, the usual complications of chronic kidney disease (CKD), such as anemia, hypertension, metabolic acidosis, hyperkalemia, or persistent secondary hyperparathyroidism, are highly prevalent after KT. However, their underlying mechanisms are different in the transplant setting (compared with the nontransplanted CKD population), and management recommendations are based on relatively poor-quality data. In recent years, new therapies have emerged, significantly improving kidney and cardiovascular outcomes of non-KT patients with CKD. Whether those new drugs could improve the outcomes of KT patients has largely been under investigated so far. In this review, we will address the challenges of the management of a KT patient with a reduced estimated glomerular filtration rate, cover the published evidence, and highlight the critical knowledge gaps.
Aboriginal and Torres Strait Islander Attitudes to Organ Donation in Central Australia: A Qualitative Pilot Study
Authors: Secombe Paul , Lankin Emslie , Beadle Rosalind , McAnulty Greg , Brown Alex , Bailey Michael , Schultz Rebecca , Pilcher David
Published: August 2024

Background.

Organ transplantation is a well-established intervention but is reliant on the donation of organs and tissues, mostly from deceased donors. The proportion of Australians proceeding to organ donation (OD) has increased, but the proportion of Indigenous Australians proceeding remains two-thirds that of non-Indigenous Australians. We sought to explore perceived barriers and enablers for the involvement of Indigenous peoples in the OD process.

Methods.

Qualitative methodology centered around focus groups was used to capture the experiences and perspectives of Indigenous people regarding OD. A purposively sampled group of Aboriginal Liaison Officers working within the Alice Springs Hospital Intensive Care Unit (ASH ICU) participated in up to 6 focus groups during 2021 with subsequent thematic analysis of the enablers and barriers to Indigenous participation in the OD process. The ASH ICU is the only ICU servicing Central Australia, and 70% of admissions are Indigenous patients.

Results.

Four primary themes emerged: OD is a new and culturally taboo topic; conversations related to OD are confronting; education is needed (both about OD and cultural education for clinicians); and lack of trust in the healthcare system.

Conclusions.

There are cultural barriers to engaging in the OD process and clinicians need more training on the delivery of culturally safe communication is needed. Despite this, there was a recognition that OD is important. Education about OD needs to be place based, culturally and linguistically appropriate, informed by local knowledge, delivered in community, and occur before a family member is admitted to ICU.
Metabolic Choreography of Energy Substrates During DCD Heart Perfusion
Authors: Trimigno Alessia , Zhao Jifang , Michaud William A. , Paneitz Dane C. , Chukwudi Chijioke , D’Alessandro David A. , Lewis Greg D. , Minie Nathan F. , Catricala Joseph P. , Vincent Douglas E. , Lopera Higuita Manuela , Bolger-Chen Maya , Tessier Shannon N. , Li Selena , O’Day Elizabeth M. , Osho Asishana A. , Rabi S. Alireza
Published: August 2024

Background.

The number of patients waiting for heart transplant far exceeds the number of hearts available. Donation after circulatory death (DCD) combined with machine perfusion can increase the number of transplantable hearts by as much as 48%. Emerging studies also suggest machine perfusion could enable allograft “reconditioning” to optimize outcomes. However, a detailed understanding of the energetic substrates and metabolic changes during perfusion is lacking.

Methods.

Metabolites were analyzed using 1-dimensional 1H and 2-dimensional 13C-1H heteronuclear spectrum quantum correlation nuclear magnetic resonance spectroscopy on serial perfusate samples (N = 98) from 32 DCD hearts that were successfully transplanted. Wilcoxon signed-rank and Kruskal-Wallis tests were used to test for significant differences in metabolite resonances during perfusion and network analysis was used to uncover altered metabolic pathways.

Results.

Metabolite differences were observed comparing baseline perfusate to samples from hearts at time points 1–2, 3–4, and 5–6 h of perfusion and all pairwise combinations. Among the most significant changes observed were a steady decrease in fatty acids and succinate and an increase in amino acids, especially alanine, glutamine, and glycine. This core set of metabolites was also altered in a DCD porcine model perfused with a nonblood-based perfusate.

Conclusions.

Temporal metabolic changes were identified during ex vivo perfusion of DCD hearts. Fatty acids, which are normally the predominant myocardial energy source, are rapidly depleted, while amino acids such as alanine, glutamine, and glycine increase. We also noted depletion of ketone, β-hydroxybutyric acid, which is known to have cardioprotective properties. Collectively, these results suggest a shift in energy substrates and provide a basis to design optimal preservation techniques during perfusion.
E-cigarettes increase the risk of adenoma formation in murine colorectal cancer model
Authors: Sayed Ibrahim M , Chakraborty Anirban , Inouye Kaili , Dugan Leanne , Tocci Stefania , Advani Ira , Park Kenneth , Hazra Tapas K , Das Soumita , Crotty Alexander Laura E.
Published: August 2024

Background

E-cigarettes (E.cigs) cause inflammation and damage to human organs, including the lungs and heart. In the gut, E.cig vaping promotes inflammation and gut leakiness. Further, E.cig vaping increases tumorigenesis in oral and lung epithelial cells by inducing mutations and suppressing host DNA repair enzymes. It is well known that cigarette (cig) smoking increases the risk of colorectal cancer (CRC). To date, it is unknown whether E.cig vaping impacts CRC development.

Methods

A mouse model of human familial adenomatous polyposis (CPC-APC) was utilized wherein a mutation in the adenomatous polyposis coli (APC) gene, CDX2-Cre-APCMin/+, leads to the development of colon adenomas within 16 weeks. Mice were exposed to air (controls), E.cig vaping, cig, or both (dual exposure). After 4 weeks of 2-hour exposures per day (1 hour of each for dual exposures), the colon was collected and assessed for polyp number and pathology scores by microscopy. Expression of inflammatory cytokines and cancer stem cell markers were quantified. DNA damage such as double-strand DNA breaks was evaluated by immunofluorescence, western blot and gene-specific long amplicon qPCR. DNA repair enzyme levels (NEIL-2, NEIL-1, NTH1, and OGG1) were quantified by western blot. Proliferation markers were assessed by RT-qPCR and ELISA.

Results

CPC-APC mice exposed to E.cig, cig, and dual exposure developed a higher number of polyps compared to controls. Inflammatory proteins, DNA damage, and cancer stemness markers were higher in E-cig, cig, and dual-exposed mice as well. DNA damage was found to be associated with the suppression of DNA glycosylases, particularly with NEIL-2 and NTH1. E.cig and dual exposure both stimulated cancer cell stem markers (CD44, Lgr-5, DCLK1, and Ki67).The effect of E.cigs on polyp formation and CRC development was less than that of cigs, while dual exposure was more tumorigenic than either of the inhalants alone.

Conclusion

E.cig vaping promotes CRC by stimulating inflammatory pathways, mediating DNA damage, and upregulating transcription of cancer stem cell markers. Critically, combining E.cig vaping with cig smoking leads to higher levels of tumorigenesis. Thus, while the chemical composition of these two inhalants, E.cigs and cigs, is highly disparate, they both drive the development of cancer and when combined, a highly common pattern of use, they can have additive or synergistic effects.
NeuroAtlas: An Artificial Intelligence-based Framework for Annotation, Segmentation and Registration of Large Scale Biomedical Imaging Data
Authors: Mahmood Hassan , Nawar Farah , Islam Syed Mohammed Shamsul , Iqbal Asim
Published: August 2024

With increasing neuroimaging modalities and data diversity, mapping brain regions to a standard atlas template has become a challenging problem. Machine learning in general and deep learning, in particular, have been providing robust solutions for several neuroimaging tasks, including brain image registration and segmentation. However, these methods require a large amount of data for groundtruth labels, annotated by human experts, which is time-consuming. In this work, we introduce NeuroAtlas, an AI-based framework for atlas generation and brain region segmentation. We showcase an end-to-end solution for brain registration and segmentation by providing i) a deep learning modeling suite with a variety of high-performing model architectures to map a brain atlas onto the input brain section and ii) a Graphical User Interface (GUI)-based plugin for large-scale data annotation with a feature of modifying the predicted labels for active learning. We demonstrate a robust performance of our framework on the human brains, captured through various imaging modalities and age groups, and demonstrate its application for mouse brains as well. NeuroAtlas tool will be open-sourced and entirely compatible with both local as well as cloud-based computing so that users can easily adapt to their neuroimaging custom datasets.
Phenotypes and Electrophysiological Features of Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) According to Physical Activities: A Single Military Hospital Experience
Authors: Kim Eun Jin
Published: August 2024

Background

The typical symptom of HNPP is focal nerve palsy with complete or near complete recovery, and it often occurs during military service with upper extremity weakness due to a brachial plexus involvement. This study aimed to analyze the clinical features and neurophysiological examination results of HNPP occurring in the Korean military to determine whether the clinical presentations and electrodiagnostic patterns differ according to the trigger activity and to obtain useful information for the early diagnosis of HNPP.

Methods

Sixty-four patients with HNPP were included over an 11-year period, and medical records and electrophysiological tests were analyzed.

Results

Thirty-five patients presented with isolated compressive neuropathy and 18 patients presented with brachial plexopathy. Analysis of phenotypes according to triggering activity revealed that 13 of 16 patients with symptom onset after military training showed a type of isolated compressive neuropathy and that 11 of 20 patients with symptom onset after push-ups or after backpack carriages showed a type of brachial plexopathy. Six patients experienced symptoms following sleep, while four reported symptoms after trauma. Atypical features were observed in 11 cases (17.2%), including 3 lower lumbosacral radiculopathy-like presentation. Abnormal findings were observed in 91.2% of distal latency of the peroneal motor nerve.

Conclusions

The phenotype varied according to the physical activity that triggered HNPP onset in soldiers. These results are expected to help in the early diagnosis of HNPP in soldiers or those who develop it after physical activity.

key messages

This study underscores the importance of recognizing clinical manifestation of HNPP in military personnel, particularly those involved in physically demanding activities, to facilitate timely diagnosis and intervention.

The phenotypes of HNPP in soldiers vary depending on the triggering activity, with isolated compressive neuropathy and brachial plexopathy being the most common presentations.

Atypical clinical manifestations were observed, including presentations resembling Guillain–Barré syndrome and lumbosacral radiculopathy.

Regardless of the location of symptoms, a peroneal motor conduction study can be valuable in diagnosing HNPP.

These findings could significantly contribute to the early diagnosis of HNPP in soldiers.
AlphaFold2knowssome protein folding principles
Authors: Chang Liwei , Perez Alberto
Published: August 2024

AlphaFold2 (AF2) has revolutionized protein structure prediction. However, a common confusion lies in equating theprotein structure predictionproblem with theprotein folding problem. The former provides a static structure, while the latter explains the dynamic folding pathway to that structure. We challenge the currentstatus quoand advocate that AF2 has indeed learned some protein folding prin- ciples, despite being designed for structure prediction. AF2’s high-dimensional parameters encode an imperfect biophysical scoring function. Typically, AF2 uses multiple sequence alignments (MSAs) to guide the search within a narrow re- gion of its learned surface. In our study, we operate AF2 without MSAs or initial templates, forcing it to sample its entire energy landscape — more akin to anab initioapproach. Among over 7,000 proteins, a fraction fold using sequence alone, highlighting the smoothness of AF2’s learned energy surface. Additionally, by combining recycling and iterative predictions, we discover multiple AF2 interme- diate structures in good agreement with known experimental data. AF2 appears to follow a “local first, global later” folding mechanism. For designed proteins with more optimized local interactions, AF2’s energy landscape is too smooth to detect intermediates even when it should. Our current work sheds new light on what AF2 has learned and opens exciting possibilities to advance our understanding of protein folding and for experimental discovery of folding intermediates.
Variations and predictability of epistasis on an intragenic fitness landscape
Authors: Baheti Sarvesh , Raj Namratha , Saini Supreet
Published: August 2024

How epistasis hinders or facilitates movement on fitness landscapes has been a longstanding question of interest. Several high throughput experiments have demonstrated that despite its idiosyncrasy, epistatic effects exhibit global statistical patterns. Recently, Papkou et. al. constructed a fitness landscape for a 9-base region in thefolAgene, which encodes for dihydrofolate reductase (DHFR), inE. coli, and demonstrated that despite being highly rugged, the landscape is highly navigable. In this work, using thefolAlandscape, we ask two questions: (1) How does the nature of epistatic interactions change as a function of the genomic background? (2) How predictable is epistasis within a gene? Our results show that epistasis is “fluid” - the nature of epistasis exhibited by a pair of mutations is strongly contingent on the genetic background. Mutations exhibit one of two binary “states”: a small fraction of mutations exhibit extremely strong patterns of global epistasis, while most do not. Despite these observations, we observe that the distribution of fitness effects (DFE) of a genotype is highly predictable based on its fitness. These results offer a new perspective on how epistasis operates within a gene, and how it can be predicted.

Significance Statement.

How a mutation changes organismal fitness is dependent on the genome in which it occurs. This phenomenon is known as epistasis and makes evolution unpredictable. Recent efforts to understand epistasis have led to the identification of statistical patterns in its manifestations. To study how epistasis operates in protein evolution, we analyze a recently reported landscape which quantifies fitness of ∼260000 sequences of anE. coligene. We show two previously unknown properties of epistasis: “fluid” (epistasis between mutations is controlled via other epistatic interactions) and “binary” (only a few mutations exhibit statistical patterns; most do not). This work sheds new light on how epistasis manifests in gene sequences. Our results have important consequences for protein & organismal evolution.
Disruption of ultrasonic vocalization with systemic administration of the non-competitive N-methyl-d-aspartate receptor antagonist MK-801 in adult male mice
Authors: Tamura Ryuto , Ujihara Yusuke , Yamamoto Mizuki , Matsushima Shuntaro , Kasahara Haruki , Nasukawa Daiki , Hayashi Kazuko , Yamada Kota , Tanaka Masashi , Toda Koji
Published: August 2024

Vocal communication is essential for survival in many animals, including humans. Mice produce ultrasonic vocalizations (USVs) in various social contexts. N-methyl-d-aspartate (NMDA) receptors are widely distributed in the central nervous system and play essential roles in synaptic plasticity, learning, and behavior. However, the role of NMDA receptors in USVs remains unclear. Here, we examined the effects of systemic administration of a noncompetitive NMDA antagonist, MK-801, on USVs during courtship and in other social and nonsocial behaviors. First, we investigated the USVs emitted by male mice. After the successful classification of USVs into 11 categories using VocalMat, an open-source computational vision and machine-learning technique, we analyzed the relationship between USV properties and approaching behavior toward female mice. Male mice produced USVs when they were close to female mice, which confirmed that USVs were associated with social signals. Second, we examined the effects of intraperitoneal injection of MK-801 on USVs and approach behavior. Intraperitoneal injection of MK-801 dose-dependently decreased the number of USVs and increased locomotor activity, but did not affect the time spent with female mice. In additional experiments, we confirmed that the injection of MK- 801 decreased the time spent with a novel same-sex individual in the social preference task, increased locomotor activity, and inhibited excretion in the open-field task. Taken together, these results demonstrate that NMDA receptors play important roles in vocal communication and social behavior.
Electronic health record biobank cohort recapitulates an association between theMUC5Bpromoter polymorphism and ARDS in critically ill adults
Authors: Kerchberger V. Eric , McNeil J. Brennan , Zheng Neil , Chang Diana , Rosenberger Carrie , Rogers Angela J. , Bastarache Julie A. , Feng QiPing , Wei Wei-Qi , Ware Lorraine B.
Published: August 2024

Background

Large population-based DNA biobanks linked to electronic health records (EHRs) may provide novel opportunities to identify genetic drivers of ARDS.

Research Question

Can we develop an EHR-based algorithm to identify ARDS in a biobank database, and can this validate a previously reported ARDS genetic risk factor?

Study Design and Methods

We analyzed two parallel genotyped cohorts: a prospective biomarker cohort of critically ill adults (VALID), and a retrospective cohort of hospitalized participants enrolled in a de-identified EHR biobank (BioVU). ARDS was identified by clinician-investigator review in VALID and an EHR algorithm in BioVU (EHR-ARDS). We tested the association between theMUC5Bpromoter polymorphism rs35705950 with development of ARDS, and assessed if age modified this genetic association in each cohort.

Results

In VALID, 2,795 patients were included, age was 55 [43, 66] (median [IQR]) years, and 718 (25.7%) developed ARDS. In BioVU, 9,025 hospitalized participants were included, age was 60 [48, 70] years, and 1,056 (11.7%) developed EHR-ARDS. We observed a significant age-related interaction effect on ARDS in VALID: among older patients, rs35705950 was associated with increased ARDS risk (OR: 1.44; 95%CI 1.08-1.92; p=0.012) whereas among younger patients this effect was absent (OR: 0.84; 95%CI: 0.62-1.14; p=0.26). In BioVU, rs35705950 was associated with increased risk for EHR-ARDS among all participants (OR: 1.20; 95%CI: 1.00-1.43, p=0.043) and this did not vary by age. The polymorphism was also associated worse oxygenation in mechanically ventilated BioVU participants, but had no association with oxygenation in VALID.

Interpretation

TheMUC5Bpromoter polymorphism was associated with ARDS in two cohorts of at-risk adults. Although age-related effect modification was observed only in VALID, BioVU identified a consistent association betweenMUC5Band ARDS risk regardless of age, and a novel association with oxygenation impairment. Our study highlights the potential for EHR biobanks to enable precision-medicine ARDS studies.
Novel RNA-binding protein YebC enhances translation of proline-rich amino acid stretches in bacteria
Authors: Ignatov Dmitriy , Shanmuganathan Vivekanandan , Ahmed-Begrich Rina , Alagesan Kathirvel , Frese Christian Karl , Wang Chu , Krause Kathrin , Charpentier Emmanuelle
Published: August 2024

The ribosome employs a set of highly conserved translation factors to efficiently synthesise proteins. Some translation factors interact with the ribosome in a transient manner and are thus challenging to identify. However, proteins involved in translation can be specifically identified by their interaction with ribosomal RNAs. Using a combination of proteomics approaches, we identified novel RNA binding proteins in the pathogenic bacteriumStreptococcus pyogenes. One of these, a universally conserved protein YebC, was shown to transiently interact with 23S rRNA near the peptidyl-transferase centre. Deletion ofyebCmoderately affected the physiology and virulence ofS. pyogenes. We performed ribosome profiling and detected increased pausing at proline-rich amino acid stretches in the absence of functional YebC. Further results obtained within vivoreporters andin vitrotranslation system suggest that YebC is a novel translation factor required for efficient translation of proteins with proline-rich motifs.
Exploring the role of the rich club in network control of neurocognitive states
Authors: Podschun Alina N. , Betzel Richard F. , Braun Urs , Markett Sebastian
Published: August 2024

We present a systematic analysis of the rich club as a possible control center of brain dynamics. Contrary to research stressing control properties of the rich club, our results indicate that the rich club and high-degree regions were not involved in optimally controlling the human connectome for a set of data-driven and task-evoked patterns of activity. Indeed, low-degree peripheral regions were more suited towards this. Findings were stable across group-level and individual-level rich club definitions, various cognitively meaningful brain state transitions, and different parameter settings. A region’s contribution to optimal control processes was associated with its affiliation with certain intrinsic connectivity networks and its position on the secondary, but not primary, cortical gradient. These results do not negate an integratory role of the rich club, but merely question its proposed role as a driver of control. Indeed, if it would inhabit such a role, we would have expected opposite results. Our findings fit with a position describing the rich club as a passive “data-highway” which, by means of its high connectivity, can be easily controlled by peripheral regions and thus facilitate relevant communication channels between them. We call for methodological expansions of the control theoretical toolbox allowing for elaborations on the temporal dynamics of control processes.
NOTCH-driven oscillations control cell fate decisions during intestinal homeostasis
Authors: Weterings Sonja D. C. , Eto Hiromune , de Leede Jan-Daniël , Giladi Amir , Hoekstra Mirjam E. , Beijk Wouter F. , Liefting Esther J. M. , van den Anker Karen B. , van Rheenen Jacco , van Oudenaarden Alexander , Sonnen Katharina F.
Published: August 2024

Intestinal homeostasis requires tight regulation of stem cell maintenance and commitment to absorptive and secretory cells, two key intestinal lineages1,2. While major signalling pathways critical for this control have been identified3, how they achieve such a tight balance in cell type composition remains unclear. Here, we uncover dynamic expression of Hes1, a direct NOTCH target3, in intestinal stem and progenitor cells, and investigate its rolein vivoandin vitro. A knock-in reporter4reveals distinct, cell-specific period lengths in Hes1 oscillations that form a gradient along the crypt-villus axis. Whereas secretory precursors oscillate at low periods, absorptive precursors oscillate at higher periods before transitioning to a differentiated state. To test the function of different oscillation periods, we innovated a microfluidic system that modulates Hes1 oscillations in organoids. We find that varying the oscillation period modulates secretory cell differentiation: While 90-min oscillations promote Paneth cells, 130-min oscillations increase formation of other secretory subtypes. Moreover, low-period oscillations support stemness and a proliferative state. Our study provides the first clear evidence that information for tissue homeostasis in the intestine is encoded in the temporal dynamics of signalling components.