bluuebunny/crossref_metadata_2025 huggingface dataset:
Hu-Zhang Qing-Mai Formulation anti-oxidative stress alleviates diabetic retinopathy: Network pharmacology analysis and in vitro experiment
Authors: Wu Xiaoyu , Mu Lin , Dong Zhiguo , Wu Jiajun , Zhang Shuyan , Su Jing , Zhang Yinjian
Published: September 2023

Background:

In this study, the potential mechanism of the Hu-Zhang Qing-Mai Formulation (HZQMF) on diabetic retinopathy (DR) in inhibiting oxidative stress was explored through network pharmacology analysis and in vitro experiments.

Methods:

The Traditional Chinese Medicine Systematic Pharmacology Analysis Platform was used to retrieve the active pharmaceutical ingredients and targets of HZQMF. DR-related genes and oxidative stress-related genes were obtained from PharmGKB, TTD, OMIM, GeneCards, and Drugbank. STRING was used to construct a protein–protein interaction network to screen core targets. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were performed using R 4.0.3. Network topology analysis was carried out using Cytoscape 3.8.2. Finally, we looked into how well the main API protected human retinal pigment epithelial cells from damage brought on by hydrogen peroxide (H2O2).

Results:

Quercetin (Que) was identified as the primary API of HZQMF through network pharmacology analysis, while JUN, MAPK1, and STAT3 were identified as the primary hub genes. Kyoto encyclopedia of genes and genomes enrichment analysis showed that the AGE-RAGE signaling pathway may be crucial to the therapeutic process. In vitro experiments confirmed that Que increased cell vitality and inhibited apoptosis.

Conclusion:

Que might significantly reduce H2O2-induced ARPE-19 cell injury by inhibiting apoptosis-related genes of the AGE-RAGE pathway (JUN, MAPK1, STAT3). This study lays the foundation for further research on HZQMF in treating DR.
Effects of emergency medical services on timely treatment and outcome in stroke patients with intravenous thrombolysis among the severity of neurologic deficits: A retrospective observational study
Authors: Chen Hongfang , Wang Jianwei , Pan Xiaoling , Zhang Meixia
Published: September 2023

Whether emergency medical service (EMS) improves the outcome of acute ischemic stroke (AIS) patients after intravenous thrombolysis (IVT) is still unknown among the severity of neurologic deficits. This study is to investigate the impact of EMS use on timely treatment and outcomes of AIS with IVT. This is a retrospective observational study. Clinical data after IVT from January 2017 to May 2020 were retrospectively analyzed, including onset-to-needle time (ONT), onset-to-door time (ODT). The patients were divided into EMS and non-EMS groups according to the method of admission. A good outcome was defined as a modified Rankin scale score of ≤2 at 3 months. The severity of neurological deficits was assessed using the national institutes of health stroke scale. A total of 2303 patients were analyzed (906 [(39.3%] female; mean age, 68 ± 13 year), and 1028 (44.6%) patients were transported by EMS and 1418 (67.9%) patients achieved good outcome. Among all patients, compared with non-EMS patients, EMS patients had shorter ONT (148 minutes vs 155 minutes, P = .002) and ODT (95 minutes vs 104 minutes, P < .001), but lower rate of good outcome (61.7% vs 73.0%, P < .001). The multivariate analysis showed that the use of EMS was negatively associated with ONT (ρ = −0.041, P = .048) and ODT (ρ = −0.051, P = .014). Among moderate to severe stroke patients, EMS was related with good outcome independently (OR: 3.101, 95%CI: 1.367–7.038, P = .007). In ischemic stroke, EMS can shorten the pre-hospital delay. Among moderate to severe stroke patients, EMS can further improve the outcome. But the study needs further validation.
Factors influencing nurses self-efficacy two years after the COVID-19 outbreak: A cross-sectional study in Wuhan, China
Authors: Li Wen , Wan Zhiying , XianYu Yunyan
Published: September 2023

This study explored the anxiety, depression, and self-efficacy of nurses in Wuhan, China 2 years after the corona virus disease 2019 outbreak. A total of 552 nurses were enrolled in the study. Four well-established test tools were applied: The 9-item patient health questionnaire, The 7-item generalized anxiety disorder, generalized self-efficacy scale, Connor Davidson resilience scale. Twenty-eight points twenty-six percentage of the nurses had mild depression, and 5.62% had moderate or severe depression. Twenty-one points seventy-four percentage of nurses had mild anxiety and 1.82% had moderate or severe anxiety. The average score of self-efficacies is negatively correlated with the average score of the 9-item patient health questionnaire (r = −0.303, P < .01), and the7-item generalized anxiety disorder (r = −0.275, P < .01). The average score of self-efficacies is correlated with the resilience score (R = 0.799, P < .01). Through multiple linear regression analysis, the tenacity dimension and monthly income are most closely related to the sense of self-efficacy. Nurses self-efficacy and resilience are important factors in promoting their psychological well-being. This study suggests that increasing the salary and providing some strategies to increase nurses mental tenacity can promote self-efficacy.
Analysis of the detection rate and related factors of fatty liver disease in physical examination of healthy population in Chengdu district
Authors: Han Qian , Guo Jiaojiao , Gong Ling , Liu Changqing , Zhang Fan
Published: September 2023

Background:

In the present study, we analyzed the detection rate and related influencing factors of fatty liver in the health examination population in Chengdu area.

Methods:

The case-control study was performed to compare the gender, age (years), body mass index (BMI), smoking, drinking, abnormal lipid metabolism, hypertension, hyperglycemia, hyperuricemia Is there any statistically significant difference in the detection rate of diseases such as metabolic syndrome, and logistic regression analysis is conducted to analyze the comprehensive impact of each influencing factor on the prevention of fatty liver disease.

Results:

Among 14,426 survey subjects, a total of 6717 patients with fatty liver were detected, with a detection rate of 47.22%. There are significant differences in the incidence of fatty liver disease among different gender groups, with the incidence rate in males being significantly higher than that in females (P < .05); The incidence of fatty liver in elderly subjects was significantly higher than that in middle-aged and young subjects (P < .05); The prevalence rate of individuals with a BMI > 24 was significantly higher than that of individuals with a BMI < 24 (P < .05). The prevalence of fatty liver in the population with abnormal lipid metabolism, hypertension, hyperglycemia, hyperuricemia, metabolic syndrome and other diseases was significantly higher (P < .05); After stratified analysis by gender and age, the incidence of fatty liver in males was significantly higher than that in females in the 3 age groups < 60 years old (P < .05); In the age group ≥ 60 years old, the difference in the incidence of fatty liver disease between males and females was significantly reduced, and the difference was not statistically significant (P > .05).

Conclusion:

The health screening of patients with fatty liver should be carried out regularly, and attention should be paid to the intervention and prevention of overweight people and people with basal metabolism diseases such as hyperglycemia and hypertension, so as to reduce the incidence of fatty liver.
Free flap reconstruction of scalp in a case of advanced lung cancer with brain metastasis: A case report
Authors: Lee Dong Yun , Lim SooA , Eo SuRak , Yoon Jung Soo
Published: September 2023

Rationale:

Reconstruction of wound complications in patients with advanced cancer with distant metastases is challenging for plastic surgeons. This may be due to the cancer patients’ hypercoagulability and potential intolerance to general anesthesia. This article aimed to discuss the risk of free-flap reconstruction in such cases.

Patient concerns:

The patient was a 58-year-old female with advanced non-small cell lung cancer and brain metastasis. The patient underwent brain radiotherapy and chemotherapy through the Ommaya Reservoir.

Diagnoses:

A year ago, she underwent several local flap closures for recurrent wound healing failure due to wound complications, including infection, wound dehiscence, and subsequent device removal.

Interventions:

A radial forearm free flap was created under general anesthesia. The patient was discharged in the third postoperative week since the flap remained stable.

Outcomes:

At follow-up a month thereafter, the patient exhibited signs of recovery without any complications even while continuing her chemotherapeutic regimen.

Lessons:

Free flap placement is not an absolute contraindication in cancer patients with distant metastases. Nevertheless, it is associated with clinical challenges and operator hesitancy. This is a case of a successful free flap in a cancer patient with hypercoagulability and suspected floating tumor cells. Postoperative management, in this case, is appropriate.
Artificial Intelligence to Assess Tracheal Tubes and Central Venous Catheters in Chest Radiographs Using an Algorithmic Approach With Adjustable Positioning Definitions
Authors: Rueckel Johannes , Huemmer Christian , Shahidi Casra , Buizza Giulia , Hoppe Boj Friedrich , Liebig Thomas , Ricke Jens , Rudolph Jan , Sabel Bastian Oliver
Published: September 2023

Purpose

To develop and validate an artificial intelligence algorithm for the positioning assessment of tracheal tubes (TTs) and central venous catheters (CVCs) in supine chest radiographs (SCXRs) by using an algorithm approach allowing for adjustable definitions of intended device positioning.

Materials and Methods

Positioning quality of CVCs and TTs is evaluated by spatially correlating the respective tip positions with anatomical structures. For CVC analysis, a configurable region of interest is defined to approximate the expected region of well-positioned CVC tips from segmentations of anatomical landmarks. The CVC/TT information is estimated by introducing a new multitask neural network architecture for jointly performing type/existence classification, course segmentation, and tip detection. Validation data consisted of 589 SCXRs that have been radiologically annotated for inserted TTs/CVCs, including an experts' categorical positioning assessment (reading 1). In-image positions of algorithm-detected TT/CVC tips could be corrected using a validation software tool (reading 2) that finally allowed for localization accuracy quantification. Algorithmic detection of images with misplaced devices (reading 1 as reference standard) was quantified by receiver operating characteristics.

Results

Supine chest radiographs were correctly classified according to inserted TTs/CVCs in 100%/98% of the cases, thereby with high accuracy in also spatially localizing the medical device tips: corrections less than 3 mm in >86% (TTs) and 77% (CVCs) of the cases. Chest radiographs with malpositioned devices were detected with area under the curves of >0.98 (TTs), >0.96 (CVCs with accidental vessel turnover), and >0.93 (also suboptimal CVC insertion length considered). The receiver operating characteristics limitations regarding CVC assessment were mainly caused by limitations of the applied CXR position definitions (region of interest derived from anatomical landmarks), not by algorithmic spatial detection inaccuracies.

Conclusions

The TT and CVC tips were accurately localized in SCXRs by the presented algorithms, but triaging applications for CVC positioning assessment still suffer from the vague definition of optimal CXR positioning. Our algorithm, however, allows for an adjustment of these criteria, theoretically enabling them to meet user-specific or patient subgroups requirements. Besides CVC tip analysis, future work should also include specific course analysis for accidental vessel turnover detection.
Right Adrenocortical Carcinoma Coexisting With Left Adrenal Sarcomatoid Carcinoma on FDG PET/CT
Authors: Chen Haotian , Dai Jiaona , Gao Fabao , Tian Rong
Published: September 2023

Bilateral adrenal glands synchronously involved by different types of pathologies are uncommon. An 80-year-old man underwent FDG PET/CT to evaluate bilateral adrenal masses, which were initially discovered by ultrasonography and confirmed by MRI. The images demonstrated elevated FDG activity in both lesions, which were subsequently diagnosed as concurrent right adrenocortical carcinoma and left adrenal sarcomatoid carcinoma respectively by histopathological examination.
Primary Angiosarcoma of Lumbar Pedicle and Transverse Process Revealed by FDG PET/CT
Authors: Yang Pei , Xiao Liu , Li Lin
Published: September 2023

The primary angiosarcoma of bone is rare. It typically occurs in tubular bones, pelvis, and trunk. However, its occurrence in the lumbar pedicle, and transverse process is infrequent. Thus, we present the imaging findings of FDG PET/CT in a rare case of primary angiosarcoma of lumbar pedicle and transverse process. It presented as solitary osteolytic bone destruction in the right pedicle and transverse process of L4 with intense FDG uptake. This case added knowledge of another rare occurrence site of primary angiosarcoma of bone, which should be considered as a differential diagnosis when we meet similar image appearance on FDG PET/CT.
A Case of Primary Esophageal Sarcomatoid Carcinoma Detected by 18F-FDG PET/CT
Authors: Chen Tao , Li Wenfei , Fan Jianzhong
Published: September 2023

Primary sarcomatoid carcinoma of the esophagus is a rare and highly malignant neoplasm with a poor prognosis. A 51-year-old man presented with difficulty in swallowing for 2 weeks. Thoracic CT revealed a huge mass in the middle-lower thoracic esophagus. 18F-FDG PET/CT showed intense 18F-FDG uptake of the esophageal tumor. Histopathology and immunohistochemistry of the esophageal lesion tissue confirmed the diagnosis of sarcomatoid carcinoma after postoperative pathological biopsy.
A Head-to-Head Comparison of 68Ga-LNC1007 and 2-18F-FDG/68Ga-FAPI-02 PET/CT in Patients With Various Cancers
Authors: Zang Jie , Lin Rong , Wen Xuejun , Wang Chao , Zhao Tianzhi , Jakobsson Vivianne , Yang Yun , Wu Xiaoming , Guo Zhide , Chen Xiaoyuan , Zhang Jingjing , Miao Weibing
Published: September 2023

Objectives

This head-to-head comparison study was designed to investigate the radiotracer uptake and clinical feasibility of using 68Ga-LNC1007, to detect the primary and metastatic lesions in patients with various types of cancer, and to compare the results with those of 2-18F-FDG PET/CT and 68Ga-FAPI-02 PET/CT.

Patients and Methods

Sixty-one patients with 10 different kinds of cancers were enrolled in this study. Among them, 50 patients underwent paired 68Ga-LNC1007 and 2-18F-FDG PET/CT, and the other 11 patients underwent paired 68Ga-LNC1007 and 68Ga-FAPI-02 PET/CT. The final diagnosis was based on histopathological results and diagnostic radiology. Immunohistochemistry for FAP and integrin αvβ3 was performed in 24 primary tumors.

Results

68Ga-LNC1007 PET/CT detected all 55 primary tumors, whereas 2-18F-FDG PET/CT was visually positive for 45 primary tumors (P = 0.002). Furthermore, subgroup analysis showed that 68Ga-LNC1007 PET/CT was superior to 2-18F-FDG PET/CT in diagnosing renal cell carcinomas and hepatocellular carcinomas. For metastatic tumors, 68Ga-LNC1007 PET/CT revealed more PET-positive lesions and higher SUVmax for skeletal metastases and peritoneal metastases compared with 2-18F-FDG. The SUVmax and tumor-to-background ratio of primary tumors on 68Ga-LNC1007 PET/CT were much higher than those on 68Ga-FAPI-02 PET/CT, the same was also observed for metastatic tumors. Immunohistochemical results showed that the SUVmean quantified from 68Ga-LNC1007 PET was correlated with FAP expression level (r = 0.564, P = 0.005).

Conclusions

68Ga-LNC1007 is a promising new diagnostic PET tracer for imaging of various kinds of malignant lesions. It may be a better alternative to 2-18F-FDG for diagnosing renal cell carcinoma, hepatocellular carcinoma, skeletal metastases, and peritoneal metastases.
Bone Lipogranuloma Mimicking Metastatic Disease on 18F-FDG PET/CT
Authors: Kesim Selin , Dede Fuat , Cesmecioglu Emine , Karaman Damlanur , Turoglu Halil Turgut
Published: September 2023

Primary bone lipogranuloma is an extremely rare disease associated with reactive inflammatory granulomatous reaction associated with exogenous or endogenous lipids. Herein, we report a case of bone lipogranuloma with intense18F-FDG uptake, which mimics metastatic disease on18F-FDG PET/CT in a patient with breast cancer.
Clinical Efficacy of Orbital Computed Tomographic Assessment in Determination of the Optimal Length of the Jones Tube in Endo CDCR
Authors: Cha Eunhyang , Lee Hyunkyu , Lee Hwa , Baek Sehyun
Published: September 2023

Purpose:

To investigate whether preoperative orbital computed tomography (CT) may be useful for predicting the optimal length of the Jones tube and determining the predictive parameters of orbital CT that are associated with the optimal length of Jones tubes in endoscopic conjunctivodacryocystorhinostomy (CDCR).

Methods:

The medical records of 36 patients (42 eyes) who underwent endoscopic CDCR with Jones tube insertion and preoperative orbital CT from March 2018 to April 2022 were retrospectively evaluated. Analyzing the orbital CT films using the Picture Archiving and Communication System, the distance from the lacrimal fossa to the nasal septum was measured in coronal and axial views.

Results:

In the successful group, the length of the inserted Jones tube was significantly correlated with the length difference between the inserted tube and the diagonal length measured in the axial view (r=−0.485, P=0.030). Equivalency of the length verified in the operating room and length measured on orbital CT were demonstrated as follows: diagonal length measured in axial view (Da), horizontal length between the medial eyeball to the nasal septum in coronal view (Hc) and the estimated length (Ej) in axial view with α=tan30° and α=tan25°.

Conclusion:

The optimal length of the Jones tube is best predicted using the length of the lacrimal fossa to nasal septum in coronal and axial views. Preoperative orbital CT assessments can be noninvasive and useful in predicting adequate lengths of the Jones tube.
How Is a Cutting Guide With Additional Anatomical References Better in Fibular-Free Flap Mandibular Reconstruction? A Technical Strategy
Authors: Yodrabum Nutcha , Tianrungroj Jirapat , Sinmaroeng Chanya , Rudeejaroonrung Krit , Pavavongsak Korn , Puncreobutr Chedtha
Published: September 2023

Background:

Computer-assisted surgery is used to design and manufacture cutting guides in mandibular reconstructions with fibula-free flaps. To improve the outcomes of the procedure, the aim of this research was to investigate and compare the accuracy of mandibular reconstruction following the use of 2 versus 3 anatomical reference cutting guides.

Methods:

Eighteen sets of prototype bone models retrieved from an ameloblastoma patient were used for mock operations. The mandibular segmental osteotomies and fibular reconstructions were performed using 2 and 3 anatomical reference cutting guides in vivo surgeries. After reconstruction, the accuracy of the placed reference points was measured by superimposition of computed tomography images.

Results:

The error in cutting guides when using 2 or 3 anatomical references showed no significant difference. The fibular and condylar errors of the cutting guide between 2 and 3 anatomical references showed no significant difference in every plate type. The difference in screw hole position errors between 2 and 3 anatomical reference cutting guides was not statistically significant.

Conclusions:

Two anatomical reference cutting guides are sufficient and reasonable enough for mandible resection. However, there were some limitations and errors in our study.
Surveillance of Individuals at High Risk of Developing Pancreatic Cancer
Authors: Paiella Salvatore , Secchettin Erica , Lionetto Gabriella , Archibugi Livia , Azzolina Danila , Casciani Fabio , Simeone Diane M , Overbeek Kasper A , Goggins Michael , Farrell James , Ponz de Leon Pisani Ruggero , Tridenti Maddalena , Corciulo Maria Assunta , Malleo Giuseppe , Arcidiacono Paolo Giorgio , Falconi Massimo , Gregori Dario , Bassi Claudio , Salvia Roberto , Capurso Gabriele
Published: September 2023

Objective:

To quantify the rate of low-yield surgery, defined as no high-grade dysplastic precursor lesions or T1N0M0 pancreatic cancer at pathology, during pancreatic cancer surveillance.

Summary Background Data:

Global efforts have been made in pancreatic cancer surveillance to anticipate the diagnosis of pancreatic cancer at an early stage and improve survival in high-risk individuals (HRI) with a hereditary predisposition. The negative impact of pancreatic cancer surveillance when surgery is performed for low-grade dysplasia or a non-neoplastic condition is not well-quantified.

Methods:

A systematic search and prevalence meta-analysis was performed for studies reporting surgery with final diagnoses other than those defined by the CAPS goals from January 2000 to July 2023. The secondary outcome was the pooled proportion of final diagnoses matching the CAPS goals (PROSPERO: #CRD42022300408).

Results:

Twenty-three articles with 5,027 patients (median 109 patients/study, IQR 251) were included. The pooled prevalence of low-yield surgery was 2.1% [95%CI 0.9-3.7], I2 83%). In the subgroup analysis, this prevalence was non-significantly higher in studies that only included familial pancreatic cancer (FPC) subjects without known pathogenic variants (PV), compared to those enrolling PV carriers. No effect modifiers were found. Overall, the pooled prevalence of subjects under surveillance who had a pancreatic resection that contained target lesions was 0.8% [95%CI 0.3-1.5], I2 24%). The temporal analysis showed that the rate of low-yield surgeries decreased in the last decades and stabilized at around 1% (test for subgroup differences P<0.01).

Conclusions:

The risk of “low-yield” surgery during pancreatic cancer surveillance is relatively low but should be thoroughly discussed with individuals under surveillance.
Erosive balanitis caused by Staphylococcus haemolyticus in a healthy, circumcised adult male
Authors: Mazuecos-Blanca José , Mazuecos-Gutiérrez José Rafael , Jiménez-Gil Ana
Published: September 2023

Introduction. Balanitis is an inflammation of the glans penis. Balanoposthitis involves both the glans penis and prepuce and occurs only in uncircumcised males. Recurrent balanoposthitis represents a strong indication for circumcision. After Candida infections, aerobic bacteria are the second most common aetiological cause of acute infectious balanoposthitis, mainly streptococci groups B and D, and staphylococci, usually

S. aureus

. Their clinical manifestations are variable inflammatory changes, including diffuse erythema and oedema. Severe balanopreputial oedema with purulent exudate occurs in painful, erosive streptococcal balanoposthitis.

Coagulase-negative staphylococci (CoNS) are commensal skin bacteria, but are also recognized pathogens of the genitourinary system, mainly related to urinary tract infections.

Staphylococcus haemolyticus

is one of the main species of CoNS that is part of the cutaneous microflora but is also associated with nosocomial infections. In addition,

S. haemolyticus

also causes other infections of the male urogenital tract, such as chronic prostatitis and epididymo-orchitis, but it has not been associated with balanitis.

Case presentation. A 45-year-old man reports having suffered several episodes of balanoposthitis in the last 3 years, which were treated with topical antifungal treatments alone or associated with corticosteroids. For this reason, he underwent a postectomy by his urologist 8 months ago to avoid further recurrences.

The patient consulted for an episode of painful, erosive and exudative lesions on the glans penis and over the post-operative scars lasting 5 days. He had no urinary discomfort or inguinal lymphadenopathy. A complete blood count, biochemical analysis, C-reactive protein (CRP), prostate-specific antigen (PSA) and urinalysis were normal. Abundant growth of

S. haemolyticus

was obtained in the culture on tryptone soya agar with sheep blood and chocolate agar with Vitox media. The MicroScan panel CIM 37 (PM37) was used to study the antimicrobial susceptibilities of the isolated bacteria. The fungal culture on Sabouraud dextrose agar was negative. Based on the antimicrobial susceptibility study, treatment with oral ciprofloxacin and topical mupirocin was started, and the genital infection was completely cured.

Conclusion. We present a healthy, non-diabetic, circumcised male patient with severe, erosive and painful balanitis probably due to

S. haemolyticus

.
Case Series on Trichomonas vaginalis Infections: Impact of Proper Sample Collection and Diagnostic Stewardship
Authors: Agarwal Ashwini , Padhi Abhishek , Chaudhary Anil , Bhise Mayuri , Chauhan Kinjal , Sharma Medhavi , Krishan Ramotra Rohini , Dubey Pankhuri
Published: September 2023

This paper elucidates the transformative impact of a strategic shift in diagnostic practices in the detection of Trichomonas vaginalis (T. vaginalis). It explores five cases where the implementation of a specific diagnostic protocol led to effective identification of the infection. In-depth discussions and a comprehensive literature review underline the necessity for precise diagnosis and the paramount importance of diagnostic stewardship in managing sexually transmitted infections.
Position Statement: Atypical Femoral Fracture from the Korean Society for Bone and Mineral Research in 2023
Authors: Nho Jae-Hwi , Jang Byung-Woong , Lee Dong Woo , Kim Jae-Hyun , Lim Tae Kang , Cha Soo Min , Seo Dong-Kyo , Park Yong-Geun , Kang Dong-Geun , Lee Young-Kyun , Ha Yong-Chan
Published: September 2023

As the aging population increases, the number of patients with osteoporosis is gradually rising. Osteoporosis is a metabolic bone disease characterized by low bone mass and the microarchitectural deterioration of bone tissue, resulting in reduced bone strength and an increased risk of low-energy or fragility fractures. Thus, the use of anti-resorptive agents, such as bisphosphonates (BPs), to prevent osteoporotic fractures is growing annually. BPs are effective in reducing hip and other fractures. However, the longer a patient takes BPs, the higher the risk of an atypical femoral fracture (AFF). The exact mechanism by which long-term BP use affects the development of AFFs has not yet been clarified. However, several theories have been suggested to explain the pathogenesis of AFFs, such as suppressed bone remodeling, impaired bone healing, altered bone quality, and femoral morphology. The management of AFFs requires both medical and surgical approaches. BPs therapy should be discontinued immediately, and calcium and vitamin D levels should be evaluated and supplemented if insufficient. Teriparatide can be used for AFFs. Intramedullary nailing is the primary treatment for complete AFFs, and prophylactic femoral nailing is recommended if signs of an impending fracture are detected.
Advances in the Administration of Vitamin D Analogues to Support Bone Health and Treat Chronic Diseases
Authors: Kanemoto Yoshiaki , Iwaki Miho , Sawada Takahiro , Nojiri Koki , Kurokawa Tomohiro , Tsutsumi Rino , Nagasawa Kazuo , Kato Shigeaki
Published: September 2023

Vitamin D (VD) exerts a wide variety of biological actions in addition to its well-known roles in calcium homeostasis. Nutritional VD deficiency induces rachitic abnormalities in growing children and osteomalacia in adults, and it has been proposed to underlie the onset and development of multiple non-communicable chronic diseases. Therefore, the administration of VD or synthetic VD analogues represents a promising therapeutic strategy; indeed, VD and a VD agonist have shown clinical promise in mitigating osteoporosis and symptoms of insufficient calcium intake. However, even though high doses of VD analogues have shown pre-clinical efficacy against several diseases, including cancers, they have not yet had wide-spread clinical success. This difference may be due to limitation of clinical doses in light of the inherent calcemic action of VD. An approach to overcome this problem involves the development of VD analogues with lower calcemic activity, which could be administered in high doses to attenuate the onset and progress of disease. In a similar strategy, selective estrogen receptor modulators have had success as anti-osteoporosis drugs, and they have shown benefit for other estrogen target organs by serving as partial antagonists or agonists of estrogen receptor α. It is thus conceivable to generate synthetic partial antagonists or agonists for the VD receptor (VDR) that would exert beneficial effects on bone and other VD target organs. In this review, we discuss the molecular basis of the development of such synthetic VDR ligands from the viewpoint of roles of VDR in gene regulation.
Receipt of respiratory vaccines among patients with heart failure in a multicenter health system registry
Authors: Dermenchyan Anna , Choi Kristen R. , Bokhoor Pooya R. , Cho David J. , Delavin Nina Lou A. , Chima-Melton Chidinma , Han Maria A. , Fonarow Gregg C.
Published: September 2023

Background

Heart failure affects people of all ages and is a leading cause of death for both men and women in most racial and ethnic groups in the United States. Infections are common causes of hospitalizations in heart failure, with respiratory infections as the most frequent diagnosis.

Vaccinations provide significant protection against preventable respiratory infections. Despite being an easily accessible intervention, prior studies suggest vaccines are underused in patients with heart failure.

Methods

An observational study of 7341 adults with heart failure was conducted using data from an integrated, multicenter, academic health system in Southern California from 2019 to 2022. Logistic regression models were used to determine the rates of influenza, pneumococcal, and COVID-19 vaccination among a population of patients with heart failure (heart failure preserved ejection fraction [HFpEF], heart failure mildly reduced ejection fraction [HFmrEF], heart failure reduced ejection fraction [HFrEF], and heart failure unspecified ejection fraction [HFuEF]) and identify whether heart failure phenotype is associated with vaccination status.

Results

Vaccination rates varied between influenza, pneumococcal, and COVID-19 vaccines. Of the three respiratory vaccines, 54.5% of patients had received an influenza vaccine, 74.7% had received a pneumococcal vaccine, and 81.3% had received a COVID-19 vaccine. There were no sex-based differences by vaccination status. Patients with HFpEF and HFmrEF had the highest vaccination levels in all three vaccine groups. In adjusted models, patients with HFpEF had higher odds of being vaccinated for influenza (aOR=1.34, 95% CI=1.19-1.53), pneumococcal (aOR=1.28, 95% CI=1.10-1.48), and COVID-19 (aOR=1.25, 95% CI=1.07-1.47) compared to HFuEF patients. Patients with HFrEF had lower odds of being vaccinated for pneumococcal (aOR=0.81, 95% CI=0.70-0.93) than patients with HFuEF.

Conclusions

Patients with HFrEF had the lowest levels of respiratory vaccination compared to other specified heart failure categories. Interventions are needed to increase vaccination education and offerings, especially to patients with HFrEF.
Single-Cell RNA Sequencing of Terminal Ileal Biopsies Identifies Signatures of Crohn’s Disease Pathogenesis
Authors: Krzak Monika , Alegbe Tobi , Taylor D Leland , Jones Gareth-Rhys , Ghouraba Mennatallah , Strickland Michelle , Harris Bradley T , Satti Reem , Arestang Kenneth , Ramirez-Navarro Lucia , Nishad Nilanga , Cheam Kimberly Ai Xian , Tutert Marcus , Ozols Matiss , Noell Guillaume , Leonard Steven , Przybilla Moritz J , Petrova Velislava , Jones Carla P , Wana Noor , Hu May Xueqi , Skelton Jason , Ostermayer Jasmin , Gu Yong , Garri Wendy , Brezina Biljana , Caballes Charry Queen , Corridoni Daniele , Parkes Miles , Iyer Vivek , Cotobal Martin Cristina , McIntyre Rebecca E , Raine Tim , Anderson Carl A
Published: September 2023

Crohn’s disease (CD) is a chronic inflammatory bowel disease exhibiting substantial heterogeneity in clinical presentation and response to therapy. To explore its molecular basis, we developed IBDverse, the largest single-cell RNA sequencing (scRNA-seq) dataset of terminal ileal biopsies, profiling over 1.1 million cells from 111 CD patients and 232 healthy controls. This resource integrates discovery and replication cohorts for robust identification of CD-associated cell types, genes, and pathways. We uncovered epithelial changes marked by interferon-driven MHC-I upregulation, persisting in progenitors after macroscopic inflammation resolution.ITGA4+macrophages were identified as key inflammatory drivers, showing enriched JAK/STAT signaling and cytokine expression (IL-6, IL-12, IL-23). Heritability analysis linked inflammatory monocytes and macrophages to CD susceptibility, implicating resident and recruited immune cells in pathogenesis. These findings establish a comprehensive cellular and molecular framework for CD, offering new insights into disease mechanisms and therapeutic opportunities.
A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts
Authors: Whitman Ethan T. , Ryan Calen P. , Abraham Wickliffe C. , Addae Angela , Corcoran David L. , Elliott Maxwell L. , Hogan Sean , Ireland David , Keenan Ross , Knodt Annchen R. , Melzer Tracy R. , Poulton Richie , Ramrakha Sandhya , Sugden Karen , Williams Benjamin S. , Zhou Jiayi , Hariri Ahmad R. , Belsky Daniel W. , Moffitt Terrie E. , Caspi Avshalom
Published: September 2023

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer’s Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3,380; total N individuals=2,322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, and thinner cortex. In two datasets, faster DunedinPACE was associated with greater burden of white matter hyperintensities. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.
Rapid, biochemical tagging of cellular activity history in vivo
Authors: Zhang Run , Anguiano Maribel , Aarrestad Isak K. , Lin Sophia , Chandra Joshua , Vadde Sruti S. , Olson David E. , Kim Christina K.
Published: September 2023

Intracellular calcium (Ca2+) is ubiquitous to cell signaling across all biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca2+levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely-behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca2+in vivo. Ca2+-activated Split-TurboID (CaST) labels activated cells within 10 minutes with an exogenously-delivered biotin molecule. The enzymatic signal increases with Ca2+concentration and biotin labeling time, demonstrating that CaST is a time-gated integrator of total Ca2+activity. Furthermore, the CaST read-out can be performed immediately after activity labeling, in contrast to transcriptional reporters that require hours to produce signal. These capabilities allowed us to apply CaST to tag prefrontal cortex neurons activated by psilocybin, and to correlate the CaST signal with psilocybin-induced head-twitch responses in untethered mice.
Convergent Sequence Features of Antiviral B Cells
Authors: Abu-Shmais Alexandra A. , Vukovich Matthew J. , Wasdin Perry T. , Suresh Yukthi P. , Rush Scott A. , Gillespie Rebecca A. , Sankhala Rajeshwer S. , Choe Misook , Joyce M. Gordon , Kanekiyo Masaru , McLellan Jason S. , Georgiev Ivelin S.
Published: September 2023

Throughout life, humans experience repeated exposure to viral antigens through infection and vaccination, building diverse antigen-specific antibody repertoires. In recent years, these repertoires have become an important source for novel antibody-based antiviral therapeutics, yet there is still limited understanding of the determinants of antibody-antigen specificity. Here, we generated a large dataset mapping antibody sequence to antigen specificity for thousands of B cells, by screening the repertoires of a set of healthy individuals against twenty viral antigens representing diverse pathogens of biomedical significance. Analysis revealed antigen-specific patterns in variable gene usage, gene pairing, and somatic hypermutation, as well as the presence of convergent antiviral signatures across multiple individuals. These results help define the characteristics of human antibody repertoires simultaneously against an unprecedented number and diversity of viral targets. Understanding the fundamental rules of antibody-antigen interactions can lead to transformative new approaches for the development of antibody therapeutics and vaccines against current and emerging viruses.
Lung cancer-intrinsic SOX2 expression mediates resistance to checkpoint blockade therapy by inducing Treg-dependent CD8+T cell exclusion
Authors: Torres-Mejia Elen , Weng Sally , Nguyen Kim , Duong Ellen , Yim Leon , Spranger Stefani
Published: September 2023

Tumor-intrinsic signaling pathways can drastically affect the tumor immune microenvironment (TME), promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor-cell intrinsic pathways have been reported to affect myeloid cell infiltration and downstream T cell infiltration. Clinical evidence suggests that the exclusion of cytotoxic T cells from the tumor core likewise mediates resistance. Here, we find that tumor cell-intrinsic SOX2 expression induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. CD8+T cell exclusion was dependent on regulatory T cell-mediated suppression of tumor vasculature. Depleting tumor-infiltrating regulatory T cells via Glucocorticoid-Induced TNFR-Related (GITR) restored CD8+T cell infiltration and reduced tumor growth in combination with checkpoint blockade therapy.

Significance

We identified tumor cell-intrinsic SOX2 expression in lung cancer as a mechanism of resistance to immunotherapy. SOX2 expression increases regulatory T cell populations in the TME, negatively affecting the tumor vasculature and blunting CD8+T cell infiltration into the tumor core. This effect could be reverted by targeting regulatory T cells with anti-GITR therapy.
AutoFocus: A hierarchical framework to explore multi-omic disease associations spanning multiple scales of biomolecular interaction
Authors: Schweickart Annalise , Chetnik Kelsey , Batra Richa , Kaddurah-Daouk Rima , Suhre Karsten , Halama Anna , Krumsiek Jan
Published: September 2023

Recent advances in high-throughput measurement technologies have enabled the analysis of molecular perturbations associated with disease phenotypes at the multi-omic level. Such perturbations can range in scale from fluctuations of individual molecules to entire biological pathways. Data-driven clustering algorithms have long been used to group interactions into interpretable functional modules; however, these modules are typically constrained to a fixed size or statistical cutoff. Furthermore, modules are often analyzed independently of their broader biological context. Consequently, such clustering approaches limit the ability to explore functional module associations with disease phenotypes across multiple scales. Here, we introduce AutoFocus, a data-driven method that hierarchically organizes biomolecules and tests for phenotype enrichment at every level within the hierarchy. As a result, the method allows disease-associated modules to emerge at any scale. We evaluated this approach using two datasets: First, we explored associations of biomolecules from the multi-omic QMDiab dataset (n = 388) with the well-characterized type 2 diabetes phenotype. Secondly, we utilized the ROS/MAP Alzheimer’s disease dataset (n = 500), consisting of high-throughput measurements of brain tissue to explore modules associated with multiple Alzheimer’s Disease-related phenotypes. Our method identifies modules that are multi-omic, span multiple pathways, and vary in size. We provide an interactive tool to explore this hierarchy at different levels and probe enriched modules, empowering users to examine the full hierarchy, delve into biomolecular drivers of disease phenotype within a module, and incorporate functional annotations.
tRNA epitranscriptomic alterations associated with opioid-induced reward-seeking and long-term opioid withdrawal
Authors: Blaze J. , Browne C. J. , Futamura R. , Zachariou V. , Nestler E. J. , Akbarian S.
Published: September 2023

DNA cytosine methylation has been documented as a potential epigenetic mechanism of transcriptional regulation underling opioid use disorder. However, methylation of RNA cytosine residues, which would drive another level of biological influence as an epitranscriptomic mechanism of gene and protein regulation has not been studied. Here, we probed whether chronic morphine exposure could alter tRNA cytosine methylation (m5C) and resulting expression levels in the medial prefrontal cortex (mPFC), a brain region crucial for reward processing and executive function that exhibits opioid-induced molecular restructuring. We identified dynamic changes in glycine tRNA (tRNAGlyGCC) cytosine methylation, corresponding to altered expression levels of this tRNA at multiple timepoints following 15 days of daily morphine. Strikingly, a robust increase in methylation, coupled with decreased expression, was present after 30 days of withdrawal, suggesting that repeated opioid administration produces changes to the tRNA regulome long after discontinuation. Furthermore, forebrain-wide knockout of neuronalNsun2, a tRNA methyltransferase, was associated with disruption of reward-seeking in the conditioned place preference paradigm, and this effect was recapitulated by regional mPFCNsun2knockout. Taken together, these studies provide a foundational link between the regulation of tRNA cytosine methylation and OUD and highlight the tRNA machinery as a potential therapeutic target in addiction.
The assembly of neutrophil inflammasomes during COVID-19 is mediated by type I interferons
Authors: Cabrera Luz E. , Jokiranta Suvi T. , Mäki Sanna , Miettinen Simo , Kant Ravi , Kareinen Lauri , Sironen Tarja , Pietilä Jukka-Pekka , Kantele Anu , Kekäläinen Eliisa , Lindgren Hanna , Mattila Pirkko , Kipar Anja , Vapalahti Olli , Strandin Tomas
Published: September 2023

The severity of COVID-19 is linked to excessive inflammation. Neutrophils represent a critical arm of the innate immune response and are major mediators of inflammation, but their role in COVID-19 pathophysiology remains poorly understood. We conducted transcriptomic profiling of neutrophils obtained from patients with mild and severe COVID-19, as well as from SARS-CoV-2 infected mice, in comparison to non-infected healthy controls. In addition, we investigated the inflammasome formation potential in neutrophils from patients and mice upon SARS-CoV-2 infection. Transcriptomic analysis of polymorphonuclear cells (PMNs), consisting mainly of mature neutrophils, revealed a striking type I interferon (IFN-I) gene signature in severe COVID-19 patients, contrasting with mild COVID-19 and healthy controls. Notably, low-density granulocytes (LDGs) from severe COVID-19 patients exhibited an immature neutrophil phenotype and lacked this IFN-I signature. Moreover, PMNs from severe COVID-19 patients showed heightened nigericin-induced caspase1 activation, but reduced responsiveness to exogenous inflammasome priming. Furthermore, IFN-I emerged as a priming stimulus for neutrophil inflammasomes, which was confirmed in a COVID-19 mouse model. These findings underscore the crucial role of neutrophil inflammasomes in driving inflammation during severe COVID-19. Altogether, these findings open promising avenues for targeted therapeutic interventions to mitigate the pathological processes associated with the disease.
Effect of the 2022 COVID-19 booster vaccination campaign in 50 year olds in England: regression discontinuity analysis in OpenSAFELY
Authors: Schaffer Andrea L , Hulme William J , Horne Elsie , Parker Edward P K , Walker Venexia , Stables Catherine , Mehrkar Amir , Bacon Seb CJ , Bates Chris , Goldacre Ben , Walker Alex J ,   The OpenSAFELY Collaborative, Hernán Miguel A , Sterne Jonathan A C
Published: September 2023

Background

SARS-CoV-2 vaccines are highly effective in preventing severe COVID-19 but require boosting to maintain protection. Changes to circulating variants and prevalent natural immunity may impact on real-world effectiveness of boosters in different time periods and in different populations.

Methods

With NHS England approval, we used linked routine clinical data from >24 million patients to evaluate the effectiveness of the 2022 combined COVID-19 autumn booster and influenza vaccine campaign in non-clinically vulnerable 50-year-olds in England using a regression discontinuity design. Our primary outcome was a composite of 6-week COVID-19 emergency attendance, COVID-19 unplanned hospitalisation, or death. The secondary outcomes were: respiratory hospitalisations or death; any unplanned hospitalisation; and any death.

Results

Our study included 1,917,375 people aged 45-54 years with no evidence of being in a high-risk group prioritised for vaccination. By 26 November 2022, booster vaccine coverage was 11.1% at age 49.75 years increasing to 39.7% at age 50.25 years. The estimated effect of the campaign on the risk of the primary outcome in 50-year-olds during weeks 7-12 after the campaign start was -0.4 per 100,000 (95% CI -7.8, 7.1). For the secondary outcomes the estimated effects were: -0.6 per 100,000 (95%CI -13.5, 12.3) for respiratory outcomes; 5.0 per 100,000 (95%CI -40.7, 50.8) for unplanned hospitalisations; and 3.0 per 100,000 (95%CI -2.7, 8.6) for any death. The results were similar when using different follow-up start dates, different bandwidths, or when estimating the effect of vaccination (rather than the campaign).

Conclusion

This study found little evidence that the autumn 2022 vaccination campaign in England was associated with a reduction in severe COVID-19-related outcomes among non-clinically vulnerable 50-year-olds. Possible explanations include the low risk of severe outcomes due to substantial pre-existing vaccine- and infection-induced immunity. Modest booster coverage reduced the precision with which we could estimate effectiveness. The booster campaign may have had effects beyond those estimated, including reducing virus transmission and incidence of mild or moderate COVID-19.