bluuebunny/crossref_metadata_2025 huggingface dataset:
GRAND PLAN: Safety and Efficacy of Glecaprevir/Pibrentasvir for the Treatment of Hepatitis C Virus Infection Among People Initially Disengaged From Health Care Who Use Drugs—A Systematic Multidisciplinary Approach
Authors: Conway Brian , Yi Shana , Yung Rossitta , Sharma Shawn
Published: March 2024

Background

GRAND PLAN is a prospective, open-label, phase 4 study. Based at a single center and with a single arm, GRAND PLAN evaluated the safety and efficacy of an 8-week course of glecaprevir/pibrentasvir (G/P) among active drug users with hepatitis C virus (HCV) infection in a population enriched for factors that may reduce treatment uptake and success, such as disengagement from health care and unstable housing.

Methods

Participants were ≥19 years old and actively using drugs and were confirmed viremic, noncirrhotic, and HCV treatment naive. All participants provided informed consent before any study procedures. They received G/P for 8 weeks within a multidisciplinary model of care, with daily, weekly, or monthly dispensing of medications to optimize adherence.

Results

We identified 117 eligible patients with a median age of 46 years (range, 22–75): 27% were female, 21.4% were Indigenous, 48.7% were unstably housed, and 95.7% were active drug users (94.9% fentanyl). One patient did not start treatment, and 4 underwent <1 week of treatment, leaving 112 completed treatments with 94.6% picking up medications weekly. HCV RNA was undetectable at the end of treatment in all 112 patients. One died of unknown causes shortly after treatment. A cure was demonstrated in 108 of 111 (97.3%) cases at the SVR12 time point (sustained virologic response at ≥12 weeks); the other 3 experienced virologic relapse. Considering the entire cohort, the intent-to-treat success rate was 92.3% (108/117). HCV reinfection was documented at SVR24 in 5 cases, 2 of which were successfully retreated.

Conclusions

GRAND PLAN demonstrates that administration of an 8-week course of G/P to inner-city residents with HCV infection leads to a cure >95%. With a short course of treatment, G/P is an attractive option for this population in helping us achieve the World Health Organization’s HCV objectives by 2030.
Meeting the Consultation Surge: A Nationwide Survey of Consult Volume and Mitigation Strategies in Infectious Diseases Fellowship Programs
Authors: Mena Lora Alfredo J , Knodle Ryan , Borgetti Scott , Matt Brionna , Osorio Georgina , Sundareshan Vidya , Rojas-Moreno Christian , Bartash Rachel , Van Schooneveld Trevor C , Reece Rebecca , Chow Brian , Prakash Katya , Butt Saira , Lastinger Allison
Published: March 2024

High patient volume in fellowship programs can affect learning, wellness, and patient outcomes. Training programs must find ways to mitigate high consultation volume to protect the learning environment. This survey describes average new consults and average censuses for infectious diseases training programs and strategies implemented to mitigate high volume.
Predicting individual differences in peak emotional response
Authors: Schoeller Felix , Christov-Moore Leonardo , Lynch Caitlin , Diot Thomas , Reggente Nicco
Published: March 2024

Why does the same experience elicit strong emotional responses in some individuals while leaving others largely indifferent? Is the variance influenced by who people are (personality traits), how they feel (emotional state), where they come from (demographics), or a unique combination of these? In this 2,900+ participants study, we disentangle the factors that underlie individual variations in the universal experience of aesthetic chills, the feeling of cold and shivers down the spine during peak experiences. Here, we unravel the interplay of psychological and sociocultural dynamics influencing self-reported chills reactions. A novel technique harnessing mass data mining of social media platforms curates the first large database of ecologically sourced chills-evoking stimuli. A combination of machine learning techniques (LASSO and SVM) and multilevel modeling analysis elucidates the interacting roles of demographics, traits, and states factors in the experience of aesthetic chills. These findings highlight a tractable set of features predicting the occurrence and intensity of chills—age, sex, pre-exposure arousal, predisposition to Kama Muta (KAMF), and absorption (modified tellegen absorption scale [MODTAS]), with 73.5% accuracy in predicting the occurrence of chills and accounting for 48% of the variance in chills intensity. While traditional methods typically suffer from a lack of control over the stimuli and their effects, this approach allows for the assignment of stimuli tailored to individual biopsychosocial profiles, thereby, increasing experimental control and decreasing unexplained variability. Further, they elucidate how hidden sociocultural factors, psychological traits, and contextual states shape seemingly “subjective” phenomena.
Effectiveness and safety of eltrombopag in connective tissue disease patients with refractory immune thrombocytopenia: a retrospective study
Authors: Jiang Xiangpin , Shu Xiaoming , Ge Yongpeng
Published: March 2024

Objectives

We aimed to investigate the safety and effectiveness of eltrombopag for adult patients with refractory immune thrombocytopenia (ITP) secondary to connective tissue disease (CTD).

Methods

This is a single-centre, retrospective cohort and propensity score-matched study. Data from CTD-ITP patients treated with eltrombopag between January 2019 and January 2023 were retrospectively analysed. Baseline characteristics and follow-up information were recorded. CTD patients without ITP were matched to identify the risk factors associated with CTD-ITP performed by Logistic regression analysis.

Results

Twenty patients were enrolled, including 5 systemic lupus erythematosus (SLE), 9 Sjögren’s syndrome (SS) and 6 undifferentiated connective tissue disease (UCTD). Nineteen (95%) patients were female, and the median age was 59 years. Logistic regression analysis showed that anaemia (OR = 8.832, P = 0.007) was associated with increased risk of ITP, while non-erosive arthritis (OR = 0.045, P = 0.001) and interstitial lung disease (OR = 0.075, P = 0.031) were associated with reduced risk. Fourteen patients (70%) achieved a complete response (CR) and one (5%) achieved a partial response (PR). The median response time was 14 days. The median platelet count was 8.5 × 109/l at baseline of eltrombopag and increased to 122 × 109/l after 4 weeks. No adverse events were observed.

Conclusions

Eltrombopag appears to be effective, safe and well-tolerated in refractory ITP patients with CTD; larger studies are needed to confirm the generalizability of these findings.
NUDC is critical for rod photoreceptor function, maintenance, and survival
Authors: Garner Mary Anne , Hubbard Meredith G. , Boitet Evan R. , Hubbard Seth T. , Gade Anushree , Ying Guoxin , Jones Bryan W. , Baehr Wolfgang , Gross Alecia K.
Published: March 2024

NUDC (nuclear distribution protein C) is a mitotic protein involved in nuclear migration and cytokinesis across species. Considered a cytoplasmic dynein (henceforth dynein) cofactor, NUDC was shown to associate with the dynein motor complex during neuronal migration. NUDC is also expressed in postmitotic vertebrate rod photoreceptors where its function is unknown. Here, we examined the role of NUDC in postmitotic rod photoreceptors by studying the consequences of a conditional NUDC knockout in mouse rods (rNudC−/−). Loss of NUDC in rods led to complete photoreceptor cell death at 6 weeks of age. By 3 weeks of age, rNudC−/− function was diminished, and rhodopsin and mitochondria were mislocalized, consistent with dynein inhibition. Levels of outer segment proteins were reduced, but LIS1 (lissencephaly protein 1), a well‐characterized dynein cofactor, was unaffected. Transmission electron microscopy revealed ultrastructural defects within the rods of rNudC−/− by 3 weeks of age. We investigated whether NUDC interacts with the actin modulator cofilin 1 (CFL1) and found that in rods, CFL1 is localized in close proximity to NUDC. In addition to its potential role in dynein trafficking within rods, loss of NUDC also resulted in increased levels of phosphorylated CFL1 (pCFL1), which would purportedly prevent depolymerization of actin. The absence of NUDC also induced an inflammatory response in Müller glia and microglia across the neural retina by 3 weeks of age. Taken together, our data illustrate the critical role of NUDC in actin cytoskeletal maintenance and dynein‐mediated protein trafficking in a postmitotic rod photoreceptor.
Extracorporeal Versus Conventional Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest: A Propensity Score Matching Cohort Study
Authors: Bian Yuan , Pan Yuhui , Zheng Jiaqi , Zheng Wen , Qin Lijie , Zhou Guangju , Sun Xifeng , Wang Mingjie , Wang Chunyi , Chen Yuguo , Xu Feng
Published: March 2024

Objective:

Comparing the effects of extracorporeal cardiopulmonary resuscitation (ECPR) and conventional cardiopulmonary resuscitation (CCPR) on outcomes in patients with in-hospital cardiac arrest (IHCA) in China. The benefits of ECPR over CCPR in patients with IHCA remain controversial.

Design:

This article analyzed data from the BASeline Investigation of In-hospital Cardiac Arrest (BASIC-IHCA) study, which consecutively enrolled patients with IHCA from July 1, 2019, to December 31, 2020. Patients who received ECPR were selected as the case group and matched with patients who received CCPR as the control group by propensity score at a ratio of 1:4. A parallel questionnaire survey of participating hospitals was conducted, to collect data on ECPR cases from January 1, 2021 to November 30, 2021. The primary outcome was survival to discharge or 30-day survival.

Setting:

We included 39 hospitals across 31 provinces in China.

Patients:

Patients receiving cardiopulmonary resuscitation and without contraindications to ECPR were selected from the BASIC-IHCA database. Patients older than 75 years, not witnessed, or with cardiopulmonary resuscitation duration less than 10 min were excluded.

Interventions:

None.

Measurements and Main Results:

A total of 4853 patients met the inclusion criteria before matching, with 34 undergoing ECPR (median age, 56.5 yr; 67.65% male) and 4819 underwent CCPR (median age, 59 yr; 64.52% male). There were 132 patients receiving CCPR and 33 patients receiving ECPR who were eventually matched. The ECPR group had significantly higher survival rates at discharge or 30-day survival (21.21% vs. 7.58%, p = 0.048). The ECPR group had significantly lower mortality rates (hazard ratio 0.57; 95% CI, 0.38–0.91) than the CCPR group at discharge or 30 days. Besides the BASIC-IHCA study, the volume of ECPR implementations and the survival rate of patients with ECPR (29.4% vs. 10.4%. p = 0.004) in participating hospitals significantly improved.

Conclusions:

ECPR may be beneficial compared with CCPR for patient survival after IHCA and should be considered for eligible patients with IHCA.
A Capture–Recapture-based Ascertainment Probability Weighting Method for Effect Estimation With Under-ascertained Outcomes
Authors: Bonander Carl , Nilsson Anton , Li Huiqi , Sharma Shambhavi , Nwaru Chioma , Gisslén Magnus , Lindh Magnus , Hammar Niklas , Björk Jonas , Nyberg Fredrik
Published: March 2024

Outcome under-ascertainment, characterized by the incomplete identification or reporting of cases, poses a substantial challenge in epidemiologic research. While capture–recapture methods can estimate unknown case numbers, their role in estimating exposure effects in observational studies is not well established. This paper presents an ascertainment probability weighting framework that integrates capture–recapture and propensity score weighting. We propose a nonparametric estimator of effects on binary outcomes that combines exposure propensity scores with data from two conditionally independent outcome measurements to simultaneously adjust for confounding and under-ascertainment. Demonstrating its practical application, we apply the method to estimate the relationship between health care work and coronavirus disease 2019 testing in a Swedish region. We find that ascertainment probability weighting greatly influences the estimated association compared to conventional inverse probability weighting, underscoring the importance of accounting for under-ascertainment in studies with limited outcome data coverage. We conclude with practical guidelines for the method’s implementation, discussing its strengths, limitations, and suitable scenarios for application.
Combined Use of Endoscopic Techniques and Virtual Surgical Planning for Intraoral Approach for Hemi-mandibular Resection and Reconstruction
Authors: Wang Yujiao , Ma Dan , Li Yun , Zhang Chunyi , Yang Yaowu , Wu Wei
Published: March 2024

Background:

The study aimed to describe our experience in using endoscopic procedures to aid hemi-mandibular reconstruction with bone flaps through transoral approach.

Methods:

Five patients with huge benign mandibular tumors underwent transoral mandibulectomy and hemi-mandibular reconstruction, using endoscopy. Facial symmetry, occlusion, bone healing, and mandibular similarity were all evaluated postoperatively. The paired-samples t test was used to compare quantitative data, and a P value less than 0.05 was considered a significant difference.

Results:

All five patients who received transoral mandibular surgery recovered in terms of TMJ functionality, facial symmetry, and aesthetic results. Endoscopy monitored and ensured that bone flaps were correctly connected and fixed. The accuracy of endoscopy-guided mandibular reconstruction was confirmed by quantitative examination for four cases, which revealed no statistically significant variations between postoperative CT analysis and preoperative virtual surgical planning data.

Conclusions:

Endoscopy-assisted virtual surgery may resolve concerns with transoral hemi-mandibular reconstruction and broaden indications for mini-invasive mandibular reconstruction. However, only patients with benign mandibular tumors were included in our study, so surgeons should be very cautious if applying this technique to malignant lesions or bony tumors invading soft tissues.
Optimized Aesthetic Outcomes When Treating Glabellar Lines with Botulinum Toxin Type A: GLO 3 + 2: A Precise Technique Based on Anatomy
Authors: Solish Nowell , Kane Michael A.C. , Brown Jessica , Gallagher Conor J.
Published: March 2024

Good patient outcomes after treatment of the glabellar complex with botulinum toxin type A entail elimination of glabellar lines and maintenance of a natural eyebrow position. A precise injection technique that accurately targets the muscles that influence eyebrow position is required to reduce the risk of adverse aesthetic outcomes or unmasking an underlying eyelid ptosis. Here, we describe the glabellar lines optimization (GLO 3 + 2) injection anatomy technique, a precise five-point injection pattern that is based on current understanding of facial functional anatomy and which aims to minimize the risk of affecting nontargeted muscles. Injection sites above the brow or that do not target the precise location of the muscles in the glabellar complex are likely to inadvertently expose the frontalis to botulinum toxin type A and result in undesirable aesthetic outcomes. Because the frontalis is a strong determinant of aesthetic outcomes, it is important to consider the overall effects of the interactions between the eyebrow depressors and the opposing forces of the frontalis on brow outcomes in both the resting brow position and during dynamic brow movement.
THE SPECTRUM OF RELENTLESS PLACOID AND ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY: A MULTIMODAL IMAGING ANALYSIS
Authors: Chan Xavier , Amoroso Johnell Renz , Hoang Quan V. , Jung Jesse J.
Published: March 2024

Purpose:

The objective of this study was to showcase the spectrum between acute posterior multifocal placoid pigment epitheliopathy and relentless placoid utilizing ultra-widefield imaging findings of a case of acute posterior multifocal placoid pigment epitheliopathy progressing to relentless placoid chorioretinitis.

Methods:

A 23-year-old White woman presented with worsening vision in both eyes. Clinical examination and multimodal imaging modalities including fundus photographs, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, and spectral domain optical coherence tomography and angiography were utilized to diagnose acute posterior multifocal placoid pigment epitheliopathy and clinically follow the patient.

Results:

Clinical examination of the patient initially revealed posterior lesions consistent with acute posterior multifocal placoid pigment epitheliopathy, but subsequent multimodal images including ultra-widefield fluorescein angiography and indocyanine green angiography revealed newer, more peripheral lesions more typical of relentless placoid chorioretinitis.

Conclusion:

When compared with standard multimodal imaging, ultra-widefield imaging is an effective tool to delineate nuances between acute posterior multifocal placoid pigment epitheliopathy and relentless placoid chorioretinitis through identification of peripheral lesions, which may be of clinical importance when determining management and therapeutics for patients.
SHWACHMAN–DIAMOND SYNDROME ASSOCIATED WITH ROD-CONE DYSTROPHY
Authors: Zhang Jingwen , de Guimaraes Thales A. C. , Thompson Dorothy , Michaelides Michel
Published: March 2024

Purpose:

The aim of this study was to report a patient with Shwachman–Diamond syndrome and concomitant rod-cone dystrophy who underwent bone marrow transplantation.

Methods:

This was a retrospective single case report.

Results:

A female patient with Shwachman–Diamond syndrome was referred to a tertiary hospital to investigate possible pigmentary retinopathy at the age of 16 years. She described poor night vision and was found to have reduced VA (6/20 right eye, 6/38 left eye). Over the 10-year follow-up, her VA remained relatively stable with no new visual symptoms. Optical coherence tomography revealed progressive, diffuse outer retinal thinning with disruption of the ellipsoid zone, which initially was relatively preserved subfoveally. Fundus autofluorescence images revealed generalized areas of hypoautofluorescence beyond the vascular arcades and a perimacular ring of increased autofluorescence. The flash electroretinogram was in keeping with a severe rod-cone dystrophy. The pattern visual evoked potential was abnormal but detectable, indicating macular pathway dysfunction, suggesting encroachment into central macular regions but with some functional preservation.

Conclusion:

The authors report a patient with Shwachman–Diamond syndrome with severe early-onset rod-cone dystrophy noted at the age of 16 years. Slow anatomical progression has been observed over the subsequent 10 years, with relative functional macular preservation to support a VA of 6/36 in both eyes.
Unilateral Multifocal Inner Ear and Internal Auditory Canal or Cerebellopontine Angle Cochleovestibular Schwannomas—Genetic Analysis and Management by Surgical Resection and Cochlear Implantation
Authors: Plontke Stefan K. , Hoffmann Katrin , Caye-Thomasen Per , Baasanjav Sevjidmaa , Kösling Sabrina , Leisz Sandra , Liebau Arne , Mawrin Christian , Rahne Torsten , Scheffler Jonas , Strauss Christian , Siebolts Udo
Published: March 2024

Objective

To describe the genetic characteristics and the management of two very rare cases of unilateral multifocal inner ear and internal auditory canal or cerebellopontine angle cochleovestibular schwannomas not being associated to full neurofibromatosis type 2-related schwannomatosis.

Patients

In a 29-year-old man and a 55-year-old woman with single-sided deafness multifocal unilateral cochleovestibular schwannomas were surgically resected, and hearing was rehabilitated with a cochlear implant (CI). Unaffected tissue was analyzed using next generation sequencing of the NF2 gene. Tumor tissue was analyzed using a 340-parallel sequencing gene panel.

Main outcome measures

Mutations in the NF2 gene, word recognition score for monosyllables at 65 dB SPL (WRS65) with CI.

Results

No disease-causing mutation was detected in the examined sequences in blood leucokytes. All tumor samples revealed, among others, somatic pathogenic NF2 mutations. While the anatomically separate tumors in case 1 were likely molecular identical, the tumors in case 2 showed different genetic patterns. WRS65 was 55% at 6 years of follow-up and 60% at 4.5 years of follow-up, respectively.

Conclusions

The occurrence of multifocal unilateral cochleovestibular schwannomas without pathogenic variants in NF2 in non-affected blood leucocytes can be associated with mosaic NF2-related schwannomatosis (case 1), or with likely sporadic mutations (case 2) and may be overlooked due to their extreme rarity. Although challenging, successful hearing rehabilitation could be achieved through surgical resection of the tumors and cochlear implantation.
Admission proteinuria predicts the incidence of acute kidney injury among patients with acute ST-segment elevation myocardial infarction: a retrospective cohort study
Authors: Wang Dingzhou , Shang Wenxuan , Jin Youkai , Gong Mengge , Huang Weijian , Shan Peiren , Liang Dongjie
Published: March 2024

Background

Proteinuria indicates renal dysfunction and is associated with the development of acute kidney injury (AKI) in several conditions, but the association between proteinuria and AKI in patients with ST-segment elevation myocardial infarction (STEMI) remains unclear. This research aims to investigate the predictive value of proteinuria for the development of AKI in STEMI patients.

Methods

A total of 2735 STEMI patients were enrolled. The present study’s endpoint was AKI incidence during hospitalization. AKI is defined according to the Kidney Disease: Improving Global Outcomes criteria. We defined proteinuria, measured with a dipstick, as mild (1+) or heavy (2+ to 4+). Multivariate logistic regression and subgroup analyses were used to testify to the association between proteinuria and AKI.

Results

Overall, proteinuria was observed in 634 (23.2%) patients. Multivariate logistic regression analyses revealed that proteinuria [odds ratio (OR), 1.58; 95% confidence interval (CI), 1.25–2.00; P < 0.001] was the independent predictive factor for AKI. Severe proteinuria was associated with a higher adjusted risk for AKI compared with the nonproteinuria group (mild proteinuria: OR, 1.35; 95% CI, 1.04–1.75; P = 0.025; severe proteinuria: OR, 2.50; 95% CI, 1.70–3.68; P < 0.001). The association was highly consistent across all studied subgroups. (all P for interaction >0.05).

Conclusion

Admission proteinuria measured using a urine dipstick is an independent risk factor for the development of AKI in STEMI patients.
Macrophage activation syndrome in a Sudanese child: a case report from Sudan
Authors: Yahia Elhassan Maha Abdalla , Hussain Idres Roua Mohammedali , Mohamed Elhassan Baraa Mohamed Salaheldin , Banaga Siddiq Naema Siddiq , Osman Mohammed Rayan Abdelwahab , Mahmmoud Fadelallah Eljack Mohammed , Mustafa Ghassan E. , Hemmeda Lina , Abbasher Hussien Mohamed Ahmed Khabab
Published: March 2024

Introduction and importance:

Macrophage activation syndrome (MAS) is a severe form of hemophagocytic lymphohistiocytosis that is frequently associated with either a flare-up of rheumatologic diseases, or infection and is characterized by intermittent fever, organomegaly, and multisystem dysfunction. Early diagnosis and treatment are crucial for outcome improvement.

Case presentation:

The authors present a 9-year-old male with systemic onset juvenile idiopathic arthritis who presented with fever, vomiting, and nose bleeding, as well as being jaundiced, and having hepatomegaly and ascites. Pancytopenia, hepatic dysfunction, and elevated ferritin levels were discovered, along with negative virological and immunological tests. He was given broad-spectrum antibiotics, and a high-dose steroid showed a good response, and he was discharged about a week later.

Clinical discussion:

It is hypothesized that decreased natural killer cells’ function could lead to the inability to clear the infection, and subsequent lymphocytes-induced macrophages activation. Despite being beneficial in this case, steroids led to no improvement in other similar cases.

Conclusion:

MAS is a real life-threatening complication for patients with systemic Juvenile idiopathic arthritis (sJIA), and early diagnosis and prompt initial treatment can both offer a favourable result against such syndrome.
Clinicopathological profile of head and neck cancers in Army Hospital of Nepal: a retrospective study
Authors: Karki Reeba , Marasini Anupama , Mahaseth Rajeev Kumar , Bista Ranishma , Dongol Suman Raj , Adhikari Yuvraj
Published: March 2024

Introduction:

Head and neck cancer is common in several parts of the world. It is sixth most prevalent neoplasms in the world. Approximately 900 000 cases diagnosed worldwide per year. It has good prognosis when timely diagnosed and treated appropriately.

Methods:

This was a retrospective study carried out in the Department of ENT-HNS of Shree Birendra Hospital, Chhauni, Kathmandu from May 2022 to April 2023. All histopathologically proven malignant cases of head and neck region were included in the study. Data were entered in Microsoft excel and managed in SPSS version 22. Analysis was done in the form of percentage and proportion and represented as table where necessary. The study has been registerd in clinical trials and has been reported in line with the STROCSS criteria.

Results:

Total 76 patients were analyzed. Age ranged from 17 to 84 years and the most common age group presenting with head and neck cancer was 61–80 years. The most common malignancy was laryngeal cancer (34%) followed by thyroid malignancies (29%). Squamous cell carcinoma was the commonest histological type (48%). Surgery with postoperative radiotherapy (RT)/radioactive iodine (RAI) was found to be the commonest treatment modality.

Conclusions:

Head and neck cancers are not uncommon and majority of patients present late with advanced stage cancer. Hence, public awareness, early diagnosis with cost-effective treatment and regular follow-up are needed to improve outcomes of these patients in our society.
Structural and functional abnormalities in the medial prefrontal cortex were associated with pain and depressive symptoms in patients with adhesive capsulitis
Authors: Li Jie , Zhao Rui , Wang Chenguang , Song Jiajun , Guo Xing , Ge Yeqi , Chu Xu
Published: March 2024

Introduction:

Chronic pain and depression have been shown to coexist in patients with adhesive capsulitis (AC). Recent studies identified the shared brain plasticity between pain and depression; however, how such neuroplasticity contributes to AC remains unclear. Here, we employed a combination of psychophysics, structural MRI, and functional MRI techniques to examine the brain's structural and functional changes in AC.

Methods:

Fifty-two patients with AC and 52 healthy controls (HCs) were included in our study. Voxelwise comparisons were performed to reveal the differences in grey matter volume (GMV) and regional homogeneity (ReHo) between AC and HCs. Furthermore, region of interest to whole brain functional connectivity (FC) was calculated and compared between the groups. Finally, Pearson correlation coefficients were computed to reveal the association between clinical data and brain alterations. Mediation analyses were performed to investigate the path association among brain alterations and clinical measures.

Results:

Three main findings were observed: (1) patients with AC exhibited a higher depression subscale of hospital anxiety and depression scale (HADS-D) score correlating with the GMV within the right medial prefrontal cortices (mPFC) compared with HCs; (2) relative to HCs, patients with AC exhibited lower ReHo within the right mPFC, which largely overlapped with the structural abnormalities; (3) the impact of pain duration on HADS-D score was mediated by ventral part of medial prefrontal cortices (vmPFC) GMV in patients with AC.

Conclusion:

In summary, our current findings suggest that vmPFC alterations correlate with both the pain duration and the emotional comorbidities experienced by patients with AC. Our research provides an enhanced comprehension of the underlying mechanisms of AC, thereby facilitating the development of more effective treatment approaches for AC.
Point Shear Wave Elastography Detected Liver Stiffness Increased in Pediatric Patient With Thalassemia Major
Authors: Tuncel Defne Ay , Pekoz Burcak Cakir , Koc Ayse Selcan , Sumbul Hilmi Erdem
Published: March 2024

Transient elastography (TE) and point shear wave elastography (pSWE) are 2 elastographic ultrasound examinations used in liver stiffness (LS) measurement. It was shown that the LS value detected by TE in pediatric β-thalassemia major patients has increased, and there was no LS evaluation obtained with pSWE in literature. Thus, in this study, it was aimed to evaluate LS with pSWE examination in children with thalassemia major and to determine LS-related parameters in these patients. Sixty-three schoolchildren with a diagnosis of β-thalassemia major and 21 healthy controls between the ages of 7 and 18 years were included. In addition to routine anamnesis, physical examination, and laboratory examinations, renal and liver ultrasounds were performed. Liver stiffness values were measured by pSWE examination. Serum levels of urea, aspartate-aminotransferase, alanine-aminotransferase, iron, and ferritin were significantly higher in patients, and serum creatinine, iron binding capacity, and hemoglobin levels were found to be significantly lower (P < 0.05 for each). Liver stiffness values were significantly higher in patients compared with healthy controls. In linear regression analysis, serum iron and iron binding capacity values were found to be closely related with LS (P < 0.001 vs. β = 0.482 and P = 0.047 vs. β = 0.237, respectively). Liver stiffness values obtained by pSWE examination increase significantly in patients. According to the results of our study, in addition to the previously known TE method, we think that the LS evaluation obtained by pSWE, a new method that can make more accurate measurements, can be used in the possible early detection of target organ damage in children with thalassemia major.
Single-cell multiomics reveals a gene regulatory circuit promoting leukemia cell differentiation
Authors: Tian Xin , Zhang Liuqingqing , Tang Yijia , Xiang Guiqiyang , Wang Zixuan , Zhu Ping , Yu Shuting , Jiang Fangying , Wang Shuai , Wang Jinzeng , Dai Yao , Zheng Desheng , Wang Jianbiao , Liu Han , Weng Xiangqin , Wang Shengyue , Tan Yun , Chen Zhu , Chen Saijuan , Liu Feng
Published: March 2024

Cancer differentiation therapy aims to induce maturation of neoplastic cells, yet how cell fate is determined in oncogenic cellular contexts is poorly understood. Here we integrate chromatin accessibility and transcriptome analysis at single-cell levels to investigate the mechanism driving the differentiation trajectory of the PML/RARα+acute promyeloid leukemia (APL) cell line model, NB4, under the induction of all-trans-retinoid acid (ATRA). We show that differentiating NB4 cells navigate through an intermediate cell fate decision point that leads to either terminal granulopoiesis or a transient immature-lymphocyte-like state. Functional perturbation studies indicate that ATRA signaling activates discrete PML/RARα-target enhancers to induce a positive feedforward gene regulatory circuit involving two myeloid-lineage transcription factors, SPI1 and CEBPE, which is both necessary and sufficient to activate a myelocytic gene expression program in NB4. Further, ectopic expression of SPI1 and CEBPE also promotes myelocytic differentiation in non-APL leukemia cell lines HL60 and K562. Together, these results shed light on the differentiation trajectory of therapy-induced cell decisions of APL and suggest a gene regulatory circuit that may be broadly exploited to promote terminal differentiation of leukemia.
HTLV-1 infected T cells cause bone loss via small extracellular vesicles
Authors: Pokhrel Nitin Kumar , Panfil Amanda , Habib Haniya , Seeniraj Sham , Joseph Ancy , Rauch Daniel , Cox Linda , Sprung Robert , Gilmore Petra Erdmann , Zhang Qiang , Townsend R Reid , Yu Lianbo , Yilmaz Ayse Selen , Aurora Rajeev , Park William , Ratner Lee , Weilbaecher Katherine N , Veis Deborah J
Published: March 2024

Adult T cell leukemia (ATL), caused by infection with human T cell leukemia virus type 1 (HTLV-1), is often complicated by hypercalcemia and osteolytic lesions. Therefore, we studied the communication between patient-derived ATL cells (ATL-PDX) and HTLV-1 immortalized CD4+ T cell lines (HTLV/T) with osteoclasts and their effects on bone mass in mice. Intratibial inoculation of some HTLV/T lead to a profound local decrease in bone mass similar to marrow-replacing ATL-PDX, despite the fact that few HTLV/T cells persisted in the bone. To study the direct effect of HTLV/T and ATL-PDX on osteoclasts, supernatants were added to murine and human osteoclast precursors. ATL-PDX supernatants from hypercalcemic patients promoted formation of mature osteoclasts, while those from HTLV/T were variably stimulatory, but had largely consistent effects between human and murine cultures. Interestingly, this osteoclastic activity did not correlate with expression of osteoclastogenic cytokine RANKL, suggesting an alternative mechanism. HTLV/T and ATL-PDX produce small extracellular vesicles (sEV), known to facilitate HTLV-1 infection. We hypothesized that these sEV also mediate bone loss by targeting osteoclasts. We isolated sEV from both HTLV/T and ATL-PDX, and found they carried most of the activity found in supernatants. In contrast, sEV from uninfected activated T cells had little effect. Analysis of sEV (both active and inactive) by mass spectrometry and electron microscopy confirmed absence of RANKL and intact virus. Viral proteins Tax and Env were only present in sEV from the active, osteoclast-stimulatory group, along with increased representation of proteins involved in osteoclastogenesis and bone resorption. sEV injected over mouse calvaria in the presence of low dose RANKL caused more osteolysis than RANKL alone. Thus, HTLV-1 infection of T cells can cause release of sEV with strong osteolytic potential, providing a mechanism beyond RANKL production that modifies the bone microenvironment, even in the absence of overt leukemia.
miR-155 expression and function in leukemic stem cells
Authors: Garzon Ramiro , Croce Carlo M
Published: March 2024

It has been reported that elevated levels of miR-155 have been reported in patients with Acute Myeloid Leukemia (AML) bearingFLT3-ITD mutations and is independent ofFLT3-ITD signaling. However, it is unclear how miR-155 is expressed in leukemic stem cells (LCS) and whether miR-155 has any role regulating LSC functions. In this manuscript, we defined the expression of miR-155 in clearly defined LCSs population and showed that miR-155 is regulating self-renewal and quiescence of LSCs.
Clinical Performance of Cas13a-based Point-of-Care Lateral Flow Assay for DetectingNeisseria gonorrhoeae
Authors: Allan-Blitz Lao-Tzu , Sanders Gabriela , Shah Palak , Adams Gordon , Jarolimova Jana , Ard Kevin , Branda John A. , Klausner Jeffrey D. , Sabeti Pardis C. , Lemieux Jacob E.
Published: March 2024

Background

Diagnosis ofNeisseria (N.) gonorrhoeaeis dependent on nucleic acid amplification testing (NAAT), which is not available in resource-limited settings where the prevalence of infection is highest. Recent advances in molecular diagnostics leveraging the high specificity of CRISPR enzymes can permit field-deployable, point-of-care lateral flow assays. We previously reported on the development andin vitroperformance of a lateral flow assay for detectingN. gonorrhoeae. Here we aimed to pair that assay with point-of-care DNA extraction techniques and assess the performance on clinical urine specimens.

Methods

We collected an additional urine specimen among individuals enrolling in an ongoing clinical trial at the Massachusetts General Hospital Sexual Health Clinic who presented with symptoms of urethritis or cervicitis (urethral or vaginal discharge, dysuria, or dyspareunia). We then assessed thermal, detergent, and combination DNA extraction conditions, varying the duration of heat at 95°C and concentration of Triton X. We assessed the efficacy of the various DNA extraction methods by quantitative polymerase chain reaction (qPCR). Once an extraction method was selected, we incubated samples for 90 minutes to permit isothermal recombinase polymerase amplification. We then assessed the performance of lateral flow Cas13a-based detection using our previously designedporA probe and primer system forN. gonorrhoeaedetection, comparing lateral flow results with NAAT results from clinical care.

Results

We assessed DNA extraction conditions on 3 clinical urine specimens. There was no consistent significant difference in copies per microliter of DNA obtained using more or less heat. On average, we noted that 0.02% triton combined with 5 minutes of heating to 95°C resulted in the highest DNA yield, however, 0.02% triton alone resulted in a quantity of DNA that was above the previously determined analytic sensitivity of the assay. Given that detergent-based extraction is more easily deployable, we selected that as our method for extraction. We treated 23 clinical specimens with 0.02% triton, which we added to the Cas13a detection system. We ran all lateral flow detections in duplicate. The Cas13a-based assay detected 8 of 8 (100%) positive specimens, and 0 of 15 negative specimens.

Conclusion

Using point-of-care DNA extraction, isothermal amplification, and Cas13a-based detection, our point-of-care lateral flowN. gonorrhoeaeassay correctly identified 23 clinical urine specimens as either positive or negative. Further evaluation of this assay among larger samples and more diverse sample types is warranted.
Photothrombosis induced cortical stroke produces electrographic epileptic biomarkers in mice
Authors: Shaw Dana C. , Kondabolu Krishnakanth , Walsh Katherine G. , Shi Wen , Rillosi Enrico , Hsiung Maxine , Eden Uri T. , Richardson Robert M. , Kramer Mark A. , Chu Catherine J. , Han Xue
Published: March 2024

Objective

Interictal epileptiform spikes, high-frequency ripple oscillations, and their co-occurrence (spike ripples) in human scalp or intracranial voltage recordings are well-established epileptic biomarkers. While clinically significant, the neural mechanisms generating these electrographic biomarkers remain unclear. To reduce this knowledge gap, we introduce a novel photothrombotic stroke model in mice that reproduces focal interictal electrographic biomarkers observed in human epilepsy.

Methods

We induced a stroke in the motor cortex of C57BL/6 mice unilaterally (N=7) using a photothrombotic procedure previously established in rats. We then implanted intracranial electrodes (2 ipsilateral and 2 contralateral) and obtained intermittent local field potential (LFP) recordings over several weeks in awake, behaving mice. We evaluated the LFP for focal slowing and epileptic biomarkers - spikes, ripples, and spike ripples - using both automated and semi-automated procedures.

Results

Delta power (1-4 Hz) was higher in the stroke hemisphere than the non-stroke hemisphere in all mice (p<0.001). Automated detection procedures indicated that compared to the non-stroke hemisphere, the stroke hemisphere had an increased spike ripple (p=0.006) and spike rates (p=0.039), but no change in ripple rate (p=0.98). Expert validation confirmed the observation of elevated spike ripple rates (p=0.008) and a trend of elevated spike rate (p=0.055) in the stroke hemisphere. Interestingly, the validated ripple rate in the stroke hemisphere was higher than the non-stroke hemisphere (p=0.031), highlighting the difficulty of automatically detecting ripples. Finally, using optimal performance thresholds, automatically detected spike ripples classified the stroke hemisphere with the best accuracy (sensitivity 0.94, specificity 0.94).

Significance

Cortical photothrombosis-induced stroke in commonly used C57BL/6 mice produces electrographic biomarkers as observed in human epilepsy. This model represents a new translational cortical epilepsy model with a defined irritative zone, which can be broadly applied in transgenic mice for cell type specific analysis of the cellular and circuit mechanisms of pathologic interictal activity.

Key Points

Cortical photothrombosis in mice produces stroke with characteristic intermittent focal delta slowing.

Cortical photothrombosis stroke in mice produces the epileptic biomarkers spikes, ripples, and spike ripples.

All biomarkers share morphological features with the corresponding human correlate.

Spike ripples better lateralize to the lesional cortex than spikes or ripples.

This cortical model can be applied in transgenic mice for mechanistic studies.
The spiking output of the mouse olfactory bulb encodes large-scale temporal features of natural odor environments
Authors: Lewis Suzanne M. , Suarez Lucas M. , Rigolli Nicola , Franks Kevin M. , Steinmetz Nicholas A. , Gire David H.
Published: March 2024

In natural odor environments, odor travels in plumes. Odor concentration dynamics change in characteristic ways across the width and length of a plume. Thus, spatiotemporal dynamics of plumes have informative features for animals navigating to an odor source. Population activity in the olfactory bulb (OB) has been shown to follow odor concentration across plumes to a moderate degree (Lewis et al., 2021). However, it is unknown whether the ability to follow plume dynamics is driven by individual cells or whether it emerges at the population level. Previous research has explored the responses of individual OB cells to isolated features of plumes, but it is difficult to adequately sample the full feature space of plumes as it is still undetermined which features navigating mice employ during olfactory guided search. Here we released odor from an upwind odor source and simultaneously recorded both odor concentration dynamics and cellular response dynamics in awake, head-fixed mice. We found that longer timescale features of odor concentration dynamics were encoded at both the cellular and population level. At the cellular level, responses were elicited at the beginning of the plume for each trial, signaling plume onset. Plumes with high odor concentration elicited responses at the end of the plume, signaling plume offset. Although cellular level tracking of plume dynamics was observed to be weak, we found that at the population level, OB activity distinguished whiffs and blanks (accurately detected odor presence versus absence) throughout the duration of a plume. Even ∼20 OB cells were enough to accurately discern odor presence throughout a plume. Our findings indicate that the full range of odor concentration dynamics and high frequency fluctuations are not encoded by OB spiking activity. Instead, relatively lower-frequency temporal features of plumes, such as plume onset, plume offset, whiffs, and blanks, are represented in the OB.
Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease
Authors: Hector Audrey , da Costa Caiado Maria João , Leduc Tanya , Delignat-Lavaud Benoît , Dufort-Gervais Julien , Bourguignon Clément , Lina Jean-Marc , Fernandes Karl , Brouillette Jonathan , Mongrain Valérie
Published: March 2024

The symptomatology of Alzheimer’s disease (AD) includes cognitive deficits and sleep disturbances. Recent findings suggest the involvement of dysfunctions in lipid metabolism, such as oleic acid build-up, in the brain of AD patients and animal models. In addition, the inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. Alterations in astrocytes and their function were reported in AD patients and animal models, and astrocytes have been implicated in the regulation of sleep. However, the relationship between sleep disturbances, astrocytes and lipid metabolism remains to be explored in AD. This project thus aimed at assessing whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associated with modifications in astrocytic function. Wild-type (WT) and 3xTg-AD female mice (4-months old) received intracerebroventricular infusion of a SCD inhibitor (SCDi) or vehicle for 28 days, and a 24-hour electrocorticographic (ECoG) recording was conducted post-treatment. Post-mortem brain slices were stained for the astrocytic markers glial fibrillary acidic protein (GFAP) and 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) to perform cell counting and/or morphological evaluation in the hippocampus, lateral hypothalamus and thalamus. The results indicate that the reduced time spent awake and increased time spent in slow wave sleep (SWS) in 3xTg-AD mice was not restored by the SCDi treatment. Similar observations were made concerning the increased number of wake and SWS bouts in 3xTg-AD mice. Rhythmic and scale-free ECoG activity were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi significantly altered these phenotypes in a different manner in mutant mice in comparison to WT mice. GFAP- and ALDH1L1-positive cell densities were elevated in the hippocampus and lateral hypothalamus/thalamus of 3x-Tg-AD mice, respectively, and SCDi rescued the increase in the CA1 region in particular. Overall, these findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not substantially restored by targeting lipid metabolism using SCD inhibition, at least for the targeted age window, but that this treatment can revert hippocampal changes in astrocytes. This work will benefit the understanding of the pathophysiology related to AD and associated sleep disturbances.
Activity of spinal RORβ neurons is related to functional improvements following combination treatment after complete SCI
Authors: Stachowski Nicholas J. , Wheel Jaimena H. , Atoche Sebastian J. , Yao Lihua , Garcia-Ramirez D. Leonardo , Giszter Simon F. , Dougherty Kimberly J.
Published: March 2024

Various strategies targeting spinal locomotor circuitry have been associated with functional improvements after spinal cord injury (SCI). However, the neuronal populations mediating beneficial effects remain largely unknown. In a mouse model of complete SCI, virally-delivered BDNF (AAV-BDNF) activates hindlimb stepping and causes hyperreflexia, whereas sub-motor threshold epidural stimulation (ES) reduced BDNF-induced hyperreflexia. Given their role in gating proprioceptive afferents and potential convergence point of BDNF and ES, we hypothesized that an enhanced excitability of inhibitory RORβ neurons would be associated with locomotor improvements. Ex vivo spinal slice recordings revealed that the excitability of RORβ neurons was decreased in mice with poor locomotor function after SCI, but was similar between the uninjured and ‘best stepping’ SCI groups. Further, chemogenetic excitation of RORβ neurons reduced BDNF-induced hyperreflexia and improved stepping, similar to ES. Our findings identify inhibitory RORβ neurons as a target population to limit hyperreflexia and enhance locomotor function after SCI.