bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-dose nalmefene pretreatment reduces etomidate-induced myoclonus: A randomized, double-blind controlled trial
Authors: Shan Guofa , Lu Haixia , Dai Fang , Liu Yan , Yin Dekun , Cao Hanzhong
Published: September 2023

Background:

This study compared the effectiveness of nalmefene and fentanyl in reducing the incidence and severity of etomidate-induced myoclonus.

Methods:

One hundred fifty patients were randomized to receive 0.25ug/kg of nalmefene, 1ug/kg of fentanyl, or the same volume of normal saline 3 minutes prior to etomidate-induced anesthesia. The primary observational indexes were the severity level and incidence of etomidate-induced myoclonus, and the secondary observational index included blood pressure, heart rate, and the incidence of adverse effects from anesthesia induction to resuscitation, such as cough, chest wall rigidity, dizziness, nausea, pain after awakening, and intraoperative awareness.

Results:

The incidence of myoclonus was significantly lower in the nalmefene group (8.0%) than in the fentanyl group (32.0%) (P = .003) and in the normal saline group (72.0%) (P = .000). The severity level of myoclonus in the nalmefene group was significantly lower than the fentanyl group (P = .001) and normal saline group (P = .000). Meanwhile, the incidences of cough and chest wall rigidity during anesthesia induction were significantly lower in the nalmefene group compared with the fentanyl group (P = .003, P = .027). There were no statistically significant differences in heart rate and mean arterial pressure among the 3 gruops (P > .05). There was no difference in the incidence of adverse effects among the 3 groups during recovery from anesthesia (P > .05).

Conclusion:

Intravenous injection of 0.25ug/kg of nalmefene 3 minutes prior to etomidate is more effective in preventing etomidate-induced myoclonus during general anesthesia than 1ug/kg of fentanyl.
Cutoffs and Characteristics of Abnormal Bowel Dilatation in Pediatric Short Bowel Syndrome
Authors: Nieminen Oona , Hukkinen Maria , Kivisaari Reetta , Mutanen Annika , Merras-Salmio Laura , Pakarinen Mikko P.
Published: September 2023

Objectives:

Although excessive intestinal dilatation associates with worsened outcomes in pediatric short bowel syndrome (SBS), little is known about the natural history and definition of pathological dilatation. We addressed fore-, mid-, and hind-gut dilatation in children with SBS, who had not undergone autologous intestinal reconstructive (AIR) surgery, in relation to controls.

Methods:

SBS children without history of AIR surgery (n = 59) and age-matched controls without any disclosed intestinal pathology (n = 140) were included. Maximum diameter of duodenum, small bowel (SB), and colon were measured in each intestinal contrast series during 2002 to 2020 and expressed as diameter ratio (DR) to L5 vertebrae height. Predictive ability of DR for weaning off parenteral nutrition (PN) was analyzed with Cox proportional hazards regression models using multiple cutoffs.

Results:

Duodenum (DDR), SB (SBDR), and colon (CDR) DR were 53%, 183%, and 23% higher in SBS patients compared to controls (P < 0.01 for all). The maximal DDR and SBDR measured during follow-up is associated with current PN dependence and young age. DDR correlated with SBDR (r = 0.586, P < 0.01). Patients with maximal DDR less than 1.5, which was also the 99th percentile for controls, were 2.5-fold more likely to wean off PN (P = 0.005), whereas SBDR and CDR were not predictive for PN duration.

Conclusions:

All segments of remaining bowel, especially SB, dilate above normal levels in children with SBS. In SBS children without AIR surgery, PN dependence and young age is associated with duodenal and small intestinal dilatation, while duodenal dilatation also predicted prolonged PN.
Children with Intestinal Failure are at Risk for Psychopathology and Trauma
Authors: Vlug Lotte E. , Legerstee Jeroen S. , Tabbers Merit M. , Demirok Aysenur , Verloop Merel W. , Bosman Lotte , Rings Edmond H.H.M. , Wijnen René M.H. , Spoel Marjolein , de Koning Barbara A.E. ,   on behalf of the PICASsO Group
Published: September 2023

Objectives:

The objective of this study is to assess the psychopathology and medical traumatic stress in children with intestinal failure (IF) and identify associated risk factors.

Methods:

Two-center study, performed from September 2019 until April 2022 (partly during COVID-19 pandemic), including children (1.5–17 years) with IF, dependent on parenteral nutrition (PN) or weaned off PN, treated by a multidisciplinary IF-team. Psychopathology in children was evaluated with a semi-structured interview assessing psychiatric classifications and validated questionnaires assessing emotional (internalizing) and behavioral (externalizing) problems. Medical traumatic stress was assessed with a validated questionnaire. Problem scores were compared with normative data. Associations between clinical characteristics and outcomes were analyzed with linear regression analyses.

Results:

Forty-one (of 111 eligible) children were included [median age 8.9 years (interquartile range, IQR 5.5–11.8), 54% female, 73% born preterm]. Median PN-duration was 17.3 months (IQR 6.9–54.0); 17 children (41%) were still PN-dependent. One third of the children met criteria for at least 1 psychiatric classification (compared with 14% in age-matched general population). Anxiety disorders and attention deficit hyperactivity disorder were most common. In school-aged children (n = 29, 6–17 years), significantly increased emotional problems were consistently reported by children (P = 0.011), parents (P < 0.001), and teachers (P = 0.004). In preschool children (n = 12, 1.5–5 years), no significant differences with normative data were found. Subclinical or clinical emotional problems were reported in 19 children (46%). Medical traumatic stress was present in 14%, and 22% of children had received psychological help for trauma before. Lower gastrointestinal related quality of life was associated with more emotional problems, but not PN-duration.

Conclusions:

Children with IF, particularly school-aged children, are at risk for psychological problems which is reflected by the high rate of received psychotherapy and the high rate of emotional problems and psychiatric classifications.
Pilot Study of Ondansetron in Improvement of Pediatric Colonoscopy Preparation Outcomes at an Urban Academic Center
Authors: Arostegui Dalia , Armaly Paige , Castro Ochoa Kenny , Lemus Vivian Vega , Peshimam Juveria , Sharma Shagun , Schwarz Steven , Wallach Thomas
Published: September 2023

Objectives:

To gather initial data on the effectiveness and tolerability of the addition of Ondansetron to bowel preparation regimens to justify a funded, larger, placebo-controlled study.

Methods:

Design, Setting, and Participants:

A total of 41 pediatric and young adult (age 2–22) patients participated in a single center, open label, parallel randomized trial, with simple randomization. All patients were recruited as outpatients, and all procedures occurred as outpatient procedures, with both recruitment and procedures occurring at a low-resource urban academic medical center in Brooklyn.

Interventions and Outcome Measures:

The intervention studied was a single dose of oral-dissolving tablet Ondansetron provided before initiation of bowel preparation using a standardized prep of Polyethylene Glycol 3350 and Bisacodyl. There were 2 arms, a study arm using typical preparation (Polyethylene Glycol 3350 and Bisacodyl) and Ondansetron, and a control arm (Polyethylene Glycol 3350 and Bisacodyl). Patients received standard weight-based dosing. The primary outcome measure assessed was the Boston Bowel Preparation Scale (BBPS) to assess efficacy of preparation. Secondary objectives included evaluation of patient satisfaction via a survey answered by each patient. The questionnaire assessed the presence of the following symptoms during bowel prep: abdominal pain, nausea, bloating, vomiting, scale of ease/difficulty, and if the entire bowel prep was completed.

Results:

No benefit to BBPS from the addition of Ondansetron to bowel preparation was observed. Statistically significant improvement in reports of abdominal pain (35% decrease in Ondansetron arm) was noted with a P = 0.019. No statistically significant improvement was noted in other symptoms although all domains showed nonsignificant improvement in the Ondansetron arm.

Conclusion:

No benefit to efficacy of preparation as measured by the BBPS was observed. A single dose of Ondansetron before bowel preparation reduced reports of abdominal pain by 35%, with other symptomatic improvements suggesting possible improvements to be confirmed by a higher-powered study. Trial registration: NCT05439772.
Intravenous Pyogenic Granuloma in the Inguinal Canal Mimicking Lymph Node Metastasis on PSMA PET/CT
Authors: Skyum Sarah MD. , Anthonsen Andrea K. , Salkus Giedrius , Kvon Dmitry , Zacho Helle D.
Published: September 2023

We present a 68-year-old man with newly diagnosed high-risk prostate cancer who was referred for PSMA PET/CT after the initial CT showed a contrast-enhanced structure resembling a lymph node in the left inguinal canal. No other findings suggesting metastatic disease were seen on CT or bone scintigraphy. PSMA PET/CT showed moderate PSMA uptake in the inguinal tissue, substantiating an unexpected location of lymph node metastasis. The uncommon location warranted an excision biopsy, and an IV pyogenic granuloma was diagnosed on histological examination, emphasizing the importance of biopsy of unexpected findings.
Renal Interstitial Fibrosis Detected on 18F-AlF-NOTA-FAPI-04 PET/CT in a Patient With Multiple Myeloma
Authors: Wang Hao , Deng Yujiao , He Limeng , Deng Yan , Zhang Wei
Published: September 2023

18F-AlF-NOTA-FAPI-04 PET/CT was performed on a 58-year-old woman newly diagnosed with multiple myeloma and acute renal insufficiency. 18F-AlF-NOTA-FAPI-04 PET/CT showed increased FAPI uptake in multiple osteolytic lesions and both kidneys. Subsequent renal aspiration biopsy confirmed renal interstitial fibrosis due to subacute tubular interstitial injury. This case suggests that 18F-AlF-NOTA-FAPI-04 PET/CT may be valuable in the evaluation of renal interstitial fibrosis in patients with multiple myeloma.
68Ga-PSMA-11 PET/CT in a Case of Isolated Parietal Peritoneal Metastasis From Prostate Adenocarcinoma
Authors: Zhao Qian , Dong Aisheng , Zuo Changjing
Published: September 2023

Isolated peritoneal metastasis of prostate cancer is extremely rare. We present 68Ga-PSMA-11 PET/CT findings in a case of isolated parietal peritoneal metastasis from prostate adenocarcinoma 35 months after radical prostatectomy. The peritoneal metastases showed multifocal intense PSMA uptake, but subtle structural abnormalities on 68Ga-PSMA-11 PET/CT. The patient was subsequently treated with androgen deprivation therapy. The peritoneal metastases progressed 25 months after the initiation of androgen deprivation therapy and were removed surgically. Histologic and immunohistochemical evaluation revealed metastatic prostate adenocarcinoma with treatment-related neuroendocrine differentiation. This case demonstrates the usefulness of 68Ga-PSMA-11 PET/CT in identifying atypical metastasis from prostate adenocarcinoma.
FDG PET/CT in Follicular Dendritic Cell Sarcoma of the Jejunum With Hepatic Metastasis
Authors: Ji Xia , Dong Aisheng , Wang Yang
Published: September 2023

Follicular dendritic cell sarcoma of the gastrointestinal tract is a rare malignancy. We describe contrast-enhanced CT and FDG PET/CT findings in a case of jejunal follicular dendritic cell sarcoma with hepatic metastasis. The primary jejunal tumor showed inhomogeneous enhancement on contrast-enhanced CT and intense FDG uptake on PET/CT mimicking adenocarcinoma or gastrointestinal stromal tumor. The hepatic metastatic tumor showed hypovascularity on contrast-enhanced CT and mild FDG uptake on PET/CT. This case indicates that follicular dendritic cell sarcoma should be included in the differential diagnosis of the hypermetabolic intestinal lesions.
Impact of 18F-DCFPyL PET/MRI in Selecting Men With Low-/Intermediate-Risk Prostate Cancer for Focal Ablative Therapies
Authors: Basso Dias Adriano , Ghai Sangeet , Ortega Claudia , Mirshahvalad Seyed Ali , Perlis Nathan , Berlin Alejandro , Avery Lisa , Veit-Haibach Patrick , van der Kwast Theodorus , Metser Ur
Published: September 2023

Purpose

To compare the diagnostic performance of multiparametric (mp) MRI to 18F-DCFPyL PET/MRI for detecting clinically significant (cs) prostate cancer (PCa) in men with low-/intermediate-risk PCa being considered for focal ablative therapy (FT), using 2 interpretation schemes, and to assess the rate of exclusion from FT for each modality.

Methods

This prospective study evaluated men with low- or intermediate-risk PCa, potential candidates for FT based on initial biopsy as per institutional protocol, who underwent 18F-DCFPyL PET/MRI. Each modality (mpMRI, PET/MRI using PROMISE classification [PET/MRI PROMISE], and PET/MRI considering any focal lesion on PET as positive [PETFL/MRI]) was assessed independently. All suspicious lesions underwent PET/MRI-ultrasound fusion biopsies. Diagnostic performances were calculated and compared using the exact binomial test on paired proportions.

Results

Thirty-four men (median age, 64 years; interquartile range, 60–70 years) were included. Overall, 40 of 67 lesions (60%) identified on mpMRI and/or PET/MRI were malignant, and 34 of 40 lesions (85%) were csPCa (≥6 mm ISUP [International Society of Urological Pathology Grade Group] GG1 or ISUP-GG ≥2). On lesion-level analysis, for detecting csPCa, sensitivity appeared higher for PETFL/MRI than mpMRI and PET/MRI PROMISE (97% vs 76% and 79%, respectively [P = 0.02 and 0.03]), whereas specificity was lower (30% vs 85% and 88%, respectively [P < 0.001]). The calculated overall accuracy rates for PETFL/MRI, mpMRI, and PET/MRI PROMISE were 64%, 81%, and 84%, respectively. PETFL/MRI, mpMRI, and PET/MRI PROMISE excluded 10 of 34 (29%), 7 of 34 (21%), and 6 of 34 (18%) men from FT, respectively.

Conclusions

18F-DCFPyL PET/MRI excluded nearly 30% of patients with low-/intermediate-risk PCa from FT, with a potential role in decreasing selection failure. Compared with mpMRI, PET/MRI had a higher sensitivity for detecting csPCa in men who were candidates for FT.

ClinicalTrials.gov identifier NCT03149861.
The Morphological and Functional Effects of the Endoscope-Assisted One-Stage Approach for Crooked Nose
Authors: Sun Yi-Dan , Xie Li-Feng , Zhen Yong-Huan , Li Dong , Zhao Zhen-Min , An Yang
Published: September 2023

Background:

A crooked nose is an external nose deformity predominantly caused by congenital aplasia or acquired secondary to trauma or surgery, often accompanied by a deviated nasal septum. Patients with crooked nose have dual needs to improve both esthetic and functional problems.

Methods:

The clinical and photographic information of 48 patients diagnosed with a crooked nose and nasal septum deviation treated from January 2018 to January 2022 was acquired. The morphology and functional effects were investigated by evaluating the general condition of the operation, measuring the esthetic indexes of the nose, and subjectively scoring.

Results:

For both morphology and function, endoscopy-assisted one-stage correction showed positive results in this study. The external nose deviation distance postoperatively measured 1.28 (0.85, 1.97) mm, which significantly decreased from the preoperative value of 3.96 (3.31, 5.29) mm. The scores of doctors and irrelevant medical students on nose morphology increased significantly from 4.75±1.88 and 3.84±0.76 to 6.48±1.21 and 7.21±0.67, respectively. The rhinoplasty outcome evaluation score and the “nasal obstruction symptom evaluation “score of patients were both significantly improved (t = −7.508 and t=6.310, respectively, P < 0.001).

Conclusion:

Endoscope-assisted one-stage correction of the crooked nose can restore nasal morphology, improve the symptoms of nasal obstruction, and achieve patient satisfaction. It is a minimally invasive, safe, effective, and fast recovery approach for patients who need to solve both esthetic and functional problems.
Magnetic Resonance Imaging Findings in Patients With Duane Retraction Syndrome
Authors: Guo Yatu , Zhang Quan , Zhang Tingting , Guo Lingzhi , Liu Shichang , Zhao Kanxing , Zhang Wei
Published: September 2023

Background:

Duane retraction syndrome (DRS) is known to relate to the absence of the abducens nucleus, with abnormal innervation of the lateral rectus (LR) muscle by branches

of the oculomotor nerve (CN III). The purposes of this study were to investigate the morphological characteristics of the oculomotor nerve (CN III), the abducens nerve (CN VI), and the extraocular muscles in patients with clinically diagnosed Duane retraction syndrome (DRS) using MRI. In addition, we assessed the association between ocular motility, horizontal rectus muscle volumes, and CN III/VI in patients with Duane retraction syndrome (DRS).

Methods:

The study comprised 20 orthotropic control subjects (40 eyes) and 42 patients with Duane syndrome (48 eyes), including 20 patients with DRS Type I (24 eyes), 5 patients with DRS Type II (6 eyes), and 17 patients with DRS Type III (18 eyes). Three-dimensional (3D) T1/2 images of the brainstem and orbit were obtained to visualize the cranial nerves, especially the abducens (VI) and oculomotor (III) nerves, as well as extraocular muscles.

Results:

Based on the clinical classification, among 42 patients, MRI showed that the abducens nerves (CN VI) on the affected side were absent in 24 of 24 eyes (100%; 20 patients) with Type I DRS and in 16 of 18 eyes (88%; 16 patients) with Type III DRS. However, CN VI was observed in 6 of 6 eyes (100%; 5 patients) with Type II DRS and in 2 of 18 eyes (11%) with Type III DRS. CN III was observed in all patients. The oculomotor nerves on the affected side were thicker than those on the nonaffected contralateral side in DRS Type I (P < 0.05) and Type III (P < 0.05), but not in DRS Type II. Smaller LR and larger MR volumes were shown in the affected eye than that in the nonaffected eye in DRS Types I and III. Based on the presence or absence of CN VI, there was a tendency for thicker oculomotor nerves in the affected eye than in the nonaffected eye in the absence groups (P < 0.05). However, no significant difference was found in the present group. In the CN VI absence groups, similar results were found in the affected eyes than in the nonaffected eyes as in DRS Types I and III. In addition, the presence of CN VI was correlated with better abduction (P = 0.008). The LR and MR volumes have positive correlations with the oculomotor nerve diameter in the affected eye. However, there was no correlation between the range of adduction/abduction and the LR/MR ratio in patients with or without an abducens nerve.

Conclusions:

Different types of DRS have different characteristic appearances of CN VI and CN III on MRI. Horizontal rectus muscles have morphological changes to adapt to dysinnervation of CN VI and aberrant innervation of CN III. Thus, these neuroimaging findings may provide a new diagnostic criterion for the classification of DRS, improving the comprehension of the physiopathogenics of this disease.
Using a polygenic score to account for genomic risk factors in a model to detect individuals with dilated ascending thoracic aortas
Authors: DePaolo John , Biagetti Gina , Judy Renae , Wang Grace J. , Kelly John , Iyengar Amit , Goel Nicholas J. , Desai Nimesh , Szeto Wilson Y. , Bavaria Joseph E. , Levin Michael G. , Damrauer Scott M.
Published: September 2023

Background

Ascending thoracic aortic dilation is a complex trait that involves modifiable and non-modifiable risk factors and can lead to thoracic aortic aneurysm and dissection. Clinical risk factors have been shown to predict ascending thoracic aortic diameter. Polygenic scores (PGS) are increasingly used to assess clinical risk for multifactorial diseases. The degree to which a PGS can improve aortic diameter prediction is not known. In this study we tested the extent to which the addition of a PGS to clinical prediction algorithms improves the prediction of aortic diameter.

Methods

The patient cohort comprised 6,790 Penn Medicine Biobank (PMBB) participants with available echocardiography and clinical data linked to genome-wide genotype data. Linear regression models were used to integrate PGS weights derived from a large genome wide association study of thoracic aortic diameter in the UK biobank and were compared to the performance of the standard and a reweighted variation of the recently published AORTA Score.

Results

Cohort participants were 56% male, had a median age of 61 years (IQR 52-70) with a mean ascending aortic diameter of 3.4 cm (SD 0.5). Compared to the AORTA Score which explained 28.4% (95% CI 28.1% to 29.2%) of the variance in aortic diameter, AORTA Score + PGS explained 28.8%, (95% CI 28.1% to 29.6%), the reweighted AORTA score explained 30.4% (95% CI 29.6% to 31.2%), and the reweighted AORTA Score + PGS explained 31.0% (95% CI 30.2% to 31.8%). The addition of a PGS to either the AORTA Score or the reweighted AORTA Score improved model sensitivity for the identifying individuals with a thoracic aortic diameter ≥ 4 cm. The respective areas under the receiver operator characteristic curve for the AORTA Score + PGS (0.771, 95% CI 0.756 to 0.787) and reweighted AORTA Score + PGS (0.785, 95% CI 0.770 to 0.800) were greater than the standard AORTA Score (0.767, 95% CI 0.751 to 0.783) and reweighted AORTA Score (0.780 95% CI 0.765 to 0.795).

Conclusions

We demonstrated that inclusion of a PGS to the AORTA Score results in a small but clinically meaningful performance enhancement. Further investigation is necessary to determine if combining genetic and clinical risk prediction improves outcomes for thoracic aortic disease.
Unraveling the role of rise in temperature on the emergence of antimicrobial resistance
Authors: Goswami Anuradha , Morris J. Jeffrey
Published: September 2023

The ability of bacteria to resist the effects of antibiotics, or antimicrobial resistance (AMR), is a growing risk to world health, making it more challenging to combat infectious health problems. The growth rate of bacteria is significantly influenced by temperature, particularly temperatures between 35 and 37°C, often considered the most suitable for the spread of human illnesses. Knowing that a rise in temperature influences bacterial growth rate, contributing to a higher infection rate, it is imperative to unravel and comprehend the association between climate change and the emergence of AMR. We hypothesized that rising temperatures could exacerbate the emergence of AMR in opportunistic and pathogenic bacteria. To test our hypothesis, we investigated the global distribution of AMR and the correlation between AMR and socioeconomic factors, climate change, and air quality in the United States. The study found high resistance rates to common infections such as Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant enterococcus (VRE) infections are prevalent in many countries. In the United States, MRSA-AMR was more common in low-income states with increased poverty rates and poor air quality. The study also found a positive correlation between the rise in temperature over the past 10 years and AMR bacterial infections. The investigation concluded that socioeconomic factors, climate change, and race collectively impact the prevalence of AMR infections. The probability of AMR infection upsurging in the next decade was highest within states with more frequent rises in temperature over the last 10 years. The model predicted that states with at least 1 °C rise in temperature over the previous 10 years are expected to experience a surge in AMR bacterial infections in coming years. Though the statistical details might vary depending on the data collected in future, the correlation between climate change and the emergence of AMR in bacterial infection is alarming. The study indicates that climate change has an essential, largely unrecognized influence on AMR bacterial infections that warrants additional research. It implies that comprehensive and integrated strategies are needed to address the AMR and climate change challenges.
An emerging Ferroptosis-Correlated Genes Character for Renal Cell Carcinoma
Authors: Zhang Lin , Zhou Ying , Zhou Jiashun
Published: September 2023

Renal Cell Carcinoma (RCC), composed of various subtypes, faces a prognostic prediction challenge. Ferroptosis, an emerging cell death form, has been considered as a vital factor for the development of cancer. However, it remains a further exploration of the predictive value for ferroptosis-correlated genes in RCC. In our work, we paid attention to the gene expression data related to clinical profiles of RCC patients which derived from public databases, TCGA and ICGC. The least absolute shrinkage and selection operator (LASSO) Cox regression performed to establish an optimally predictive model based on the TCGA data. The RCC patients derived from ICGC applied to the validation of the predictive model above. Under expectation, our observation indicated that major ferroptosis-correlated genes (75%) expressed significantly between tumorous and adjacently normal cells in the TCGA cohort. Combined with the differentially expressed genes (DEGs) (P< 0.05) and overall survival (OS), there were twenty-seven genes eventually approached the subsequent analyses. With the optimal 12-genes model screened by LASSO analysis, we aimed to classify RCC patients into the high-risk or low-risk groups based on the median scores. And we created a novel predictive model based on the 12-genes’ risk score. Compared with the two groups, our work discovered that patients in the high-risk group presented more observably shrunken OS than the low (P < 0.05). Through the multivariate cox regression, the predictive model became an independent risk factor in OS (HR =2.053, P<0.001). Moreover, the receiver operating characteristic (ROC) curve proved the significantly predictive value for our predictive model. Functional research unexpectedly showed the immune cells and immune function pathways enriched differently, which emphasized the immune role for the progress of RCC. In a word, an emerging ferroptosis-correlated signature might be popular for medical prediction in RCC. The targeted treatment on ferroptosis may be a potential schedule for RCC.
Development and Characterization of Proteomic Aging Clocks in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Wang Authors: Shuo , Rao Zexi , Cao Rui , Blaes Anne H. , Coresh Josef , Joshu Corinne E. , Lehallier Benoit , Lutsey Pamela L. , Pankow James S. , Sedaghat Sanaz , Tang Weihong , Thyagarajan Bharat , Walker Keenan A. , Ganz Peter , Platz Elizabeth A. , Guan Weihua , Prizment Anna
Published: September 2023

Biological age may be estimated by proteomic aging clocks (PACs). Previous published PACs were constructed either in smaller studies or mainly in White individuals, and they used proteomic measures from only one-time point. In the Atherosclerosis Risk in Communities (ARIC) study of about 12,000 persons followed for 30 years (around 75% White, 25% Black), we created de novo PACs and compared their performance to published PACs at two different time points. We measured 4,712 plasma proteins by SomaScan in 11,761 midlife participants, aged 46-70 years (1990-92), and 5,183 late-life pariticpants, aged 66-90 years (2011-13). All proteins were log2-transformed to correct for skewness. We created de novo PACs by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and compared their performance to three published PACs. We estimated age acceleration (by regressing each PAC on chronological age) and its change from midlife to late life. We examined their associations with mortality from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in all remaining participants irrespective of health. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. The ARIC PACs had a slightly stronger correlation with chronological age than published PACs in healthy participants at each time point. Associations with mortality were similar for the ARIC and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per one standard deviation were 1.65 and 1.38 (both p<0.001) for all-cause mortality, 1.37 and 1.20 (both p<0.001) for CVD mortality, 1.21 (p=0.03) and 1.04 (p=0.19) for cancer mortality, and 1.46 and 1.68 (both p<0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to those observed for late-life age acceleration. The association between the change in age acceleration and cancer mortality was insignificant. In this prospective study, the ARIC and published PACs were similarly associated with an increased risk of mortality and advanced testing in relation to various age-related conditions in future studies is suggested.
Enhancer-driven regulatory network of forebrain human development provides insights into autism
Authors: Jourdon Alexandre , Mariani Jessica , Wu Feinan , Capauto Davide , Norton Scott , Tomasini Livia , Amiri Anahita , Schreiner Jeremy , Nguyen Cindy Khanh , Nolan Neal , Szekely Anna , McPartland James C. , Pelphrey Kevin , Chawarska Katarzyna , Ventola Pamela , Abyzov Alexej , Vaccarino Flora M.
Published: September 2023

Cell differentiation involves shifts in chromatin organization allowing transcription factors (TFs) to bind enhancer elements and modulate gene expression. The TF-enhancer-gene regulatory interactions that control the formation of neuronal lineages have yet to be charted in humans. Here, we mapped enhancer elements and conducted an integrative analysis of epigenomic and transcriptomic profiles across 60 days of differentiation of human forebrain organoids derived from 10 individuals with autism spectrum disorder (ASD) and their neurotypical fathers. This multi-omics profiling allowed us to build an enhancer-driven gene regulatory network (GRN) of early neural development. We validated the GRN by performing a loss-of-function experiment with FOXG1 – one of the master TFs in the development of the mammalian brain. Analysis of the constructed GRN identified regulatory hierarchies driving the specification of neuronal cell types. By analyzing differential gene expression in ASD through the GRN hierarchy, we associated the ASD transcriptomic signatures to altered activity of key TFs. We found that macrocephalic ASD was principally driven by an increased activity of BHLHE22, FOXG1, EOMES, and NEUROD2, which are major regulators of excitatory neuron fate. Normocephalic ASD, on the contrary, was driven by decreased activity of those same TFs and by an increased activity of LMX1B and FOXB1 – two upstream TF repressors of FOXG1. These findings suggest that ASD is characterized by an altered early gene regulatory program that specifies neuronal cell lineages in the fetal brain. Thus, constructing a GRN of early brain development modeled in organoids provides insights into the etiology of ASD and can guide future experimental approaches to establish its genetic causes and treatment strategies.
Serum levels of adipokines and insulin are associated with markers of brain atrophy and cognitive decline in the spectrum of Alzheimer’s Disease
Authors: Garcia-Garcia Isabel , Kamal Farooq , Donica Olga , Dadar Mahsa ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2023

The discovery that metabolic alterations often coexist with neurodegenerative conditions has sparked interest in the examination of gastrointestinal factors as potential modulators of brain health. Here, we examined the role of adipokines (leptin, adiponectin, resistin, and IL6) and insulin on different markers of brain atrophy in participants on the spectrum of Alzheimer’s Disease. We included 566 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset with 1063 follow-up time points (average follow-up: one year); and examined the association between gastrointestinal factors and volumetric MRI values, white matter hyperintensities, and measures of cognitive impairment. Higher leptin, resistin, IL6, and insulin were associated with markers of cerebral atrophy, such as lower total brain volume, or higher ventricular volume. Higher leptin and resistin were also associated with greater impairment in daily life activities. Higher adiponectin was associated with lower ventricle volume. There was no association between adipokines or insulin with white matter hyperintensities. Our findings indicate a co-occurrence between alterations in gastrointestinal factors and in brain volume along the preclinical to clinical spectrum of Alzheimer’s Disease. These results suggest that strategies aimed at promoting metabolic health may positively impact brain health.
Neurovascular Mechanisms of Cognitive Aging: Sex-Related Differences in the Average Progression of Arteriosclerosis, White Matter Atrophy, and Cognitive Decline
Authors: Bowie Daniel C. , Low Kathy A. , Rubenstein Samantha L. , Islam Samia S. , Zimmerman Benjamin , Camacho Paul B. , Sutton Bradley P. , Gratton Gabriele , Fabiani Monica
Published: September 2023

Arterial stiffness (arteriosclerosis) has been linked to heightened risks for cognitive decline, and ultimately for Alzheimer’s disease and other forms of dementia. Importantly, neurovascular outcomes generally vary according to one’s biological sex. Here, capitalizing on a large sample of participants with neuroimaging and behavioral data (N= 203, age range = 18-87 years), we aimed to provide support for a hierarchical model of neurocognitive aging, which links age-related declines in cerebrovascular health to the rate of cognitive decline via a series of intervening variables, such as white matter integrity. By applying a novel piecewise regression approach to our cross-sectional sample to support Granger-like causality inferences, we show that, on average, a precipitous decline in cerebral arterial elasticity (measured with diffuse optical imaging of the cerebral arterial pulse; pulse-DOT)temporally precedesan acceleration in the development of white matter lesions by nearly a decade, with women protected from these deleterious effects until approximately age 50, the average onset of menopause. By employing multiple-mediator path analyses while controlling for sex, we show that age may impair cognition via the sequential indirect effects of arteriosclerosis and white matter atrophy on fluid, but not crystallized, abilities. Importantly, we replicate these results using pulse pressure, an independent index of arterial health, thereby providing converging evidence for the central role of arteriosclerosis as an accelerating factor in normal and pathological aging and identifying robust sex-related differences in the progression of cerebral arteriosclerosis and white matter degradation.
Red blood cell distribution width/albumin ratio is a novel risk factor of incidence and long-term mortality in chronic heart failure patients: three large cohorts from China and America
Authors: Zhang Lin , Zhou Ying , Wang Kaiyue , Wang Liming , Teka Tekleab , Zhou Jiashun , Zhang Houliang , Fu Xuebin , Zhang Lele , Zhang Xuemei , Fu Zhifei , Han Lifeng , Gao Xiumei
Published: September 2023

Aims

Red blood cell distribution width/albumin ratio (RAR) is a novel parameter associated with inflammation. Previous studies have not focused on the role of RAR in the incidence and long-term prognosis of chronic heart failure (CHF). This study included three cohorts, two prospective and one retrospective study. The aim was to investigate the value of RAR in the incidence of CHF and the long-term prognosis of CHF.

Methods

Three cohorts were investigated, including MIMIC, NHANES, and JHDH. The included patients of MIMIC, NHANES, and JHDH were 22,672 from 2001-2012, 60,754 from 1999-2020, and 15,102 from 2021-2022, respectively. According to whether the patients have CHF-related risk factors, the patients were classified into non-CHF, pre-CHF, and CHF groups. The median follow-up time of MIMIC and NHANES was 364 days and 62 months. Logistic regression, Cox regression, restricted cubic spline (RCS), and Kaplan–Meier (KM) curves were used to analyze the value of RAR in CHF patients.

Result

In NHANES, the CHF prevalence in quartiles of RAR (Q1, Q2, Q3, and Q4) were 8.88%, 16.86%, 27.65%, and 46.61%, respectively. MIMIC and JHDH showed a similar trend. Among the non-CHF and CHF patients, the odds ratio (OR) was 1.45 (JHDH 95% CI 1.33-1.58) and 1.93 (NHANES 95% CI 1.41-2.65). In NHANES, the RAR OR value of Q2, Q3 and Q4 were 2.02(CI 1.19-3.43), 3.24(CI 1.95-5.39), and 4.95(CI 2.44-10.02) compared with Q1, respectively. And the OR was 1.05 (MIMIC 95% CI 1.02-1.07) in pre-CHF and CHF patients. The CHF mortality showed an adjusted hazard ratio (HR) is 1.12 (MIMIC 95% CI 1.1-1.14) and 2.26 (NHANES 95% CI 1.52-3.36). KM demonstrates that higher RAR (>3.4 in NHANES and >5.06 in MIMIC) prognoses lead to poor survival in CHF patients. CHF mortality in the 19th quartile of the RAR was 1.4 times higher than in the first quartile, compared with 1.22 times in the red blood cell distribution width (RDW). The 19-quartile mortality curves of the RAR were more stable than RDW and albumin (ALB).

Conclusion

RAR is an independent risk factor for incidence and all-cause long-term mortality in CHF patients. The predictive value of RAR for all-cause mortality in CHF is superior to ALB and RDW. RAR may be a potential clinical indicator for future treatment of CHF.
Revisiting the trafficking of insulin and its receptor in rat liver:in vivoand cell-free studies
Authors: Tahiri Khadija , Fouque Françoise , Postel-Vinay Marie-Catherine , Desbuquois Bernard
Published: September 2023

Endosomes are the main locus where, upon endocytosis in liver cells, insulin and the activated insulin receptor accumulate and insulin is degraded. In this study, ligand and receptor pathways in rat liver have been revisited using analytical subcellular fractionation. Density gradient analysis of microsomal and light mitochondrial fractions confirmed that, uponin vivouptake into liver, [125I]-insulin was rapidly translocated from plasma membranes to endosomes. Internalized [125I]-labeled proinsulin and biotinylated insulin, which are less degraded than insulin in endosomes, were in part transferred to lysosomes. Following injection of native insulin, receptor and ligand were also both translocated from the plasma membrane to endosomes, with a maximum at 15-30 min. Receptor translocation was reversed by 2-3 hours and neither endocytosis nor recycling were affected byin vivocycloheximide treatment. Fractionation of endosomes of insulin-treated rats on density gradients showed that the insulin receptor was recovered at low density, whereas insulin progressively migrated from low to high densities towards the position of acid phosphatase. On SDS polyacrylamide gels, insulin receptor α and β subunits were identified in plasma membrane, endosomal and lysosomal fractions by affinity crosslinking and Western immunoblotting, respectively. Following insulin treatment, insulin receptor expression rapidly decreased in plasma membranes while increasing in endosomes. In a cell-free system, [125I]-insulin was in part transferred from endosomes to lysosomes, as was, with organelle content mixing, [125I]-biotinylated insulin. In summary: 1) the low lysosomal association of [125I]-insulinin vivois linked to its endosomal degradation; 2) upon ligand-induced endocytosis, the insulin receptor progressively segregates from insulin and is recycled; 3) neither endocytosis no recycling of the receptor requires protein synthesis.
Fluorinated cGAMP analogs, which act as STING agonists and are not cleavable by poxins: structural basis of their function
Authors: Klima Martin , Dejmek Milan , Duchoslav Vojtech , Eisenreichova Andrea , Sala Michal , Chalupsky Karel , Chalupska Dominika , Novotná Barbora , Birkuš Gabriel , Nencka Radim , Boura Evzen
Published: September 2023

The Stimulator of Interferon Genes (STING) plays a crucial role in the cGAS-STING pathway of innate immunity, detecting DNA in the cytoplasm and defending against certain cancers, viruses, and bacteria. We designed and synthesized fluorinated carbocyclic cGAMP analogs, MD1203 and MD1202D (MDs), to enhance their stability against nucleases and their affinity for STING. These compounds demonstrated exceptional activity against wild-type STING and all its allelic variations, including the hard-to-target REF isoform. Despite their distinct chemical modifications relative to the canonical CDNs, such as the substitution of guanine with hypoxanthine and the fluorination of the (pseudo)ribose ring, crystallographic analysis revealed a consistent binding mode with STING. Importantly, these compounds were resistant to cleavage by viral poxin nucleases. The crystallographic analysis of poxin/MD complexes unveiled their binding mode at the interface of poxin monomers, with dynamic adenine base orientations. Interestingly, MDs-bound poxin adopted an unliganded-like conformation, distinct from the conformation of cGAMP-bound poxin. Moreover, when MDs were in complex with poxin, they exhibited a different conformation than cGAMP when bound to poxin; in fact, it closely resembled the conformation observed when MDs were bound to STING. In conclusion, the development of MD1203 and MD1202D, showcases their potential as potent STING activators with remarkable stability against poxin-mediated degradation—a crucial characteristic for future development of antivirals.
Optogenetic control of a GEF of RhoA uncovers a signaling switch from retraction to protrusion
Authors: De Seze Jean , Bongaerts Maud , Boulevard Benoit , Coppey Mathieu
Published: September 2023

The ability of a single protein to trigger different functions is an assumed key feature of cell signaling, yet there are very few examples demonstrating it. Here, using an optogenetic tool to control membrane localization of RhoA nucleotide exchange factors (GEFs), we present a case where the same protein can trigger both protrusion and retraction when recruited to the plasma membrane, polarizing the cell in two opposite directions. We show that the basal concentration of the GEF prior to activation predicts the resulting phenotype. A low concentration leads to retraction, whereas a high concentration triggers protrusion. This unexpected protruding behavior arises from the simultaneous activation of Cdc42 by the GEF and sequestration of active RhoA by the GEF PH domain at high concentrations. We propose a minimal model that recapitulates the phenotypic switch, and we use its predictions to control the two phenotypes within selected cells by adjusting the frequency of light pulses. Our work exemplifies a unique case of control of antagonist phenotypes by a single protein that switches its function based on its concentration or dynamics of activity. It raises numerous open questions about the link between signaling protein and function, particularly in contexts where proteins are highly overexpressed, as often observed in cancer.
Effects of forest urbanization on the interplay between small mammal communities and their gut microbiota
Authors: Bouilloud Marie , Galan Maxime , Pradel Julien , Loiseau Anne , Ferrero Julien , Gallet Romain , Roche Benjamin , Charbonnel Nathalie
Published: September 2023

Urbanization significantly impacts wild populations, favoring urban dweller species over those that are unable to adapt to rapid and abrupt changes. One possible explanation for differential adaptative abilities between these species is that the microbiome may modulate the host phenotype rapidly through a high degree of flexibility. Conversely, under such anthropic perturbations, the microbiota composition of some species could be disrupted, resulting in dysbiosis and negative impacts on host fitness, potentially causing local extirpation. The links between the impact of urbanization on host communities and their gut microbiota have only been scarcely explored. In this study, we tested the hypothesis that the gut microbiota (GM) could play a role in host adaptation to urban environments. We addressed this question by studying several species of small terrestrial mammals sampled in forested areas along a forested gradient of urbanization (from rural forests to urban parks) during 2020 fall. The gut was collected and bacteria were described using a 16S metabarcoding approach. We tested whether urbanization led to changes in small mammal communities and in their GM. We analyzed these changes in terms of the presence and abundance of taxa and their putative functions to decipher the processes underlying these changes. We found that urbanization had marked impacts on small mammal communities and their GM, either directly or indirectly depending on small mammal species categories. The urban dweller species had a lower taxonomic diversity but a higher functional diversity and a different composition compared to urban adapter species. Their GM assembly was mostly governed by stochastic effects, which could indicate dysbiosis in these urban species. Selection processes and an overabundance of functions were detected that could be associated with adaptation to urban environments despite potential dysbiosis. Urbanization could also impact the diversity and taxonomic composition of GM in urban adapter species. However, their functional diversity and composition remained relatively stable. This observation can be explained by functional redundancy, where certain taxa express the same function. This could explain the adaptation of urban adapter species in various environments, including urban settings. We can therefore assume that there are feedback loops between the gut microbiota and the host species within communities, enabling rapid and flexible adaptation.
THE STRUCTURE OF DNA IN ANABIOTIC AND MUMMIFIED CELLS
Authors: Krupyanskii Yurii F. , Kovalenko Vladislav , Loiko Nataliya , Tereshkin Eduard , Tereshkina Ksenia , Popov Alexander
Published: September 2023

Investigations of structural organization of DNA for stressed (increased stress resistance), anabiotic and mummified cells obtained by introducing 4-hexylresorcinol at different concentrations for different stages of cell culture growth using diffraction of synchrotron radiation were done. Experimental studies allow us to conclude that 4-hexylresorcinol is the initiator of the cell transition to the anabiotic and mummified states at stationary state. At pre-stationary state of growth 4-hexylresorcinol initiates a transition of cells to a mummified state but not to anabiotic one. The structure of DNA within a cell in the anabiotic dormant state (practically complete absence of metabolism) and the dormant state (starvation stress) coincide (formsnanocrystallinestructures). Our data suggest the universality of DNA condensation or the universality of DNA protection by a protein Dps for dormant state, regardless of the type of stress. Mummified state (the complete absence of metabolism) is very different in structure (has no ordering within a cell).