bluuebunny/crossref_metadata_2025 huggingface dataset:
An integrative multi-omics analysis based on liquid–liquid phase separation delineates distinct subtypes of lower-grade glioma and identifies a prognostic signature
Authors: Zheng Jianglin , Wu Zhipeng , Qiu Yue , Wang Xuan , Jiang Xiaobing
Published: January 2022

Background

Emerging evidences have indicated that the aberrant liquid–liquid phase separation (LLPS) leads to the dysfunction of biomolecular condensates, thereby contributing to the tumorigenesis and progression. Nevertheless, it remains unclear whether or how the LLPS of specific molecules affects the prognosis and tumor immune microenvironment (TIME) of patients with lower-grade glioma (LGG).

Methods

We integrated the transcriptome information of 3585 LLPS-related genes to comprehensively evaluate the LLPS patterns of 423 patients with LGG in The Cancer Genome Atlas (TCGA) cohort. Then, we systematically demonstrated the differences among four LLPS subtypes based on multi-omics analyses. In addition, we constructed the LLPS-related prognostic risk score (LPRS) for individualized integrative assessment.

Results

Based on the expression profiles of 85 scaffolds, 355 regulators, and 3145 clients in LGG, we identified four LLPS subtypes, namely LS1, LS2, LS3 and LS4.

We confirmed that there were significant differences in prognosis, clinicopathological features, cancer hallmarks, genomic alterations, TIME patterns and immunotherapeutic responses among four LLPS subtypes. In addition, a prognostic signature called LPRS was constructed for individualized integrative assessment. LPRS exhibited a robust predictive capacity for prognosis of LGG patients in multiple cohorts. Moreover, LPRS was found to be correlated with clinicopathological features, cancer hallmarks, genomic alterations and TIME patterns of LGG patients. The predictive power of LPRS in response to immune checkpoint inhibitor (ICI) therapy was also prominent.

Conclusions

This study provided a novel classification of LGG patients based on LLPS. The constructed LPRS might facilitate individualized prognosis prediction and better immunotherapy options for LGG patients.
Electrical stimulation of the cochlea for treatment of chronic disabling tinnitus: an open-label trial towards the development of an implantable device
Authors: Marinelli John P. , Anzalone C. Lane , Prummer Christoph M. , Poling Gayla L. , Staab Jeffrey P. , Tombers Nicole M. , Lohse Christine M. , Carlson Matthew L.
Published: January 2022

Background

Chronic tinnitus affects millions of people globally and constitutes the most commonly compensated disability among military service members in the United States. Existing treatment options largely surround helping patients cope with their disease as opposed to directly suppressing tinnitus perception. The current study investigated the efficacy of electrical stimulation of the cochlea on chronic disabling tinnitus.

Methods

In this single-arm, open-label clinical trial, 22 adult subjects with severe-range asymmetric or unilateral non-pulsatile tinnitus underwent electrical stimulation of the cochlea through use of an extra-cochlear electrode positioned on the cochlear promontory. Each subject underwent 3 stimulation treatments over 3 weeks at 7-day intervals. Tinnitus severity was determined by Tinnitus Handicap Inventory (THI), Tinnitus Functional Index (TFI), and Tinnitus Visual Analog Scale (VAS). Inclusion criteria required subjects have no worse than moderate sensorineural hearing loss determined by pre-enrollment audiometric testing. The primary outcome was nadir post-treatment THI scores, obtained at seven timepoints following electrical stimulation, with clinically significant improvement defined as a decrease of  ≥ 7.

Results

All 22 (100%) subjects experienced clinically significant improvement in the THI during the study period with a mean decrease in scores of − 31 (95% CI − 38 to − 25) from a baseline of 48. Twenty (91%) experienced clinically significant improvement detectable on at least two of the three tinnitus survey instruments and 17 (77%) experienced clinically significant improvement detectable on all three survey instruments (i.e., THI, TFI, and VAS). Eight (36%) subjects reported either complete (THI of 0; n  = 3) or near-complete (THI 1–4; n  = 5) suppression of their tinnitus following a stimulation session. Thirteen (59%) subjects reported a nadir following stimulation at or below the threshold for “no or slight handicap” on the THI (≤ 16). No adverse events were observed.

Conclusions

These findings establish the foundation for the development of an extra-cochlear implantable device that delivers electrical stimulation to the cochlea for the treatment of disabling tinnitus. For patients considering device implantation, trans-tympanic cochlear promontory stimulation can facilitate patient selection.

Trial Registration ClinicalTrials.gov Identifier: NCT03759834. URL: https://clinicaltrials.gov/ct2/show/NCT03759834
Joint involvement, disease activity and quality of life in pediatric Crohn’s disease – a cross-sectional study
Authors: Derfalvi Beata , Boros Kriszta Katinka , Szabo Doloresz , Bozsaki Gabor , Cseh Aron , Rudas Gabor , Muller Katalin Eszter , Veres Gabor
Published: January 2022

Background

Few published data describe how joint involvement, the most prevalent extraintestinal manifestation, affects quality of life (QoL) of children with Crohn’s disease (CD). Arthritis and arthralgia rates in pediatric CD patients are reportedly 3–24% and 17–22%, respectively, but studies on pre-emptive and systematic screening of joint involvement with detailed musculoskeletal rheumatological exam are lacking. More detailed data collection on joint involvement improves our understanding of how arthropathy relates to disease activity and QoL measured by the Pediatric CD Activity Index (PCDAI) and IMPACT-III questionnaire. Our study aims were to assess joint involvement in pediatric CD and correlate it with the PCDAI and IMPACT-III.

Methods

In this cross-sectional, observational study, a pediatric gastroenterologist assessed consecutively-seen pediatric CD patients at a tertiary care center. Patients were screened for prevalence of current and previous arthropathy, including arthritis, enthesitis and arthralgia. A single experienced pediatric rheumatologist evaluated detailed musculoskeletal history, joint status, and modified Juvenile Arthritis Multidimensional Assessment Reports (JAMAR). PCDAI, IMPACT-III, sacroiliac MRI, and HLA-B27 genetic testing were also completed.

Results

A total of 82 (male:female, 1.2:1; age, 13.7 ± 3.2 years) patients were involved in this study. Mean disease duration at time of study was 21.6 ± 21 months; eight of the patients were newly-diagnosed. Of the 82 patients, 29 (35%) had evidence of arthritis; for 24 of those, this was revealed by physical exam during cross-sectional screening, and by prior documentation for the remaining five patients. Joint examination confirmed active arthritis in 8/24 (33%), active enthesitis in 1/24 (4%), and evidence of previous arthritis in 15/24 (62.5%) patients. Hip (41%) and knee (38%) joints were most commonly affected. Cumulative incidence of arthralgia was 48% (39/82), and 46% (18/39) of those patients had only arthralgia without arthritis, usually affecting the knee. Axial involvement was present in 10/82 (12%) patients. Joint involvement correlated with more severe CD disease activity, specifically higher PCDAI and lower IMPACT-III scores, and increased requirement for infliximab treatment. Sacroiliitis and HLA-B27 positivity were insignificant factors in this cohort.

Conclusions

When a rheumatologist performed the assessment, joint involvement in pediatric CD was more prevalent than previously reported, in this cross-sectional study. Arthritis was associated with more severe CD disease activity and lower QoL.
MORPHIOUS: an unsupervised machine learning workflow to detect the activation of microglia and astrocytes
Authors: Silburt Joseph , Aubert Isabelle
Published: January 2022

Background

In conditions of brain injury and degeneration, defining microglial and astrocytic activation using cellular markers alone remains a challenging task. We developed the MORPHIOUS software package, an unsupervised machine learning workflow which can learn the morphologies of non-activated astrocytes and microglia, and from this information, infer clusters of microglial and astrocytic activation in brain tissue.

Methods

MORPHIOUS combines a one-class support vector machine with the density-based spatial clustering of applications with noise (DBSCAN) algorithm to identify clusters of microglial and astrocytic activation. Here, activation was triggered by permeabilizing the blood–brain barrier (BBB) in the mouse hippocampus using focused ultrasound (FUS). At 7 day post-treatment, MORPHIOUS was applied to evaluate microglial and astrocytic activation in histological tissue. MORPHIOUS was further evaluated on hippocampal sections of TgCRND8 mice, a model of amyloidosis that is prone to microglial and astrocytic activation.

Results

MORPHIOUS defined two classes of microglia, termed focal and proximal, that are spatially adjacent to the activating stimulus. Focal and proximal microglia demonstrated activity-associated features, including increased levels of ionized calcium-binding adapter molecule 1 expression, enlarged soma size, and deramification. MORPHIOUS further identified clusters of astrocytes characterized by activity-related changes in glial fibrillary acidic protein expression and branching. To validate these classifications following FUS, co-localization with activation markers were assessed. Focal and proximal microglia co-localized with the transforming growth factor beta 1, while proximal astrocytes co-localized with Nestin. In TgCRND8 mice, microglial and astrocytic activation clusters were found to correlate with amyloid-β plaque load. Thus, by only referencing control microglial and astrocytic morphologies, MORPHIOUS identified regions of interest corresponding to microglial and astrocytic activation.

Conclusions

Overall, our algorithm is a reliable and sensitive method for characterizing microglial and astrocytic activation following FUS-induced BBB permeability and in animal models of neurodegeneration.
TRPV4 contributes to ER stress and inflammation: implications for Parkinson’s disease
Authors: Liu Na , Bai Liping , Lu Zhipeng , Gu Rou , Zhao Dongdong , Yan Fang , Bai Jie
Published: January 2022

Background

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Its molecular mechanism is still unclear, and pharmacological treatments are unsatisfactory. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective Ca2+ channel. It has recently emerged as a critical risk factor in the pathophysiology of neuronal injuries and cerebral diseases. Our previous study reported that TRPV4 contributed to endoplasmic reticulum (ER) stress in the MPP+-induced cell model of PD. In the present study, we detected the role and the mechanism of TRPV4 in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice.

Methods

Intracerebral injection of an adeno-associated virus (AAV) into the substantia nigra (SN) of mice was used to knockdown or upregulate the expression of TRPV4 and intraperitoneal injection of MPTP. Rotarod and pole tests were used to evaluate the locomotor ability of mice. We used immunohistochemistry, Nissl staining and Western blot to detect the alterations in the number of tyrosine hydroxylase (TH)-positive neurons, Nissl-positive neurons, the levels of ER stress-associated molecules and proinflammatory cytokines in the SN.

Results

The SN was transfected with AAV for 3 weeks and expressed the target protein with green fluorescence. Knockdown of TRPV4 via injection of a constructed AAV-TRPV4 shRNAi into the SN alleviated the movement deficits of PD mice. Upregulation of TRPV4 via injection of a constructed AAV-TRPV4 aggravated the above movement disorders. The expression of TRPV4 was upregulated in the SN of MPTP-treated mice. Injection of AAV-TRPV4 shRNAi into the SN rescued the number of TH-positive and Nissl-positive neurons in the SN decreased by MPTP, while injection of AAV-TRPV4 induced the opposite effect. Moreover, MPTP-decreased Sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and pro-cysteinyl aspartate specific proteinase-12 (procaspase-12), MPTP-increased Glucose-regulated protein 78 (GRP78), Glucose-regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP) were inhibited by AAV-TRPV4 shRNAi infection, and enhanced by AAV-TRPV4. In the same way, MPTP-decreased procaspase-1, MPTP-increased Interleukin-18 (IL-18), Cyclooxgenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) were inhibited by AAV-TRPV4 shRNAi, or further exacerbated by AAV-TRPV4.

Conclusions

These results suggest that TRPV4 mediates ER stress and inflammation pathways, contributing to the loss of dopamine (DA) neurons in the SN and movement deficits in PD mice. Moreover, this study provides a new perspective on molecular targets and gene therapies for the treatment of PD in the future.
Inflammatory monocytes and microglia play independent roles in inflammatory ictogenesis
Authors: Howe Charles L. , LaFrance-Corey Reghann G. , Overlee Brittany L. , Johnson Renee K. , Clarkson Benjamin D. S. , Goddery Emma N.
Published: January 2022

Background

The pathogenic contribution of neuroinflammation to ictogenesis and epilepsy may provide a therapeutic target for reduction of seizure burden in patients that are currently underserved by traditional anti-seizure medications. The Theiler's murine encephalomyelitis virus (TMEV) model has provided important insights into the role of inflammation in ictogenesis, but questions remain regarding the relative contribution of microglia and inflammatory monocytes in this model.

Methods

Female C57BL/6 mice were inoculated by intracranial injection of 2 × 105, 5 × 104, 1.25 × 104, or 3.125 × 103 plaque-forming units (PFU) of the Daniel’s strain of TMEV at 4–6 weeks of age. Infiltration of inflammatory monocytes, microglial activation, and cytokine production were measured at 24 h post-infection (hpi). Viral load, hippocampal injury, cognitive performance, and seizure burden were assessed at several timepoints.

Results

The intensity of inflammatory infiltration and the extent of hippocampal injury induced during TMEV encephalitis scaled with the amount of infectious virus in the initial inoculum. Cognitive performance was preserved in mice inoculated with 1.25 × 104 PFU TMEV relative to 2 × 105 PFU TMEV, but peak viral load at 72 hpi was equivalent between the inocula. CCL2 production in the brain was attenuated by 90% and TNFα and IL6 production was absent in mice inoculated with 1.25 × 104 PFU TMEV. Acute infiltration of inflammatory monocytes was attenuated by more than 80% in mice inoculated with 1.25 × 104 PFU TMEV relative to 2 × 105 PFU TMEV but microglial activation was equivalent between groups. Seizure burden was attenuated and the threshold to kainic acid-induced seizures was higher in mice inoculated with 1.25 × 104 PFU TMEV but low-level behavioral seizures persisted and the EEG exhibited reduced but detectable abnormalities.

Conclusions

The size of the inflammatory monocyte response induced by TMEV scales with the amount of infectious virus in the initial inoculum, despite the development of equivalent peak infectious viral load. In contrast, the microglial response does not scale with the inoculum, as microglial hyper-ramification and increased Iba-1 expression were evident in mice inoculated with either 1.25 × 104 or 2 × 105 PFU TMEV. Inoculation conditions that drive inflammatory monocyte infiltration resulted in robust behavioral seizures and EEG abnormalities, but the low inoculum condition, associated with only microglial activation, drove a more subtle seizure and EEG phenotype.
Designing and validation of a reproductive health need assessment tool for women experienced domestic violence
Authors: Dolatian Mahrokh , Ebadi Abbas , Hasanpoor-Azghady Seyedeh Batool , NayebiNia Anvar Sadat
Published: January 2022

Background

Violence as a serious health problem and one of the main manifestations of gender inequality brings about adverse health effects for women. Therefore, it is of utmost importance to recognize the reproductive health status of women subjected to violence in order to provide the health services they need. Considering that one of the ways to determine reproductive health status is the use of valid questionnaires in this field, this study aimed to determine the components of reproductive health in domestic violated women and design a valid and reliable assessment tool.

Methods

The present study was conducted based on a mixed-method design. The first part of the study (qualitative section) was conducted based on conventional content analysis. In this part, unstructured in-depth interviews were conducted with 18 violated women and 9 experts. In the next stage, the item pool was formed and the Reproductive Health Needs of Violated Women Scale was designed based on the review of the literature and the results of the qualitative section with 39 items using the Waltz approach. For psychometric assessment of the above instrument, face and content validity, item analysis, and construct validity were examined using exploratory factor analysis.

Results

Based on the results of factor analysis, the four following factors were extracted with a total variance of 47.62: "men's participation", "self-care", "support and health services", as well as "sexual and marital relationships. The internal consistency of the instrument was calculated at α = 0.70–0.89 and α = 0.94 for different constructs and the whole instrument, respectively. Moreover, intra-cluster correlation coefficients were obtained at ICC = 0.96–0.99 and ICC = 0.98 for constructs and the whole instruments, respectively.

Conclusions

Based on the results of the current study, the present scale is a tool that specifically assesses the reproductive health needs of violated women and has appropriate validity and reliability. The results of the assessment using the aforementioned instruments can be of great help in promoting the reproductive health of women subjected to violence.
Associated factors of first-birth interval among women in reproductive age, addressing maternal and child health
Authors: Dehesh Tania , Malekmohammadi Neda , Dehesh Paria
Published: January 2022

Background

The first-birth interval directly influences family size and maternal and child mortality. The objective of this study is to investigate factors associated with the time of the first-birth after the first marriage among women in Iran.

Methods

In this cross-sectional study, the first birth history of 1350 women aged 15–49 years was collected in Kerman (southern Iran) in 2018. To assess the predictor variables of the first-birth interval and calculate the adjusted hazard ratios, multivariate Cox regression was used. The P-value < 0.05 was considered as significant. The statistical analysis of data was performed using SPSS version 22.

Results

The average of the first-birth interval was 2.5 ∓ 0.8 years. Woman’s age at marriage (HR 1.48, 95% CI 1.32–2.48), husband’s age at marriage (HR 1.88, 95% CI 1.62–2.03), age at the first menstruation (HR 1.53, 95% CI 1.24–2.53), being rural residents (HR 2.041, 95% CI 1.26–2.95), and having engagement period (HR 1.85, 95% CI 1.52–3.05) were associated with short first-birth interval, and woman’s BMI (HR 1.72, 95% CI 1.54–2.77), woman’s university educational level (HR 1.47, 95% CI 1.35–2.57), husband’ s university educational level (HR 1.39, 95% CI 1.32–2.51), contraception use (HR 2.28, 95% CI 1.12–2.86) and income sufficiency (HR 2.25, 95% CI 1.12–2.96) were associated with long first-birth interval.

Conclusions

Being a rural resident is the most influential predictor of short first-birth interval and income sufficiency is the most influential predictor of long first-birth interval.
Assessing effects of exoskeleton misalignment on knee joint load during swing using an instrumented leg simulator
Authors: Bessler-Etten Jule , Schaake Leendert , Prange-Lasonder Gerdienke B. , Buurke Jaap H.
Published: January 2022

Background

Exoskeletons are working in parallel to the human body and can support human movement by exerting forces through cuffs or straps. They are prone to misalignments caused by simplified joint mechanics and incorrect fit or positioning. Those misalignments are a common safety concern as they can cause undesired interaction forces. However, the exact mechanisms and effects of misalignments on the joint load are not yet known. The aim of this study was therefore to investigate the influence of different directions and magnitudes of exoskeleton misalignment on the internal knee joint forces and torques of an artificial leg.

Methods

An instrumented leg simulator was used to quantify the changes in knee joint load during the swing phase caused by misalignments of a passive knee brace being manually flexed. This was achieved by an experimenter pulling on a rope attached to the distal end of the knee brace to create a flexion torque. The extension was not actuated but achieved through the weight of the instrumented leg simulator. The investigated types of misalignments are a rotation of the brace around the vertical axis and a translation in anteroposterior as well as proximal/distal direction.

Results

The amount of misalignment had a significant effect on several directions of knee joint load in the instrumented leg simulator. In general, load on the knee joint increased with increasing misalignment. Specifically, stronger rotational misalignment led to higher forces in mediolateral direction in the knee joint as well as higher ab-/adduction, flexion and internal/external rotation torques. Stronger anteroposterior translational misalignment led to higher mediolateral knee forces as well as higher abduction and flexion/extension torques. Stronger proximal/distal translational misalignment led to higher posterior and tension/compression forces.

Conclusions

Misalignments of a lower leg exoskeleton can increase internal knee forces and torques during swing to a multiple of those experienced in a well-aligned situation. Despite only taking swing into account, this is supporting the need for carefully considering hazards associated with not only translational but also rotational misalignments during wearable robot development and use. Also, this warrants investigation of misalignment effects in stance, as a target of many exoskeleton applications.
The phosphatase and tensin homolog gene inserted between NP and P gene of recombinant Newcastle disease virus oncolytic effect test to glioblastoma cell and xenograft mouse model
Authors: Jang Sung Hoon , Jung Bo-Kyoung , An Yong Hee , Jang Hyun
Published: January 2022

Background

Glioblastoma is one of the most serious brain cancer. Previous studies have demonstrated that PTEN function disorder affects the causing and exacerbation of glioblastoma. Newcastle disease virus (NDV) has been studied as a cancer virotherapeutics. In this study, PTEN gene was delivered to glioblastoma by recombinant NDV (rNDV) and translated into protein at the cytoplasm of the glioblastoma.

Methods

We did comparison tests PTEN protein expression efficiency and oncolytic effect depend on the PTEN gene insertion site at the between NP and P genes and the between P and M gene. PTEN protein mRNA transcription, translation in glioblastoma cell, and functional PTEN protein effect of the rNDV in vitro and in vivo test performed using western blotting, RT-qPCR, MTT assay, and Glioblastoma xenograft animal model test.

Results

The result of this study demonstrates that rNDV-PTEN kills glioblastoma cells and reduces cancer tissue better than rNDV without the PTEN gene. In molecular immunological and cytological assays, PTEN expression level was high at located in the between NP and P gene, and PTEN gene was successfully delivered to the glioblastoma cell using rNDV and PTEN gene translated to functional protein and inhibits hTERT and AKT gene.

Conclusions

PTEN gene enhances the oncolytic effect of the rNDV. And our study demonstrated that NP and P gene site is better than P and M gene site which is commonly and conventionally used. PTEN gene containing rNDV is a good candidate virotherapeutics for glioblastoma.
Association between intraoperative computed tomography navigation system and incidence of surgical site infection in patients with spinal surgeries: a retrospective analysis
Authors: Kumagai Gentaro , Wada Kanichiro , Tanaka Sunao , Asari Toru , Nitobe Yohshiro , Ishibashi Yasuyuki
Published: January 2022

Purpose

Although the use of intraoperative computed tomography (CT)-based navigation systems is unlikely to cause intraoperative contamination more than the use of intraoperative fluoroscopy, the association between intraoperative CT/navigation and surgical site infections (SSIs) remains unclear. We investigated the incidence of SSIs and the association between intraoperative CT/navigation and SSIs for spinal surgeries.

Methods

Of the 512 patients who underwent spinal surgery between April 2016 and December 2020, 304 underwent C-arm intraoperative fluoroscopy and/or Medtronic O-arm intraoperative CT/navigation system. We investigated the incidence of SSIs in patients with four techniques; no intraoperative imaging C-arm only, O-arm only, and both O- and C-arm used. Multivariate logistic analyses were conducted using the prevalence of SSIs as the dependent variable. The independent variables were age, sex, and potential confounders including preoperative Japanese Orthopaedic Association (JOA) score, use of instrumentation, C-arm, and/or O-arm.

Results

The incidence of the SSIs in patients with no imaging, C-arm only, O-arm only, and both modalities used was 1.9%, 7.3%, 4.7%, and 8.3%, respectively. There was no significant difference in the incidence of SSIs between the four techniques. Multivariate logistic analyses showed a significant correlation between the prevalence of SSI and JOA scores (odds ratio, 0.878; 95% CI 0.759–0.990) and use of instrumentation (odds ratio, 6.241; 95% CI 1.113–34.985), but not use of O-arm.

Conclusions

The incidence of the SSIs in patients with only O-arm used was 4.7%. Preoperative clinical status and use of instrumentation, but not use of the O-arm, were associated with SSIs after spinal surgeries.
Impact of valvuloarterial impedance on left ventricular reverse remodeling after aortic valve neocuspidization
Authors: Yamamoto Naoki , Ito Hisato , Inoue Kentaro , Futsuki Ayano , Hirano Koji , Shomura Yu , Ozu Yasuhisa , Katayama Yoshihiko , Komada Takuya , Takao Motoshi
Published: January 2022

Background

Aortic valve neocuspidization (AVNeo) has emerged as a promising aortic valve procedure, and is expected to have a larger effective orifice area (EOA) than commercially available bioprostheses. It is, however, unclear which indices could facilitate left ventricular (LV) reverse remodeling after AVNeo. The aim of this study is to verify the impact of global left ventricular afterload on the LV reverse remodeling following AVNeo.

Methods

Data-available consecutive 38 patients (median age, 77; interquartile range, 72.8–82.0) undergoing AVNeo for severe aortic stenosis were enrolled in this study. Preoperative and the last follow-up echocardiographic data were retrospectively analyzed including the valvuloarterial impedance (Zva), a marker of global LV afterload. Reduction in LV geometry index (LVGI) and relative wall thickness (RWT) were used as an indicator for LV reverse remodeling.

Results

The Zva reduced in 24 patients (63.2%) during the follow-up period (median, 12 months). Reduction in Zva significantly correlated to improvement of LV geometry (LVGI (r = 0.400, p = 0.013) and RWT (r = 0.627, p < 0.001)), whereas increase in EOA index did not significantly correlate to LVGI (r = 0.009, p = 0.957), or RWT (r = 0.105, p = 0.529)). The reduction in Zva was the multivariate predictor of LV reverse remodeling.

Conclusions

Low global LV afterload led to significant LV reverse remodeling even after AVNeo, which could achieve better valve performance than the conventional bioprostheses.
Phelan-McDermid syndrome: a classification system after 30 years of experience
Authors: Phelan Katy , Boccuto Luigi , Powell Craig M. , Boeckers Tobias M. , van Ravenswaaij-Arts Conny , Rogers R. Curtis , Sala Carlo , Verpelli Chiara , Thurm Audrey , Bennett William E. , Winrow Christopher J. , Garrison Sheldon R. , Toro Roberto , Bourgeron Thomas
Published: January 2022

Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype consistent with PMS. The association between SHANK3 and PMS led investigators to consider disruption/deletion of SHANK3 to be a prerequisite for diagnosing PMS. This narrow definition of PMS based on the involvement of SHANK3 has the adverse effect of causing patients with interstitial deletions of chromosome 22 to “lose” their diagnosis. It also results in underreporting of individuals with interstitial deletions of 22q13 that preserve SHANK3. To reduce the confusion for families, clinicians, researchers, and pharma, a simple classification for PMS has been devised. PMS and will be further classified as PMS-SHANK3 related or PMS-SHANK3 unrelated. PMS can still be used as a general term, but this classification system is inclusive. It allows researchers, regulatory agencies, and other stakeholders to define SHANK3 alterations or interstitial deletions not affecting the SHANK3 coding region.
Key patient-reported outcomes in children and adolescents with intoxication-type inborn errors of metabolism: an international Delphi-based consensus
Authors: Bösch Florin , Zeltner Nina A. , Baumgartner Matthias R. , Huemer Martina , Landolt Markus A.
Published: January 2022

Background

Acute intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders and non-acute IT-IEM such as phenylketonuria (PKU) and their treatment have a major impact on the life of affected children and families. Yet patients’ and parents’ perspectives on the burdens of IT-IEM and its effects on everyday functioning and well-being have rarely been addressed. Patient- and observer-reported outcomes (PROs/ObsROs) are critically important to evaluate and target health care and treatment efficacy. Therefore, it is mandatory to define PROs/ObsROs relevant to patients with IT-IEM, their families, and health care professionals and to provide valid, standardised and reliable measuring instruments. To achieve consensus we performed a two-round, electronic-based modification of a Delphi survey including 27 parents of affected children, nine teenage patients and 35 health professionals (physicians, nutritionists, psychologists). The final set of PROs/ObsROs was discussed and defined in an online consensus meeting with a subsample of three health professionals, three parents and two patients. For this final set, appropriate measures (PROMs/ObsROMs) were assembled.

Results

Seventeen PROs/ObsROs constitute the final core set for paediatric IT-IEM. They cover social (e.g. social participation), emotional (e.g. positive affect), and disease-related aspects (e.g. attitude towards treatment) of patients’ lives as well as the experience of parents (e.g. parental stress).

Conclusion

To promote a holistic treatment approach, this consensus-driven set of relevant PROs/ObsROs should be incorporated into daily IT-IEM care and considered as the key psychological outcomes in clinical trials. We have identified existing—psychometrically and contextual—appropriate PROMs/ObsROMs with open access to facilitate this process.
The increased in vivo firing of pyramidal cells but not interneurons in the anterior cingulate cortex after neuropathic pain
Authors: Zhu Da-Yu , Cao Ting-Ting , Fan Hong-Wei , Zhang Ming-Zhe , Duan Hao-Kai , Li Jing , Zhang Xia-Jing , Li Yun-Qing , Wang Pan , Chen Tao
Published: January 2022

Chronic pain damages the balance between excitation and inhibition in the sensory cortex. It has been confirmed that the activity of cortical glutamatergic pyramidal cells increases after chronic pain. However, whether the activity of inhibitory interneurons synchronized changed remains obscure, especially in in vivo conditions. In the present study, we checked the firing rate of pyramidal cells and interneurons in the anterior cingulate cortex, a main cortical area for the regulation of nociceptive information in mice with spared nerve injury by using in vivo multi-channel recording system. We found that the firing rate of pyramidal cells but not interneurons increased in the ACC, which was further confirmed by the increased FOS expression in pyramidal cells but not interneurons, in mice with neuropathic pain. Selectively high frequency stimulation of the ACC nociceptive afferent fibers only potentiated the activity of pyramidal cells either. Our results thus suggest that the increased activity of pyramidal cells contributes to the damaged E/I balance in the ACC and is important for the pain hypersensitivity in mice with neuropathic pain.
Impact of frontline treatment approach on outcomes in patients with secondary AML with prior hypomethylating agent exposure
Authors: Short Nicholas J. , Venugopal Sangeetha , Qiao Wei , Kadia Tapan M. , Ravandi Farhad , Macaron Walid , Dinardo Courtney D. , Daver Naval , Konopleva Marina , Borthakur Gautam , Shpall Elizabeth J. , Popat Uday , Champlin Richard E. , Mehta Rohtesh , Al-Atrash Gheath , Oran Betul , Jabbour Elias , Garcia-Manero Guillermo , Issa Ghayas C. , Montalban-Bravo Guillermo , Yilmaz Musa , Maiti Abhishek , Kantarjian Hagop
Published: January 2022

Background

Treated secondary acute myeloid leukemia (ts-AML)—i.e., AML arising from a previously treated antecedent hematologic disorder—is associated with very poor outcomes. The optimal frontline treatment regimen for these patients is uncertain.

Methods

We retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54).

Results

Compared with IC or LIT without venetoclax, HMA plus venetoclax resulted in higher CR/CRi rates (39% and 25%, respectively; P = 0.02) and superior OS (1-year OS 34% and 17%, respectively; P = 0.05). The benefit of HMA plus venetoclax was restricted to patients with non-adverse risk karyotype, where HMA plus venetoclax resulted in a median OS of 13.7 months and 1-year OS rate of 54%; in contrast, for patients with adverse risk karyotype, OS was similarly dismal regardless of treatment approach (median OS 3–5 months). A propensity score analysis accounting for relevant clinical variables confirmed the significant OS benefit of HMA plus venetoclax, as compared with other frontline treatment approaches. In a landmark analysis, patients with ts-AML who underwent subsequent hematopoietic stem cell transplantation (HSCT) had superior 3-year OS compared to non-transplanted patients (33% vs. 8%, respectively; P = 0.003).

Conclusions

The outcomes of ts-AML are poor but may be improved with use of an HMA plus venetoclax-based regimen, followed by HSCT, particularly in those with a non-adverse risk karyotype.
Neoantigens and the tumor microenvironment play important roles in the prognosis of high-grade serous ovarian cancer
Authors: Yang Hua , Yu Mei , Zhong Sen , You Yan , Feng Fengzhi
Published: January 2022

Background

Despite the consistency of patient age, disease stage and treatment options, the prognosis of different high-grade serous ovarian carcinoma (HGSOC) patients is different. Here, we sought to measure predictive biomarkers for distinct responses to platinum-based chemotherapy and immunotherapy benefits.

Methods

Sixteen HGSOC patients receiving debulking surgery and adjuvant first-line combination chemotherapy at Peking Union Medical College Hospital (PUMCH) were enrolled. Whole exome sequencing (WES) and RNA-seq were performed on tumor and normal tissues of these patients.

Results

The tumor mutational burden (TMB) and intratumoral heterogeneity (ITH) of the platinum-resistant group were significantly higher than those of the platinum-sensitive group (P=0.0321 and P=0.0452, respectively). TMB, neoantigen and ITH had certain predictive value according to the area under the receiver operating characteristic (ROC) curve (AUC 0.7778 for TMB, 0.7619 for neoantigen, 0.7778 for ITH). The infiltration of other immune cells in tumor tissues was different between the two groups, but the difference was not significant. Univariate Cox proportional hazard analysis revealed poorer progression-free survival (PFS) for those patients who carried a higher number of neoantigens (P =0.0069), higher TMB (P =0.0083), and higher ITH (P =0.0249). Further Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis indicated the Differentially expressed genes (DEGs) in platinum-resistant and platinum-sensitive patients were mainly enriched in the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) signaling pathway and focal adhesion pathway, which are associated with platinum resistance.

Conclusions

Higher TMB, neoantigen and ITH may account for the worse prognosis of patients with platinum-based chemotherapy and higher TMB was observed in the platinum-resistant group, which could make the patients in the platinum-resistant group to be the better candidates for immunotherapy.
Impact of receiving recorded mental health recovery narratives on quality of life in people experiencing non-psychosis mental health problems (NEON-O Trial): updated randomised controlled trial protocol
Authors: Rennick-Egglestone Stefan , Elliott Rachel , Newby Chris , Robinson Clare , Slade Mike
Published: January 2022

Background

Mental health recovery narratives are first-person lived experience accounts of recovery from mental health problems, which refer to events or actions over a period of time, and which include elements of adversity or struggle, and also self-defined or observable strengths, successes, or survival. Recorded recovery narratives are those presented in invariant form, including text, audio, or video. In a previous publication, we presented a protocol for three pragmatic trials of the Narrative Experiences Online (NEON) Intervention, a web application recommending recorded recovery narratives to participants. The aim of the definitive NEON Trial was to understand whether the NEON Intervention benefitted people with experience of psychosis. The aim of the smaller NEON-O and NEON-C trials was to evaluate the feasibility of conducting definitive trials of the NEON Intervention with people (1) experiencing non-psychosis mental health problems and (2) who informally care for others experiencing mental health problems.

An open recruitment strategy with a 60-week recruitment period was developed. Recruitment for the NEON Trial and NEON-O Trial targeted mental health service users and people not using mental health services. The NEON Trial recruited to time and target. The NEON-O Trial achieved its target in 10 weeks. Analysis considered by a Programme Steering Committee after the target was achieved demonstrated a definitive result could be obtained if the trial was adapted for recruitment to continue. The UK Health Research Authority approved all needed amendments following ethical review.

Purpose of this article

To describe the decision-making process for amending the NEON-O Trial and to describe amendments made to the NEON-O Trial to enable a definitive result. The article describes amendments to the aims, objectives, design, power calculation, recruitment rate, process evaluation design, and informed consent documents. The extended NEON-O Trial adopts analysis principles previously specified for the NEON Trial. The article provides a model for other studies adapting feasibility trials into definitive trials.

Trial registration

All trials prospectively registered. NEON Trial: ISRCTN11152837. Registered on 13th August 2018. NEON-C Trial: ISRCTN76355273. Registered on 9th January 2020. NEON-O Trial: ISRCTN63197153. Registered on 9th January 2020. The NEON-O Trial ISRCTN was updated when amendments were approved. Amendment details: NOSA2, 30th October 2020.
Making sense of the linear genome, gene function and TADs
Authors: Long Helen S. , Greenaway Simon , Powell George , Mallon Ann-Marie , Lindgren Cecilia M. , Simon Michelle M.
Published: January 2022

Background

Topologically associating domains (TADs) are thought to act as functional units in the genome. TADs co-localise genes and their regulatory elements as well as forming the unit of genome switching between active and inactive compartments. This has led to the speculation that genes which are required for similar processes may fall within the same TADs, allowing them to share regulatory programs and efficiently switch between chromatin compartments. However, evidence to link genes within TADs to the same regulatory program is limited.

Results

We investigated the functional similarity of genes which fall within the same TAD. To do this we developed a TAD randomisation algorithm to generate sets of “random TADs” to act as null distributions. We found that while pairs of paralogous genes are enriched in TADs overall, they are largely depleted in TADs with CCCTC-binding factor (CTCF) ChIP-seq peaks at both boundaries. By assessing gene constraint as a proxy for functional importance we found that genes which singly occupy a TAD have greater functional importance than genes which share a TAD, and these genes are enriched for developmental processes. We found little evidence that pairs of genes in CTCF bound TADs are more likely to be co-expressed or share functional annotations than can be explained by their linear proximity alone.

Conclusions

These results suggest that algorithmically defined TADs consist of two functionally different groups, those which are bound by CTCF and those which are not. We detected no association between genes sharing the same CTCF TADs and increased co-expression or functional similarity, other than that explained by linear genome proximity. We do, however, find that functionally important genes are more likely to fall within a TAD on their own suggesting that TADs play an important role in the insulation of these genes.
Obesity is not associated with adverse outcomes among hospitalized patients with Clostridioides difficile infection
Authors: Malick Alyyah , Wang Ying , Axelrad Jordan , Salmasian Hojjat , Freedberg Daniel
Published: January 2022

Background

Obesity is associated with increased risk for death in most infections but has not been studied as a risk factor for mortality in Clostridioides difficile infection (CDI). This study tested obesity as a risk factor for death in patients hospitalized with CDI. This was a three-center retrospective study that included hospitalized adults with CDI at Columbia University Irving Medical Center, Brigham and Women’s Hospital, and NYU Langone from 2010 to 2018. Multivariate logistic regression was used to assess the relationship between obesity, measured by body mass index, and death from any cause within 30 days after the index CDI test.

Results

Data for 3851 patients were analyzed, including 373 (9.7%) who died within 30 days following a diagnosis of CDI. After adjusting for other factors, BMI was not associated with increased risk for death in any BMI category [adjusted OR (aOR) 0.96, 95% CI 0.69 to 1.34 for BMI > 30 vs BMI 20–30; aOR 1.02, 95% CI 0.53 to 1.87 for BMI > 40 vs BMI 20–30]. After stratifying into three groups by age, there were trends towards increased mortality with obesity in the middle-aged (56–75 vs ≤ 55 years old) yet decreased mortality with obesity in the old (> 75 vs ≤ 55) (p = NS for all). Advanced age and low albumin were the factors most strongly associated with death.

Conclusions

We found no association between obesity and death among patients with CDI, in contrast to most other infections. Obesity is not likely to be useful for risk-stratifying hospitalized patients with CDI.
Repeated mild traumatic brain injury impairs fracture healing in male mice
Authors: Kesavan Chandrasekhar , Rundle Charles , Mohan Subburaman
Published: January 2022

Objectives

The goal of this study was to evaluate the long-term impact of repeated (r) mild traumatic brain injury (mTBI) on the healing of fractures in a mouse model. Ten week-old male mice were subjected to r-mTBI once per day for 4 days followed by closed femoral fracture using a three-point bending technique, 1 week post impact and fracture healing phenotype evaluated at 20 weeks of age.

Results

Micro-CT analysis of the fracture callus region at nine weeks post fracture revealed reduced bone volume (30%,p < 0.05) in the r-mTBI fracture group compared to the control-fracture group. The connectivity density of the fracture callus bone was reduced by 40% (p < 0.01)in the r-mTBI fracture group. Finite element analysis of the fracture callus region showed reduced failure load (p = 0.08) in the r-mTBI group compared to control group. There was no residual cartilage in the fracture callus region of either the r-mTBI or control fracture group. The reduced fracture callus bone volume and mechanical strength of fracture callus in r-mTBI mice 9 weeks post fracture are consistent with negative effects of r-mTBI on fracture healing over a long-term resulting in decreased mechanical strength of the fracture callus.
A proof-of-concept study of growth hormone in children with Phelan–McDermid syndrome
Authors: Sethuram S. , Levy T. , Foss-Feig J. , Halpern D. , Sandin S. , Siper P. M. , Walker H. , Buxbaum J. D. , Rapaport R. , Kolevzon A.
Published: January 2022

Background

Phelan–McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS.

Methods

rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study.

Results

rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms.

Limitations

Results should be interpreted with caution given the small sample size and lack of a placebo control.

Conclusions

Overall, findings are promising and indicate the need for larger studies with rhGH in PMS.

Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207.