bluuebunny/crossref_metadata_2025 huggingface dataset:
The Face of Another: Isozaki, Deme, and the Postmodern Turn
Authors: Blanciak François
Published: March 2022

Focusing on the early work and collaborations of the Japanese architect Arata Isozaki, this paper researches links between the robotic culture of postwar Japan and the surge of figuration in postmodernism, challenging the commonly held view that this architectural movement emerged in the West. Specifically, the paper looks at how Isozaki's robotic creation for Expo '70 embodied the notion of theatrical mask, which characterized both postmodern ideals and early Japanese robotics, and influenced his own architectural work. Delving into Isozaki's creative exchanges with the film director Hiroshi Teshigahara and the novelist Kōbō Abe, coming into contact with each other in the 1950s, a synergy between cinema, literature, and architecture is highlighted, considering their speculations about possible technological means of reconstructing the human face in light of the symbolic dimension of this enterprise for Japan as a nation, and for architecture as a discipline.
Epidendrum alejandrinae (Orchidaceae: Laeliinae), a new species from the high Andean forests of central Peru
Authors: QUISPE-MELGAR HAROLD RUSBELTH , LLACUA-TINEO YASHIRA STEFANI , AMES-MARTÍNEZ FRESSIA NATHALIE , HUAYTA DAVID , LAGONES POMA KATHERINE LUCERO , HÁGSATER ERIC
Published: March 2022

The high Andean forests harbor great and unique biodiversity. Here, we report a new species of Epidendrum from Peru. Epidendrum alejandrinae is described, illustrated and compared with the morphologically similar Epidendrum ochoae, Epidendrum pachydiscum and Epidendrum aida-alvareziae. We performed a systematic review of herbarium information on the species reported for the Region of Huancavelica and compared the morphological features of the closest species to rule out possible matches. The new species is characterized by a short, foliate aggregate stems, an apical pendulous inflorescence formed from the stem, green resupinate flowers opening in succession, the petals and sepals semi-extended, a 3-lobed lip, lateral lobes obliquely ovoid, median lobe broadly cuneate, bicallose, and four, obovoid, laterally compressed pollinia. The novelty represents an important record for the flora associated with the high Andean forest dominated by Polylepis and Gynoxys in central Peru.
Malaria-associated adhesion molecule activation facilitates the destruction of uninfected red blood cells
Authors: Dalimot Jill J. , Klei Thomas R. L. , Beuger Boukje M. , Dikmen Zeynep , Bouwman Suzan A. M. , Mombo-Ngoma Ghyslain , Zoleko-Manego Rella , Ndzebe-Ndoumba Wilfrid F. , Egée Stéphane , Kuijpers Taco W. , Grobusch Martin P. , van Bruggen Robin
Published: March 2022

Severe malarial anemia (SMA) is the main cause of malaria-associated infant mortality in malaria endemic countries. One major factor that contributes to SMA is the accumulation of uninfected red blood cells (uRBCs) in the spleen. We report the activation of adhesion molecules Lutheran/basal cell adhesion molecule (Lu/BCAM) and CD44 on uRBCs from Plasmodium falciparum in vitro cultures and patients with malaria that mediates adherence to the splenic extracellular matrix (ECM) components laminin-α5 and hyaluronic acid (HA), respectively. This tight ECM-adhesion molecule interaction was associated with elevated intracellular Ca2+ levels, increased shedding of microvesicles, and Lu/BCAM clustering on altered uRBCs. Moreover, we observed that a soluble parasite-derived factor promoted the adhesive phenotype of uRBCs, as the incubation of RBCs with filtered malaria-conditioned medium reproduced the same adhesive effect in malaria culture–derived uRBCs. Eventually, Lu/BCAM and CD44 activation facilitate the adherence to ECM components of the red pulp, resulting in the enhanced splenic retention of uRBCs. Our results suggest a novel adhesion molecule–dependent mechanism that augments malaria-induced anemia.
Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia
Authors: Gill Saar , Vides Vanessa , Frey Noelle V. , Hexner Elizabeth O. , Metzger Susan , O'Brien Megan , Hwang Wei-Ting , Brogdon Jennifer L. , Davis Megan M. , Fraietta Joseph A. , Gaymon Avery L. , Gladney Whitney L. , Lacey Simon F. , Lamontagne Anne , Mato Anthony R. , Maus Marcela V. , Melenhorst J. Joseph , Pequignot Edward , Ruella Marco , Shestov Maksim , Byrd John C. , Schuster Stephen J. , Siegel Donald L. , Levine Bruce L. , June Carl H. , Porter David L.
Published: March 2022

In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.
Comparison of plasma levobupivacaine concentrations with and without epinephrine following erector spinae plane block for breast cancer surgery: a randomized controlled trial
Authors: Shigeta Hiroe , Yasumura Rie , Kotake Yoshifumi
Published: March 2022

Background

The erector spinae plane (ESP) block requires a large volume of local anesthetic to provide effective analgesia, which has the potential to cause local anesthetic systemic toxicity (LAST). Adjunctive epinephrine slows the entry of local anesthetic into the plasma and decreases its toxic effect on vulnerable tissues. We compared plasma levobupivacaine concentrations with and without epinephrine after ESP blocks for breast cancer surgery.

Methods

In this prospective, double-blinded, randomized controlled trial, 35 patients who underwent elective unilateral partial mastectomy with sentinel lymph node biopsy were enrolled. The patients were randomized to group L (ESP block with 2 mg/kg levobupivacaine) or LE (ESP block with 2 mg/kg levobupivacaine and 5 μg/mL epinephrine). Blood samples were obtained at 2.5, 5, 7.5, 10, 12.5, 15, 30, 60, and 120 min after the ESP block, and plasma concentrations of levobupivacaine were compared.

Results

Twenty-nine patients were included in the analysis. The maximum plasma concentration (Cmax) and the time to maximum concentration (Tmax) were, respectively, 1.24 μg/mL and 6.0 min in group L and 0.62 μg/mL and 7.2 min in group LE. The two groups showed no significant differences in the numerical rating scale scores immediately after extubation and 5 and 9 h after the ESP block, or in the interval from the ESP block to the first rescue analgesia. No patient developed symptoms suggestive of LAST.

Conclusions

A single bolus of 2 mg/kg levobupivacaine in the ESP block resulted in a short Tmax with high Cmax. Adding epinephrine to levobupivacaine decreased the Cmax and delayed the Tmax after ESP blocks but had no effect on postoperative analgesia.

Trial registration

UMIN Clinical Trials Registry, UMIN000034479. The trial was retrospectively registered on October 13, 2018.
Use of levosimendan combined with Shenfu injection to treat acute heart failure patients with hypotension: a prospective randomized controlled single-blind study
Authors: Li Miaomiao , Zhang Yue , Wan Qianli , Li Yiou , Qu Tianzhen , Yuan Fang
Published: March 2022

Background

Levosimendan can improve clinical symptoms and the cardiorenal rescue success rate, and stabilize hemodynamic parameters in individuals suffering from acute decompensated heart failure. In addition, Shenfu injection (SFI) has been shown to protect the ischemic heart and enhance myocardial contractility.

Methods

For this randomized control single-blind study, 101 patients with acute decompensated heart failure (ADHF) were enrolled and randomly assigned to control levosimendan (n = 51) and levosimendan + SFI injection (n = 50) groups. Attending physicians were not blinded for which arm the patients were allocated. Blood pressure, heart rate, the electrocardiogram, respiratory rate, fluid intake and urine output were all recorded 2 h and 24 h after drug infusions had commenced, and the cardiac index (CI) was monitored by ultrasonic cardiac output monitors.

Results

Median blood pressure was markedly increased in the levosimendan + SFI group after 2 h and 24 h from the initiation of infusions compared to levosimendan administration alone. Brain natriuretic peptide (BNP) concentrations were reduced after administrations of levosimendan + SFI or solely levosimendan (both P < 0.001). Alterations in BNP concentrations were not different in the combination and control groups. No differences were found between the 2 groups in heart rate or severe hypotension, but blood pressure (systolic blood pressure, diastolic blood pressure) and hemodynamic parameters including CI, cardiac output and stroke volume index responded better in the levosimendan + SFI group compared to the monotherapy levosimendan group.

Conclusions

Levosimendan + SFI was superior to treat ADHF patients compared to levosimendan monotherapy and produced significant improvements in hemodynamic parameters especially for ADHF patients with hypotension.

Trail registration The study was prospectively registered at Chinese Clinical Trial Registry with registration number [ChiCTR2000039385] (10/25/2020).
Incidence of symptomatic COVID-19 in close contacts of patients after discharge from hospital
Authors: Ahmadi Ayat , Poopak Amirhossein , Nazemi Sina , Mohammadi Negin , Eslami Bita , Seyyedsalehi Monireh Sadat , Doshmangir Leila , Allameh Seyyed Farshad , Zendehdel Kazem
Published: March 2022

Background

There is a little evidence about the infectiousness of recovered COVID-19 patients. Considering that the circumstance of the isolation of the COVID-19 patients after-discharge is not always optimal, it is not very unlikely that viral transmission still occurs after hospital discharge. This study aims to investigate the incidence of symptomatic COVID-19 in close contacts of recovered patients after discharge from hospital.

Methods

Four hundred fifty discharged COVID-19 patients discharged from the largest public treatment center in Tehran, capital city of Iran, were followed up. Demographic and clinical data of participants were collected from medical records. Follow-up data were acquired via telephone call interviews with patients or their main caregivers at home.

Results

The study’s response rate was 93.77% (422 participated in the study). 60.90% patients were male and 39.10% were female (sex ratio = 1.55 male). The most prevalent comorbidities in these patients were hypertension (29.68%) and diabetes (24.80%). The mean of home isolation after discharge was 25.85. Forty-one (9.71%) patients had at least one new case in their close contacts, up to 3 weeks after they were discharged. There was a significant association between having at least a comorbidity with the odds of getting infected in close contacts [OR (CI) 2.22 (1.05–4.68)]. Density of inhabitant per room in a house’ and the quality of isolation had significant associations with observing new cases in the patients’ close contacts [high to moderate; OR (CI) 2.44 (1.06–5.61], [bad to good; OR (CI) 2.31 (1.17–4.59)], respectively.

Conclusion

After hospital discharge, COVID-19 transmission can still occur, when a large number of people lives together in a single house. Another explanation can be that the less precaution measures are taken by recovered patients’ cohabitants. Such conditions are also likely to happen when the recovered patient has other chronic diseases and requires additional care.
Enigma of COVID-19: is “multisystem inflammatory syndrome in adults” (MIS-A) predictable?
Authors: Serin Istemi , Sari Nagehan Didem , Gunaltili Murat , Karakilic Ayse , Gulesir Begum , Kal Kolik Beyza , Cevik Gulnihal , Sungurlu Hilal , Keskin Melike , Baltik Muhammed , Cakmak Onurhan , Cinli Tahir Alper
Published: March 2022

Background

Severe inflammation and one or more extrapulmonary organ dysfunctions have been reported and this clinical picture is defined as "multisystem inflammatory syndrome in adults" (MIS-A) in severe coronavirus disease-2019 (COVID-19). We aimed to determine the effect of LDH/lymphocyte ratio (LLR) on the development of MIS-A.

Methods

The data of 2333 patients were retrospectively analyzed.

Results

MIS-A rate was found to be 9.9% and MIS-A related mortality was 35.3%. LRR level above 0.24 was found to predict MIS-A development with 70% sensitivity and 65.2% specificity. The risk of MIS-A development was found to be 3.64 times higher in those with LRR levels above 0.24 compared to those with 0.24 and below. In patients with MIS-A, LRR level above 0.32 predicts mortality with 78% sensitivity and 70% specificity.

Conclusions

Early detection of MIS-A with high sensitivity and specificity in a practical ratio is very important in terms new studies.
Biomechanical modelling of the pelvic system: improving the accuracy of the location of neoplasms in MRI-TRUS fusion prostate biopsy
Authors: Qasim Muhammad , Puigjaner Dolors , Herrero Joan , López Josep M. , Olivé Carme , Fortuny Gerard , Garcia-Bennett Josep
Published: March 2022

Background

An accurate knowledge of the relocation of prostate neoplasms during biopsy is of great importance to reduce the number of false negative results. Prostate neoplasms are visible in magnetic resonance images (MRI) but it is difficult for the practitioner to locate them at the time of performing a transrectal ultrasound (TRUS) guided biopsy. In this study, we present a new methodology, based on simulation, that predicts both prostate deformation and lesion migration during the biopsy.

Methods

A three-dimensional (3-D) anatomy model of the pelvic region, based on medical images, is constructed. A finite element (FE) numerical simulation of the organs motion and deformation as a result of the pressure exerted by the TRUS probe is carried out using the Code-Aster open-source computer software. Initial positions of potential prostate lesions prior to biopsy are taken into consideration and the final location of each lesion is targeted in the FE simulation output.

Results

Our 3-D FE simulations show that the effect of the pressure exerted by the TRUS probe is twofold as the prostate experiences both a motion and a deformation of its original shape. We targeted the relocation of five small prostate lesions when the TRUS probe exerts a force of 30 N on the rectum inner wall. The distance travelled by these lesions ranged between 5.6 and 13.9 mm.

Conclusions

Our new methodology can help to predict the location of neoplasms during a prostate biopsy but further studies are needed to validate our results. Moreover, the new methodology is completely developed on open-source software, which means that its implementation would be affordable to all healthcare providers.
Suicide decline and improved psychiatric treatment status: longitudinal survey of suicides and serious suicide attempters in Tokyo
Authors: Otaka Yasushi , Arakawa Ryosuke , Narishige Ryuichiro , Okubo Yoshiro , Tateno Amane
Published: March 2022

Background

Connecting individuals in need of psychiatric treatment with adequate medical services has been a major strategy for suicide prevention in Japan. By investigating serious suicide attempters admitted to our Critical Care Medical Center (CCM), we aimed to examine longitudinal changes in the psychiatric treatment status of high-risk suicidal individuals, and to explore the association between any improvement in psychiatric treatment status and suicide decline.

Methods

Subjects from two periods, 2006–2011 and 2012–2017, were enrolled. We collected the data of 32,252 suicides in Tokyo from police reports and the data of 942 suicide attempters admitted to CCM from medical records. Data were annually collected by both age and gender for the number of suicide completers, the number of suicide attempters, and the psychiatric treatment rates, respectively.

ANOVA and t-test were used to examine whether there were differences in the number of suicides and attempers between the two periods. The difference in psychiatric treatment rate between the two periods was examined by chi-square test. Additionally, we used Pearson’s correlation coefficient to analyze any correlation between annual treatment rate and the number of suicide completers in subgroups with altered psychiatric treatment rates.

Results

The number of suicide attempters in the 20–39-year age group of decreased together with the number of suicides. Psychiatric treatment rates of male attempters aged 20–59 years improved significantly from 48.7 to 70.6% and this improvement correlated with a decrease in suicides. However, psychiatric treatment rates in the elderly, which have the highest number of suicides in both genders, did not improve and remain low.

Conclusions

The number of suicide attempters, as well as that of suicides, decreased in Tokyo. Improvement of psychiatric treatment status in high-risk suicidal male adults may have contributed to the reduction of suicides in Tokyo. However, the continuing low rate of psychiatric treatment in the elderly is a pressing issue for future suicide prevention.
Association between experiences of intimate partner sexual violence and cigarette smoking among women in union in Papua New Guinea: evidence from a nationally representative survey
Authors: Asare Bernard Yeboah-Asiamah , Agyemang-Duah Williams , Adomako Emmanuel Brenyah , Puri Parul , Ogundare Deborah Odunayo , Vishwakarma Deepanjali , Peprah Prince
Published: March 2022

Background

Intimate partner sexual violence (IPSV) is a prevalent public health problem affecting millions of people each year globally, particularly in developing countries like Papua New Guinea (PNG). Although over two-thirds of women in PNG are estimated to experience some form of sexual violence in their lifetime, empirical evidence is limited on the association between IPSV and cigarette smoking. Thus, the present study aims to examine the prevalence of IPSV and its association with cigarette smoking among women in union  in PNG.

Methods

This cross-sectional study used data from the first demographic and health survey of PNG conducted between 2016 and 2018. A total of 9,943 women aged 15–49 years in intimate unions were included in this study. We estimated the relative risk of smoking cigarette using modified Poisson regression models with a robust variance and 95% confidence intervals.

Results

The rates of IPSV and current cigarette smoking were 25.9% and 26.8%, respectively. The modified Poisson regression results showed that IPSV was significantly associated with an elevated risk for cigarette smoking. Women with IPSV history were more likely to smoke cigarette relative to their counterparts with no IPSV history (RR: 1.33, 95% CI: 1.18–1.50) in the absence of covariates. After controlling for demographic, social and economic factors, the association between IPSV and cigarette smoking remained statistically significant (RR: 1.24, 95% CI: 1.08–1.42).

Conclusions

The rates of IPSV and cigarette smoking among women in union in PNG in the current study were relatively high. Irrespective of diverse demographic, social and economic factors, IPSV was still significantly associated with cigarette smoking among women in union in PNG. The findings presented call the attention of policy-makers and relevant authorities in PNG to an important association that needs to be addressed. Counseling, awareness creation, service provision and program design on IPSV are urgently required to minimize cigarette smoking and IPSV among women in union in PNG.
Higher exposure to childhood adversity associates with lower adult flourishing
Authors: Wang Lin , Yu Zhiyuan , Chen Wenyi , Zhang Juan , Bettencourt Amie F.
Published: March 2022

Background

Adverse childhood experiences (ACEs) are prevalent and associated with negative health and social outcomes. However, our understanding of how patterns of ACEs exposure relate to positive outcomes in adulthood remains limited. This study aims to identify patterns of ACEs and examine associations with flourishing in a sample of Chinese young adults.

Methods

This cross-sectional study was conducted from August to November 2020. Young adults, ages 18–35, enrolled in undergraduate or graduate programs at universities in Mainland China were recruited through convenience and snowball sampling to participate in a survey. The exposure to ACEs was measured by the twelve-item Chinese version of the ACE-International Questionnaire. Additional measures included six domains of flourishing assessed using the Chinese version of the Flourishing Measure, and demographic covariates (i.e., gender, age, year in university, marital status). Descriptive statistical analysis and latent class analysis (LCA) were performed using SPSS 27 and Mplus 8.5.

Results

Participants included 9468 young adults (mean age = 20.1 years). Majority of participants were female (75.3%), undergraduate students (96.4%), and single (79.8%). Approximately 56% of participants reported at least one ACE; 7.0% reported four or more ACEs. Emotional neglect (33.2%), household violence (20.6%), and parental separation/divorce (13.9%) were the most frequently reported ACEs. LCA identified three ACEs classes: multiple maltreatment and household violence (4.7%), emotional neglect and household violence (16.2%), and low ACEs (79.1%). Individuals in the low ACEs class had the highest level of flourishing whereas individuals in multiple maltreatment and household violence had the lowest level of flourishing in all six domains. There were no significant differences in flourishing between the multiple maltreatment and household violence and the emotional neglect and household violence classes except in the physical and mental health (means = 6.17 vs 6.51, p = 0.02) and the financial and material stability domains (means = 5.25 vs 5.66, p = 0.04).

Conclusions

Patterns of multiple ACEs exposures were associated with lower levels of flourishing. Our findings have implications for efforts to prevent ACEs exposure through monitoring and promoting family well-being and routine screening to identify those with ACEs exposure to prevent negative social and health sequelae.
An educational intervention using the health belief model for improvement of oral health behavior in grade-schoolers: a randomized controlled trial
Authors: Sanaeinasab Hormoz , Saffari Mohsen , Taghavi Hassan , Karimi Zarchi Aliakbar , Rahmati Fatemeh , Al Zaben Faten , Koenig Harold G.
Published: March 2022

Background

Oral health problems especially dental caries are common in school children, and education programs may help to prevent these conditions. The aim of current study was to examine the effects of an educational program based on a Health Belief Model (HBM) to improve oral health behaviors of elementary school children.

Methods

A total of 112 children ages 6–12 years old accompanied by one of their parents were randomly assigned to intervention/test and control groups. In the intervention group, five consecutive weekly educational sessions based on the HBM were provided, while the control group received only routine education delivered by the dental clinic. The Decayed, Missing, and Filled Teeth (DMFT) score, papillary bleeding index, and responses to the HBM questionnaire were assessed in the intervention and control groups at baseline and three-month follow-up after the intervention was completed. Within-group and between-group differences were examined using the Student’s t-test and analysis of covariance.

Results

All HBM domains were improved at follow-up in the intervention group compared to the control group (p < 0.001). The largest change was in perceived susceptibility, whereas the smallest changes were in perceived severity and perceived benefits. The papillary bleeding index demonstrated a significant change from baseline to follow-up in the intervention group (reduction of 0.7, 95% CI = − 0.9 to − 0.5). All components of the DMFT score except missing teeth also improved in the intervention group compared to controls. However, no significant difference was found in total DMFT score between intervention and control groups.

Conclusion

An education program based on HBM may be more effective than current methods used to educate children and their parents on optimal oral health behaviors. Administration of interventions of this type along with other school-based programs to prevent dental caries may be helpful in grade-school children.
Domestic violence against married women during the COVID-19 pandemic in Egypt
Authors: Abu-Elenin Mira M. , Elshora Ahmed A. , Sadaka Mohamed Saad , Abdeldaim Doaa E.
Published: March 2022

Background

In face of the COVID-19 pandemic, many countries including Egypt implemented stay indoor rules. These regulations slowed the propagation of the coronavirus, meanwhile they contributed to increase mental health issues, particularly the risk of experiencing intimate partner violence (IPV). That might lead to adverse health and social outcomes on the abused women and the children. This study aimed to examine the effect of the COVID-19 pandemic on the incidence of intimate partner violence against married women in Egypt.

Methods

A cross-sectional study enrolled 2068 married women through an electronic survey link. An anonymous self-administered questionnaire was used. It included demographic data and assessed the frequency of exposure to various forms of spousal violence before and after the COVID-19 pandemic.

Results

The mean age of respondents was 33.8 ± 6.3 years. The commonest types of violent behaviors that have been increased significantly after the COVID-19 pandemic were: twisting arms/pulling the hair (pre 32.8%, post 75%), leaving the house without informing or giving the wife money (pre 12.2%, post 30.3%), restricting interaction with her family members (pre 26.1, post 40.4%), treating her as a servant (pre 28.7%, post 36.7%) and insulting her in front of others (pre 22.9%, post 30.8%).The associated determinants for higher violence rate were; low women education, young age at marriage, low educational and job rank of husband, husband’s tobacco use and reduced family income (p < 0.05).

Conclusions

The overall prevalence of economic and some types of physical and emotionally abusive behaviors have been increased after the emergence of COVID-19 pandemic. Special intervention should be designed to address this issue in collaboration with public health organizations.
Analysis of the genotype–phenotype correlation of MYO15A variants in Chinese non-syndromic hearing loss patients
Authors: Fu Ying , Huang Shasha , Gao Xue , Han Mingyu , Wang Guojian , Kang Dongyang , Yuan Yongyi , Dai Pu
Published: March 2022

Background

Mutations in the MYO15A gene are a widely recognized cause of autosomal recessive non-syndromic sensorineural hearing loss (NSHL) globally. Here, we examined the role and the genotype–phenotype correlation of MYO15A variants in a cohort of Chinese NSHL cases.

Methods

Eighty-one cases with evidenced MYO15A variants from the 2263 Chinese NSHL cases, who underwent next-generation sequencing (NGS), were enrolled in the study. We investigated the association of MYO15A variants with the severity, progression and age of onset of hearing loss, as well as compared it to the previous reports in different nationalities. The cases were divided into groups according to the number of truncating variants: 2 truncating, 1 truncating and 1 non-truncating, 2 non-truncating variants, and compared the severity of HL among the groups.

Results

MYO15A accounted for 3.58% (81/2263) of all NSHL cases. We analyzed 81 MYO15A-related NSHL cases, 73 of whom were with congenital bilateral, symmetric or severe-to-profound hearing loss (HL), however, 2 of them had a postlingual, asymmetric, mild or moderate HL. There were 102 variants identified in all MYO15A structural domains, 76.47% (78/102) of whom were novel. The most common types of detected variants were missense (44/102, 43.14%), followed by frameshift (27/102, 26.47%), nonsense (14/102, 13.72%), splice site (10/102, 9.80%), in frame (4/102, 3.92%), non-coding (2/102, 1.96%) and synonymous (1/102, 0.98%). The most recurrent variant c.10245_10247delCTC was detected in 12 cases. We observed that the MYO15A variants, located in its N-terminal, motor and FERM domains, led to partial deafness with better residual hearing at low frequencies. There were 34 cases with biallelic truncating variants, 37 cases with monoallelic truncating variants, and 13 cases with biallelic non-truncating variants. The biallelic non-truncating variants group had the least number of cases (12/81), and most of them (10/12) were with profound NSHL.

Conclusions

MYO15A is a major gene responsible for NSHL in China. Cases with MYO15A variants mostly showed early-onset, symmetric, severe-to-profound hearing loss. This study is by far the largest focused on the evaluation of the genotype–phenotype correlations among the variants in the MYO15A gene and its implication in the outcome of NSHL. The biallelic non-truncating MYO15A variants commonly caused profound HL, and the cases with one or two truncating MYO15A variants tended to increase the risk of HL. Nevertheless, further investigations are needed to clarify the causes for the variable severities and progression rates of hearing loss and the detected MYO15A variants in these cases.
Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice
Authors: Pergande Melissa R. , Kang Christina , George Diann , Sutter Pearl A. , Crocker Stephen J. , Cologna Stephanie M. , Givogri Maria I.
Published: March 2022

Background

Recent findings show that extracellular vesicle constituents can exert short- and long-range biological effects on neighboring cells in the brain, opening an exciting avenue for investigation in the field of neurodegenerative diseases. Although it is well documented that extracellular vesicles contain many lipids and are enriched in sphingomyelin, cholesterol, phosphatidylserines and phosphatidylinositols, no reports have addressed the lipidomic profile of brain derived EVs in the context of Metachromatic Leukodystrophy, a lysosomal storage disease with established metabolic alterations in sulfatides.

Methods

In this study, we isolated and characterized the lipid content of brain-derived EVs using the arylsulfatase A knockout mouse as a model of the human condition.

Results

Our results suggest that biogenesis of brain-derived EVs is a tightly regulated process in terms of size and protein concentration during postnatal life. Our lipidomic analysis demonstrated that sulfatides and their precursors (ceramides) as well as other lipids including fatty acids are altered in an age-dependent manner in EVs isolated from the brain of the knockout mouse.

Conclusions

In addition to the possible involvement of EVs in the pathology of Metachromatic Leukodystrophy, our study underlines that measuring lipid signatures in EVs may be useful as biomarkers of disease, with potential application to other genetic lipidoses.
Establishment of a finite element model and stress analysis of intra-articular impacted fragments in posterior malleolar fractures
Authors: Xie Wenyong , Lu Hao , Zhan Sizheng , Liu Yijun , Quan Yuan , Xu Hailin , Fu Zhongguo , Zhang Dianying
Published: March 2022

Background

Intra-articular impacted fragments (IAIFs) are considered articular surface fragments resulting from impact and compressive forces. The malreduction of IAIFs in posterior malleolar fractures has been associated with talar subluxation and long-term post-traumatic arthritis. In this study, we establish IAIF defect finite element models of different sizes in posterior malleolar fractures and explored how IAIF defects predict the onset of post-traumatic arthritis.

Methods

A reliable three-dimensional finite element model of the normal ankle was established. Finite element models with different sizes of IAIF defects were created to calculate ankle joint contact stress. The finite element data were recorded and analyzed.

Results

There was a linear relationship between the size of the IAIF defect and MCS with IAIF defects in the posterolateral region. The result of Pearson linear correlation analysis was r = 0.963, P = 0.009. The regression equation was MCS = 0.087*AI + 2.951 (AI, area of IAIF) by simple linear regression analysis. When the IAIF defect was in the posteromedial region, there was also a linear relationship between the size of the IAIF defect and MCS. The result of Pearson linear correlation analysis was r = 908, P = 0.033. The regression equation was MCS = 0.065*AI + 1.841. The MCS was increased mainly in the border of the IAIF defect.

Conclusions

A small IAIF defect in the posterior malleolus will result in a high MCS, and the MCS in the posterolateral region is larger than the MCS in the posteromedial region when the size of the IAIF defect is the same. We obtain the regression equation of MCS and area of IAIF defect. This indicates that patients are more prone to post-trauma arthritis when the size of IAIF defects is more than 17.8 mm2 in the posterolateral region and more than 40.9 mm2 in the posteromedial region.

Trial registration Retrospectively registered.
Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease
Authors: Visser Pieter Jelle , Reus Lianne M. , Gobom Johan , Jansen Iris , Dicks Ellen , van der Lee Sven J. , Tsolaki Magda , Verhey Frans R. J. , Popp Julius , Martinez-Lage Pablo , Vandenberghe Rik , Lleó Alberto , Molinuevo José Luís , Engelborghs Sebastiaan , Freund-Levi Yvonne , Froelich Lutz , Sleegers Kristel , Dobricic Valerija , Lovestone Simon , Streffer Johannes , Vos Stephanie J. B. , Bos Isabelle ,   ADNI, Smit August B. , Blennow Kaj , Scheltens Philip , Teunissen Charlotte E. , Bertram Lars , Zetterberg Henrik , Tijms Betty M. , Smit August B. , Blennow Kaj , Scheltens Philip , Teunissen Charlotte E. , Bertram Lars , Zetterberg Henrik , Tijms Betty M.
Published: March 2022

Background

Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels.

Methods

We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer’s Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study.

Results

We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood–brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins.

Conclusions

CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood–brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.
Psychogenic fever and postural tachycardia syndrome among school-aged children and adolescents with fever of unknown origin
Authors: Ishizaki Yuko , Yanagimoto Yoshitoki , Fujii Yuri , Yamamoto Mana , Kaneko Kazunari
Published: March 2022

Background

Although fever is a common symptom in pediatric practice, its origin is often unknown in pediatric patients. Psychogenic fever is a stress-related, psychosomatic disease observed especially in young women. This study aimed to estimate the prevalence of psychogenic fever in pediatric patients with fever of unknown origin by surveying the medical records of school-aged children and adolescents.

Methods

The study subjects included 47 patients aged 6–15 years who visited the Department of Pediatrics in Kansai Medical University Medical Center between January 2006 and December 2020 with fever of unknown origin. Data on age, sex, final estimated diagnosis, and comorbid psychosocial issues were collected from the medical records.

Results

The study was composed of 47 patients, including 22 male and 25 female patients (male/female ratio, 1:1.36). The mean age was 10.1 (standard deviation, 2.4) years for boys and 11.6 (standard deviation, 2.7) years for girls (p = .047). The final estimated diagnoses were psychogenic fever, physical disorder, infection of unknown origin, and miscellaneous in 18, 12, 12, and 5 patients, respectively. The most common comorbidity in these pediatric patients with psychogenic fever was postural tachycardia syndrome.

Conclusion

Psychogenic fever was a common cause of fever of unknown origin in pediatric patients, and postural tachycardia was prevalent among children with psychogenic fever. Enhanced sympathetic response to stress might play an important role in both psychogenic fever and postural tachycardia.
Immune cell atlas of cholangiocarcinomas reveals distinct tumor microenvironments and associated prognoses
Authors: Xia Tao , Li Keyu , Niu Nan , Shao Yingkuan , Ding Ding , Thomas Dwayne L. , Jing Hao , Fujiwara Kenji , Hu Haijie , Osipov Arsen , Yuan Chunhui , Wolfgang Christopher L. , Thompson Elizabeth D. , Anders Robert A. , He Jin , Mou Yiping , Murphy Adrian G. , Zheng Lei
Published: March 2022

Background

Immunotherapy has demonstrated a limited clinical efficacy in approximately 5% of cholangiocarcinoma. The main challenges for an effective immunotherapy response in cholangiocarcinoma arise from the tumor microenvironment, which is poorly understood.

Methods

For a comprehensive analysis of the tumor microenvironment in cholangiocarcinoma, we performed multiplex immunohistochemistry with two 15-marker immune panels and Nanostring assays for a comprehensive analysis of 104 surgically resected cholangiocarcinomas including intrahepatic, hilar, and distal cholangiocarcinoma. We also validated some key findings with a batch integration analysis of published single cell RNA sequencing data.

Results

This study found that natural killer cells occupy the largest immune cell compartment in cholangiocarcinoma. Granzyme-B+CD8+ effector T cells are significantly associated with better overall survival in both intrahepatic and distal cholangiocarcinoma. Above 85% of intrahepatic cholangiocarcinomas with higher density of PD-1−EOMES−CD8+ effector T cells are associated with long-term survival. However, only the density of PD-1−EOMES−CD8+ T cells in the tumor areas, but not in the peripheries of the tumors, is prognostic. In all three cholangiocarcinoma subtypes, T regulator cells are significantly associated with a poor prognosis; however, M1 and M2 tumor-associated macrophages or PD-L1+ tumor-associated macrophage demonstrate different prognostic values. Combining PD-L1+ M1 or M2, PD-L1− M1 or M2 tumor-associated macrophages, and T regulator cells to subgroup intrahepatic and distal cholangiocarcinoma, the prognosis is significantly better distinguished. Moreover, PD-L1− M2 tumor-associated macrophages is associated with a good prognosis in intrahepatic and distal cholangiocarcinoma, suggesting this subtype of M2 tumor-associated macrophages may be antitumoral. Interestingly, lower densities of various types of immunosuppressive cells are associated with decreased infiltration of effector T cells in distal and hilar cholangiocarcinoma, but not in intrahepatic cholangiocarcinoma. In intrahepatic cholangiocarcinoma, PD-L1+ tumor-associated macrophages exert their immunosuppressive function likely through promoting T cell exhaustion.

Conclusions

This study suggests that the densities of Granzyme-B+CD8+ effector T cells and non-exhausted PD-1−EOMES−CD8+ T cells and the PD-L1 status in the tumor-associated macrophages are prognostic makers in cholangiocarcinomas. The study also supports targeting PD-L1+ tumor-associated macrophages as the immunotherapy for cholangiocarcinoma.
Reduction in pediatric growth hormone deficiency and increase in central precocious puberty diagnoses during COVID 19 pandemics
Authors: Peinkhofer Martina , Bossini Benedetta , Penco Arturo , Giangreco Manuela , Pellegrin Maria Chiara , Vidonis Viviana , Vittori Giada , Grassi Nicoletta , Faleschini Elena , Barbi Egidio , Tornese Gianluca
Published: March 2022

Background

While several studies have been published so far on the effect of COVID-19 pandemic on health care for non-COVID-19 diseases, to date no study evaluated the impact of the COVID-19 pandemic on the entire field of pediatric endocrinology. This study aimed to evaluate differences in pediatric endocrine stimulation tests after the advent of COVID-19 pandemics.

Methods

Retrospective study with data collection for pediatric endocrine stimulation tests performed in 2019 and 2020 in a tertiary center.

Results

Overall, 251 tests were performed on 190 patients in 2020, compared to 278 tests on 206 patients in 2019 (− 10% tests; − 8% children evaluated). A significant reduction was found in tests to diagnose growth hormone deficiency (GHD) (− 35%), while LHRH tests increased (+ 22%). A reduction of 30% in GHD diagnosis was observed. Central precocious puberty (CPP) diagnosis increased by 38% compared to 2019, mainly in females.

Conclusion

This study found a significant reduction of tests investigating GHD during COVID-19 pandemics. It also showed a clinically meaningful increase in cases of CPP in girls. These results suggest the need for families and pediatricians to monitor children’s growth during isolation and enlighten new perspectives towards conditions associated with lockdown restrictions as increased screen time, social isolation, and children’s anxiety as possible triggers of CPP.
Tolerance induction through non-avoidance to prevent persistent food allergy (TINA) in children and adults with peanut or tree nut allergy: rationale, study design and methods of a randomized controlled trial and observational cohort study
Authors: Trendelenburg Valérie , Dölle-Bierke Sabine , Unterleider Nathalie , Alexiou Aikaterina , Kalb Birgit , Meixner Lara , Heller Stephanie , Lau Susanne , Lee Young- Ae , Fauchère Florent , Braun Julian , Babina Magda , Altrichter Sabine , Birkner Till , Roll Stephanie , Dobbertin-Welsch Josefine , Worm Margitta , Beyer Kirsten
Published: March 2022

Background

Peanuts (PN) and tree nuts (TN) are among the most frequent elicitors of food allergy and can lead to life-threatening reactions. The current advice for allergic patients is to strictly avoid the offending food independently of their individual threshold level, whereas sensitized patients without allergic symptoms should frequently consume the food to avoid (re-)development of food allergy. The aim of this trial is to investigate (I) whether the consumption of low allergen amounts below the individual threshold may support natural tolerance development and (II) to what extent regular allergen consumption in sensitized but tolerant subjects prevents the (re-)development of PN or TN allergy.

Methods

The TINA trial consisting of (part I) a randomized, controlled, open, parallel group, single-center, superiority trial (RCT), and (part II) a prospective observational exploratory cohort study. Children and adults (age 1–67 years) with suspected or known primary PN and/or TN allergy will undergo an oral food challenge (OFC) to determine their clinical reactivity and individual threshold. In the RCT, 120 PN or TN allergic patients who tolerate ≥100 mg of food protein will be randomized (1:1 ratio) to consumption of products with low amounts of PN or TN on a regular basis or strict avoidance for 1 year. The consumption group will start with 1/100 of their individual threshold, increasing the protein amount to 1/50 and 1/10 after 4 and 8 months, respectively. The primary endpoint is the clinical tolerance to PN or TN after 1 year assessed by OFC. In the cohort study, 120 subjects sensitized to PN and/or TN but tolerant are advised to regularly consume the food and observed for 1 year. The primary endpoint is the maintenance of clinical tolerance to PN and/or TN after 1 year assessed by challenging with the former tolerated cumulative dose.

Discussion

This clinical trial will help to determine the impact of allergen consumption versus avoidance on natural tolerance development and whether the current dietary advice for PN or TN allergic patients with higher threshold levels is still valid.

Trial registration

German Clinical Trials Register; ID: DRKS00016764 (RCT), DRKS00020467 (cohort study). Registered on 15 January 2020, http://www.drks.de.