bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review
Authors: Daou Karim N. , Barhoumi Abir , Bassyouni Amina , Karam Pascale E.
Published: August 2021

Background: Hereditary tyrosinemia type 1 is a rare genetic disorder leading to liver cirrhosis and hepatocellular carcinoma. Few decades ago, dietary measures and ultimately liver transplant constituted the only treatment modalities. Nowadays, early diagnosis and therapy with nitisinone can reverse the clinical picture. In developing countries, diagnostic and therapeutic challenges may affect the outcome of this disease. The choice of the treatment modality may depend on the economic status of each country. Few reports on the long-term outcome of hereditary tyrosinemia type 1 are available from developing and Arab countries.

Methods: A retrospective study of charts of Lebanese patients diagnosed with tyrosinemia type 1 and followed, at the American University of Beirut, during a 12-year period was performed. Clinical presentation and liver biochemical profile at diagnosis were analyzed, along with therapeutic modalities and long-term outcome.

Results: Twenty-two children were diagnosed and followed during the study period. Median age at diagnosis was 7 months (range: one day to 35 months). Most of the patients presented with hepatomegaly and jaundice. Four patients were referred for atypical presentations with developmental delay and seizures, secondary to undiagnosed hypoglycemia episodes. Around half of the patients presented with failure to thrive. Transaminitis, cholestasis and increased α-fetoprotein level were variably present at diagnosis (36% to 50%). All patients had elevated plasma tyrosine and urinary succinylacetone levels. Genetic testing was performed in 9%. Only one third could be treated with nitisinone. Liver transplant was electively performed in 9% of cases, to overcome the long-term cost of nitisinone. One third of the patients died between the age of 1 month and 11 years. Surviving patients are still candidates for liver transplant.

Conclusion: Our experience reflects the challenges of diagnosis and treatment of hereditary tyrosinemia type 1 in a developing country. In the absence of specific neonatal screening, early diagnosis relies mostly on the clinical awareness of the physician. Long-term nitisinone use may be deterred by its high cost and liver transplantation carries risks of surgical complications. New, effective, and less expensive treatments are needed, especially for developing countries.
Case Report: Is Pneumoperitoneum the Only Indication for Surgery in Necrotizing Enterocolitis?
Authors: Wei Ying , Zhu Yanhong , Luo Xiaoping , Chen Ling , Hu Xiaolin
Published: August 2021

Objective: This study aims to explore whether pneumoperitoneum is the only surgical indication for neonates with necrotizing enterocolitis (NEC) and to analyze when early surgical intervention should be considered.

Methods: A retrospective case series study was conducted including six neonates with stage 2a−2b NEC who received surgeries without absolute indication but with failed conservative treatment. In the meantime, seven infants who received surgery due to pneumoperitoneum and 32 infants treated with conservative treatment were also included for comparison.

Results: Our results indicated that the six infants who received surgical treatment without pneumoperitoneum had a better prognosis compared to the seven infants who underwent surgical treatment after the onset of pneumoperitoneum. None of the infants who received early surgical treatment developed short bowel syndrome or neurodevelopmental impairment, while four out of six infants exhibited growth retardation. On the other hand, a total of five out of the seven infants who received surgical treatment after pneumoperitoneum forfeited further treatment, two developed short bowel syndrome, and one experienced neurodevelopmental impairment. Lower gestational age and birth weight, fetal growth restriction (FGR), perinatal asphyxia, postnatal steroid and vascular active drug use, blood transfusion, and hemodynamic significant patent ductus arteriosus were identified as risk factors associated with surgical repair for infants with NEC. In a laboratory test, infants who needed surgeries had a lower platelet count and a higher C-reactive protein value.

Conclusion: Aggressive surgical treatment should be considered in infants with severe necrotizing enterocolitis before the onset of pneumoperitoneum. Lower gestational age and birth weight, FGR, perinatal asphyxia, postnatal steroid and vascular active drug use, blood transfusion, and hsPDA may be associated with surgical repair for infants with NEC.
Risk of Fracture During Androgen Deprivation Therapy Among Patients With Prostate Cancer: A Systematic Review and Meta-Analysis of Cohort Studies
Authors: Wu Cheng Chih , Chen Po Yen , Wang Shih Wei , Tsai Meng Hsuan , Wang Yu Chin Lily , Tai Ching Ling , Luo Hao Lun , Wang Hung-Jen , Chen Chung Yu
Published: August 2021

Background: Androgen deprivation therapy (ADT) suppresses the production of androgen, and ADT is broadly used for intermediate or higher risk disease including advanced and metastatic cancer. ADT is associated with numerous adverse effects derived from the pharmacological properties. Previous meta-analysis on fracture risk among ADT users possessed limited data without further subgroup analysis. Risk estimation of updated real-world evidence on ADT-related fracture remains unknown.

Objectives: To assess the risk of fracture and fracture requiring hospitalization associated with ADT among prostate cancer population on different disease conditions, treatment regimen, dosage level, fracture sites.

Methods: The Cochrane Library, PubMed, and Embase databases were systematically screened for eligible cohort studies published from inception to March 2020. Two authors independently reviewed all the included studies. The risks of any fracture and of fracture requiring hospitalization were assessed using a random-effects model, following by leave-one-out, stratified, and sensitivity analyses. The Grading of Recommendations Assessments, Development and Evaluations (GRADE) system was used to grade the certainty of evidence.

Results: Sixteen eligible studies were included, and total population was 519,168 men. ADT use is associated with increasing fracture risk (OR, 1.39; 95% CI, 1.26–1.52) and fracture requiring hospitalization (OR, 1.55; 95% CI, 1.29–1.88). Stratified analysis revealed that high-dose ADT results in an elevated risk of fracture with little statistical heterogeneity, whereas sensitivity analysis restricted to adjust for additional factors indicated increased fracture risks for patients with unknown stage prostate cancer or with no restriction on age with minimal heterogeneity. The GRADE level of evidence was moderate for any fracture and low for fracture requiring hospitalization.

Conclusion: Cumulative evidence supports the association of elevated fracture risk with ADT among patients with prostate cancer, including those with different disease conditions, treatment regimens, dose levels, and fracture sites. Further prospective trials with intact information on potential risk factors on fracture under ADT use are warranted to identify the risky population.
Efficacy and Safety of Qinghao Biejia Decoction in the Treatment of Systemic Lupus Erythematosus: A Systematic Review and Meta-Analysis
Authors: Li Xiaobo , He Zhouqing , Ru Li , Yuan Yueming , Yuan Zheng , Chen Pengfei , Xu Zhiyong , Wang Qi , Song Jianping , Xu Qin
Published: August 2021

Objective: This meta-analysis aimed to systematically assess the therapeutic efficacy and safety of Qinghao Biejia decoction combined with conventional chemical medicine in patients with systemic lupus erythematosus (SLE), and to provide reference for clinical medication.

Methods: Multiple databases were retrieved by computer for randomized controlled trials (RCTs) of treating SLE with Qinghao Biejia decoction combining chemical medicine, from the establishment of the database to January 2021. Study screening, data collection, and quality assessment were performed independently by two reviewers. RevMan 5.4 and Stata 15.1 software were used for Meta-analysis.

Results: Nine eligible studies, involving 655 SLE participants, were included. Meta-analysis showed that the additional use of Qinghao Biejia decoction superior to chemical medicine alone in people with SLE in improving the overall response rate (RR = 1.30, 95% CI [1.19, 1.41], p < 0.00001, heterogeneity p = 0.61, I2 = 0%), and can decrease SLE Disease Activity Index (SLEDAI) and TCM symptom scores, improve immunological indexes (C3, C4, IgG, IgA, IFN-γ, IL-4, Th1/Th2), reduce the occurrence of adverse events in treatment (P ≤ 0.05).

Conclusion: Based on this meta-analysis, the additional use of Qinghao Biejia decoction has more advantages in the treatment of SLE than conventional chemical medication alone, which could enhance the efficacy and reduce adverse reactions, and is worthy of clinical promotion. However, more and higher quality RCTs are still need to confirm our findings.
Heart Muscle Microphysiological System for Cardiac Liability Prediction of Repurposed COVID-19 Therapeutics
Authors: Charrez Bérénice , Charwat Verena , Siemons Brian A. , Goswami Ishan , Sakolish Courtney , Luo Yu-Syuan , Finsberg Henrik , Edwards Andrew G. , Miller Evan W. , Rusyn Ivan , Healy Kevin E.
Published: August 2021

Despite global efforts, it took 7 months between the proclamation of global SARS-CoV-2 pandemic and the first FDA-approved treatment for COVID-19. During this timeframe, clinicians focused their efforts on repurposing drugs, such as hydroxychloroquine (HCQ) or azithromycin (AZM) to treat hospitalized COVID-19 patients. While clinical trials are time-consuming, the exponential increase in hospitalizations compelled the FDA to grant an emergency use authorization for HCQ and AZM as treatment for COVID-19, although there was limited evidence of their combined efficacy and safety. The authorization was revoked 4 months later, giving rise to controversial political and scientific debates illustrating important challenges such as premature authorization of potentially ineffective or unsafe therapeutics, while diverting resources from screening of effective drugs. Here we report on a preclinical drug screening platform, a cardiac microphysiological system (MPS), to rapidly identify clinically relevant cardiac liabilities associated with HCQ and AZM. The cardiac MPS is a microfabricated fluidic system in which cardiomyocytes derived from human induced pluripotent stem cells self-arrange into a uniaxially beating tissue. The drug response was measured using outputs that correlate with clinical measurements such as action potential duration (proxy for clinical QT interval) and drug-biomarker pairing. The cardiac MPS predicted clinical arrhythmias associated with QT prolongation and rhythm instabilities in tissues treated with HCQ. We found no change in QT interval upon acute exposure to AZM, while still observing a significant increase in arrhythmic events. These results suggest that this MPS can not only predict arrhythmias, but it can also identify arrhythmias even when QT prolongation is absent. When exposed to HCQ and AZM polytherapy, this MPS faithfully reflected clinical findings, in that the combination of drugs synergistically increased QT interval when compared to single drug exposure, while not worsening the overall frequency of arrhythmic events. The high content cardiac MPS can rapidly evaluate the cardiac safety of potential therapeutics, ultimately accelerating patients’ access to safe and effective treatments.
Exploring the Potential Molecular Mechanism of Scutellaria baicalensis Georgi in the Treatment of Gastric Cancer Based on Network Pharmacological Analysis and Molecular Docking Technology
Authors: Tu Yi , Wu Quanli , He Jiarui , Xu Jiasheng , Yu Shasha , Wang Qingfei , Cheng Yunqi , Yang Qijun , Xu Shan , Cao Yi
Published: August 2021

Objective: To explore the molecular mechanism of Scutellaria baicalensis Georgi in treating gastric cancer by network pharmacological analysis and molecular docking.

Methods: Taking Scutellaria baicalensis Georgi as the object, the active components and corresponding potential drug targets in Scutellaria baicalensis Georgi were obtained from the database of TCM Pharmacological System Analysis Platform (TCMSP). GeneCards/OMIM/DrugBank and other databases were used to collect gastric cancer-related genes, and the obtained genes were intersected with drug targets to obtain the target genes of Scutellaria baicalensis Georgi on gastric cancer. Furthermore, the interaction network of Scutellaria baicalensis Georgi-active ingredients-target-gastric cancer-related genes was constructed. Protein–protein interaction analysis and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on target genes. The PubChem website was used to screen the compounds corresponding to the target genes, and the target protein and 3D structure pdb format files were obtained from the PDB database. Finally, the molecular docking calculation was performed by the AutoDock Vina program. The in vivo cell experiments on the effect of Scutellaria baicalensis on proliferation and migration of gastric cancer cells were used to determine the therapeutic effect of Scutellaria baicalensis on gastric cancer, and the two genes ESR1 and FOS are the key targets of Scutellaria baicalensis on gastric cancer.

Results: A total of 10 gastric cancer-related target genes were screened out, and Scutellaria baicalensis Georgi contained 10 active compounds targeting 10 gene sites. There are 30 effective compounds in Scutellaria baicalensis Georgi targeted to treat gastric cancer, and there are 91 corresponding targeting gene sites, involving a total of 10 pathways. The results of molecular docking show that ESR1, FOS, and Scutellaria baicalensis Georgi have good binding free energy and docking fraction. The docking fraction of FOS is −4.200 and the binding free energy is −27.893 kcal/mol. The docking fraction of ESR1 is −5.833 and the binding free energy is −30.001 kcal/mol. The effect of Scutellaria baicalensis Georgi on gastric cancer was verified by in vitro cell experiments and Western blotting.

Conclusion:Scutellaria baicalensis Georgi can target and regulate multiple signal pathways by acting on ESR1 and FOS gene loci, thus having a potential therapeutic effect on gastric cancer.
Acid-Suppressive Drugs and Risk of Fracture in Children and Young Adults: A Meta-Analysis of Observational Studies
Authors: Li Jiangbi , Xie Xiaoping , Liu Weibing , Gu Feng , Zhang Ke , Su Zilong , Wen Qiangqiang , Sui Zhenjiang , Zhou Pengcheng , Yu Tiecheng
Published: August 2021

Background: Recent studies have suggested that proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs) may increase the risk of fracture. We performed a meta-analysis to evaluate the risk of fracture with PPIs and H2RAs use in children and young adults.

Methods: PubMed, EMBASE database, Cochrane Library, and Web of Science for relevant articles published before May 2021 were searched. We included all the observational studies reporting on the risk of fracture with acid-suppressive drug (PPIs and H2RAs) use in children and young adults. We calculated pooled risk ratios (RRs) for fracture using random-effects models and conducted subgroup analyses.

Results: A total of six studies were included in our analysis. Pooled analysis of PPIs use showed significant risk for fracture (RR = 1.23; 95% CI, 1.12–1.34; I2 = 79.3), but not significant for PPIs combined with H2RAs use (RR = 1.22; 95% CI, 0.94–1.60; I2 = 44.0%), as well as for H2RAs use alone (RR = 1.08; 95% CI, 0.94-1.24; I2 = 84.1%). Grouping of studies by region showed a significantly increased fracture risk with PPIs use in North America (RR = 1.24; 95% CI, 1.16–1.32; I2 =0.0%) than in Europe (RR = 1.23; 95% CI, 1.00–1.52; I2 = 94.6%) and Asia (RR = 1.10; 95% CI, 0.96–1.25). However, there was no significant association between the H2RAs use and the fracture risk in North America (RR = 1.08; 95% CI, 1.00–1.09; I2 = 0.0%). Moreover, PPIs use showed an increased risk of fracture in women (RR = 1.13; 95% CI, 1.07–1.19; I2 = 0.0%), whereas there was no significant association between the PPIs use and the risk of fracture in men (RR = 0.93; 95% CI, 0.66–1.31; I2 = 0.0%).

Conclusion: PPIs use alone could increase the risk of fracture in children and young adults, but not for PPIs combined with H2RAs use or H2RAs use alone. Clinicians should exercise caution when prescribing PPIs for patients.
An Integrated Metabolomic Study of Osteoporosis: Discovery and Quantification of Hyocholic Acids as Candidate Markers
Authors: Deng Dawei , Pan Chen , Wu Zeming , Sun Yujiao , Liu Chang , Xiang Hong , Yin Peiyuan , Shang Dong
Published: August 2021

Osteoporosis is becoming a highly prevalent disease in a large proportion of the global aged population. Serum metabolite markers may be important for the treatment and early prevention of osteoporosis. Serum samples from 32 osteoporosis and 32 controls were analyzed by untargeted metabolomics and lipidomic approaches performed on an ultra-high performance liquid chromatography and high-resolution mass spectrometry (UHPLC-HRMS) system. To find systemic disturbance of osteoporosis, weighted gene correlation network analysis (WGCNA) and statistical methods were employed for data-mining. Then, an in-depth targeted method was utilized to determine potential markers from the family of key metabolites. As a result, 1,241 metabolites were identified from untargeted methods and WGCNA indicated that lipids metabolism is deregulated and glycerol phospholipids, sphingolipids, fatty acids, and bile acids (BA) are majorly affected. As key metabolites of lipids metabolism, 66 bile acids were scanned and 49 compounds were quantified by a targeted method. Interestingly, hyocholic acids (HCA) were found to play essential roles during the occurrence of osteoporosis and may be potential markers. These metabolites may be new therapeutic or diagnosis targets for the screening or treatment of osteoporosis. Quantified measurement of potential markers also enables the establishment of diagnostic models for the following translational research in the clinic.
Eucommia ulmoides Polysaccharides Attenuate Rabbit Osteoarthritis by Regulating the Function of Macrophages
Authors: Sun Yaqiong , Huang Kui , Mo Linhai , Ahmad Akhlaq , Wang Dejia , Rong Zijie , Peng Honghui , Cai Honghua , Liu Guihua
Published: August 2021

Background and purpose:Eucommia ulmoides polysaccharides (EUP) can regulate the immunity of macrophages, but the functional status of macrophages is related to osteoarthritis and synovial inflammation. The purpose of this study is to explore whether EUP has the effect of inhibiting osteoarthritis and its possible mechanism.

Methods: MTT test was used to evaluate the appropriate concentration of EUP and real-time quantitative polymerase chain reaction (RT-qPCR) was conducted to detect the effect of EUP on gene expression in RAW 264.7 cells. The osteoarthritis model was constructed by the anterior cruciate ligament transection (ACLT) in the rabbits. These rabbits were divided into three groups, sham operation group, OA group, and EUP group. The changes in articular cartilage were detected by gross observation and histological staining, and Micro-CT tested subchondral bone. Finally, the changes of macrophages in synovial tissue were studied by immunohistochemistry.

Results: The results showed that EUP at the concentration of 50ug/mL and 100ug/mL were beneficial to the proliferation of macrophages. The qPCR results indicated that EUP inhibited the expression of inflammation-related genes IL-6, IL-18 and IL-1β, and promoted the expression of osteogenic and cartilage-related genes BMP-6, Arg-1 and transforming growth factor beta (TGF-β). The results of in vivo experiments suggested that the degree of destruction of articular cartilage in the EUP group was significantly reduced, and the Osteoarthritis Research Society International (OARSI) score was significantly reduced. Compared with the OA group, the subchondral cancellous bone density of the EUP group increased, the number and thickness of trabecular bone increased, and the separation of trabecular bone decreased. Synovial macrophage immunohistochemistry results manifested that EUP, on the one hand, reduced M1 polarized macrophages, on the other hand, accumulated M2 polarized macrophages.

Conclusion: EUP can promote articular cartilage repair and subchondral bone reconstruction. The regulation of the polarization state of macrophages may be one of its mechanisms to delay the progression of osteoarthritis.
The Role of Macrophages in Kidney Fibrosis
Authors: Wang Xiaoling , Chen Jianwei , Xu Jun , Xie Jun , Harris David C. H. , Zheng Guoping
Published: August 2021

The phenotypic heterogeneity and functional diversity of macrophages confer on them complexed roles in the development and progression of kidney diseases. After kidney injury, bone marrow-derived monocytes are rapidly recruited to the glomerulus and tubulointerstitium. They are activated and differentiated on site into pro-inflammatory M1 macrophages, which initiate Th1-type adaptive immune responses and damage normal tissues. In contrast, anti-inflammatory M2 macrophages induce Th2-type immune responses, secrete large amounts of TGF-β and anti-inflammatory cytokines, transform into αSMA+ myofibroblasts in injured kidney, inhibit immune responses, and promote wound healing and tissue fibrosis. Previous studies on the role of macrophages in kidney fibrosis were mainly focused on inflammation-associated injury and injury repair. Apart from macrophage-secreted profibrotic cytokines, such as TGF-β, evidence for a direct contribution of macrophages to kidney fibrosis is lacking. However, under inflammatory conditions, Wnt ligands are derived mainly from macrophages and Wnt signaling is central in the network of multiple profibrotic pathways. Largely underinvestigated are the direct contribution of macrophages to profibrotic signaling pathways, macrophage phenotypic heterogeneity and functional diversity in relation to kidney fibrosis, and on their cross-talk with other cells in profibrotic signaling networks that cause fibrosis. Here we aim to provide an overview on the roles of macrophage phenotypic and functional diversity in their contribution to pro-fibrotic signaling pathways, and on the therapeutic potential of targeting macrophages for the treatment of kidney fibrosis.
Transcriptomic Analysis of Salivary Glands of Ornithodoros brasiliensis Aragão, 1923, the Agent of a Neotropical Tick-Toxicosis Syndrome in Humans
Authors: Reck Jose , Webster Anelise , Dall’Agnol Bruno , Pienaar Ronel , de Castro Minique H. , Featherston Jonathan , Mans Ben J.
Published: August 2021

Tick salivary glands produce and secrete a variety of compounds that modulate host responses and ensure a successful blood meal. Despite great progress made in the identification of ticks salivary compounds in recent years, there is still a paucity of information concerning salivary molecules of Neotropical argasid ticks. Among this group of ticks, considering the number of human cases of parasitism, including severe syndromes and hospitalization, Ornithodoros brasiliensis can be considered one of the major Neotropical argasid species with impact in public health. Here, we describe the transcriptome analysis of O. brasiliensis salivary glands (ObSG). The transcriptome yielded ~14,957 putative contigs. A total of 368 contigs were attributed to secreted proteins (SP), which represent approximately 2.5% of transcripts but ~53% expression coverage transcripts per million. Lipocalins are the major protein family among the most expressed SP, accounting for ~16% of the secretory transcripts and 51% of secretory protein abundance. The most expressed transcript is an ortholog of TSGP4 (tick salivary gland protein 4), a lipocalin first identified in Ornithodoros kalahariensis that functions as a leukotriene C4 scavenger. A total of 55 lipocalin transcripts were identified in ObSG. Other transcripts potentially involved in tick-host interaction included as: basic/acid tail secretory proteins (second most abundant expressed group), serine protease inhibitors (including Kunitz inhibitors), 5' nucleotidases (tick apyrases), phospholipase A2, 7 disulfide bond domain, cystatins, and tick antimicrobial peptides. Another abundant group of proteins in ObSG is metalloproteases. Analysis of these major protein groups suggests that several duplication events after speciation were responsible for the abundance of redundant compounds in tick salivary glands. A full mitochondrial genome could be assembled from the transcriptome data and confirmed the close genetic identity of the tick strain sampled in the current study, to a tick strain previously implicated in tick toxicoses. This study provides novel information on the molecular composition of ObSG, a Brazilian endemic tick associated with several human cases of parasitism. These results could be helpful in the understanding of clinical findings observed in bitten patients, and also, could provide more information on the evolution of Neotropical argasids.
Mindsets and Neural Mechanisms of Automatic Reactions to Negative Feedback in Mathematics in Elementary School Students
Authors: Puusepp Ita , Linnavalli Tanja , Huuskonen Milla , Kukkonen Karoliina , Huotilainen Minna , Kujala Teija , Laine Sonja , Kuusisto Elina , Tirri Kirsi
Published: August 2021

Neuroscientific research regarding mindsets is so far scarce, especially among children. Moreover, even though research indicates the importance of domain specificity of mindsets, this has not yet been investigated in neuroscientific studies regarding implicit beliefs. The purpose of this study was to examine general intelligence and math ability mindsets and their relations to automatic reactions to negative feedback in mathematics in the Finnish elementary school context. For this, event-related potentials of 97 elementary school students were measured during the completion of an age-appropriate math task, where the participants received performance-relevant feedback throughout the task. Higher growth mindset was marginally associated with a larger P300 response and significantly associated with a smaller later peaking negative-going waveform. Moreover, with the domain-specific experimental setting, we found a higher growth mindset regarding math ability, but not general intelligence, to be associated with these brain responses elicited by negative feedback regarding errors in math. This suggests that it might be important to address domain-specific and even academic-domain-specific beliefs in addition to general mindsets in research and practice.
A Qualitative Approach to Understanding the Holistic Experience of Psychotherapy Among Clients
Authors: Seow Lee Seng Esmond , Sambasivam Rajeswari , Chang Sherilyn , Subramaniam Mythily , Lu Huixian Sharon , Assudani Hanita Ashok , Tan Chern-Yee Geoffrey , Vaingankar Janhavi Ajit
Published: August 2021

Background: The study of the experience of clients across multiple service encounters (or touchpoints) is important from the perspective of service research. Despite the availability of effective psychotherapies, there exists a significant gap in the optimal delivery of such interventions in the community. Therefore, the aim of this study was to explore the experience of psychotherapy among clients integrating the before–during–after service encounters using a qualitative approach.

Methods: A total of 15 clients of outpatient psychotherapy were interviewed, and data saturation was reached. The topics included pathways and reasons to seeking psychotherapy, aspects of the therapy process that have been helpful or unhelpful, and perceived change after receiving psychotherapy. Information was analyzed using the inductive thematic analysis method. Emergent themes pertaining to pre-psychotherapy encounters were mapped onto major components that were identified in Andersen's Health Service Utilization Model.

Results: Mental health stigma and the lack of understanding about psychotherapy were the predisposing factors that impeded service use while the preference for non-pharmacological intervention promoted its use. Enabling factors such as affordability and service availability were also of concern, along with perceived and evaluated needs. The attributes of therapists, application of techniques, and the resistance of the client were found to impact the therapeutic alliance. While the majority of the clients experienced positive change or had engaged in self-help strategies after receiving psychotherapy, some cited limited impact on the recovery of symptoms or problematic self-coping without the therapists.

Conclusion: This study proposes to expand on Andersen's Behavioral Model by including therapy-related factors so as to provide a more holistic understanding of the use of psychotherapy among the clients. More importantly, the study identified several barriers to access and negative experiences or outcomes, which should be addressed to promote uptake of the psychotherapy intervention.
Appetite for Destruction: A Psychometric Examination and Prevalence Estimation of Destructive Leadership in Sweden
Authors: Lundmark Robert , Stenling Andreas , von Thiele Schwarz Ulrica , Tafvelin Susanne
Published: August 2021

There is a growing awareness that destructive leadership has a significant negative impact on employe outcomes. However, little is known about the content and dimensionality of this multidimensional concept, and there are few reliable measures available for organizations and researchers to evaluate these behaviors. Based on a representative sample (N= 1132) of the Swedish workforce, the aim of this study is threefold: first, to examine the factor structure and validity of an easy-to-use multidimensional destructive leadership measure (Destrudo-L)in the general Swedish work context; second, to identify destructive leadership profiles using latent profile analysis (LPA), and determine in what way they are related to employe outcomes; third, to examine the prevalence of destructive leadership using population weights to estimate responses of a population total in the Swedish workforce (N= 3100282). Our analysis supported the structural validity of Destrudo-L, reflecting both a global factor and specific subdimensions. We identified seven unique destructive leadership profiles along a passive and active continuum of destructive leadership behaviors, with the active showing a less favorable relation to employe outcomes. Finally, we found that a substantial proportion of the Swedish workforce report being exposed to destructive leadership (36.4–43.5%, depending on method used). Active destructive leadership was more common in the public sector and passive destructive leadership in the private. Given the potentially severe effects and the commonness of these behaviors, we argue that organizations should work actively with strategies to identify and intervene, to prevent and to handle the manifestation of these harmful behaviors.
COVID-19-Fear Affects Current Safety Behavior Mediated by Neuroticism—Results of a Large Cross-Sectional Study in Germany
Authors: Fink Madeleine , Bäuerle Alexander , Schmidt Kira , Rheindorf Nadine , Musche Venja , Dinse Hannah , Moradian Sheila , Weismüller Benjamin , Schweda Adam , Teufel Martin , Skoda Eva-Maria
Published: August 2021

Objectives: Although many research studies concerning changes in personality and behavior in time of COVID-19 pandemic emerged, important questions still have not been answered. This study with a large sample aimed to give insights into the impact of personality on pandemic fear and behavior by investigating the Big Five traits, COVID-19-fear, and associated behavioral changes in a large German-speaking sample.

Methods: About 14,048 healthy respondents (65.5% female, 34.2% male, and 0.32% other gender/gender queer; range = 18–85 years, median age 35–44 years) participated in the survey during the COVID-19 pandemic. Two scales, “adherent” safety behavior (ASB, α = 0.857) and “dysfunctional” safety behavior (DSB, α = 0.876), three items each, measured pandemic-associated behavior. The Big Five Inventory-10 (BFI-10) tested personality traits.

Results: While ASB correlated negatively with extraversion (rho = −0.053, ≤ 0.001), the other four traits were positively associated, with the highest association for neuroticism (rho = 0.116, ≤ 0.001), whereas neuroticism showed a positive correlation (rho = 0.142, ≤ 0.001) with DSB, extraversion (rho = −0.042, ≤ 0.001), agreeableness (rho = −0.028, ≤ 0.001), and conscientiousness (rho = −0.025, ≤ 0.001) correlated negatively with it. Regression analyses showed a small extent of the effect of personality traits. Moreover, neuroticism mediated the association between COVID-19-fear and DSB (positive-directed).

Conclusions: Even though our results on correlations between personality, pandemic fear, and related behavior are in line with the existing literature studies, the analyses clearly show that the impact of personality traits, including neuroticism, on pandemic behavior is very small. Rather, pandemic fear has a much larger influence on the safety behavior mediated through neuroticism. Further studies should bear in mind that personality traits can not only have influencing effects but also mediating effects.
Temporal Behavioral Parameters of On-Going Gaze Encounters in a Virtual Environment
Authors: Hartz Arne , Guth Björn , Jording Mathis , Vogeley Kai , Schulte-Rüther Martin
Published: August 2021

To navigate the social world, humans heavily rely on gaze for non-verbal communication as it conveys information in a highly dynamic and complex, yet concise manner: For instance, humans utilize gaze effortlessly to direct and infer the attention of a possible interaction partner. Many traditional paradigms in social gaze research though rely on static ways of assessing gaze interaction, e.g., by using images or prerecorded videos as stimulus material. Emerging gaze contingent paradigms, in which algorithmically controlled virtual characters can respond flexibly to the gaze behavior of humans, provide high ecological validity. Ideally, these are based on models of human behavior which allow for precise, parameterized characterization of behavior, and should include variable interactive settings and different communicative states of the interacting agents. The present study provides a complete definition and empirical description of a behavioral parameter space of human gaze behavior in extended gaze encounters. To this end, we (i) modeled a shared 2D virtual environment on a computer screen in which a human could interact via gaze with an agent and simultaneously presented objects to create instances of joint attention and (ii) determined quantitatively the free model parameters (temporal and probabilistic) of behavior within this environment to provide a first complete, detailed description of the behavioral parameter space governing joint attention. This knowledge is essential to enable the modeling of interacting agents with a high degree of ecological validity, be it for cognitive studies or applications in human-robot interaction.
Effects of Ayahuasca on Personality: Results of Two Randomized, Placebo-Controlled Trials in Healthy Volunteers
Authors: Mendes Rocha Juliana , Rossi Giordano Novak , Osório Flávia L. , Bouso Saiz José Carlos , Silveira Gabriela De Oliveira , Yonamine Mauricio , Crevelin Eduardo José , Queiroz Maria Eugênia , Cecílio Hallak Jaime E. , Dos Santos Rafael Guimarães
Published: August 2021

Rationale: Previous studies with the serotonergic hallucinogens LSD and psilocybin showed that these drugs induced changes in personality traits, such as increases in Openness. However, results are inconsistent, and the effects of ayahuasca on personality were never investigated in a controlled trial.

Objectives: To assess the effects of ayahuasca on personality in two randomized, placebo-controlled trials in healthy volunteers.

Methods: Data from two parallel-group, randomized, placebo-controlled trials in healthy volunteers were included. In the first trial, 15 volunteers ingested ayahuasca or placebo, while in the second trial 15 volunteers received placebo+ayahuasca or cannabidiol (CBD)+ayahuasca. Personality was assessed with the NEO-Five Factor Inventory (NEO-FFI) at baseline and 21 days post-treatment.

Results: There were significant differences between groups in baseline Openness scores, but not on day 21. A significant increase in Openness scores was observed in the placebo + ayahuasca group in study 2. No other within-group differences were observed for any other domain.

Conclusions: Ayahuasca produced inconsistent effects on personality since it induced significant increase in Openness 21 days post-drug intake only in one of the trials. The absence of significant differences in the other ayahuasca groups could be due to small sample sizes and baseline differences among groups. The effects of ayahuasca and other serotonergic hallucinogens on personality should be further investigated in clinical samples.
Advancing Autism Research From Mice to Marmosets: Behavioral Development of Offspring Following Prenatal Maternal Immune Activation
Authors: Santana-Coelho Danielle , Layne-Colon Donna , Valdespino Roslyn , Ross Corinna C. , Tardif Suzette D. , O'Connor Jason C.
Published: August 2021

Understanding the mechanism(s) by which maternal immune activation (MIA) during gestation may disrupt neurodevelopment and increase the susceptibility for disorders such as autism spectrum disorder (ASD) or schizophrenia is a critical step in the development of better treatments and preventive measures. A large body of literature has investigated the pathophysiology of MIA in rodents. However, a translatability gap plagues pre-clinical research of complex behavioral/developmental diseases and those diseases requiring clinical diagnosis, such as ASD. While ideal for their genetic flexibility, vast reagent toolkit, and practicality, rodent models often lack important elements of ethological validity. Hence, our study aimed to develop and characterize the prenatal MIA model in marmosets. Here, we adapted the well-characterized murine maternal immune activation model. Pregnant dams were administered 5 mg/kg poly-L-lysine stabilized polyinosinic-polycytidylic acid (Poly ICLC) subcutaneously three times during gestation (gestational day 63, 65, and 67). Dams were allowed to deliver naturally with no further experimental treatments. After parturition, offspring were screened for general health and vigor, and individual assessment of communication development and social behavior was measured during neonatal or adolescent periods. Similar to rodent models, offspring subjected to MIA exhibited a disruption in patterns of communication during early development. Assessment of social behavior in a marmoset-modified 3-chamber test at 3 and 9 months of age revealed alterations in social behavior that, in some instances, was sex-dependent. Together, our data indicate that marmosets are an excellent non-human primate model for investigating the neurodevelopmental and behavioral consequences of exposure to prenatal challenges, like MIA. Additional studies are necessary to more completely characterize the effect of prenatal inflammation on marmoset development and explore therapeutic intervention strategies that may be applicable in a clinical setting.
Between No Help and Coercion: Toward Referral to Involuntary Psychiatric Admission. A Qualitative Interview Study of Stakeholders' Perspectives
Authors: Wormdahl Irene , Husum Tonje Lossius , Kjus Solveig Helene Høymork , Rugkåsa Jorun , Hatling Trond , Rise Marit B.
Published: August 2021

Objective: Paths toward referral to involuntary psychiatric admission mainly unfold in the contexts where people live their everyday lives. Modern health services are organized such that primary health care services are often those who provide long-term follow-up for people with severe mental illness and who serve as gatekeepers to involuntary admissions at the secondary care level. However, most efforts to reduce involuntary admissions have been directed toward the secondary health care level; interventions at the primary care level are sparse. To adapt effective measures for this care level, a better understanding is needed of the contextual characteristics surrounding individuals' paths ending in referrals for involuntary admission. This study aims to explore what characterizes such paths, based on the personal experiences of multiple stakeholders.

Method: One hundred and three participants from five Norwegian municipalities participated in individual interviews or focus groups. They included professionals from the primary and secondary care levels and people with lived experience of severe mental illness and/or involuntary admission and carers. Data was subject to constant comparison in inductive analysis inspired by grounded theory.

Results: Four main categories emerged from the analysis: deterioration and deprivation, difficult to get help, insufficient adaptation of services provided, and when things get acute. Combined, these illustrate typical characteristics of paths toward referral for involuntary psychiatric admission.

Conclusion: The results demonstrate the complexity of individuals' paths toward referral to involuntary psychiatric admission and underline the importance of comprehensive and individualized approaches to reduce involuntary admissions. Furthermore, the findings indicate a gap in current practice between the policies to reduce involuntary admissions and the provision of, access to, and adaptation of less restrictive services for adults with severe mental illness at risk of involuntary admissions. To address this gap, further research is needed on effective measures and interventions at the primary care level.
The Phenotypic Profile Associated With the FMR1 Premutation in Women: An Investigation of Clinical-Behavioral, Social-Cognitive, and Executive Abilities
Authors: Maltman Nell , Guilfoyle Janna , Nayar Kritika , Martin Gary E. , Winston Molly , Lau Joseph C. Y. , Bush Lauren , Patel Shivani , Lee Michelle , Sideris John , Hall Deborah A. , Zhou Lili , Sharp Kevin , Berry-Kravis Elizabeth , Losh Molly
Published: August 2021

The FMR1 gene in its premutation (PM) state has been linked to a range of clinical and subclinical phenotypes among FMR1 PM carriers, including some subclinical traits associated with autism spectrum disorder (ASD). This study attempted to further characterize the phenotypic profile associated with the FMR1 PM by studying a battery of assessments examining clinical-behavioral traits, social-cognitive, and executive abilities in women carrying the FMR1 PM, and associations with FMR1-related variability. Participants included 152 female FMR1 PM carriers and 75 female controls who were similar in age and IQ, and screened for neuromotor impairments or signs of fragile X-associated tremor/ataxia syndrome. The phenotypic battery included assessments of ASD-related personality and language (i.e., pragmatic) traits, symptoms of anxiety and depression, four different social-cognitive tasks that tapped the ability to read internal states and emotions based on different cues (e.g., facial expressions, biological motion, and complex social scenes), and a measure of executive function. Results revealed a complex phenotypic profile among the PM carrier group, where subtle differences were observed in pragmatic language, executive function, and social-cognitive tasks that involved evaluating basic emotions and trustworthiness. The PM carrier group also showed elevated rates of ASD-related personality traits. In contrast, PM carriers performed similarly to controls on social-cognitive tasks that involved reliance on faces and biological motion. The PM group did not differ from controls on self-reported depression or anxiety symptoms. Using latent profile analysis, we observed three distinct subgroups of PM carriers who varied considerably in their performance across tasks. Among PM carriers, CGG repeat length was a significant predictor of pragmatic language violations. Results suggest a nuanced phenotypic profile characterized by subtle differences in select clinical-behavioral, social-cognitive, and executive abilities associated with the FMR1 PM in women.
Age-Adjusted Associations Between Comorbidity and Outcomes of COVID-19: A Review of the Evidence From the Early Stages of the Pandemic
Authors: Mason Kate E. , Maudsley Gillian , McHale Philip , Pennington Andy , Day Jennifer , Barr Ben
Published: August 2021

Objectives:Early in the COVID-19 pandemic, people with underlying comorbidities were overrepresented in hospitalised cases of COVID-19, but the relationship between comorbidity and COVID-19 outcomes was complicated by potential confounding by age. This review therefore sought to characterise the international evidence base available in the early stages of the pandemic on the association between comorbidities and progression to severe disease, critical care, or death, after accounting for age, among hospitalised patients with COVID-19.

Methods:We conducted a rapid, comprehensive review of the literature (to 14 May 2020), to assess the international evidence on the age-adjusted association between comorbidities and severe COVID-19 progression or death, among hospitalised COVID-19 patients – the only population for whom studies were available at that time.

Results:After screening 1,100 studies, we identified 14 eligible for inclusion. Overall, evidence for obesity and cancer increasing risk of severe disease or death was most consistent. Most studies found that having at least one of obesity, diabetes mellitus, hypertension, heart disease, cancer, or chronic lung disease was significantly associated with worse outcomes following hospitalisation. Associations were more consistent for mortality than other outcomes. Increasing numbers of comorbidities and obesity both showed a dose-response relationship. Quality and reporting were suboptimal in these rapidly conducted studies, and there was a clear need for additional studies using population-based samples.

Conclusions:This review summarises the most robust evidence on this topic that was available in the first few months of the pandemic. It was clear at this early stage that COVID-19 would go on to exacerbate existing health inequalities unless actions were taken to reduce pre-existing vulnerabilities and target control measures to protect groups with chronic health conditions.