bluuebunny/crossref_metadata_2025 huggingface dataset:
Enumerating contributions of fentanyls and other factors to the unprecedented 2020 rise in opioid overdose deaths: model-based analysis
Authors: Stringfellow Erin J , Lim Tse Yang , DiGennaro Catherine , Hasgul Zeynep , Jalali Mohammad S
Published: March 2023

In 2020, the ongoing US opioid overdose crisis collided with the emerging COVID-19 pandemic. Opioid overdose deaths (OODs) rose an unprecedented 38%, due to a combination of COVID-19 disrupting services essential to people who use drugs, continued increases in fentanyls in the illicit drug supply, and other factors. How much did these factors contribute to increased OODs? We used a validated simulation model of the opioid overdose crisis, SOURCE, to estimate excess OODs in 2020 and the distribution of that excess attributable to various factors. Factors affecting OODs that could have been disrupted by COVID-19, and for which data were available, included opioid prescribing, naloxone distribution, and receipt of medications for opioid use disorder. We also accounted for fentanyls’ presence in the heroin supply. We estimated a total of 18,276 potential excess OODs, including 1,792 lives saved due to increases in buprenorphine receipt and naloxone distribution and decreases in opioid prescribing. Critically, growth in fentanyls drove 43% (7,879) of the excess OODs. A further 8% is attributable to first-ever declines in methadone maintenance treatment and extended-released injectable naltrexone treatment, most likely due to COVID-19-related disruptions. In all, 49% of potential excess OODs remain unexplained, at least some of which are likely due to additional COVID-19-related disruptions. While the confluence of various COVID-19-related factors could have been responsible for more than half of excess OODs, fentanyls continued to play a singular role in excess OODs, highlighting the urgency of mitigating their effects on overdoses.
Topological modularity of supermoonshine
Authors: Albert Jan , Kaidi Justin , Lin Ying-Hsuan
Published: March 2023

The theory of topological modular forms (TMF) predicts that elliptic genera of physical theories satisfy a certain divisibility property, determined by the theory’s gravitational anomaly. In this note we verify this prediction in Duncan’s supermoonshine module, as well as in tensor products and orbifolds thereof. Along the way we develop machinery for computing the elliptic genera of general alternating orbifolds and discuss the relation of this construction to the elusive “periodicity class” of TMF.
Referral Decision-Making and Care Continuity in Physical Therapist Practice
Authors: Peterson Seth , Heick John
Published: March 2023

Efficient referral pathways have held promise in improving clinical outcomes, raising patient satisfaction, and reducing costs. Referral decision-making presents a distinct challenge because it requires the consideration of such variables as technology, health-care systems, and local resources. However, best practices for generating a high-value referral and improving care continuity are rarely discussed in the context of physical therapist practice. With physical therapists in some states obtaining explicit imaging privileges and a renewed focus on the physical therapist’s role in primary care and patient management over the lifespan, it is time to focus on this underappreciated area of practice. This perspective discusses referral decision-making and provides recommendations for making a high-value referral and improving care continuity. Improving referral and care continuity has potential to enhance clinical outcomes and patient satisfaction and to reduce costs. This perspective explicitly defines and describes strategies to improve physical therapist decision-making about referral and care continuity to improve overall patient management.
Cognitive Remediation Works But How Should We Provide It? An Adaptive Randomized Controlled Trial of Delivery Methods Using a Patient Nominated Recovery Outcome in First-Episode Participants
Authors: Wykes Til , Stringer Dominic , Boadu Janette , Tinch-Taylor Rose , Csipke Emese , Cella Matteo , Pickles Andrew , McCrone Paul , Reeder Clare , Birchwood Max , Fowler David , Greenwood Kathryn , Johnson Sonia , Perez Jesus , Ritunnano Rosa , Thompson Andrew , Upthegrove Rachel , Wilson Jon , Kenny Alex , Isok Iris , Joyce Eileen M
Published: March 2023

Background and Hypothesis

Cognitive remediation (CR) benefits cognition and functioning in psychosis but we do not know the optimal level of therapist contact, so we evaluated the potential benefits of different CR modes.

Study Design

A multi-arm, multi-center, single-blinded, adaptive trial of therapist-supported CR. Participants from 11 NHS early intervention psychosis services were independently randomized to Independent, Group, One-to-One, or Treatment-as-usual (TAU). The primary outcome was functional recovery (Goal Attainment Scale [GAS]) at 15-weeks post randomization. Independent and TAU arms were closed after an interim analysis, and three informative contrasts tested (Group vs One-to-One, Independent vs TAU, Group + One-to-One vs TAU). Health economic analyses considered the cost per Quality Adjusted Life Year (QALY). All analyses used intention-to-treat principles.

Study Results

We analyzed 377 participants (65 Independent, 134 Group, 112 One-to-One, 66 TAU). GAS did not differ for Group vs One-to-One: Cohen’s d: 0.07, −0.25 to 0.40 95% CI, P = .655; Independent vs TAU: Cohen’s d: 0.07, −0.41 to 0.55 95% CI, P = .777. GAS and the cognitive score improved for Group + One-to-One vs TAU favoring CR (GAS: Cohen’s d: 0.57, 0.19–0.96 95% CI, P = .003; Cognitive score: Cohens d: 0.28, 0.07–0.48 95% CI, P = .008). The QALY costs were £4306 for Group vs TAU and £3170 for One-to-One vs TAU. Adverse events did not differ between treatment methods and no serious adverse events were related to treatment.

Conclusions

Both active therapist methods provided cost-effective treatment benefiting functional recovery in early psychosis and should be adopted within services. Some individuals benefited more than others so needs further investigation.

Trial registration

ISRCTN14678860 https://doi.org/10.1186/ISRCTN14678860Now closed.
Multivariate Associations Among White Matter, Neurocognition, and Social Cognition Across Individuals With Schizophrenia Spectrum Disorders and Healthy Controls
Authors: Calarco Navona , Oliver Lindsay D , Joseph Michael , Hawco Colin , Dickie Erin W , DeRosse Pamela , Gold James M , Foussias George , Argyelan Miklos , Malhotra Anil K , Buchanan Robert W , Voineskos Aristotle N
Published: March 2023

Background and Hypothesis

Neurocognitive and social cognitive abilities are important contributors to functional outcomes in schizophrenia spectrum disorders (SSDs). An unanswered question of considerable interest is whether neurocognitive and social cognitive deficits arise from overlapping or distinct white matter impairment(s).

Study Design

We sought to fill this gap, by harnessing a large sample of individuals from the multi-center Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) dataset, unique in its collection of advanced diffusion imaging and an extensive battery of cognitive assessments. We applied canonical correlation analysis to estimates of white matter microstructure, and cognitive performance, across people with and without an SSD.

Study Results

Our results established that white matter circuitry is dimensionally and strongly related to both neurocognition and social cognition, and that microstructure of the uncinate fasciculus and the rostral body of the corpus callosum may assume a “privileged role” subserving both. Further, we found that participant-wise estimates of white matter microstructure, weighted by cognitive performance, were largely consistent with participants’ categorical diagnosis, and predictive of (cross-sectional) functional outcomes.

Conclusions

The demonstrated strength of the relationship between white matter circuitry and neurocognition and social cognition underscores the potential for using relationships among these variables to identify biomarkers of functioning, with potential prognostic and therapeutic implications.
Open science–related policies in Europe
Authors: Moradi Sh , Abdi S
Published: March 2023

This study aims to review the open science (OS) policy documents, identify their subject areas, and distinguish the topics of OS support policies in seven European countries, providing a platform for practical cooperation between countries in science popularization. With a qualitative–inductive approach, all pertinent policy documents in OS were collected through documentary study, and thematic analysis was conducted to identify OS policies for each country. Finally, forty-six policy documents extracted up to December 2020 were thematically analyzed through a qualitative–inductive case study. All selected countries had developed OS policies, and these supportive policies were generally related to the three dimensions of ‘open input, open process, and open output’. In ‘open input’, recommendations for the performance of research data repositories, as well as management criteria, are considered. Most countries adopted ‘open output’ protectionist policies. Multiple policies in the ‘open process’ indicate the need for an appropriate OS platform.
Time to rest a hypothesis? Accumulating evidence that periodic leg movements during sleep are not increased in children with attention-deficit hyperactivity disorder (ADHD): results of a case–control study and a meta-analysis
Authors: Fulda Stephany , Miano Silvia
Published: March 2023

Study Objectives

To address the hypothesis that periodic leg movements during sleep (PLMS) are more frequent in children with attention-deficit hyperactivity disorder (ADHD) when compared with typically developing (TD) children. To that end, we analyzed PLMS in a recent case–control study and conducted a systematic review and meta-analysis of PLMS frequency in children with ADHD and TD children.

Methods

In our case–control study, we compared the PLMS frequency of 24 children with ADHD (mean age 11 years, 17 males) to that of 22 age-matched typically developing (TD) children (mean age 10 years, 12 males). A subsequent meta-analysis included 33 studies that described PLMS frequency in groups of children with ADHD and/or groups of TD children.

Results

The case–control study did not show any differences in the frequency of PLMS between children with ADHD and TD children, a result that was consistent across a range of different definitions of PLMS, which in turn had a significant and systematic effect on PLMS frequency. The meta-analysis compared the average PLMS indices and the proportion of children with elevated PLMS indices between children with ADHD and TD children and across a number of analyses did not find any meta-analytic results that supported the hypothesis that PLMS are more frequent in children with ADHD.

Conclusions

Our results suggest that PLMS are not more frequent in children with ADHD compared with TD children. A finding of frequent PLMS in a child with ADHD should therefore be considered a separate disorder and prompt specific diagnostic and therapeutic strategies.
Characterization of Intestinal Mesenchymal Stromal Cells From Patients With Inflammatory Bowel Disease for Autologous Cell Therapy
Authors: Anbazhagan Murugadas , Geem Duke , Venkateswaran Suresh , Pelia Ranjit , Kolachala Vasantha L , Dodd Anne , Maddipatla Sushma C , Cutler David J , Matthews Jason D , Chinnadurai Raghavan , Kugathasan Subra
Published: March 2023

Therapy with mesenchymal stromal cells (MSCs) has shown promise in inflammatory bowel disease—leveraging their immunosuppressive and regenerative properties. However, the potential immunogenic complications of allogenic MSCs sourced from different tissues raise concern. Thus, we assessed the fitness and functionality of autologous intestinal MSCs as a potential platform for cellular therapy. Mucosal biopsy-derived MSCs from Crohn’s disease (n = 11), ulcerative colitis (n = 12), and controls (n = 14) were analyzed by microscopy and flow cytometry for doubling-time, morphology, differentiation potential, and immunophenotype. Gene expression, cell-subtype composition, along with surface marker and secretome changes after IFN-γ priming were measured by bulk and single-cell RNA sequencing coupled with a 30-plex Luminex panel. MSCs expanded ex vivo demonstrate canonical MSC markers, similar growth kinetics, and tripotency regardless of the patient phenotype. Global transcription patterns were similar at baseline though inflammatory bowel disease (IBD) rectal MSCs showed changes in select immunomodulatory genes. IFN-γ priming resulted in upregulation of shared immunoregulatory genes (particularly in PD-1 signaling) and overrode the transcriptional differences observed at baseline. Furthermore, MSCs secrete key immunomodulatory molecules at baseline and in response to IFN-γ including CXCL10, CXCL9, and MCP-1. Overall, MSCs from IBD patients have normal transcriptional and immunomodulatory properties with therapeutic potential and can be sufficiently expanded.
Metabolic Rewiring and Stemness: A Critical Attribute of Pancreatic Cancer Progression
Authors: Ogunleye Ayoola O , Nimmakayala Rama Krishna , Batra Surinder K , Ponnusamy Moorthy P
Published: March 2023

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases with a poor 5-year survival rate. PDAC cells rely on various metabolic pathways to fuel their unlimited proliferation and metastasis. Reprogramming glucose, fatty acid, amino acid, and nucleic acid metabolisms contributes to PDAC cell growth. Cancer stem cells are the primary cell types that play a critical role in the progression and aggressiveness of PDAC. Emerging studies indicate that the cancer stem cells in PDAC tumors are heterogeneous and show specific metabolic dependencies. In addition, understanding specific metabolic signatures and factors that regulate these metabolic alterations in the cancer stem cells of PDAC paves the way for developing novel therapeutic strategies targeting CSCs. In this review, we discuss the current understanding of PDAC metabolism by specifically exploring the metabolic dependencies of cancer stem cells. We also review the current knowledge of targeting these metabolic factors that regulate CSC maintenance and PDAC progression.
Construction of a mini-RNA replicon inEscherichia coli
Authors: Kashiwagi Akiko , Yomo Tetsuya
Published: March 2023

How the ribonucleic acid (RNA) world transited to the deoxyribonucleic acid (DNA) world has remained controversial in evolutionary biology. At a certain time point in the transition from the RNA world to the DNA world, ‘RNA replicons’, in which RNAs produce proteins to replicate their coding RNA, and ‘DNA replicons’, in which DNAs produce RNA to synthesize proteins that replicate their coding DNA, can be assumed to coexist. The coexistent state of RNA replicons and DNA replicons is desired for experimental approaches to determine how the DNA world overtook the RNA world. We constructed a mini-RNA replicon in Escherichia coli. This mini-RNA replicon encoded the β subunit, one of the subunits of the Qβ replicase derived from the positive-sense single-stranded Qβ RNA phage and is replicated by the replicase in E. coli. To maintain the mini-RNA replicon persistently in E. coli cells, we employed a system of α complementation of LacZ that was dependent on the Qβ replicase, allowing the cells carrying the RNA replicon to grow in the lactose minimal medium selectively. The coexistent state of the mini-RNA replicon and DNA replicon (E. coli genome) was successively synthesized. The coexistent state can be used as a starting system to experimentally demonstrate the transition from the RNA–protein world to the DNA world, which will contribute to progress in the research field of the origin of life.
Effect of dietary cation-anion difference on dry matter intake, digestibility, body weight gain, blood parameters, and carcass traits in Zandi lambs
Authors: Khani M , Fattah A , Ebrahimi-Mahmoudabad S R , Joezy-Shekalgorabi S
Published: March 2023

The dietary cation-anion difference (DCAD) has gotten much attention recently; however, there is not much evidence on organic matter digestibility, blood parameters, dry matter intake, body weight, and carcass features of male sheep fed with different DCAD diets. The effects of dietary cation-anion difference (DCAD) on these traits in male lambs under the environmental high temperatures were investigated in this study. Forty male lambs (average body weight of 39 kg) were randomly assigned to one of five treatments with eight replicates. Lambs were fed diets with DCAD levels ranging from 150 (control group) to 300, 450, 600, and 750 mEq/kg dry matter. This study lasted 100 days and used a 21-day adaptation. The results showed that the control group had the highest dry matter intake, dry matter digestibility, and crude protein digestibility (p= 0.02). Also, the lowest amount of average body weight was observed in the control group (p= 0.01). The results showed the different DCAD levels affected the statistically significant in terms of live weight, carcass weight, length and width of muscle cross section, lung weight, spleen weight, and abdominal fat (p= 0.04). As well, the highest ruminal pH was observed in the control group (p= 0.4). The results of the blood glucose parameter showed that control group had a significant effect on the blood glucose level (p= 0.04). Furthermore, the highest abdominal fat weight was observed in the control group (p= 0.04). There was no statistically significant difference between other traits, including skin weight, head weight, leg weight, carcass length, liver weight, kidney weight, heart weight, testicle weight, tail weight, rumen weight, and lactation weight. In summary, increasing DCAD in the diet could improve the production and carcass quality in lambs under environmental high temperatures.
A model template approach for rapid evaluation and application of physiologically based pharmacokinetic models: extension to volatile organic compounds
Authors: Bernstein Amanda S , Prasad Bidya , Schlosser Paul M , Kapraun Dustin F
Published: March 2023

Chemical risk assessors use physiologically based pharmacokinetic (PBPK) models to perform dosimetric calculations, including extrapolations between exposure scenarios, species, and populations of interest. Assessors should complete a thorough quality assurance (QA) review to ensure biological accuracy and correct implementation prior to using these models. This process can be time-consuming, and we developed a PBPK model template that allows for faster, more efficient QA review. The model template consists of a single model “superstructure” with equations and logic commonly found in PBPK models, allowing users to implement a wide variety of chemical-specific PBPK models. QA review can be completed more quickly than for conventional PBPK model implementations because the general model equations have already been reviewed and only parameters describing chemical-specific model and exposure scenarios need review for any given model implementation. We have expanded a previous version of the PBPK model template by adding features commonly included in PBPK models for volatile organic compounds (VOCs). We included multiple options for representing concentrations in blood, describing metabolism, and modeling gas exchange processes to allow for inhalation exposures. We created PBPK model template implementations of published models for seven VOCs: dichloromethane, methanol, chloroform, styrene, vinyl chloride, trichloroethylene, and carbon tetrachloride. Simulations performed using our template implementations matched published simulation results to a high degree of accuracy (maximum observed percent error: 1%). Thus, the model template approach can now be applied to a broader class of chemical-specific PBPK models while continuing to bolster efficiency of QA processes that should be conducted prior to using models for risk assessment applications.
No-Test Medication Abortion: A Systematic Review
Authors: Shapiro Marit Pearlman , Dethier Divya , Kahili-Heede Melissa , Kaneshiro Bliss
Published: March 2023

The use of medication abortion has increased significantly in the past several years, in part due to the increased adoption of telemedicine during the COVID-19 pandemic. Several leading organizations have established recommendations for the practice of providing a medication abortion without a prior pelvic examination or ultrasonogram (no-test medication abortion). Evidence demonstrates that gestational age can be accurately measured with patient screening questions and the risk of ectopic pregnancy among women seeking medication abortion is very low. Given this paradigm shift in abortion access, increasing numbers of health care professionals worldwide have adopted these practices and published their results.

This systematic review aimed to summarize the efficacy and safety outcomes of medication abortion performed without prior pelvic examination or ultrasound. Ongoing and published clinical trials were identified, and randomized control trials and comparative cohort trials discussing the provision of no-test medication abortion were eligible. The primary study outcome was successful medication abortion, defined as complete abortion without the need for surgical management. Failure was thus defined as the need for surgical intervention to complete the abortion. Medication regimens, efficacy rates, complication rates, and adverse events were abstracted from eligible studies.

A total of 21 studies were included in this review, including cases performed in over 24 countries. Ultimately, 15 studies were sufficiently homogenous in terms of design and comparator to create aggregate data with summary statistics for the primary outcome. The overall efficacy rate of no-test medication abortion was found to be 96.4% (95% confidence interval [CI], 96.0–96.7) in the 10,693 patients included in this review. Among pregnancies at less than 70 days' gestation (n = 8166), the efficacy rate was 95.2% (95% CI, 94.7–95.7). The rate of surgical intervention was 4.4% (95% CI, 4.0–4.9), and at less than 70 days' gestation was 3.8% (95% CI, 3.3–4.3). The ectopic pregnancy rate was 0.06% (95% CI, 0.02–0.15), blood transfusion rate ranged from 0% to 0.7%, and there were no deaths reported.

The results of this systematic review encompassing data on 10,693 patients showed demonstrate that no-test medication abortion is likely effective and safe. The rates of surgical evacuation and complication were comparable with the rate among those undergoing medication abortion with pretreatment ultrasound, and significantly lower than the rates seen with unsafe methods of abortion.
Spontaneous Hemoperitoneum in Pregnancy and Endometriosis: A New Challenge in a Known Disease
Authors: Zilberman Sharon Nataly , Shiber Yair , Vaknin Zvi , Betser Moshe , Copel Laurian , Maymon Ron
Published: March 2023

Importance

Spontaneous hemoperitoneum in pregnancy (SHiP) is a rare life-threatening event previously associated with endometriosis. Although pregnancy is thought to improve the symptoms of endometriosis, abrupt intraperitoneal bleeding can occur, jeopardizing both maternal and fetal outcomes.

Objective

The aim of this study was to review the published information regarding SHiP pathophysiology, presentation, diagnosis, and management in a flowchart approach.

Evidence Acquisition

A descriptive review of published articles in the English-language was carried out.

Results

SHiP most commonly presents in the second half of pregnancy with a combination of abdominal pain, hypovolemia, a decline in hemoglobin level, and fetal distress. Nonspecific gastrointestinal symptoms are not uncommon. Surgical management is suitable in most scenarios and avoids complications such as recurrent bleeding and infected hematoma. Maternal outcome has improved greatly, whereas perinatal mortality remained unchanged. In addition to physical strain, SHiP was reported to have a psychosocial sequela.

Conclusions and Relevance

A high index of suspicion is required when patients present with acute abdominal pain and signs of hypovolemia. Early use of sonography contributes to narrowing down the diagnosis. Health care providers should be familiar with the SHiP diagnosis because early identification is crucial when attempting to safeguard maternal and fetal outcomes. Maternal and fetal requirements are often contradictory, creating a greater challenge in decision-making and treatment. A multidisciplinary team approach should coordinate the treatment, whenever a SHiP diagnosis is suspected.

Target Audience

Obstetricians and gynecologists, family physicians.

Learning Objectives

After completing this activity, the learner should be better able to identify SHiP symptoms and contributing factors; propose recommendations for diagnosis and differential diagnosis; and describe the treatment options, emphasizing multidisciplinary approach.
The Role of Lung Ultrasound in Systemic Sclerosis
Authors: Gomes Guerra Miguel , Machado Pinto Tânia , Águeda Ana , Rodrigues Joana , Marona José , Violante António , Oliveira Margarida
Published: March 2023

Background

In systemic sclerosis (SSc), high-resolution computed tomography (HRCT) of the chest is the standard criterion for the diagnosis of interstitial lung disease (ILD). However, recent evidence suggests that lung ultrasound (LUS) can also detect ILD, without radiation exposure. Thus, our goal was to perform a systematic review, aiming to clarify the role of LUS in the detection of ILD in SSc.

Methods

A systematic review was carried out in PubMed and EMBASE (PROSPERO register number CRD42022293132), to identify studies that compared LUS with HRCT in the detection of ILD in patients with SSc. Risk of bias was assessed with the QUADAS-2 () tool.

Results

Three hundred seventy-five publications were identified. After screening, 13 were included in the final analysis. No study presented high risk of bias. Lung ultrasound protocol was highly heterogeneous between authors, specifically concerning transducer, intercostal spaces evaluated, exclusion criteria, and definition of positive LUS. Most authors evaluated the presence of B-lines as a surrogate of ILD, with only 4 focusing on pleural changes. A positive correlation between LUS findings and ILD detected by HRCT was reported. Results also revealed high sensitivity (74.3%–100%) but variable specificity (16%–99%). Positive predictive value varied between 16% and 95.1%, and negative predictive value between 51.7% and 100%.

Conclusion

Lung ultrasound is sensitive in the detection of ILD, but specificity must be optimized. The value of pleural evaluation also requires further investigation. Moreover, a consensus is needed to define a uniform LUS protocol to implement in future investigations.
Glucagon-Like Peptide 1 Receptor Agonists in Patients With Inflammatory Arthritis or Psoriasis
Authors: Karacabeyli Derin , Lacaille Diane
Published: March 2023

Obesity is a proinflammatory state associated with increased disease severity in various types of inflammatory arthritis. Weight loss is associated with improved disease activity in certain forms of inflammatory arthritis such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We conducted a scoping review summarizing the literature evaluating the effect of glucagon-like peptide 1 (GLP-1) receptor agonists on weight and disease activity in patients with inflammatory arthritis or psoriasis. MEDLINE, PubMed, Scopus, and Embase were searched for publications evaluating the role of GLP-1 analogs in RA, PsA, psoriasis, axial spondyloarthritis, systemic lupus erythematosus, systemic sclerosis, gout, and calcium pyrophosphate deposition disease. Nineteen studies were included: 1 gout study, 5 RA studies (3 basic science, 1 case report, and 1 longitudinal cohort), and 13 psoriasis studies (2 basic science, 4 case reports, 2 combined basic science/clinical studies, 3 longitudinal cohorts, and 2 randomized controlled trials). No psoriasis study reported on PsA outcomes. Basic science experiments demonstrated weight-independent immunomodulatory effects of GLP-1 analogs through inhibition of the NF-κB pathway (via AMP-activated protein kinase phosphorylation in psoriasis and prevention of IκBα phosphorylation in RA). In RA, improved disease activity was reported. In psoriasis, 4 of 5 clinical studies demonstrated significant improvements in Psoriasis Area Severity Index and weight/body mass index with no major adverse events. Common limitations included small sample sizes, short follow-up periods, and lack of control groups. GLP-1 analogs safely cause weight loss and have potential weight-independent anti-inflammatory effects. Their role as an adjunct in patients with inflammatory arthritis and obesity or diabetes is understudied, warranting future research.
Genotype-Phenotype Associations of Children With Familial Mediterranean Fever in a Cohort Consisting of M694V Mutation and Implications for Colchicine-Resistant Disease
Authors: Kisaoglu Hakan , Baba Ozge , Kalyoncu Mukaddes
Published: March 2023

Objectives

The aim of this study was to investigate the clinical associations of the second allele mutations and the effect of genotype and presenting features on colchicine resistance in children with familial Mediterranean fever (FMF), carrying at least one M694V variant.

Methods

The medical records of the patients diagnosed with FMF, in whom at least one allele M694V mutation was detected, were reviewed. Patients were grouped according to the genotype as M694V homozygotes, compound heterozygote M694V with an exon 10 mutation, compound heterozygote M694V with a variant of unknown significance (VUS), and M694V heterozygotes. Disease severity was assessed with the International Severity Scoring System for FMF.

Results

Among the 141 patients included, homozygote M694V (43.3%) was the most frequent MEFV genotype. Clinical manifestations of FMF at diagnosis were not significantly different according to genotypic alterations except homozygote M694V. Besides, homozygous M694V was associated with a more severe disease, with more frequent comorbidities and colchicine-resistant disease. A lower disease severity score was observed in compound heterozygotes with VUS than in M694V heterozygotes (median 1 vs 2, p = 0.006). Regression analysis revealed that homozygous M694V, arthritis, and frequency of attacks were associated with an increased risk of colchicine-resistant disease.

Conclusions

Clinical manifestations of FMF at diagnosis with a M694V allele were predominantly influenced by the M694V rather than the second allele mutations. Although homozygous M694V was associated with the most severe form, the presence of compound heterozygosity with a VUS did not affect disease severity or clinical features. Homozygous M694V confers the highest risk of colchicine-resistant disease.
CIRC_0012535 CONTRIBUTES TO LIPOPOLYSACCHARIDE-INDUCED FETAL LUNG FIBROBLAST APOPTOSIS AND INFLAMMATION TO REGULATE INFANTILE PNEUMONIA DEVELOPMENT BY MODULATING THE MIR-338-3P/IL6R SIGNALING
Authors: Fang Xing , Mei Wenjing , Zeng Rihua , Zou Li , Zeng Xuefei , Tang Shanghong
Published: March 2023

Background: Infantile pneumonia is a respiratory infection disease, seriously threatening the life of neonatal patients. Circular RNA (circRNA) dysregulation is reported to be involved in pneumonia pathogenesis. Circ_0012535 was previously displayed to be upregulated in blood samples of patients with community-acquired pneumonia. However, circ_0012535’s role in this disorder remains unclear. We thus aim to unveil the functions of circ_0012535 in infantile pneumonia. Methods: Fetal lung fibroblasts (WI38) treated with LPS were used as pneumonia cell models. Expression analysis for circ_0012535, miR-338-3p and IL6R was performed using quantitative real-time polymerase chain reaction. Cell counting kit 88), 5-ethynyl-2′-deoxyuridine, and flow cytometry assays were implemented for cell function detection. The release of inflammatory factors, and superoxide dismutase activity and malonaldehyde content were ascertained using commercial kits. The putative binding between miR-338-3p and circ_0012535 or IL6R was validated by dual-luciferase analysis, RIP analysis, and pull-down analysis. Results: Circ_0012535 was highly expressed in LPS-treated WI38 cells. Knockdown of circ_0012535 recovered LPS-inhibited cell viability and proliferation and attenuated LPS-induced cell apoptosis, cell cycle arrest, inflammation, and oxidative stress. Circ_0012535 bound to miR-338-3p and negatively regulated miR-338-3p expression. Inhibition of miR-338-3p reversed the role of circ_0012535 knockdown, thereby recovering LPS-induced WI38 cell apoptosis and inflammation. MiR-338-3p bound to IL6R 3′UTR, and circ_0012535 shared miR-338-3p binding site with IL6R. IL6R overexpression reversed the role of miR-338-3p, thereby recovering LPS-induced WI38 cell apoptosis and inflammation. Conclusion: Circ_0012535 supported LPS-induced WI38 cell apoptosis and inflammation to promote the progression of infantile pneumonia, and circ_0012535 functioned partly by targeting the miR-338-3p/IL6R signaling.
Characteristics and Predictors of Patients with Sepsis who are Candidates for Minimally Invasive Approach Outside of Intensive Care Unit
Authors: Wahab Abdul , Smith Ryan J. , Lal Amos , Flurin Laure , Malinchoc Michael , Dong Yue , Gajic Ognjen
Published: March 2023

Objective

To identify and describe characteristics of patients with sepsis who could be treated with minimally invasive sepsis (MIS) approach without ICU admission, and to develop a prediction model to select candidates for MIS approach.

Methods

A secondary analysis of the electronic database of patients with sepsis at Mayo Clinic, Rochester, MN. Candidates for the MIS approach were adults with septic shock and < 48 hours of ICU stay, who did not require advanced respiratory support and were alive at hospital discharge. Comparison group consisted of septic shock patients with an ICU stay of >48 hours without advanced respiratory support at the time of ICU admission.

Results

Out of 1795 MICU admissions, 106 patients (6 %) met MIS approach criteria. Predictive variables (age > 65 years, oxygen flow >4 L/min, temperature < 37 °C, creatinine >1.6 mg/dL, lactate >3 mmol/L, white blood cells >15 x 109/L, heart rate > 100 beats/min, and respiration rate > 25 breaths/min) selected through logistic regression were translated into an 8-point score. Model discrimination yielded ROC: AUC of 79 % and was well fitted (Hosmer-Lemeshow p = 0.94) and calibrated. MIS score cut-off of 3 resulted in a model OR of 0.15 (95% CI: 0.08 – 0.28) and a negative predictive value of 91% (95% CI: 88.69- 92.92).

Conclusion

This study identifies a subset of low-risk septic shock patients that can potentially be managed outside the ICU. Once validated in an independent, prospective sample our prediction model can be used to identify candidates for MIS approach.
Changes in the urine proteome after massage in healthy people
Authors: Yijin Bao , Xuanzhen Pan , Youhe Gao
Published: March 2023

This study aimed to explore the effect of massage on the urine proteome of healthy people. In this study, participants underwent 1-hour whole body massage. Urine samples were collected at 0, 2, and 24h after the massage and urine proteins were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Compared with the control (before massage), 41 differential proteins were identified in the group 2h after the massage, the random mean number of differentially produced proteins was 11 with 73% confidence, and the biological process of protein enrichment was catecholamine biosynthesis, which was related to the promotion of metabolism and the regulation of neural activities. While 29 differential proteins were identified in the group 24h after the massage, the random average number of differential proteins produced was 10, with the confidence of the difference decreased to 65%, and the effective biological process could not be enriched at this time. The results suggested that the difference in urine protein was greater at 2h after the massage and gradually decreased at 24h after the massage. The proteome of urine may reflect changes in the body following minor massage stimuli, providing a potential way to evaluate the effects of massage therapy.
SARS-CoV-2 post-vaccine surveillance studies in Australian children and adults with cancer: SerOzNET Statistical Analysis Plan
Authors: Body Amy , Martin Catherine , Busija Lucy , Lal Luxi , Ahern Elizabeth , MacIntyre Raina C , Segelov Eva
Published: March 2023

COVID-19 disease is associated with higher morbidity and mortality in cancer patients. Our study aimed to characterize the optimal strategy to improve vaccine induced protection against COVID-19 in children and adolescents with cancer. Results from The SerOzNET study will contribute comprehensive data on serology, cellular immune correlates from functional T-cell assays, quality of life data, and associated toxicity in relation to COVID-19 vaccination in children and adults with cancer.

In this plan, we describe the statistics that will be used to report results of the SerOzNET study. SerOzNET examines COVID-19 vaccine response in children and adolescents with cancer.

We have no conflicts of interest to disclose.
Disease modeling and pharmacological rescue of autosomal dominant Retinitis Pigmentosa associated withRHOcopy number variation
Authors: Kandoi Sangeetha , Martinez Cassandra , Chen Kevin Xu , Reddy L Vinod K. , Mehine Miika , Mansfield Brian C. , Duncan Jacque L. , Lamba Deepak A.
Published: March 2023

Retinitis pigmentosa (RP), a heterogenous group of inherited retinal disorder causes slow progressive vision loss with no effective treatments available. Mutations in the rhodopsin gene (RHO), account for ∼25% cases of autosomal dominant RP (adRP). In this study, we describe the disease characteristics of the first ever reported mono-allelic copy number variation (CNV) inRHOas a novel cause of adRP. We (1) show advanced retinal degeneration in a male patient (60-70 year old) harboring four transcriptionally active intact copies of rhodopsin, (2) recapitulated the clinical phenotypes using retinal organoids, and (3) assessed the utilization of a small molecule, Photoregulin3 (PR3), as a clinically viable strategy to target and modify disease progression in RP patients associated withRHO-CNV. Patient retinal organoids showed photoreceptors dysgenesis, with rod photoreceptors displaying stunted outer segments with occasional elongated cilia-like projections (microscopy); increasedRHOmRNA expression (qRT-PCR and bulk RNA-sequencing); and elevated levels and mislocalization of rhodopsin protein (RHO) within the cell body of rod photoreceptors (western blotting and immunohistochemistry) over the extended (300-days) culture time period when compared against control organoids. Lastly, we utilized PR3 to targetNR2E3, an upstream regulator ofRHO, to alterRHOexpression and observed a partial rescue of RHO protein localization from the cell body to the inner/outer segments of rod photoreceptors in patient organoids. These results provide a proof-of-principle for personalized medicine and suggest thatRHOexpression requires precise control. Taken together, this study supports the clinical data indicating that adRP due toRHO-CNV develops due protein overexpression overloading the photoreceptor post-translational modification machinery.
Synapse-specific trapping of Syntaxin1a into nanoclusters by the general anesthetic isoflurane
Authors: Hines Adam D. , Anggono Victor , Bademosi Adekunle T. , van Swinderen Bruno
Published: March 2023

General anesthetics disrupt brain network dynamics through multiple pathways, predominately through post-synaptic potentiation of GABAAR and pre-synaptic inhibition of neuroexocytosis. Common clinical general anesthetic drugs, such as propofol and isoflurane, have been shown to interact and interfere with a core component of the exocytic release machinery, Syntaxin1A, to cause impaired neurotransmitter release. Recent in vitro studies however suggest that these drugs to not affect all synapse subtypes equally. We investigated the role of Syntaxin1A in multiple neurotransmitter systems under isoflurane general anesthesia in the adultDrosophilabrain using live-cell super resolution microscopy and optogenetic readouts of exocytosis. We found that effects of isoflurane anesthesia were neuron specific and only impaired Syntaxin1A activity in excitatory neurons at cholinergic synapses, but not inhibitory GABAergic or glutamatergic neurons. These results indicate that general anesthetics could work by producing successive bouts of inhibition across the brain, by reducing neuroexocytosis from excitatory neurons specifically as well as silencing arousal systems through GABAAR potentiation.
A dynamic bactofilin cytoskeleton cooperates with an M23 endopeptidase to control bacterial morphogenesis
Authors: Pöhl Sebastian , Osorio-Valeriano Manuel , Cserti Emöke , Harberding Jannik , Hernández-Tamayo Rogelio , Biboy Jacob , Sobetzko Patrick , Vollmer Waldemar , Graumann Peter L. , Thanbichler Martin
Published: March 2023

Bactofilins have emerged as a widespread family of cytoskeletal proteins with important roles in bacterial morphogenesis, but their precise mode of action is still incompletely understood. In this study, we identify the bactofilin cytoskeleton as a key regulator of cell growth in the stalked budding alphaproteobacteriumHyphomonas neptunium. We show that, in this species, bactofilin polymers localize dynamically to the stalk base and the bud neck, with their absence leading to unconstrained growth of the stalk and bud compartments, indicating a central role in the spatial regulation of cell wall biosynthesis. Database searches reveal that in a range of different species bactofilin genes are clustered with genes for cell wall hydrolases of the M23 peptidase family, suggesting a functional connection between these two types of proteins. In support of this notion, we find that theH. neptuniumM23 peptidase homolog LmdC interacts directly with bactofilinin vitroand is required for proper cell shapein vivo. Complementary studies in the spiral-shaped alphaproteobacteriumRhodospirillum rubrumagain reveal a close association of its bactofilin and LmdC homologs, which co-localize at the inner curve of the cell, modulating the degree of cell curvature. Collectively, these findings demonstrate that bactofilins and M23 peptidases form a conserved functional module that promotes local changes in the mode of cell wall biosynthesis, thereby driving cell shape determination in morphologically complex bacteria.
Global transcriptional analysis ofGeobacter sulfurreducens gsu1771mutant biofilm grown on two different support structures
Authors: Jaramillo-Rodríguez Juan B. , Vega-Alvarado Leticia , Rodríguez-Torres Luis M. , Huerta-Miranda Guillermo A. , Hernández-Eligio Alberto , Juarez Katy
Published: March 2023

Electroactive biofilms formation by the metal-reducing bacteriumGeobacter sulfurreducensis a crucial for bioelectricity generation and bioremediation. The transcriptional regulator GSU1771 controls the expression of essential genes involved in electron transfer and biofilm formation inG. sulfurreducens, with GSU1771-deficient producing thicker and more electroactive biofilms. Here, RNA-seq analyses were conducted to compare the global gene expression patterns of wild-type and Δgsu1771mutant biofilms grown on non-conductive (glass) and conductive (graphite electrode) materials. The Δgsu1771biofilm grown on the glass surface exhibited 467 differentially expressed (DE) genes (167 upregulated and 300 downregulated) versus the wild-type biofilm. In contrast, the Δgsu1771biofilm grown on the graphite electrode exhibited 119 DE genes (79 upregulated and 40 downregulated) versus the wild-type biofilm. Among these DE genes, 67 were also differentially expressed in the Δgsu1771biofilm grown on glass (56 with the same regulation and 11 exhibiting counter-regulation). Among the upregulated genes in the Δgsu1771biofilms, we identified potential target genes involved in exopolysaccharide synthesis (gsu1961-63,gsu1959,gsu1972-73,gsu1976-77). RT-qPCR analyses were then conducted to confirm the differential expression of a selection of genes of interest. DNA-protein binding assays demonstrated the direct binding of the GSU1771 regulator to the promoter region ofpgcA,pulF,relA, andgsu3356. Furthermore, heme-staining and western blotting revealed an increase inc-type cytochromes including OmcS and OmcZ in Δgsu1771biofilms. Collectively, our findings demonstrated that GSU1771 is a global regulator that controls extracellular electron transfer and exopolysaccharide synthesis inG. sulfurreducens, which is crucial for electroconductive biofilm development.

Importance

Biofilm formation is a multi-stage process that is finely coordinated by signal transduction and complex gene regulation mechanisms. Given the importance of biofilms and their biotechnological applications, understanding these processes inG. sulfurreducensis of great significance. Here, we studied the transcriptional profile of the Δgsu1771strain biofilms formed on two different supporting materials: (1) glass, a non-conductive surface and (2) a graphite electrode-based microbial fuel cell (MFC), which enabled us to assess the transcriptional responses of this strain during current production. By analyzing these two conditions, our study elucidated genes of interest that could be essential for biofilm production and extracellular electron transfer (EET) and provides new insights into the mechanisms that control these complex processes inG. sulfurreducens.
Regression calibration of self-reported mobile phone use to optimize quantitative risk estimation in the COSMOS study
Authors: Reedijk Marije , Portengen Lützen , Auvinen Anssi , Kojo Katja , Heinävaara Sirpa , Feychting Maria , Tettamanti Giorgio , Hillert Lena , Elliott Paul , Toledano Mireille B , Smith Rachel B , Heller Joël , Schüz Joachim , Deltour Isabelle , Poulsen Aslak Harbo , Johansen Christoffer , Verheij Robert , Peeters Petra , Rookus Matti , Traini Eugenio , Huss Anke , Kromhout Hans , Vermeulen Roel ,   COSMOS Study Group
Published: March 2023

The Cohort Study of Mobile Phone Use and Health (COSMOS) study has repeatedly collected both self-reported and operator-recorded data on mobile phone use. Assessing health effects using self-reported information only is prone to measurement error, but operator data were available prospectively for only part of the study population and did not cover past mobile phone use. To optimize the available data and reduce bias, we evaluated different statistical approaches for constructing mobile phone exposure histories within COSMOS. We evaluated and compared the performance of complete case-analysis, different regression calibration methods, and multiple imputation in a simulation study with a binary health outcome. We used self-reported and operator-recorded mobile phone call data collected at baseline (2007-2012) from participants in Denmark, Finland, the Netherlands, Sweden, and the UK. Parameter estimates obtained using regression calibration methods were associated with less bias and lower mean squared error than those obtained with complete-case analysis or multiple-imputation. Our simulation study showed that regression calibration methods resulted in more accurate estimation of the relation between mobile phone use and health outcomes, by combining self-reported data with objective operator- recorded data available for a subset of the participants.