bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunotherapy as a treatment modality for mucosal melanoma of the head and neck: A systematic review
Authors: Wehbe Jad , Jaikaransingh Dominic , Walker Abigail
Published: August 2022

Introduction:

Mucosal melanoma (MM) is a rare disease, accounting for approximately 1.4% of all melanomas and only 0.03% of all new cancer diagnoses. Traditionally, it has been associated with a poor prognosis, with an overall 5-year survival rate of <25%. Progress in treatment has been hindered by its rarity and lack of evidence. However, studies on the treatment of subcutaneous melanoma with immunotherapy have demonstrated significant improvement in survival rates and have become a core part of oncological strategies. This paper discusses the revision of the evidence for the use of immunotherapy in the head and neck.

Methods:

This systematic review was conducted on January 19, 2019. The Medline and Embase databases were searched. In total, 509 articles were collated and screened. Inclusion criteria for the study included treatment-naive cohorts, cohorts with recurrent disease, primary outcomes with overall survival and disease-free survival at 5 years and at the longest follow-up, and studies of adults with MM in whom immunotherapy was reported as a treatment strategy. The exclusion criteria included duplicate papers, anatomical sites other than the head and neck, case reports, and those not published in English.

Results:

Fifty-two papers out of the 509 collated papers met the inclusion criteria. The results are shown as a comparison of yearly survival rates following different treatment modalities (immunotherapy vs nonimmunotherapy) at 2, 3, and 5 years. It was found that, with immunotherapy, survival rates at all intervals were higher than those without immunotherapy.

Discussion:

Immunotherapy outcomes in small studies have shown good data for increasing survival rates at yearly intervals in MM of the head and neck. Larger clinical trials are needed to accurately distinguish the efficacy and survival outcomes of immunotherapy when compared with treatment modalities, excluding immunotherapy. However, the ability to perform larger trials is limited by the rarity of MM of the head and neck.
Novel blood derived hemostatic agents for bleeding therapy and prophylaxis
Authors: Hegde Shailaja , Zheng Yi , Cancelas Jose A.
Published: August 2022

Purpose of review

Hemorrhage is a major cause of preventable death in trauma and cancer. Trauma induced coagulopathy and cancer-associated endotheliopathy remain major therapeutic challenges. Early, aggressive administration of blood-derived products with hypothesized increased clotting potency has been proposed. A series of early- and late-phase clinical trials testing the safety and/or efficacy of lyophilized plasma and new forms of platelet products in humans have provided light on the future of alternative blood component therapies. This review intends to contextualize and provide a critical review of the information provided by these trials.

Recent findings

The beneficial effect of existing freeze-dried plasma products may not be as high as initially anticipated when tested in randomized, multicenter clinical trials. A next-generation freeze dried plasma product has shown safety in an early phase clinical trial and other freeze-dried plasma and spray-dried plasma with promising preclinical profiles are embarking in first-in-human trials. New platelet additive solutions and forms of cryopreservation or lyophilization of platelets with long-term shelf-life have demonstrated feasibility and logistical advantages.

Recent trials have confirmed logistical advantages of modified plasma and platelet products in the treatment or prophylaxis of bleeding. However, their postulated increased potency profile remains unconfirmed.
How should low-density lipoprotein cholesterol be calculated in 2022?
Authors: Martins Janine , Rossouw H. Muller , Pillay Tahir S.
Published: August 2022

Purpose of review

The reference method for low-density lipoprotein-cholesterol (LDL-C) quantitation is β-quantification, a technically demanding method that is not convenient for routine use. Indirect calculation methods to estimate LDL-C, including the Friedewald equation, have been used since 1972. This calculation has several recognized limitations, especially inaccurate results for triglycerides (TG) >4.5 mmol/l (>400 mg/dl). In view of this, several other equations were developed across the world in different datasets.

The purpose of this review was to analyze the best method to calculate LDL-C in clinical practice by reviewing studies that compared equations with measured LDL-C.

Recent findings

We identified 45 studies that compared these formulae. The Martin/Hopkins equation uses an adjustable factor for TG:very low-density lipoprotein-cholesterol ratios, validated in a large dataset and demonstrated to provide more accurate LDL-C calculation, especially when LDL <1.81 mmol/l (<70 mg/dl) and with elevated TG. However, it is not in widespread international use because of the need for further validation and the use of the adjustable factor. The Sampson equation was developed for patients with TG up to 9 mmol/l (800 mg/dl) and was based on β-quantification and performs well on high TG, postprandial and low LDL-C samples similar to direct LDL-C.

The choice of equation should take into the level of triglycerides. Further validation of different equations is required in different populations.
Quality of Life, Participation, and Individualized Support in a Community-Based Yoga Class: A Case Series
Authors: Tischler Dana , O'Leary Melanie
Published: August 2022

Purpose:

To assess quality of life and participation in children with disabilities following a community-based yoga class, to examine the feasibility of implementing a community-based program with individualized support, and to make recommendations for the development of future programs.

Summary of Key Points:

Four children participated in a 10-week yoga class, with doctor of physical therapy students providing individualized physical and behavioral support. Children improved in components of the Children's Assessment of Participation and Enjoyment (CAPE) following the program; however, changes in quality of life on the Pediatric Quality of Life Inventory (PedsQL) were inconsistent. Parents provided feedback regarding the family's experience and reported that the children improved behavior, communication, and relationships following the yoga class.

What This Case Adds to Evidence-Based Practice:

A community-based yoga class for children with disabilities using individualized support is feasible and can improve participation and enjoyment in recreational activities.
The lower limb stiffness, moments and work mode during stair descent among the older adults
Authors: Ma Gang , Cao Chuanbao , Zhang Teng , Zheng Huifen , Song Qipeng , Zhang Cui , Sun Wei , Wang Jiangna
Published: August 2022

Objective

Lower limb stiffness strategies and work mode changes between young and older adults during stair descent are unclear. This study investigated the effect of aging on the lower limb stiffness, moments and joint work mode during stair descent.

Design

Twenty young adults and Twenty older adults were recruited from the local community for stair descent test. Kinematics and kinetics data were collected by Vicon system and Kistler force plate. The lower limb stiffness, moments and work mode were calculated and assess between groups.

Results

No significant differences in gait parameters were detected between groups. Compared with young adults, older adults have decreased leg stiffness, knee and ankle stiffness, increased peak hip extension moment, hip stiffness and ankle work contribution.

Conclusion

The older adults actively reduce the lower limb stiffness to reduce the risk of injury during stair descent. The hip joint strategy reduces the risk of forwarding falls, and ankle joint compensation work mode to make up for the lack of knee extension strength. This provides a reference for the focus of exercise intervention and rehabilitation strategies for older adults.
Single Institution Evolution in Defining an Algorithm for Prevention and Management of Severe Complications in Direct-to-Implant Breast Reconstruction
Authors: Yin Zhuming , Wang Huiqing , Liu Yue , Wang Yan , Chang Edward I. , Yin Jian
Published: August 2022

Background:

Complications including infection and wound dehiscence are major concerns for direct-to-implant (DTI) breast reconstruction. However, the risk factors associated with severe complications and implant salvage remain unclear.

Methods:

Retrospective study of all patients undergoing unilateral DTI breast reconstruction from 2014 through 2019. The risk factors associated with complications and prosthesis explantation were identified using multivariate logistic regression modeling and interaction analyses.

Results:

Among 1027 patients enrolled, 90 experienced severe complications, 41of which underwent prosthesis explantation, while 49 were successfully salvaged. Multivariate analysis demonstrated that patients with larger implant size (p=0.003), use of bovine mesh (p<0.001), adjuvant radiotherapy (p=0.047), low plasma albumin (p=0.013), and elevated blood glucose (p=0.006) were significantly more likely to suffer complications. Adjuvant radiation (OR: 7.44; 95%CI, 1.49-37.18; p = 0.014) and obesity (OR, 4.17; 95%CI, 1.17-14.88; p = 0.028) had significantly lower rates of implant salvage as well as surgical site infection (SSI) and wound dehiscence, while mastectomy skin flap necrosis was not associated with device explanation. There were no differences in complication and explantation rates between nipple-sparing and skin-sparing mastectomies. However, the combined impact of SSI and wound dehiscence added over fourteen-fold higher risk of prosthesis explantation (95%CI, 9.97-19.53).

Conclusion:

Success in direct-to-implant breast reconstruction is multifactorial. Larger implant size, adjuvant radiation therapy, diabetes, and malnutrition demonstrate increased risk of complications in the DTI approach. Surgical site infections and wound dehiscence should be treated aggressively, but the combination of both complications portends poor salvage rates.
Microsurgical Breast Reconstruction in Patients with Disorders of Hemostasis – Perioperative Risks and Management
Authors: Speck Nicole E. , Hellstern Peter , Farhadi Jian
Published: August 2022

Background:

Surgical and technological advances have resulted in the widespread adoption of microsurgical breast reconstruction. Many comorbidities that potentially might impair vasculature and wound healing are no longer considered contraindications for these procedures. However, some uncertainty still prevails regarding the perioperative management of patients with disorders of hemostasis.

Patients and Methods:

The authors combined a literature review with a retrospective chart review of patients with disorders of hemostasis who had undergone microsurgical breast reconstruction at the senior author’s center between 2015 to 2020. Several disorders associated with thrombotic and/or hemorrhagic complications were identified, and a standardized risk assessment and management strategy was developed in cooperation with a hematologist.

Results:

Overall, ten studies were identified comprising 29 patients who had a defined disorder of hemostasis and underwent microsurgical breast reconstruction. 17 microsurgical breast reconstructions were performed on eleven patients at the senior author’s center. High factor VIII levels, heterozygous Factor V Leiden, and heterozygous prothrombin mutation G20210A were the most common genetic or mixed genetic/acquired thrombophilic conditions. As expected, hereditary antithrombin, protein C, or protein S deficiencies were rare. Among hemorrhagic disorders, thrombocytopenia, platelet dysfunction, and von Willebrand disease or low von Willebrand factor levels were those factors most frequently associated with increased perioperative bleeding.

Conclusion:

Patients should be screened for elevated risk of thrombosis or bleeding before undergoing microsurgical breast reconstruction, and positive screening should prompt a complete hematologic evaluation. Interdisciplinary management of these disorders with a hematologist is essential to minimize risks and to obtain optimal reconstructive results.
Transplantation for chagas’ disease: closing the knowledge gap
Authors: La Hoz Ricardo M.
Published: August 2022

Purpose of the Review

This review examines the most recent literature on the epidemiology and treatment of Chagas Disease and the risk of Chagas Disease Reactivation and donor-derived disease in solid organ transplant recipients.

Recent Findings

Chagas disease is caused by infection with the parasite Trypansoma cruzi. In nonendemic countries the disease is seen primarily in immigrants from Mexico, Central America and South America where the disease is endemic. Benznidazole or nifurtimox can be used for treatment. Posaconazole and fosravuconazole did not provide any additional benefit compared to benznidazole alone or in combination. A phase 2 randomized controlled trial suggests that shorter or reduced dosed regimes of benznidazole could be used. Based on a large randomized controlled trial, benznidazole is unlikely to have a significant preventive effect for established Chagas cardiomyopathy. Transplantation has become the treatment of choice for individuals with refractory Chagas cardiomyopathy. Cohort studies show similar posttransplant outcomes for these patients compared to other indications. Transplant candidates and donors with chronic T. cruzi infection are at risk for Chagas disease reactivation and transmitting infection. Screening them via serology is the first line of prevention. Recipients with chronic infection and those receiving organs from infected donors should undergo sequential monitoring with polymerase chain reaction for early detection of reactivation and preemptive treatment with antitrypanosomal therapy.

Patients with chronic T. cruzi infection can be safely transplanted and be noncardiac organ donors.
Intraoperative Fluorescence Angiography in Implant-Based Breast Reconstruction
Authors: Samuel Ankhita R. , Stranix John T. , DeGeorge Brent R. , Black Jonathan S. , Campbell Chris A.
Published: August 2022

Background

Intraoperative fluorescence angiography (FA) has been described as a useful adjunct to physical examination in predicting mastectomy skin flap viability for immediate breast reconstruction. Its use has been described as a screening tool for mastectomy skin flap viability as well as a test used only for patients at high risk for mastectomy skin flap loss. We performed a national database review of implant-based breast reconstruction surgeries to determine the practice patterns of FA in this patient cohort and to determine if this technology impacted clinical outcomes.

Methods

A national insurance claims database was reviewed to select patients having undergone direct-to-implant (DTI) and immediate tissue expander (TE) placement with and without intraoperative FA as well as patients who had FA at the time of mastectomy without reconstruction. Patient characteristics that prompted FA and postoperative outcomes with and without FA were evaluated to determine its clinical impact in the observed practice pattern.

Results

Of the 48,464 patients identified, 836 had FA. More than twice as many patients undergoing DTI had FA than patients undergoing immediate TE placement (10.4% vs 5%, P < 0.0001). Twelve percent of patients receiving FA at the time of mastectomy had reconstruction delayed. Fluorescence angiography was associated with a trend toward lower overall complication rates in DTI patients (8.0% vs 11.9% without FA) but a significantly higher overall complication rate with immediate TE placement (13.8% vs 10.5% without FA, P = 0.018) and was associated with higher reoperation (12.0% vs 8.3% without FA, P = 0.037) in the TE group. There was no difference in other individual complications, readmission, or explantation for either clinical group with and without FA. Regression analysis identified obesity (odds ratio, 1.32; P < 0.001) and younger age (odds ratio, 1.74; P < 0.001) to be associated with performing FA, whereas obesity, diabetes, and tobacco use were associated with higher complication rates.

Conclusions

Younger and otherwise healthier obese patients were more likely to have FA. A greater proportion of DTI patients had FA than TE patients with improved outcomes in the former group and worse outcomes in the latter group. Obesity, tobacco use, and diabetes were associated with worse outcomes, whereas only obesity was associated with FA use.
Analysis of the Utility of CO2 and Pulse-Dye Lasers Together and Separately in the Treatment of Hypertrophic Burn Scars
Authors: Cooper Laura E. , Nuutila Kristo , Kemp Bohan Philip M. , Diaz Victoria , Batchinsky Maria , Carlsson Anders H. , Cancio Leopoldo C. , Chan Rodney K.
Published: August 2022

Introduction

Hypertrophic burn scars (HTBSs) remain a significant source of morbidity. Contemporary treatment has evolved to use CO2 lasers and/or pulse-dye lasers (PDLs) to reduce scar thickness (ST) and erythema. This study seeks to compare treatment efficacy with CO2 or PDL individually and in combination.

Methods

Patients undergoing laser treatments for HTBSs were enrolled. Three 3 × 3 cm squares of HTBSs were randomized to receive treatment with CO2 laser, PDL or CO2 + PDL. Patients underwent 3 treatments, 4 to 6 weeks apart and were followed up over 3 to 6 months. Scar assessments occurred at each visit before treatment and consisted of photographs, ultrasound, colorimetry, and the Patient and Observer Scar Assessment Score.

Results

Twenty-five patients were enrolled. Twenty completed 2 treatments (80%) and 11 completed all 3 treatments (44%). Median initial ST was 0.3 cm. Median time since injury was 8 months. Hypertrophic burn scars treated with CO2 or PDL showed a significant decrease in Patient and Observer Scar Assessment Scale score from visit 1 to 3 (P = 0.01 and 0.01, respectively). When separated by ST, thick scars (≥0.3 cm) showed a significant decrease in thickness between visit 1 and 2 using all laser modalities (CO2 + PDL, P = 0.01; CO2, P = 0.02; PDL, P = 0.03). Thin scars (<0.3 cm) showed a reduction in thickness by visit 3 after CO2 + PDL or PDL alone (P = 0.01 and 0.04, respectively). Separating scars by age, younger scars (<9 months) showed a significant reduction in thickness between visit 1 and 2 for CO2 treatment (P = 0.04), and between visit 2 and 3 for CO2 + PDL treatment (P = 0.04). Hypertrophic burn scars treated with PDL did not demonstrate a significant reduction in thickness until visit 3 (P = 0.002). Older scars (≥9 months) showed a significant reduction in thickness between visit 1 and 2 only after CO2 + PDL (P = 0.01).

Conclusions

Hypertrophic burn scars of varying ages, etiologies, and thicknesses were examined in this study with greater degree of early reduction seen in thicker scars using all laser modalities of CO2, PDL or in combination. However, there was no clinically meaningful benefit found with combination as compared with individual treatment. These data support the use of laser to improve HTBS but does not support one modality or combination of modalities over another.
Incidence and Relative Burden of Surgical Site Infections in Children Undergoing Nonemergent Surgery
Authors: He Katherine , Iwaniuk Marie , Goretsky Michael J. , Cina Robert A. , Saito Jacqueline M. , Hall Bruce , Grant Catherine , Cohen Mark E. , Newland Jason , Hall Matthew , Ko Clifford Y. , Rangel Shawn J.
Published: August 2022

Objective:

To establish surgical site infection (SSI) performance benchmarks in pediatric surgery and to develop a prioritization framework for SSI prevention based on procedure-level SSI burden.

Background:

Contemporary epidemiology of SSI rates and event burden in elective pediatric surgery remain poorly characterized.

Methods:

Multicenter analysis using sampled SSI data from 90 hospitals participating in NSQIP-Pediatric and procedural volume data from the Pediatric Health Information System (PHIS) database. Procedure-level incisional and organ space SSI (OSI) rates for 17 elective procedure groups were calculated from NSQIP-Pediatric data and estimates of procedure-level SSI burden were extrapolated using procedural volume data. The relative contribution of each procedure to the cumulative sum of SSI events from all procedures was used as a prioritization framework.

Results:

A total of 11,689 nonemergent procedures were included. The highest incisional SSI rates were associated with gastrostomy closure (4.1%), small bowel procedures (4.0%), and gastrostomy (3.7%), while the highest OSI rates were associated with esophageal atresia/tracheoesophageal fistula repair (8.1%), colorectal procedures (1.8%), and small bowel procedures (1.5%). 66.1% of the cumulative incisional SSI burden from all procedures were attributable to 3 procedure groups (gastrostomy: 27.5%, small bowel: 22.9%, colorectal: 15.7%), and 72.8% of all OSI events were similarly attributable to 3 procedure groups (small bowel: 28.5%, colorectal: 26.0%, esophageal atresia/tracheoesophageal fistula repair: 18.4%).

Conclusions:

A small number of procedures account for a disproportionate burden of SSIs in pediatric surgery. The results of this analysis can be used as a prioritization framework for refocusing SSI prevention efforts where they are needed most.
Novel pathophysiological insights in autoimmune myasthenia gravis
Authors: Masi Gianvito , O’Connor Kevin C.
Published: August 2022

Purpose of review

This review summarizes recent insights into the immunopathogenesis of autoimmune myasthenia gravis (MG). Mechanistic understanding is presented according to MG disease subtypes and by leveraging the knowledge gained through the use of immunomodulating biological therapeutics.

Recent findings

The past two years of research on MG have led to a more accurate definition of the mechanisms through which muscle-specific tyrosine kinase (MuSK) autoantibodies induce pathology. Novel insights have also emerged from the collection of stronger evidence on the pathogenic capacity of low-density lipoprotein receptor-related protein 4 autoantibodies. Clinical observations have revealed a new MG phenotype triggered by cancer immunotherapy, but the underlying immunobiology remains undetermined. From a therapeutic perspective, MG patients can now benefit from a wider spectrum of treatment options. Such therapies have uncovered profound differences in clinical responses between and within the acetylcholine receptor and MuSK MG subtypes. Diverse mechanisms of immunopathology between the two subtypes, as well as qualitative nuances in the autoantibody repertoire of each patient, likely underpin the variability in therapeutic outcomes. Although predictive biomarkers of clinical response are lacking, these observations have ignited the development of assays that might assist clinicians in the choice of specific therapeutic strategies.

Recent advances in the understanding of autoantibody functionalities are bringing neuroimmunologists closer to a more detailed appreciation of the mechanisms that govern MG pathology. Future investigations on the immunological heterogeneity among MG patients will be key to developing effective, individually tailored therapies.
The Treatment of Myelin Oligodendrocyte Glycoprotein Antibody Disease: A State-of-the-Art Review
Authors: Chwalisz Bart K. , Levy Michael
Published: August 2022

Background:

Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is an important etiology of neurologic morbidity and specifically, atypical, and relapsing optic neuritis. This review summarizes acute treatment and long-term prevention approaches in MOGAD.

Evidence Acquisition:

PubMed and Google Scholar databases were manually searched and reviewed.

Results:

We review the evidence base for acute treatment of MOGAD with corticosteroids and adjunct therapies, such as intravenous immunoglobulin (IVIg) and plasma exchange. We discuss the utility of prolonged corticosteroid tapering after the acute attack. We then summarize the commonly used disease-modifying treatments for relapsing MOGAD, including chronic low-dose corticosteroids, classic antirheumatic immune suppressants, biologic agents, and IVIg.

Conclusions:

While acute MOGAD attacks are usually treated with high-dose IV corticosteroids, longer oral corticosteroid tapers may prevent rapid relapse. Multiple long-term treatment strategies are being employed in recurrent MOGAD, with IVIg is emerging as probably the most effective therapy.
Predicting Clinical Outcomes in Infants With Cystic Fibrosis From Stool Microbiota using Random Forest Algorithms
Authors: Valls Rebecca A. , Hampton Thomas H. , Price Courtney E. , Barrack Kaitlyn E. , O’Toole George A. , Coker Modupe O. , Madan Juliette C.
Published: August 2022

The gut-lung axis describes the interaction between microbiota in the gut and health status of the airway, whereby there is a bidirectional relationship facilitated by systemic transport of microbially-derived metabolites and immune factors. Cystic fibrosis (CF) is a genetic disease that is associated with dysbiosis of the gut microbiota. Recent literature has shown that the microbial dysbiosis in the CF gut can alter the hosts’ inflammatory status and that there are distinct microbial compositions in children with CF who have low versus high intestinal inflammation. These distinct microbial profiles can be used as signatures in children with CF (cwCF) to predict health outcomes. Here, we use supervised machine learning to train a random forest model on the distinct microbial composition of cwCF to predict: age (as a validation of the method), frequency of upper respiratory infection (URIfreq), and neutrophil to lymphocyte ratio (NLR), a clinical marker for systemic inflammation that negatively correlates with lung function. We find that the out of bag error, a measure of model accuracy, is lower when predicting age for cwCF compared to children without CF, consistent with previous data. We are able to predict high URIfreq with only 16% error and high NLR with 27% error. This machine learning pipeline may allow physicians and microbiome researchers to use the stool microbiota of cwCF as a tool for identifying individuals with the more negative airway clinical outcomes from this population, and potentially allow for early intervention.

Importance

Children with CF (cwCF) often experience chronic respiratory infections, leading to progressive, irreversible lung function decline and significant morbidity and premature mortality. Modulator therapy has revolutionized the treatment of eligible adults with CF. cwCF as young as age 6 are now eligible to receive modulator therapy, although by early childhood many children have already experienced pulmonary exacerbations. Here we show that for cwCF, stool microbiota composition is associated with higher upper respiratory infection frequency and increased systemic inflammation. Our findings may aid in developing diagnostic tools that can allow physicians further understanding of which intestinal microbiota profiles are associated with health outcomes and to identify targets for preventative treatment for cwCF.
Effects of finfish farms on pelagic protist communities in a semi-closed stratified embayment
Authors: Da Silva R.R.P. , White C.A. , Bowman J.P. , Ross D.J.
Published: August 2022

Coastal aquaculture operations for feed additive species results in the release of waste into the surrounding environment, with the potential for adverse environmental change. Ubiquitous pelagic protists are sensitive to environmental changes making them potential sentinels for detecting and monitoring impacts. This study used 18S rRNA high-throughput amplicon sequencing as a molecular tool to study the pelagic protist community, with the aim of evaluating their potential as bioindicators of aquaculture activity in a low-oxygen, highly stratified marine embayment. Sampling occurred at three different depths along a distance gradient from two leases and at three control sites. Our results showed that the diversity and composition of both phytoplankton and other protist communities were more strongly influenced by depth stratification than the aquaculture activity. Nonetheless, differential abundance and machine learning analyses revealed a suite of potential bioindicators for aquaculture activity; this included the phytoplankton taxa Chrysophyceae, Gymnodiniphycidae (Gyrodinium), Cryptomonadales and Ciliophora (Philasterides armatalis, Plagiopylida, and Strombidium). Among the other protists, ciliates were also more abundant in closer proximity to the leases in both surface and bottom samples. Overall, our findings indicated that the use of 18S rRNA sequencing of protist communities is a promising tool for identifying environmental changes from aquaculture in the water column.
Bilallelic germline mutations inMAD1L1induce a novel syndrome of aneuploidy with high tumor susceptibility
Authors: Villarroya-Beltri Carolina , Osorio Ana , Torres-Ruiz Raúl , Gómez-Sánchez David , Trakala Marianna , Sánchez-Belmonte Agustin , Mercadillo Fátima , Pitarch Borja , Hernández-Núñez Almudena , Gómez-Caturla Antonio , Rueda Daniel , Perea José , Rodríguez-Perales Sandra , Malumbres Marcos , Urioste Miguel
Published: August 2022

Aneuploidy is a frequent feature of human tumors. Germline mutations leading to aneuploidy are very rare in humans, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations inMAD1L1, the gene encoding the Spindle Assembly Checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias, including five malignant tumors. Functional studies in peripheral blood cells demonstrated lack of full-length protein and deficient SAC response, resulting in ∼30-40% of aneuploid cells as detected by cytogenetic and single-cell (sc) DNA analysis. scRNA-seq analysis of patient blood cells identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFkB signaling. The inference of chromosomal aberrations from scRNA-seq analysis detected inflammatory signals both in aneuploid and euploid cells, suggesting a non-cell autonomous response to aneuploidy. In addition to random aneuploidies,MAD1L1mutations resulted in specific clonal expansions of γδ T-cells with chromosome 18 gains and enhanced cytotoxic profile, as well as intermediate B-cells with chromosome 12 gains and transcriptomic signatures characteristic of chronic lymphocytic leukemia cells. These data point toMAD1L1mutations as the cause of a new aneuploidy syndrome with systemic inflammation and unprecedented tumor susceptibility.
Orbitofrontal cortex populations are differentially recruited to support actions
Authors: Cazares Christian , Schreiner Drew C. , Valencia Mariela Lopez , Gremel Christina M.
Published: August 2022

The ability to use information from one’s prior actions is necessary for decision-making. While Orbitofrontal cortex (OFC) has been hypothesized as key for inferences made using cue and value-related information, whether OFC populations contribute to the use of information from volitional actions to guide behavior is not clear. Here, we used a self-paced lever-press hold down task in which mice infer prior lever press durations to guide subsequent action performance. We show that activity of genetically identified lateral OFC subpopulations differentially instantiate current and prior action information during ongoing action execution. Transient state-dependent lOFC circuit disruptions of specified subpopulations reduced the encoding of ongoing press durations but did not disrupt the use of prior action information to guide future action performance. In contrast, a chronic functional loss of lOFC circuit activity resulted in increased reliance on recently executed lever press durations and impaired contingency reversal, suggesting the recruitment of compensatory mechanisms that resulted in repetitive action control. Our results identify a novel role for lOFC in the integration of action information to guide adaptive behavior.
When does a Lotka-Volterra model represent microbial interactions? Insights from in-vitro nasal bacterial communities
Authors: Dedrick Sandra , Warrier Vaishnavi , Lemon Katherine P. , Momeni Babak
Published: August 2022

To alter microbial community composition for therapeutic purposes, an accurate and reliable modeling framework capable of predicting microbial community outcomes is required. Lotka-Volterra (LV) equations have been utilized to describe a breadth of microbial communities, yet, the conditions in which this modeling framework is successful remain unclear. Here, we propose that a set of simple in vitro experiments--growing each member in cell-free filtrates obtained from other members--can be used as a test to decide whether a LV model is appropriate for describing microbial interactions of interest. We show that for LV to be a good candidate, the ratio of growth rate to carrying capacity of each isolate when grown in the cell-free spent medium of other isolates should remain constant. Using an in vitro community of human nasal bacteria as a tractable system, we find that LV can be a good approximation when the environment is low-nutrient (i.e., when growth is limited by the availability of nutrients) and complex (i.e., when multiple resources, rather than a few, determine growth). These findings can help clarify the range of applicability of LV models and reveal when a more complex model may be necessary for predictive modeling of microbial communities.
Activation of the urotensin-II receptor by anti-COVID-19 drug remdesivir induces cardiomyocyte dysfunction
Authors: Ogawa Akiko , Ohira Seiya , Ikuta Tatsuya , Kato Yuri , Yanagida Shota , Ishii Yukina , Kanda Yasunari , Nishida Motohiro , Inoue Asuka , Wei Fan-Yan
Published: August 2022

Remdesivir is an antiviral drug used for COVID-19 treatment worldwide. Cardiovascular (CV) side effects have been associated with remdesivir; however, the underlying molecular mechanism remains unknown. Here, we performed a large-scale G-protein-coupled receptor (GPCR) screening in combination with structural modeling and found that remdesivir is a selective agonist for urotensin-II receptor (UTS2R). Functionally, remdesivir treatment induced prolonged field potential in human induced pluripotent stem cell (iPS)-derived cardiomyocytes and reduced contractility in neonatal rat cardiomyocytes, both of which mirror the clinical pathology. Importantly, remdesivir-mediated cardiac malfunctions were effectively attenuated by antagonizing UTS2R signaling. Finally, we characterized the effect of 110 single-nucleotide variants (SNVs) in UTS2R gene reported in genome database and found four missense variants that show gain-of-function effects in the receptor sensitivity to remdesivir. Collectively, our study illuminates a previously unknown mechanism underlying remdesivir-related CV events and that genetic variations of UTS2R gene can be a potential risk factor for CV events during remdesivir treatment, which collectively paves the way for a therapeutic opportunity to prevent such events in the future.

One Sentence Summary

Remdesivir‘s activity as a selective agonist of urotensin-II receptor underlies its known cardiotoxicity in anti-viral therapy.
The concerted action of SEPT9 and EPLIN modulates the adhesion and migration of human fibroblasts
Authors: Hecht Matthias , Marrhofer Pia , Johnsson Nils , Gronemeyer Thomas
Published: August 2022

Septins are cytoskeletal proteins that participate in cell adhesion, migration and polarity establishment. The septin subunit SEPT9 directly interacts with the single LIM domain of EPLIN, an actin bundling protein. Using a human SEPT9 KO fibroblast cell line we show that cell adhesion and migration are regulated by the interplay between both proteins. The low motility of SEPT9-depleted cells could be partly rescued by increased levels of EPLIN. The normal organization of actin-related filopodia and stress fibers was directly dependent on the expression level of SEPT9 and EPLIN. Increased levels of SEPT9 and EPLIN enhanced the size of focal adhesions in cell protrusions, correlating with a stabilization of actin bundles, whereas decreased levels have the opposite effect. Our work thus establishes the interaction between SEPT9 and Eplin as important link between the septin and the actin cytoskeleton that influences cell adhesion and motility.
Delineating the activity of the potent nicotinic acetylcholine receptor agonists (+)-anatoxin-a and (−)-hosieine-A
Authors: Parker Holly P. , Dawson Alice , Jones Mathew J. , Yan Rui , Ouyang Jie , Hong Ran , Hunter William N.
Published: August 2022

The affinity and thermodynamic parameters for the interactions of two naturally occurring neurotoxins, (+)-anatoxin-a and (−)-hosieine-A, with acetylcholine-binding protein were investigated using a fluorescence-quenching assay and isothermal titration calorimetry. The crystal structures of their complexes with acetylcholine-binding protein from Aplysia californica (AcAChBP) were determined and reveal details of molecular recognition in the orthosteric binding site. Comparisons treating AcAChBP as a surrogate for human α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) suggest that the molecular features involved in ligand recognition and affinity for the protein targets are conserved. The ligands exploit interactions with similar residues as the archetypal nAChR agonist nicotine, but with greater affinity. (−)-Hosieine-A in particular has a high affinity for AcAChBP driven by a favorable entropic contribution to binding. The ligand affinities help to rationalize the potent biological activity of these alkaloids. The structural data, together with comparisons with related molecules, suggest that there may be opportunities to extend the hosieine-A scaffold to incorporate new interactions with the complementary side of the orthosteric binding site. Such a strategy may guide the design of new entities to target human α4β2 nAChR that may have therapeutic benefit.
Native glycosylation and binding of the antidepressant paroxetine in a low-resolution crystal structure of human myeloperoxidase
Authors: Krawczyk Lucas , Semwal Shubham , Soubhye Jalal , Lemri Ouadriri Salma , Prévost Martin , Van Antwerpen Pierre , Roos Goedele , Bouckaert Julie
Published: August 2022

Human myeloperoxidase (MPO) utilizes hydrogen peroxide to oxidize organic compounds and as such plays an essential role in cell-component synthesis, in metabolic and elimination pathways, and in the front-line defence against pathogens. Moreover, MPO is increasingly being reported to play a role in inflammation. The enzymatic activity of MPO has also been shown to depend on its glycosylation. Mammalian MPO crystal structures deposited in the Protein Data Bank (PDB) present only a partial identification of their glycosylation. Here, a newly obtained crystal structure of MPO containing four disulfide-linked dimers and showing an elaborate collection of glycans is reported. These are compared with the glycans identified in proteomics studies and from 18 human MPO structures available in the PDB. The crystal structure also contains bound paroxetine, a blocker of serotonin reuptake that has previously been identified as an irreversible inhibitor of MPO, in the presence of thiocyanate, a physiological substrate of MPO.
Optimal design of space assembly microsatellite structure based on sequential quadratic programming
Authors: Feng Yanbo , Wu Xiande , Chen Weidong , Xie Yaen , Yu Taihang , Hao Yong
Published: August 2022

Purpose

On-orbit assembly technology is a promising research topic in spaceflight field. For purposes of studying the dynamic performance and reducing weight of an on-orbit assembly satellite structure frame, this paper aims to propose a structural optimization design method based on natural frequency.

Design/methodology/approach

The dynamic stability of the satellite under working condition depends on the mechanical properties of the structure matrix. A global structural optimization model is established, with the objective of mass minimization and the constraints of given natural frequencies and given structure requirements. The structural optimization and improvement design method is proposed using sequential quadratic programming calculation.

Findings

The optimal result of objective function is effectively obtained, and the best combination of structural geometric parameters is configurated. By analyzing the relationship between the structural variables and optimization parameters, the primary and secondary factors to the mass optimization process of the microsatellite satisfying the dynamic performance requirements are obtained, which improves the effectiveness and accuracy of the system optimization design.

Originality/value

This method can coordinate the relation between satellite vibration stability and weight reduction, which provides an effective way for the optimization design of on-orbit assembly microsatellite. It has reference significance for the similar spacecraft framework structure design.
Organizational learning in the context of product development processing: a case study in an automotive company
Authors: Alliprandini Dario Henrique , Scur Gabriela , Vilas Boas Viveiros Lopes Ana Paula , Wakatsuki Mariana Maciel
Published: August 2022

Purpose

This study identifies and analyzes practices related to declarative knowledge of organizational learning in the product development process (PDP) that uses the Stage-Gate (SG) system.

Design/methodology/approach

The field research was conducted with a qualitative approach through a case study. The study object was a multinational company in the automotive sector that is highly competent in truck chassis design with a PDP based on the SG system.

Findings

The authors identified PDPs associated with the elements of declarative knowledge of organizational learning in intra- and inter-development teams. Rather than merely being a checklist, each gate in the SG system has the potential to become a more effective and robust intra-team learning practice and promote inputs for continuous improvement in the process through its use as a checkpoint of the five elements of declarative knowledge during the development activities.

Research limitations/implications

The case study was conducted in a multinational company in the automotive sector, whose business units are divided by competencies. The unit studied is a reference in truck chassis and is located in the State of São Paulo, Brazil.

Practical implications

The research model presented can be used to evaluate how companies exploit their activities and practices to leverage organizational learning in PDP. That is, the model can be used as a diagnostic reference for declarative knowledge in companies that apply the SG system to manage PDP.

Originality/value

The study focuses on a model of PDP analysis, aspects of organizational learning and declarative knowledge, in that the model it assists in the collection, distribution and use of information to the development team members with a view for products with greater innovation potential.
Simultaneous identification of multi-parameter for power hardening elastoplastic problems in three-dimensional geometries
Authors: Zhang Chunyun , Mei Jie , Bai Yushuai , Cui Miao , Peng Haifeng , Gao X. W.
Published: August 2022

Purpose

The purpose of this study is to simultaneously determine the constitutive parameters and boundary conditions by solving inverse mechanical problems of power hardening elastoplastic materials in three-dimensional geometries.

Design/methodology/approach

The power hardening elastoplastic problem is solved by the complex variable finite element method in software ABAQUS, based on a three-dimensional complex stress element using user-defined element subroutine. The complex-variable-differentiation method is introduced and used to accurately calculate the sensitivity coefficients in the multiple parameters identification method, and the Levenberg–Marquardt algorithm is applied to carry out the inversion.

Findings

Numerical results indicate that the complex variable finite element method has good performance for solving elastoplastic problems of three-dimensional geometries. The inversion method is effective and accurate for simultaneously identifying multi-parameters of power hardening elastoplastic problems in three-dimensional geometries, which could be employed for solving inverse elastoplastic problems in engineering applications.

Originality/value

The constitutive parameters and boundary conditions are simultaneously identified for power hardening elastoplastic problems in three-dimensional geometries, which is much challenging in practical applications. The numerical results show that the inversion method has high accuracy, good stability, and fast convergence speed.
Getting the measure of remote e-working: a revision and further validation of the E-work life scale
Authors: Charalampous Maria , Grant Christine Anne , Tramontano Carlo
Published: August 2022

Purpose

This paper aimed to revise and further validate the published e-work life (EWL) scale. The EWL scale was originally developed to assess theoretically relevant aspects of the remote e-working experience related to four main areas: organisational trust, flexibility, work–life interference and productivity.

Design/methodology/approach

A number of changes were implemented to the scale (i.e. including new items, rewording of existing items) following a recent qualitative study conducted by the authors. The two studies outlined in this paper, conducted within discrete remote e-working populations, resulted in a validated and adjusted 20-item version of the scale.

Findings

Study 1 performs confirmatory factor analysis (CFA) on data from a sample of 399 remote e-workers (57.9% female) in UK to check the factor structure of the revised version of the EWL scale and the reliability of the posited dimensions. Results provided support for a 20-item scale, replicating the factorial structure of the original version. Study 2 tests and confirms the factorial structure of the final 20-item EWL scale in an independent sample of 366 remote e-workers (48.6% female) in UK. Study 2 provides further evidence of EWL scale's reliability and validity, with the four factors of the scale being significantly correlated with positive mental health, detachment from work and technostress.

Originality/value

The EWL scale is a very timely and important tool which provides an overall framework of the key areas that are affecting remote e-workers’ life; whose greater understanding may better prepare organisations to adapt work arrangements and introduce support policies and guidance.