bluuebunny/crossref_metadata_2025 huggingface dataset:
Robotic Ventral Hernia Repair and Concomitant Procedures
Authors: Kudsi Omar Yusef , Kaoukabani Georges , Bou-Ayash Naseem , Gokcal Fahri
Published: February 2023

Background:

Ventral hernia remains as one of the most performed procedures worldwide. With the aging of the population and increasing comorbidities, it is common for ventral hernia to coexist with other pathologies that require surgery. Patients may opt for concomitant repairs while undergoing ventral hernia surgery. Therefore, the purpose of this study is to investigate the clinical outcomes of robotic ventral hernia repair (RVHR) in patients undergoing concomitant repairs.

Materials and Methods:

Patients who underwent RVHR with concomitant repairs over a period of 9 years were included in this retrospective study. Pre, intra, and postoperative variables including the patient’s demographics, hernia characteristics, complications, and hernia recurrence were reported. Univariate analysis was performed to evaluate potential variables associated with increased risk of postoperative complications

Results:

A total of 109 (33% females) patients were included in this study. Mean age and body mass index were 59.9±12.7 years and 30.5±5.7 kg/m2, respectively. Concomitant repairs were mostly abdominal wall procedures (inguinal hernia repairs, 88.1%). Other procedures included nonabdominal wall surgeries. Incisional hernia repairs were higher than primary repairs (55% vs 45%, respectively). Median operative time and hospital length of stay were 145 min (102 to 245) and 1 day (0 to 1), respectively. Mean postoperative follow-up was 39.2 (4.1 to 93.6) months. In total, 24 patients had postoperative complications, out of which 16 (14.7%) were Clavien-Dindo grade I and II, and 10 (9.2%) were grade III and IV. Nine patients had surgical site events, and two recurrences were recorded. Postoperative complications were associated with incisional hernias [Odds ratio (OR)=8.4; P=0.003; 95% CI=2.092-33.423], nonabdominal wall concomitant procedures (OR=5.9; P=0.013; 95% CI=1.453-24.451), and history of wound infection (OR=3.473; P=0.047; 95% CI=1.016-11.872).

Conclusions:

This is the first study to report outcomes of concomitant repairs with RVHR, with notable Clavien-Dindo grade III and IV complications of 9%. Incisional hernia repairs, nonabdominal wall procedures, and a history of wound infection were risk factors for postoperative complications.
Profiling microRNA from peripheral blood mononuclear cells in early-onset familial Alzheimer’s disease
Authors: Li Daojing , Chen Yanan , Zhang Tong , Lv Zhanyun , Zhang Liangliang , Li Xiaohai , Zhang Aimei
Published: January 2023

MicroRNAs (miRNAs) refer to short in-length, noncoding RNAs that regulate numerous cellular functions by targeting mRNA, and numerous types of research have shown that miRNA is vitalin Alzheimer’s disease. For identifying differentially expressed miRNAs in the peripheral blood mononuclear cell (PBMC) of early-onset familial Alzheimer’s disease (EOFAD), we conducted this study which might give a reference for potential therapeutic targets or biomarkers for this disease. On the basis of high-throughput sequencing, we screened the miRNAs expression profiles in PBMC regarding both EOFAD patients and healthy controls, and the biological information was analyzed. Compared with the PBMC of healthy controls, 142 miRNAs were differentially expressed in EOFAD patients (P < 0.05), including 48 significantly differentially expressed miRNAs, 37 of which were significantly upregulated, including miR-3614-5p, miR-193A-5p, miR-2115-5p, miR-143-3p, etc. and 11 were significantly downregulated, including miR-484, miR-708-5p, miR-205-5p, miR-31-5p, etc. According to biological information analysis, 768 miRNA target genes were differentially expressed, which may be involved in multiple gene functions and cell cycle, cell senescence, and several signaling pathways, including FoxO, MAPK, Ras, mTOR, neurotrophin, etc. There are differential expressions of miRNAs in PBMC of EOFAD patients and controls, revealing their importance in Alzheimer’s disease as indicated by co-expression network analysis; this may support basic information for new biomarkers or treatment exploring.
Tolerability, Attrition Rates, and Survival Outcomes of Neoadjuvant FOLFIRINOX for Non-Metastatic Pancreatic Adenocarcinoma: Intent-to-Treat Analysis
Authors: Fong Zhi Ven , Verdugo Fidel Lopez , Fernandez-del Castillo Carlos , Ferrone Cristina R , Allen Jill N , Blaszkowsky Lawrence S , Clark Jeffrey W , Parikh Aparna R , Ryan David P , Weekes Colin D , Hong Theodore S , Wo Jennifer Y , Lillemoe Keith D , Qadan Motaz
Published: February 2023

Background:

Neoadjuvant FOLFIRINOX is increasingly utilized in the management of pancreatic ductal adenocarcinoma (PDAC). However, neoadjuvant therapy is associated with toxicity, possible disease progression, and biopsy and biliary-related complications that may preclude operative exploration. Data on the true attrition rate outside of clinical trials or resected surgical series are lacking.

Study Design:

Patients with non-metastatic PDAC who initiated FOLFIRINOX from 2015 to 2020 were identified from our institution’s pharmacy records. Multivariable regression and Cox proportional hazard models were used for adjusted analyses of categorical and survival outcomes, respectively.

Results:

Of 254 patients who initiated first-line neoadjuvant FOLFIRINOX, 199 (78.3%) underwent exploration. Fifty-four (21.3%) patients did not complete their chemotherapy cycles due to poor tolerability (46.3%), poor response (31.5%), and disease progression (14.8%), among other causes (7.4%). A total of 109 (42.9%) patients experienced grade 3/4 FOLFIRINOX-related toxicity, of whom 73 (28.7%) and 100 (39.4%) required an ED visit or inpatient admission, respectively. Finally, not undergoing surgical exploration was associated with impaired overall survival (OS) (HR 7.0, 95% CI 3.8-12.8, p<0.001). Independent predictors of not undergoing exploration were remote history of chemotherapy receipt (OR 0.06, p=0.02), inability to complete FOLFIRINOX cycles (OR 0.2, p=0.003), increase in ECOG score (OR 0.2, p<0.001), and being single or divorced (OR 0.3, p=0.018).

Conclusions:

Among 254 patients with non-metastatic PDAC initiated on FOLFIRINOX, of whom 52% were locally advanced, a total of 199 (78.3%) were explored, 142 (71.4%) underwent successful resection, and 129 (90.8%) were resected with negative margins. Despite 109 (42.9)% of patients experiencing significant toxicity, most patients could be managed through treatment-related complications to complete planned neoadjuvant chemotherapy and undergo planned surgical exploration.
Postoperative Venous Thromboembolism in Colon and Rectal Cancer: Do Tumor Location and Operation Matter?
Authors: McKenna Nicholas P , Bews Katherine A , Behm Kevin T , Habermann Elizabeth B , Cima Robert R
Published: February 2023

Introduction:

Existing venous thromboembolism (VTE) risk scores help identify patients at increased risk of postoperative VTE who warrant extended prophylaxis in the first 30 days. However, these methods do not address factors unique to colorectal surgery, wherein tumor location and operation performed vary widely. Further, VTE risk may extend past 30 days. Therefore, we aimed to determine the roles of tumor location and operation in VTE development and evaluate VTE incidence through 90 days postoperatively.

Study Design:

Adult patients undergoing surgery for colorectal cancer between January 1, 2005 and December 31, 2021 at a single institution were identified. Patients were then stratified by cancer location and by operative extent. VTEs were identified using diagnosis codes in the electronic medical record and consisted of extremity deep venous thromboses (DVTs), portomesenteric venous thromboses (PMVTs), and pulmonary emboli (PE).

Results:

6,844 operations were identified (72% segmental colectomy, 22% proctectomy, 6% total (procto)colectomy), and tumor location was most commonly in the ascending colon (32%), followed by the rectum (31%), with other locations less common (sigmoid 16%, rectosigmoid junction 9%, transverse colon 7%, descending colon 5%). The cumulative incidence of any VTE was 3.1% at 90 days with a relatively steady increase across the entire 90-day interval. Extremity DVTs were the most common VTE type accounting for 37% of events, while PEs and PMVTs made up 33% and 30% of events respectively. More distal tumor locations and more anatomically extensive operations had higher VTE rates.

Conclusions:

When considering extended VTE prophylaxis following colorectal surgery, clinicians should account for the operation performed and the location of the tumor. Further study is necessary to determine the optimal length of VTE prophylaxis in high-risk individuals.
PARP1 Inhibition and Effect on Burn Injury-Induced Inflammatory Response and Cardiac Function
Authors: Wen Jake J , Dejesus Jana , Radhakrishnan Geetha L , Radhakrishnan Ravi S
Published: February 2023

Introduction:

Burn injury induces multiple signaling pathways leading to a significant inflammatory storm that adversely affects multiple organs, including the heart. PARP1 inhibition, with specific agents such as PJ34, is effective in reducing oxidative stress and cytokine expression in the heart. We hypothesized that PARP1 inhibition would reduce inflammatory signaling and protect against burn injury induced cardiac dysfunction.

Methods:

Male Sprague-Dawley rats (8-week-old, 300-350 gms) were randomized to Sham injury (Sham), 60% TBSA burn (24hpb), or 60% TBSA burn with IP administration of PJ34 (20mg/kg, 24hpb + PJ34) and sacrificed 24 hours post injury. Cardiac function was determined using Vevo 2100 echocardiography (ECHO). Genetic expression of 84 specific TLR-mediated signal transduction and innate immunity genes were examined using microarray to evaluate cardiac tissue. Qiagen GeneGlobe Data Analysis Center was used to analyze expression and genetic clustering was performed using TreeView V2.0.8 software. Real-time qPCR was utilized to validate identified differentially expressed genes.

Results:

Burn injury significantly altered multiple genes in the TLR signaling, IL-17 signaling, TNF signaling, and NF-κB signaling pathways and led to significant cardiac dysfunction. PARP1 inhibition with PJ34 normalized these signaling pathways to sham levels as well as improved cardiac function to sham levels.

Conclusions:

PARP1 inhibition normalizes multiple inflammatory pathways that are altered after burn injury and improves cardiac dysfunction. PARP1 pathway inhibition may provide a novel methodology to normalize multiple burn injury induced inflammatory pathways in the heart.
Pre-Treatment Health-Related Quality of Life Status and Survival in Pancreatobiliary Surgical Patients
Authors: Manisundaram Naveen , Portuondo Jorge I , Erstad Derek , Silberfein Eric , Hsu Cary , Barakat Omar , Wood Amy , Navarro-Cagigas Martina , Van Buren George , Fisher William E , Camp E Ramsay
Published: February 2023

Background:

Pancreatobiliary (PB) disorders, especially cancer, negatively impact patients’ health-related quality of life (HRQoL). However, the influence of baseline, pre-intervention HRQoL on peri-operative and oncologic outcomes has not been well-defined. We hypothesized that low baseline HRQoL is associated with worse peri-operative and long-term survival outcomes for PB surgical patients.

Study Design:

Pre-treatment FACT-Hep survey results and clinical data from PB patients (2008-2016) from a single center’s prospective database were analyzed. Survey responses were aggregated into composite scores and divided into quintiles. Patients in the highest quintile of HRQoL were compared to patients in the bottom four quintiles combined. Overall (OS) and disease-free (DFS) were analyzed using the Kaplan-Meier method. Logistic and cox regressions were used to determine associations between quintiles of HRQoL scores and 30-day complications and long-term survival, respectively.

Results:

Of 162 patients evaluated, 99 had malignancy, and 63 had benign disease. Median follow-up was 31 months. Baseline HRQoL scores were similar for benign and malignant disease (p=0.42) and were not associated with the development of any (p=0.08) or major complications (p=0.64). Patients with highest quintile HRQoL scores had longer 3-year OS (84.6 vs 61.7%, p = 0.03) compared to patients in the lowest four quintiles of HRQoL. Among cancer patients only, those with highest quintile scores had longer 3-year OS (81.6 vs 47.4%, p = 0.02). On multivariable analysis, highest quintile HRQoL scores were associated with longer OS and DFS for patients with malignancy.

Conclusions:

Pre-treatment HRQoL was associated with both OS and DFS among PB patients and might have prognostic utility. Future studies are necessary to determine whether patients with poorer HRQoL may benefit from targeted psycho-social interventions.
Low vs Standard-Dose Indocyanine Green in the Identification of Biliary Anatomy Using Near-Infrared Fluorescence Imaging: A Multicenter Randomized Controlled Trial
Authors: Ladd Alexandra D , Zarate Rodriguez Jorge , Lewis Duncan , Warren Curtis , Duarte Sergio , Loftus Tyler J , Nassour Ibrahim , Soma Daiki , Hughes Steven J , Hammill Chet , Zarrinpar Ali
Published: February 2023

Background:

Near-infrared fluorescence (NIRF) imaging using intravenous indocyanine green (ICG) facilitates intraoperative identification of biliary anatomy. We hypothesize that a much lower dose of ICG than the standard decreases hepatic and background fluorescence and improves bile duct visualization.

Study Design:

In this multicenter randomized controlled trial, 55 adult patients undergoing laparoscopic cholecystectomy were randomized to low dose (0.05 mg) or standard dose (2.5 mg) ICG preoperatively on the day of surgery. A quantitative assessment was performed on recorded videos from the operation using ImageJ software to quantify the fluorescence intensity of the bile duct, liver, and surrounding/background fat. Operating surgeons blinded to ICG dose provided a qualitative assessment of various aspects of the visualization of the extrahepatic biliary tree comparing NIRF to standard visible light imaging using a scale of 1-5 (1=unsatisfactory, 5=excellent). Quantitative and qualitative scores were compared between the groups to determine any significant differences between the doses.

Results:

The bile duct-to-liver and bile duct-to-background fat fluorescence intensity ratios were significantly higher for the low dose group compared to the standard dose group (3.6 vs 0.68; p<0.0001 and 7.5 vs 3.3; p<0.0001, respectively). Low dose ICG had a slightly higher (i.e., better) mean score on the qualitative assessment compared to the standard dose, although the differences were not statistically significant.

Conclusion:

Low dose ICG leads to quantitative improvement of biliary visualization using NIRF imaging by minimizing liver fluorescence; this further facilitates routine use during hepatobiliary operations.
ACS NSQIP Risk Calculator Accuracy Using a Machine Learning Algorithm Compared to Regression
Authors: Liu Yaoming , Ko Clifford Y , Hall Bruce L , Cohen Mark E
Published: February 2023

Background:

The ACS NSQIP risk calculator (RC) uses regression to make predictions for 14, 30-day surgical outcomes. While this approach provides accurate (discrimination and calibration) risk estimates, they might be improved by machine learning (ML). To investigate this possibility, accuracy for regression-based risk estimates were compared to estimates from an extreme gradient boosting (XGB) ML algorithm.

Methods:

A cohort of 5,020,713 million NSQIP patient records was randomly divided into 80% for model construction and 20% for validation. Risk predictions using regression and XGB-ML were made for 13 RC binary 30-day surgical complications and 1 continuous outcome (length of stay, LOS). For the binary outcomes, discrimination was evaluated using AUROC (area under the receiver operating characteristic curve) and AUPRC (area under the precision recall curve), and calibration was evaluated using Hosmer-Lemeshow (H-L) statistics. Mean squared error (MSE) and a calibration curve analog were evaluated for the continuous LOS outcome.

Results:

For every binary outcome, discrimination (AUROC and AUPRC) was slightly greater for XGB-ML than for regression (mean [across the outcomes] AUROC was 0.8299 versus 0.8251, and mean AUPRC was 0.1558 versus 0.1476, for XGB-ML and regression, respectively). For each outcome miscalibration was greater (larger H-L values) with regression; there was statistically significant miscalibration for all regression-based estimates but only for 4 of 13 when XGB-ML was used. For LOS, MSE was lower for XGB-ML.

Conclusions:

XGB-ML provided more accurate risk estimates than regression in terms of discrimination and calibration. Differences in calibration between regression and XGB-ML were of substantial magnitude and support transitioning the RC to XGB-ML.
Is Chest X-Ray a Reliable Screening Tool for Blunt Thoracic Aortic Injury? Results from the American Association for the Surgery of Trauma/Aortic Trauma Foundation Prospective Blunt Thoracic Aortic Injury Registry
Authors: Crapps Joshua L , Efird Jessica , DuBose Joseph J , Teixeira Pedro G , Shrestha Binod , Brown Carlos VR
Published: January 2023

Purpose:

Traditional teaching continues to espouse the value of initial trauma CXR as a screening tool for blunt thoracic aortic injury (BTAI). The ability of this modality to yield findings that reliably correlate with grade of injury and need for subsequent treatment, however, requires additional multicenter prospective examination. We hypothesize that CXR is not a reliable screening tool, even at the highest grades of blunt thoracic aortic injury.

Methods:

The ATF / AAST prospective BTAI registry was utilized to correlate initial CXR findings to the Society for Vascular Surgery (SVS) injury grade identified on computed tomographic angiography (CTA).

Results:

708 confirmed BTAI injuries with recorded CXR findings and subsequent CTA injury characterization from February 2015 – August 2021 were analyzed. The presence of any of the classic CXR findings was observed in only 57.6% (408/708) of injuries, with increasing presence correlating with advanced SVS BTAI grade (39.1% [75/192] G1; 55.6% [50/90] G2; 65.2% [227/348] G3; 71.8% [56/78] G4). The most consistent single finding identified was widened mediastinum, but this was only present in 27.7% of all confirmed BTAIs and only 47.4% of G4 injuries (7.8%% G1, 23.3%, G2, 35.3% G3, 47.4% G4).

Conclusions:

CXR is not a reliable screening tool for the detection of BTAI, even at the highest grades of injury. Further investigations of specific high-risk criteria for screening that incorporate imaging, mechanism and physiologic findings are warranted.
Dopamine supersensitivity psychosis and delay of clozapine treatment in patients with treatment-resistant schizophrenia
Authors: Masumo Yuto , Kanahara Nobuhisa , Kogure Masanobu , Yamasaki Fumiaki , Nakata Yusuke , Iyo Masaomi
Published: January 2023

Both the underutilization of clozapine and treatment resistance of patients to clozapine are serious problems worldwide. Identifying clinical markers predicting response to clozapine would help clinicians more effectively utilize clozapine treatment. The present study retrospectively assessed dopamine supersensitivity psychosis (DSP) in addition to other measures such as age at disease onset and delay of clozapine introduction for a total of 47 treatment-resistant schizophrenia (TRS) patients. The response to clozapine was judged with CGI-C at 1 and 2 years from clozapine introduction. Results revealed that the DSP group tended to have a longer delay between designation of TRS and introduction of clozapine and continued to have slightly more severe psychopathology after treatment with clozapine, showing only slight improvement. The logistic regression analysis showed that the age at disease onset was the only significant indicator, predicting responsiveness to clozapine: patients with an onset age <20 years had a significantly better response to clozapine than patients with an onset age ≥20 years. The present study suggests that DSP might be related to a longer delay in clozapine introduction and the persistence of refractory symptoms despite clozapine treatment, whereas early age of disease onset might be related to a better response to clozapine.
Cardiovascular risk factors and metabolic syndrome in patients treated with long-acting injectables antipsychotics: a retrospective study
Authors: De Carlo Vera , Grancini Benedetta , Cassina Niccolò , Casati Lorenzo , Piccoli Eleonora , Vismara Matteo , Gobbo Dario , Zanaschi Raffaella , Lupo Susanna , Olivieri Silvia , Dell’Osso Bernardo
Published: February 2023

The present cross-sectional, retrospective study aimed to assess the prevalence of cardiovascular disease (CVD) risk factors and metabolic syndrome in a sample of psychiatric patients treated with long-acting injectable antipsychotics (LAIs). The clinical charts of 120 patients, mainly diagnosed with schizophrenia (30.0%), schizoaffective disorder (15.0%), and bipolar disorder (13.3%) on LAIs therapy – initiated in the period from 2013 to 2019 and lasting at least one year – were retrospectively reviewed and related socio-demographic, clinical and laboratory variables were collected. The 70.8% of patients were treated with first-generation LAIs, and the remaining 29.2% with second-generation LAIs. The overall sample showed low compliance in performing the required exams and evaluations related to CVD risk factors. The prevalence of metabolic syndrome was 30.8%, and, considering specific CVD risk factors, 55% of the total sample reported abdominal obesity, 43.3% arterial hypertension, 41.7% low HDL-cholesterol, 25.8% hypertriglyceridemia, and 20.8% fasting hyperglycemia. Lastly, 6.7% showed prolonged corrected QT (QTc) interval at the ECG. Patients treated with LAIs should be regularly monitored for metabolic changes and CVD risk factors. Metabolic changes rapidly develop after initiating an antipsychotic therapy and these often involve parameters, that can be easily recorded in an outpatient setting (e.g. abdominal obesity and hypertension).
Emotional dysregulation, alexithymia and neuroticism: a systematic review on the genetic basis of a subset of psychological traits
Authors: Castellini Giovanni , Merola Giuseppe Pierpaolo , Baccaredda Boy Ottone , Pecoraro Vincenzo , Bozza Bernardo , Cassioli Emanuele , Rossi Eleonora , Bessi Valentina , Sorbi Sandro , Nacmias Benedetta , Ricca Valdo
Published: February 2023

Neuroticism, alexithymia and emotion dysregulation are key traits and known risk factors for several psychiatric conditions. In this systematic review, the aim is to evaluate the genetic contribution to these psychological phenotypes. A systematic review of articles found in PubMed was conducted. Search terms included ‘genetic’, ‘GWAS’, ‘neuroticism’, ‘alexithymia’ and ‘emotion dysregulation’. Risk of bias was assessed utilizing the STREGA checklist. Two hundred two papers were selected from existing literature based on the inclusion and exclusion criteria. Among these, 27 were genome-wide studies and 175 were genetic association studies. Single gene association studies focused on selected groups of genes, mostly involved in neurotransmission, with conflicting results. GWAS studies on neuroticism, on the other hand, found several relevant and replicated intergenic and intronic loci affecting the expression and regulation of crucial and well-known genes (such as DRD2 and CRHR1). Mutations in genes coding for trascriptional factors were also found to be associated with neuroticism (DCC, XKR6, TCF4, RBFOX1), as well as a noncoding regulatory RNA (LINC00461). On the other hand, little GWAS data are available on alexythima and emotional dysregulation.
Rhizopus homothallicus, an emerging pathogen causing cavitary lung lesions
Authors: Taneja juhi , Chatterjee Kuhu , Sachdeva Ruchi Arora , Abbas S Zafar , Sen MK
Published: January 2023

Introduction:  Rhizopus homothallicus is a new emerging pathogen causing Mucormycosis.
Case Presentation: We report a case of pneumonia caused by Rhizopus homothallicus in a 54 year old type 2 diabetic patient. The organism was isolated from bronchoalveolar lavage fluid and preliminary identified by fungal morphology and finally by sequencing of the internal transcribed spacer region.
Conclusion: Mucormycosis may be associated with cavitary lung lesions in the backdrop of poorly controlled diabetes or other immunosuppressed states. Pulmonary mucormycosis may have variable clinical and radiological presentations. Therefore, strong clinical suspicion and prompt management can prevent high fatality associated with the disease.
Optimisation of aurodox production by Streptomyces goldiniensis.
Authors: E McHugh Rebecca , Giard Josephine , Braes Robyn E , McKean Iain , Roe Andrew J , Hoskisson Paul A
Published: January 2023

Aurodox is a specialised metabolite of Streptomyces goldiniensis originally identified for its anti-streptococcal and anti-staphylococcal activity. More recently, there has been a renewed focus on the study of aurodox as the compound has been shown to inhibit virulence in both Enteropathogenic and Enterohemorrhagic Escherichia coli (EPEC/EHEC). Aurodox is able to inhibit host colonization in EPEC and EHEC infections via the downregulation of the Type III Secretion System – a major virulence factor in these pathogens. To further investigate activity, increased quantities of the compound are required for in-depth mechanism of action studies. To identify suitable aurodox production conditions, a number of relevant fermentation media were tested for enhanced aurodox yield, followed by bioassay and Liquid Chromatography Mass Spectrometry analysis. Glucose Yeast Extract medium (GYM) was identified as the leading production medium tested. Further analysis of S. goldiniensis growth in GYM medium established the optimum temporal range for aurodox production. A minimum growth period of 154 hours is required for detectable aurodox production in S. goldiniensis fermentations in liquid GYM medium. To improve overall aurodox titres, a heterologous expression (HE) approach was taken and four potential HE hosts were investigated. These data indicated that the aurodox biosynthetic gene cluster can be heterologously expressed in both S. collinus Tü365 and S. coelicolor M1152, with increased aurodox titres compared to those of S. goldiniensis. This work demonstrates how traditional physiological analysis and modern genetic techniques can be combined to improve natural product production for detailed mode-of-action studies.
Effects of the COVID-19 Pandemic on Individuals with Fibromyalgia – a Systematic Scoping Review Protocol
Authors: Sahar Tali , Jalali Ali , Toupin Sylvie , Verner Maria , Mitrovic Sabrina , Minerbi Amir , Shir Yoram , Fitzcharles Mary-Ann , Pagé M. Gabrielle
Published: January 2023

Objective

The objectives of this review are to systematically search databases and identify studies that examined the effects of COVID-19 pandemic on symptomatology of adults who had fibromyalgia prior to the pandemic, in order to map the existing knowledge and identify knowledge gaps.

Introduction

The COVID-19 pandemic has affected people worldwide in multiple ways. Some suffered infection of varying severity and many experienced stressors associated with quarantine restrictions, lockdowns, and the consequences of social distancing. An initial literature search indicates that the pandemic had different and sometime contradicting effects on individuals with fibromyalgia; while some people experienced worsening of symptoms, others reported symptom relief because of the reduced pace and demands of daily life.

Inclusion criteria

Any studies that explored the experience of adults with fibromyalgia syndrome during the COVID-19 pandemic. We will review only studies with participants who were diagnosed with fibromyalgia prior to the pandemic.

Methods

Following a pilot search, we developed a full search strategy for Medline, Embase, CINAHL and PsycInfo. The reference list of all included sources of evidence will be screened for additional studies. Sources of unpublished studies to be searched: clinical trial.gov, OPENGREY.EU and MedRxiv. Studies in any language will be included. Abstracts will be screened for inclusion by two reviewers. Similarly, two independent reviewers will systematically extract the data from the included articles. Disagreements in any stage will be resolved through consensus. The results will be presented in tables and will be accompanied by a narrative analysis.
Systems biological assessment of the temporal dynamics of immunity to a viral infection in the first weeks and months of life
Authors: Wimmers Florian , Burrell Allison R. , Feng Yupeng , Zheng Hong , Arunachalam Prabhu S. , Hu Mengyun , Spranger Sara , Nyhoff Lindsay , Joshi Devyani , Trisal Meera , Awasthi Mayanka , Bellusci Lorenza , Ashraf Usama , Kowli Sangeeta , Konvinse Katherine C. , Yang Emily , Blanco Michael , Pellegrini Kathryn , Tharp Gregory , Hagan Thomas , Chinthrajah R. Sharon , Grifoni Alba , Sette Alessandro , Nadeau Kari C. , Haslam David B. , Bosinger Steven E. , Wrammert Jens , Maecker Holden T. , Utz Paul J. , Wang Taia T. , Khurana Surender , Khatri Purvesh , Staat Mary A. , Pulendran Bali
Published: January 2023

The dynamics of innate and adaptive immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to SARS-CoV-2 infection in infants and young children in the first weeks and months of life by analyzing blood samples collected before, during, and after infection with Omicron and Non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, were stably maintained for >300 days. Antigen-specific memory B cell (MCB) responses were durable for 150 days but waned thereafter. Somatic hypermutation of V-genes in MCB accumulated progressively over 9 months. The innate response was characterized by upregulation of activation markers on blood innate cells, and a plasma cytokine profile distinct from that seen in adults, with no inflammatory cytokines, but an early and transient accumulation of chemokines (CXCL10, IL8, IL-18R1, CSF-1, CX3CL1), and type I IFN. The latter was strongly correlated with viral load, and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell transcriptomics. Consistent with this, single-cell ATAC-seq revealed enhanced accessibility of chromatic loci targeted by interferon regulatory factors (IRFs) and reduced accessibility of AP-1 targeted loci, as well as traces of epigenetic imprinting in monocytes, during convalescence. Together, these data provide the first snapshot of immunity to infection during the initial weeks and months of life.
Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection
Authors: Liu Aoxing , Genovese Giulio , Zhao Yajie , Pirinen Matti , Zekavat Maryam M. , Kentistou Katherine , Yang Zhiyu , Yu Kai , Vlasschaert Caitlyn , Liu Xiaoxi , Brown Derek W. , Hudjashov Georgi , Gorman Bryan , Dennis Joe , Zhou Weiyin , Momozawa Yukihide , Pyarajan Saiju , Tuzov Vlad , Pajuste Fanny-Dhelia , Aavikko Mervi , Sipilä Timo P. , Ghazal Awaisa , Huang Wen-Yi , Freedman Neal , Song Lei , Gardner Eugene J. ,   FinnGen,   BCAC,   MVP, Sankaran Vijay G. , Palotie Aarno , Ollila Hanna M. , Tukiainen Taru , Chanock Stephen J. , Mägi Reedik , Natarajan Pradeep , Daly Mark J. , Bick Alexander , McCarroll Steven A. , Terao Chikashi , Loh Po-Ru , Ganna Andrea , Perry John R.B. , Machiela Mitchell J.
Published: January 2023

Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants inFBXO10which confer a two-fold increased risk of mLOX. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion.
Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis
Authors: Luan Yi , Hu Jiajia , Wang Qijun , Li Wenxue , Wang Xujun , Qu Rihao , Rajendran Barani Kumar , Zhou Hongyue , Liu Peng , Shi Yu , Liu Yansheng , Lu Jun , Tang Wenwen , Wu Dianqing
Published: January 2023

WNT5A and WNT5B are two close homologs, both of which are implicated in the pathogenesis of inflammatory bowel diseases. However, the roles these two proteins play in the disease remain largely uncharacterized. Here, we report that double knockout ofWnt5aandWnt5b(Wnt5DKO) protects mice from Dextran Sodium Sulfate (DSS)-induced colitis in mice, accompanied with greater splenomegaly, stronger expansion of peripheral myeloid cells, and less colonic CD8+T cell granzyme B expression than those of the control mice. Depletion of neutrophils or splenectomy abrogates the phenotypic differences betweenWnt5DKO and control mice largely by exacerbating colitis phenotypes and increasing colonic CD8+T cell GZMB expression in theWnt5DKO mice. In addition, neutrophils from theWnt5DKO colitic mice exert stronger suppression of CD8+T cells than those from the control mice in culture. Single-cell RNA sequencing and proteomic analyses indicate that neutrophils from DSS-treatedWnt5DKO mice are of hyper-immunosuppressive and hypo-inflammatory characteristics and are distinct from those of DSS-treated control mice as well as myeloid-derived suppressor cells in tumor-bearing mice. Thus, our study reveals that the lack of WNT5 reprograms neutrophils in spleens to limit colonic injury during DSS-induced colitis.
Kinetic modelling of sterol transport between plasma membrane and endo-lysosomes based on quantitative fluorescence and X-ray imaging data
Authors: Wüstner Daniel , Juhl Alice Dupont , Egebjerg Jacob Marcus , Werner Stephan , McNally James , Schneider Gerd
Published: January 2023

Niemann Pick type C1 and C2 (NPC1 and NPC2) are two sterol-binding proteins which, together, orchestrate cholesterol transport through late endosomes and lysosomes (LE/LYSs). NPC2 can facilitate sterol exchange between model membranes severalfold, but how this is connected to its function in cells is poorly understood. Using fluorescent analogs of cholesterol and quantitative fluorescence microscopy, we have recently measured the transport kinetics of sterol between plasma membrane (PM), recycling endosomes (REs) and LE/LYSs in control and NPC2 deficient fibroblasts. Here, we employ kinetic modeling of this data to determine rate constants for sterol transport between intracellular compartments. Our model predicts that sterol is trapped in intraluminal vesicles (ILVs) of LE/LYSs in the absence of NPC2, causing delayed sterol export from LE/LYSs in NPC2 deficient fibroblasts. Using soft X-ray tomography, we confirm, that LE/LYSs of NPC2 deficient cells but not of control cells contain enlarged, carbon-rich intraluminal vesicular structures, supporting our model prediction of lipid accumulation in ILVs. By including sterol export via exocytosis of ILVs as exosomes and by release of vesicles – ectosomes – from the PM, we can reconcile measured sterol efflux kinetics and show that both pathways can be reciprocally regulated by the intraluminal sterol transfer activity of NPC2 inside LE/LYSs. Our results thereby connect the in vitro function of NPC2 as sterol transfer protein between membranes with its in vivo function.
Programmable RNA detection with CRISPR-Cas12a
Authors: Rananaware Santosh R. , Vesco Emma K. , Shoemaker Grace M. , Anekar Swapnil S. , Sandoval Luke Samuel W. , Meister Katelyn S. , Macaluso Nicolas C. , Nguyen Long T. , Jain Piyush K.
Published: January 2023

CRISPR is a prominent bioengineering tool and the type V CRISPR-associated protein complex, Cas12a, is widely used in diagnostic platforms due to its innate ability to cleave DNA substrates. Here we demonstrate that Cas12a can also be programmed to directly detect RNA substrates without the need for reverse transcription or strand displacement. We discovered that while the PAM-proximal “seed” region of the crRNA exclusively recognizes DNA for initiatingtrans-cleavage, the PAM-distal region or 3’-end of the crRNA can tolerate both RNA and DNA substrates. Utilizing this property, we developed a method named Split Activators for Highly Accessible RNA Analysis or ‘SAHARA’ to detect RNA sequences at the PAM-distal region of the crRNA by merely supplying a short ssDNA or a PAM containing dsDNA to the seed region. Notably, SAHARA is Mg2+concentration- and pH-dependent, and it was observed to work robustly at room temperature with multiple orthologs of Cas12a. SAHARA also displayed a significant improvement in the specificity for target recognition as compared to the wild-type CRISPR-Cas12a, at certain positions along the crRNA. By employing SAHARA we achieved amplification-free detection of picomolar concentrations of miRNA-155 and hepatitis C virus RNA. Finally, SAHARA can use a PAM-proximal DNA as a switch to control the trans-cleavage activity of Cas12a for the detection of both DNA and RNA targets. With this, multicomplex arrays can be made to detect distinct DNA and RNA targets with pooled crRNA/Cas12a complexes. In conclusion, SAHARA is a simple, yet powerful nucleic acid detection platform based on Cas12a that can be applied in a multiplexed fashion and potentially be expanded to other CRISPR-Cas enzymes.

Abstract Figure
A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers
Authors: Kenanova Dyana N. , Visser Emira J. , Virta Johanna M. , Sijbesma Eline , Centorrino Federica , Vickery Holly R. , Zhong Mengqi , Neitz R. Jeffrey , Brunsveld Luc , Ottmann Christian , Arkin Michelle R.
Published: January 2023

Protein-protein interactions (PPIs) are responsible for the proper function of biological processes and, when dysregulated, commonly lead to disease. PPI stabilization has only recently been systematically explored for drug discovery despite being a powerful approach to selectively target intrinsically disordered proteins and hub proteins, like 14-3-3, with multiple interaction partners. Disulfide tethering is a site-directed fragment-based drug discovery (FBDD) methodology for screening small molecules in a quantitative, high-throughput manner. We explore the scope of the disulfide tethering technology for the discovery of selective fragments as starting points for the development of potent small molecule PPI stabilizers and molecular glues using the hub protein 14-3-3σ. The complexes with 5 biologically and structurally diverse phospho-peptides, derived from the 14-3-3 client proteins ERα, FOXO1, C-RAF, USP8, and SOS1, were screened for hit identification. Stabilizing fragments could be found for 4/5 client complexes with a diversified hit-rate and stabilizing efficacy for the different 14-3-3/client phospho-peptides. Extensive structural elucidation revealed the ability and adaptivity of the peptide to make productive interactions with the tethered fragments as key criterion for cooperative complex formation. We validated eight fragment stabilizers, six of which showed selectivity for one phospho-peptide client, and structurally characterized two nonselective hits and four fragments that selectively stabilized C-RAF or FOXO1. The most efficacious of these fragments increased 14-3-3σ/C-RAF phospho-peptide affinity by 430-fold. Disulfide tethering to the wildtype C38 in 14-3-3σ provided diverse structures for future optimization of 14-3-3/client stabilizers and highlighted a systematic method to discover molecular glues.
Overexpression of ADAR1 in mice does not initiate or accelerate cancer formationin vivo
Authors: Ruiz Shannon Mendez , Chalk Alistair M , Goradia Ankita , Heraud-Farlow Jacki , Walkley Carl R
Published: January 2023

Adenosine to inosine editing (A-to-I) in regions of double stranded RNA (dsRNA) is mediated by adenosine deaminase acting on RNA 1 (ADAR1) or ADAR2. ADAR1 and A-to-I editing levels are increased in many human cancers. It is not established if elevated ADAR1 represents a driver or passenger during cancer formation. We established a series of murine alleles to allowin vivooverexpression of ADAR1, its individual isoforms or mutant forms of ADAR1 to understand how it contributes to cancer pathogenesis. The widespread overexpression of ADAR1 or either the p110 or p150 isoforms as sole lesions was well tolerated and did not result in cancer formation. Therefore, ADAR1 overexpression alone is not sufficient to initiate cancer. We demonstrate that endogenous ADAR1 and A-to-I editing levels increased upon immortalization by loss of p53 in murine cells, consistent with the observations from human cancers. We tested if ADAR1 overexpression could co- operate with cancer initiated by loss of tumour suppressors using a model of osteosarcoma. We did not see a disease potentiating or modifying effect of overexpressing ADAR1 or its isoforms. We conclude that the increase in ADAR1 expression and A-to-I editing in cancers is a passenger, rather than a driver, of tumor formation.
Heterozygous Nonsense Variants in the Ferritin Heavy Chain GeneFTH1Cause a Novel Pediatric Neuroferritinopathy
Authors: Shieh Joseph T , Tintos-Hernández Jesus A , Murali Chaya N. , Penon-Portmann Monica , Flores-Mendez Marco , Santana Adrian , Bulos Joshua A. , Du Kang , Dupuis Lucie , Damseh Nadirah , Mendoza-Londoño Roberto , Berera Camilla , Lee Julieann C , Phillips Joanna J , Alves César A P F , Dmochowski Ivan J , Ortiz-González Xilma R
Published: January 2023

Ferritin, the iron storage protein, is composed of light and heavy chain subunits, encoded byFTLandFTH1, respectively. Heterozygous variants inFTLcause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants inFTH1have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients withde novoheterozygousFTH1variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. NonsenseFTH1variants were identified using whole exome sequencing, with a recurrentde novovariant (p.F171*) identified in three unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. VariantFTH1mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminus variants inFTH1truncate ferritin’s E-helix, altering the four-fold symmetric pores of the heteropolymer and likely diminish iron-storage capacity.FTH1pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon ofFTH1cause a novel disorder in the spectrum of NBIA. Targeted knock-down of mutantFTH1transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this novel pediatric neurodegenerative disorder.
Real-time evaluation and adaptation to facilitate rapid recruitment in a large cohort
Authors: Honushefsky Ashley , Wagner Eric S. , Sheridan Kathleen , Spickard Kathleen M. , LeMasters William R. , Walter Carroll N. , Beaver Taryn , Rahm Alanna Kulchak , Buchanan Adam H.
Published: January 2023

Objectives

Recruiting large, diverse cohorts efficiently can speed the translation of findings into care across a range of scientific disciplines and medical specialties. Yet, efficient recruitment can be hampered by factors such as financial barriers, logistical concerns, and lack of resources for patients and clinicians. Here we use a case study of a large, prospective trial of a multi-cancer early detection test to describe how the study team tracked enrollment, protocol fidelity, and participant experience and iteratively adapted procedures.

Methods

While conducting a large, prospective trial of a multi-cancer early detection blood test at Geisinger, an integrated health system in central Pennsylvania, we monitored recruitment progress, fidelity to protocol procedures, and participants’ satisfaction. Tracking mechanisms such as paper records, electronic health records, research databases, dashboards, and electronic files were utilized to measure each outcome. We then reviewed study procedures and timelines to list the implementation strategies that were used to address barriers to recruitment, protocol fidelity and participant satisfaction.

Results

We enrolled 10,006 women ages 65-75 over 22 months. Adaptations to recruitment and enrollment methods that contributed to achieving the enrollment goal included adopting group consenting, improving visit convenience, increasing electronic capture and tracking of data and source documents, staffing optimization via leveraging resources external to the study team when appropriate, and integrating the disclosure of study results into routine clinical care without adding unfunded work for physicians. We maintained high protocol fidelity and positive participant experience as exhibited by a very low protocol deviation rate and a low number of participant complaints.

Conclusion

Recruiting rapidly for large studies – and thereby facilitating clinical translation – requires a nimble, creative approach that marshals available resources and changes course according to data. Planning a rigorous assessment of a study’s implementation outcomes prior to study recruitment can further ground study adaptations and facilitate translation into practice. This can be accomplished by proactively and continuously assessing and revising implementation strategies.

Strengths and limitations of this study

Synthesis and tracking of various data

Real-time identification of necessary adaptations

Mapping of adaptations to problems and consequences

Analysis of results post-hoc

Inability to analyze the value or impact of a single adaptation