bluuebunny/crossref_metadata_2025 huggingface dataset:
Blinding and sham control methods in trials of physical, psychological, and self-management interventions for pain (article II): a meta-analysis relating methods to trial results
Authors: Hohenschurz-Schmidt David , Draper-Rodi Jerry , Vase Lene , Scott Whitney , McGregor Alison , Soliman Nadia , MacMillan Andrew , Olivier Axel , Cherian Cybill Ann , Corcoran Daniel , Abbey Hilary , Freigang Sascha , Chan Jessica , Phalip Jules , Sørensen Lea Nørgaard , Delafin Maite , Baptista Margarida , Medforth Naomi R. , Ruffini Nuria , Andresen Stephanie Skøtt , Ytier Sylvain , Ali Dorota , Hobday Harriet , Ngurah Agung Adhiyoga Santosa Anak Agung , Vollert Jan , Rice Andrew S.C.
Published: July 2022

Sham interventions in randomized clinical trials (RCTs) of physical, psychological, and self-management (PPS) therapies for pain are highly variable in design and believed to contribute to poor internal validity. However, it has not been formally tested whether the extent to which sham controls resemble the treatment under investigation consistently affects trial outcomes, such as effect sizes, differential attrition, participant expectancy, and blinding effectiveness. Placebo- or sham-controlled RCTs of PPS interventions of clinical pain populations were searched in 12 databases. The similarity of control interventions to the experimental treatment was rated across 25 features. Meta-regression analyses assessed putative links between employed control interventions, observed effect sizes in pain-related outcomes, attrition, and blinding success. The sample included 198 unique control interventions, dominated by manual therapy and chronic musculoskeletal pain research. Meta-analyses indicated small-to-moderate benefits of active treatments over control interventions, across subgroups of manual therapies, exercise, and rehabilitation, and psychological intervention trials. Multiple meta-regression modelling demonstrated that similarity between sham control and tested interventions predicted variability in pain-related outcomes, attrition, and blinding effectiveness. Influential variables were differences relating to the extent of intervention exposure, participant experience, and treatment environments. The results support the supposed link between blinding methods and effect sizes, based on a large and systematically sourced overview of methods. However, challenges to effective blinding are complex and often difficult to discern from trial reports. Nonetheless, these insights have the potential to change trial design, conduct, and reporting and will inform guideline development.
Pregnancy outcomes in women with pemphigus exposed to rituximab before or during pregnancy
Authors: Dehghanimahmoudabadi Azin , Kianfar Nika , Akhdar Marwa , Dasdar Shayan , Balighi Kamran , Mahmoudi Hamidreza , Daneshpazhooh Maryam
Published: July 2022

Background:

Rituximab (RTX) is an effective treatment for pemphigus; however, the drug labeling recommends not to use RTX within 1 year before conception.

Objectives:

To report pregnancy outcomes of patients with pemphigus who were treated with RTX before or during pregnancy.

Methods:

We identified 19 pregnancies with RTX exposure before or during pregnancy. All had previously been advised not to get pregnant within 1 year of RTX administration. The cases were categorized into 3 groups of exposure of within 6 months (group A), between 6 and 12 months (group B), and longer than 12 months of conception (group C). The pregnancy outcomes of different RTX exposure intervals were compared.

Results:

Group A included 9 pregnancies, of which 3 had received RTX accidentally after conception. Group B and C included 4 and 6 pregnancies, respectively. There was no significant difference between the groups regarding pregnancy outcomes. Overall, there were 17 live births, 1 spontaneous abortion, and 1 termination. Of the live births, 3 preterm deliveries and 4 low-birth-weight neonates were noted. Moreover, 1 neonate was hospitalized due to early-onset neonatal sepsis, and 1 had hydronephrosis. Disease flare-up occurred in 5 patients during pregnancy (4 minor and 1 major relapses) and in 5 patients after delivery (3 minor and 2 major relapses).

Conclusions:

Except for 1 case of neonatal sepsis which survived following medical treatment, no serious relevant adverse pregnancy outcome that could be attributed to RTX exposure before and during early pregnancy in women with pemphigus was detected. Nevertheless, RTX should not be administered within 1 year before planned pregnancy, as not enough data is available yet.
Midline Catheters
Authors: Hadaway Lynn , Mermel Leonard A.
Published: July 2022

In the past 30 years, midline catheter use has grown rapidly. For several reasons, many providers and facilities are attempting to reduce the number of central venous catheters and subsequent central line–associated bloodstream infections (CLABSIs) by using midline catheters. Vessel preservation requires attention to all vascular access device (VAD)-associated complications and not only central line bloodstream infection. There is still much confusion about the appropriate tip location and the characteristics of fluids and medications that can safely be infused through a midline catheter residing in a peripheral vein. TheInfusion Therapy Standards of Practice(theStandards) focuses on assessment of characteristics of infusion therapies that must be considered for VAD selection as an evidence-based list of fluids and medications for infusion through peripheral veins has yet to be established. This review of midline catheter studies evaluates the evidence regarding the substitution of a midline catheter for a central venous catheter. Many issues need to be addressed, such as studies that include an outcome list that mixes defined clinical complications (eg, thrombosis) with signs and symptoms of complications (eg, leaking). Another issue is basing a major change of clinical practice on retrospective chart reviews. Although a midline catheter may be appropriate for some patients, additional studies of a higher level of evidence are needed before this major practice change should occur.
Board Certification in Cosmetic Surgery: An Analysis of Punitive Actions
Authors: Gabrick Kyle , Makhoul Alan T. , Riccelli Vincent , Perdikis Galen , Janis Jeffrey E. , Drolet Brian C.
Published: July 2022

Background:

American Board of Plastic Surgery (ABPS) Diplomates complete training in aesthetic surgery through an ACGME-accredited program. American Board of Cosmetic Surgery (ABCS) diplomates complete residency training in a “related” specialty, some historically non-surgical, followed by an American Association of Cosmetic Surgery (AACS) fellowship. Unlike the ABPS, the ABCS is not recognized by the American Board of Medical Specialties (ABMS) as an equivalent certifying board. This study evaluated differences in the rates of punitive action against Diplomates of the ABPS and the ABCS.

Methods:

Diplomats were accessed from their respective society's websites (ABCS&ABPS). Punitive action data were obtained by search of publicly available state medical board databases. A comparative analysis was performed between ABPS and ABCS.

Results:

One thousand two-hundred and eight physicians were identified for comparative analysis. Two hundred and sixty-six (22%) were members of the ASPS, 549 (49%) were members of the TAS. ABCS Diplomates had significantly higher rates of disciplinary administrative action by their respective state medical boards [31 (9.0%)] when compared with ABPS members [TAS: 26 (4.4%) and ASPS: 8 (3.1%); p=0.003] with a higher; proportion of repeat offenders. In addition, ABCS Diplomates had more public letters of reprimand [ABCS:12 (3.5%) vs. TAS: 6 (1.2%) and ASPS: 2 (0.8%); p=0.015].

Conclusions:

ABCS Diplomates have significantly higher rates of punitive actions than ABPS Diplomates. Although the reasons for this discrepancy warrant further investigation, punitive data should be transparently and publicly available to aid patients in informed decision-making.
The Usefulness of Computer-Aided Detection of Brain Metastases on Contrast-Enhanced Computed Tomography Using Single-Shot Multibox Detector: Observer Performance Study
Authors: Sakamoto Naoya , Amemiya Shiori , Takao Hidemasa , Kato Shimpei , Yamashita Hiroshi , Fujimoto Kotaro , Nakaya Moto , Kanemaru Noriko , Miyo Rintaro , Hosoi Reina , Mizuki Masumi , Abe Osamu
Published: July 2022

Objective

This study aimed to test the usefulness of computer-aided detection (CAD) for the detection of brain metastasis (BM) on contrast-enhanced computed tomography.

Methods

The test data set included whole-brain axial contrast-enhanced computed tomography images of 25 cases with 62 BMs and 5 cases without BM. Six radiologists from 3 institutions with 2 to 4 years of experience independently reviewed the cases, both in conditions with and without CAD assistance. Sensitivity, positive predictive value, number of false positives, and reading time were compared between the conditions using paired t tests. Subanalysis was also performed for groups of lesions divided according to size. A P value <0.05 was considered statistically significant.

Results

With CAD, sensitivity significantly increased from 80.4% to 83.9% (P = 0.04), whereas positive predictive value significantly decreased from 88.7% to 84.8% (P = 0.03). Reading time with and without CAD was 112 and 107 seconds, respectively (P = 0.38), and the number of false positives was 10.5 with CAD and 7.0 without CAD (P = 0.053). Sensitivity significantly improved for 6- to 12-mm lesions, from 71.2% without CAD to 80.3% with CAD (P = 0.02). The sensitivity of the CAD (95.2%) was significantly higher than that of any reader (with CAD: P = 0.01; without CAD: P = 0.005).

Conclusions

Computer-aided detection significantly improved BM detection sensitivity without prolonging reading time while marginally increased the false positives.
Adenoidal-Nasopharyngeal Ratio in Healthy Adults on Cone Beam Computed Tomography
Authors: Chan King Chong , Vasilyeva Daria , Bansal Tarika , Moonis Gul
Published: July 2022

Objective

This study aimed to quantify the adenoidal-nasopharyngeal ratio (ANR) in a cohort of healthy adults on cone beam computed tomography (CT) using the Fujioka method, which is a reproducible measure of adenoid size and nasopharyngeal patency.

Methods

Electronic health records and maxillofacial cone beam CT in 202 consecutive patients aged 16 years and older were retrospectively reviewed. Patients with a history of adenoidectomy, sinonasal disease, lymphoproliferative disorders, and cleft palate were excluded from the study. The midsagittal reconstructed cone beam CT image was used to determine the ANR. Statistical analysis was conducted using 1-way analysis of variance.

Results

Of the 202 subjects, 131 were female and 71 were male. The mean ± SD subject age was 45.43 ± 20.79 years (range, 16–91 years). The mean ± SD ANR in all subjects was 0.22 ± 0.13 (range, 0.03–0.75) and in each decade of adult life was as follows: younger than 21 years, 0.39 ± 0.12; 21 to 30 years, 0.29 ± 0.11; 31 to 40 years, 0.21 ± 0.09; 41 to 50 years, 0.20 ± 0.07; 51 to 60 years, 0.16 ± 0.10; 61 to 70 years, 0.13 ± 0.05; 71 to 80 years, 0.12 ± 0.05; 81 to 90 years, 0.11 ± 0.04; and 91 years or older, 0.10 ± 0. The differences in mean ANR among the age subgroups were statistically significant (P < 0.001).

Conclusions

The mean ANR gradually decreased from 0.39 in the second decade of life to 0.16 in the sixth decade of life and plateaued at approximately 0.10 thereafter.
Elucidating the virulence genes harboured by carbapenemase- and non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae rectal isolates from patients admitted to intensive care units using whole-genome sequencing in Kuwait
Authors: Al Fadhli Amani H. , Jamal Wafaa Y. , Rotimi Vincent O.
Published: July 2022

Introduction.

Klebsiella pneumoniae

is a Gram-negative pathogen responsible for community- and nosocomial-acquired infections. The presence of an accessory genome determines the bacterial pathogenicity and the host immune response, and thus indicates multidrug-resistant strains or more virulent groups. Little is known about the virulence genes in

K. pneumoniae

in Kuwait.

Hypothesis/Gap Statement. The diversity of virulence genes and capsule loci in

K. pneumoniae

isolates warrants further genomic studies to better understand their transmission within the hospitals in Kuwait.

Aim. We aimed to investigate the virulence genes harboured by

K. pneumoniae

isolated from rectal swabs of intensive care unit (ICU) patients in two Kuwaiti teaching hospitals.

Methodology. Six isolates from patients in the ICUs of Al Razi and Mubarak hospitals, designated RZH144, RZH132 RZH108 and RZH173, and MKH381 and MKH347, respectively, were subjected to whole-genome sequencing (WGS) assays. RZH144 and RZH132 were non-carbapenemase-producing

K. pneumoniae

(NCKP) isolates negative for genes encoding carbapenemase production by PCR assays, and the remaining four were carbapenemase-producing

K. pneumoniae

(CPKP) isolates. Isolates were characterized by phenotypic, PCR and WGS methods. Susceptibility testing was performed by E test and clonality by multilocus sequence typing. Analysis of the isolates’ assembled contigs was carried out using Kleborate (https://pathogen.watch).

Results. An NCPE RZH132

K. pneumoniae

isolate belonged to ST231-wzi104 and harboured gene clusters encoding the biosynthesis of the siderophore aerobactin (iuc5) on 62-3LV. The capsular locus variants were KL51 and O locus O1v2. Another NCPKP RZH144 isolate was confirmed as ST43-wzi412 and harboured KL61 and O1v1. The four CPKP isolates harboured two virulence loci – ybt14 and iuc5 – encoding the siderophores yersiniabactin and aerobactin, respectively. They belonged to ST231-wzi104 and harboured yersiniabactin on ICEKp5. The sequence type of ybt was YbST145-1LV. Strain RZ108 was devoid of virulence loci. Its sequence type was ST15-wzi151 and harboured KL48 and O1V1. ST231 clonal lineage isolates shared common virulence plasmid variants.

Conclusion. The CPKP ST231 had the highest virulence score and contained iuc5, which was found for the first time in ST231-CPKP isolates in Kuwait.
Cytocapsular cancer evolution analyses of 311 kinds of cancers
Authors: Yi Tingfang , Wagner Gerhard
Published: July 2022

Cancer is a leading cause of human lethality. Cytocapsular tube, a newly discovered cancer cell specific organelle in vivo, plays pleiotropic biological functions and its generation distinguishes incomplete from complete cancer cells. It is essential for complete malignant tumor growth, cancer metastasis, conventional cancer drug pan-resistance, and cancer relapse. However, mechanisms of cytocapsular cancer evolution are still elusive. Here, we investigated cytocapsular cancer evolution in 311 kinds/subtype of cancers, including 265 types/subtypes of solid cancers and 46 types/subtypes of liquid/hematological cancers. We analyzed 9,856 pieces of annotated clinical tissue samples from 9,682 cancer patients in the asymptotic early stage, Stages I-IV, and before, during and after cancer treatments. We discovered that cytocapsular cancer evolution in solid cancers includes: transformation, formation of incomplete cancer cells, transition to complete cancer cells surrounded by cytocapsulae (CC), merging of complete cancer cells by devolution, formation of cytocapsular tubes (CCTs) and complete malignant tumors in superlarge CC. This is followed by generation of CCT networks, cancer metastasis, CCT network-tumor system (CNTS), CCT degradation and decomposition, and spatiotemporal moving CNTS. In addition, cytocapsular cancer evolution related to liquid (hematological) cancers including bone marrow, thymus, lymph nodes, and spleen, mirrors the process in solid cancers, except that cancer cells in the blood only form CCs but not CCTs. In summary, our study established a cytocapsular cancer evolution atlas, which may pave an avenue for the research on therapy of both solid and liquid cancers.
Microbubbles for improved nucleic acid extraction in wastewater samples for viral RNA detection
Authors: Wegner Casey , Roussey Jon , Carey Maureen , Macintyre Brittany , Snow Tiffany , Sieglaff Douglas , Bridi Aline , Battiste Shauntina , Livi Carolina B. , McNaughton Brandon
Published: July 2022

The use of wastewater-based epidemiology has increased in recent years due to the publication of COVID-19 online trackers and the focus of the media on the pandemic. Yet the analysis of viromes in wastewater has been widely applied for several decades in conjunction with traditional chemical analysis approaches. However, even though real time quantitative polymerase chain reaction (RT-qPCR) based molecular detection methods are now mainstream in large and small labs alike, wastewater sampling and nucleic acid extraction procedures are not yet standardized or optimized to enable routine and robust analysis and results interpretation. Here, we employ a flotation-based nucleic acid extraction method using microbubbles that allows for simple direct collection and lysis of total wastewater samples without the requirement for pasteurization or filtration of solid components prior to analysis. An additional advantage discovered during testing was reduced sample input needs while maintaining sensitivity compared to precipitation and ultrafiltration-based methods. Microbubbles designed to bind nucleic acids enable convenient workflows, fast extraction, and concentration and purification of RNA and DNA that is compatible with downstream genomic analyses.

Microbubble-based capture of nucleic acids from raw (unpasteurized) and unfiltered (containing solids) wastewater with subsequent elution offers several advantages over existing methods. Using microbubbles, the required sample input and protocol duration are reduced while sensitivity of downstream genomic analysis is increased.
A RT-qPCR system using a degenerate probe for specific identification and differentiation of SARS-CoV-2 Omicron (B.1.1.529) Variants of Concern
Authors: Jessen Randi , Nielsen Line , Larsen Nicolai Balle , Cohen Arieh Sierra , Gunalan Vithiagaran , Marving Ellinor , Alfaro-Núñez Alonzo , Polacek Charlotta ,   The Danish COVID-19 Genome Consortium (DCGC), Fomsgaard Anders , Spiess Katja
Published: July 2022

Fast surveillance strategies are needed to control the spread of new emerging SARS-CoV-2 variants and gain time for evaluation of their pathological potential. This was essential for the Omicron variant (B.1.1.529) that replaced the Delta variant (B.1.617.2) and is currently the dominant SARS-CoV-2 variant circulating worldwide. RT-qPCR strategies complement whole genome sequencing, especially in resource lean countries, but mutations in the targeting primer and probe sequences of new emerging variants can lead to a failure of the existing RT-qPCRs. Here, we introduced an RT-qPCR platform for detecting the Delta- and the Omicron variant simultaneously using a degenerate probe targeting the key ΔH69/V70 mutation in the spike protein. By inclusion of the L452R mutation into the RT-qPCR platform, we could detect not only the Delta and the Omicron variants, but also the Omicron sub-lineages BA.1, BA.2 and BA.4/BA.5. The RT-qPCR platform was validated in small- and large-scale. It can easily be incorporated for continued monitoring of Omicron sub-lineages, and offers a fast adaption strategy of existing RT-qPCRs to detect new emerging SARS-CoV-2 variants using degenerate probes.
Development of an Accurate and Rapid Antigen Assay for COVID-19 Diagnostics Using Saliva
Authors: Troup Camille , Mukhopadhyay Debnath , Chakrabarty Tania , Madan Anup , Satyanarayana Sri , Mehta Shreefal , Dwarakanath Su
Published: July 2022

The global outbreak of COVID-19 highlighted the need for rapid and accurate diagnostic testing to control the spread of this highly contagious disease (1-5). Here, we describe the nCoVega COVID-19 antigen rapid test (∼ 15min) that can detect the presence of the SARS-COV-2 virus particles from saliva sample on a portable device. The portable reader instrument, the Vega-200, has a small footprint and is designed for use at point of care settings. The test detects the fluorescence signal using wide-field illumination from antigen-antibody complexes captured on a special filter matrix (6). Results of this clinical evaluation of 183 subjects demonstrates that the nCoVega COVID-19 test performs at par with qRT-PCR tests (7) (gold standard) for both symptomatic and asymptomatic patients, with a strong inverse correlation between RFU (relative fluorescence units) and Ct counts (from RT-PCR) maintaining detection accuracy even at very low viral loads. The test has an analytical performance of 15.3 TCID50/mL, and 100% specificity for COVID-19 as compared to other human respiratory viruses, including other human coronaviruses. The working principle of this assay and test system can be used for developing other rapid, inexpensive antigen assays and it can offer an end-to-end, point-of-care solution to meet the continuous demand in tackling existing and emerging infectious diseases across the globe.
The effectiveness and safety of acupuncture kinesitherapy after percutaneous coronary intervention in patients with coronary heart disease: study protocol for a randomized controlled trial
Authors: Zhang Di , Lu Huaimin , Jin Song , Guo Hong , Liu Xiaoxiao , Xiao Wensheng , Li Hongpeng , Ma Jiang
Published: July 2022

Background

Coronary heart disease(CHD) is a common disease of the cardiovascular system. Percutaneous coronary intervention(PCI) has been proven an effective treatment. Various complications after PCI may further affect the long-term efficacy of PCI. Previous trials have showed that both kinesitherapy(KT) and acupuncture are beneficial to patients with CHD, but need further confirmation. Acupuncture kinesitherapy(AKT) is a kind of combination therapy of acupuncture with exercise training. In this study, we plan to conduct a randomized controlled trial(RCT) to confirm the superior efficacy of AKT compared to KT and conventional medical therapy(MT) in post-PCI rehabilitation for CHD patients, and to further guide the clinical strategy.

Methods

This is a single-center randomized controlled trial with 3 parallel arms. We will recruit 102 CHD patients after PCI and randomly assign them to 3 groups. Participants in 3 groups will receive 2-week MT. Besides, participants in AKT and KT groups will also receive acupuncture kinesitherapy and kinesitherapy alone, respectively. They will be treated once a day, 5-day a week, and the treatment course will last for a total of 2-week with a 2-day off during the course. The primary outcome is the changes in cardiac function. The secondary outcomes include aerobic capacity, muscle strength, flexibility, balance, coordination, mental status, and activity of daily living. All outcomes will be measured at baseline and 2-week after treatment. Adverse events also will be recorded. The cardiac function and activities of daily living will be followed up at 1, 3 and 6 months after treatment.

Discussion

We expect findings of trial will provide important insight into application of AKT as a safety and more effective method for CHD patients. Successful completion of this proposed study will also contribute to promotion of AKT in the clinic in the future.

Trial registration

Chinese clinical trial registry (Register Number: ChiCTR2100048960) http://www.chictr.org.cn/index.aspx.
Experience of Saudi Dental Practitioners with Intraoral Scanners
Authors: Al-Ibrahim Ibrahim K. , Alotaibi Anfal H. , Alshammari Alanoud S. , Madfa Ahmed A.
Published: July 2022

Background

The objective of this study was to investigate the experience of Saudi dental practitioners with intraoral scanners, investigate the current knowledge and improve the practice accordingly.

Methods

At random, electronic surveys were distributed to Saudi dental practitioners. The study received 400 questionnaires, with 310 judged valid for the study. The questionnaire was divided into the following sections: (i) Practitioners’ demographic information such as gender, practice level, and practice experience. (ii) Experience and benefits of intraoral scanners. (iii) Require skills and training of IOS. (iv) Knowledge of IOS usage. Descriptive statistics such as numbers and percentages were used to analyze the collected data. The Chi-square and Fisher’s Exact tests were used to assess the results.

Results

There were 161 women (51.8%) and 149 men among the participants (47.9%). General practitioners (198, or 63.7%) had the most subjects, followed by specialists (80, or 25.7%) and consultants (32, or 10.3%). In terms of IOS use in dental practice, most participants (70.6%) do not use it, while less than one-third do. The majority of participants (52.3%) intend to purchase IOS with significant variations based on gender, experience, and level of practice (p<0.05). Compared to traditional, most participants believe that IOS will eventually replace it, improve quality, and be more aesthetically pleasing. Most dentists believe that using IOS requires special skills and training. More than half of dentists believe IOSs have the same level of accuracy as conventional in producing three units FPDs, implant prosthesis, and complete denture.

Conclusion

It can be concluded that dentists have a high level of satisfaction and a favorable attitude toward using IOS technology in clinical dentistry practice.
FMRP directly interacts with R-loop and shows complex interplay with the DHX9 helicase
Authors: Chakraborty Arijita , Dutta Arijit , Dettori Leonardo G. , Li Jing , Gonzalez Leticia , Xue Xiaoyu , Hehnly Heidi , Sung Patrick , Bah Alaji , Feng Wenyi
Published: July 2022

The author has withdrawn this manuscript due to a duplicate posting of manuscript number 440759. Therefore, the author does not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author
Obtaining polygenic transcriptome risk scores (PTRS) directly from GWAS summary statistics
Authors: Liang Yanyu
Published: July 2022

Polygenic Transcriptome Risk Scores (PTRS) are variations of Polygenic Risk Scores (PRS) that use genetically predicted transcriptome as features for prediction instead of directly using genetic variants. We have shown that when PTRS is combined with PRS, they can yield improved prediction performance and portability across populations (Liang et al., 2022). Given the difficulty of training PTRS using large scale individual-level data (due to both computational burden and the lack of data access), we developed a user friendly software that infers PTRS using GWAS summary results and reference LD. We tested three summary statistics-based PTRS approaches: i) Clumping and thresholding (clump-PTRS), keeping trait associated genes while removing highly correlated ones; ii) Summary statistics-based elastic net PTRS (S-EN-PTRS), an extension of lassosum (Mak et al., 2017) to predicted transcriptome; iii) Naive-PTRS, the sum of predicted expressions of significantly associated genes weighted by PrediXcan-estimated effect sizes (Gamazon et al., 2015). Despite reports that individual-level trained elastic net PTRS outperformed clump-PTRS in (Liang et al., 2022), for most of the 11 traits used in the comparison, clump-PTRS outperformed S-EN-PTRS, which outperformed naive-PTRS.
Valence-dependent self-agency is disturbed in depression and anxiety
Authors: Mehta Marishka M , Na Soojung , Gu Xiaosi , Murrough James W , Morris Laurel S
Published: July 2022

Background

The sense of agency, or the belief in action causality, is an elusive construct that impacts day-to-day experience and decision-making. Despite its relevance in a range of neuropsychiatric disorders, it is widely under-studied and remains difficult to measure objectively in patient populations. We developed and tested a novel cognitive measure of valence-modulated agency perception in an in-person and online cohort.

Methods

The in-person cohort consisted of 52 healthy control subjects and 20 subjects with depression and anxiety disorders (DA), including major depressive disorder and generalized anxiety disorder. The online sample consisted of 254 participants. The task consisted of an effort task for monetary rewards with computerized visual feedback interference and trial-by-trial ratings of self versus other agency.

Results

All subjects across both cohorts demonstrated higher self-agency after receiving positive-win feedback, compared to negative-loss feedback when the level of computer inference was kept constant. Patients with DA showed reduced positive valence-dependent agency compared to healthy controls. Finally, in both cohorts, lower self-agency following negative-loss feedback was associated with worse anhedonia symptoms.

Conclusion

Together this work suggests how positive and negative environmental information impacts the sense of self-agency in healthy subjects, and how it is perturbed in patients with depression and anxiety.
Improved Xerostomia Prediction in Head and Neck Cancer Patients with Dixon Magnetic Resonance Imaging of Glandular Adiposity: Validation of Semi-Quantitative Parotid T1 Signal Intensity Metrics for Biomarker Pre-Qualification
Authors:   Joint Head and Neck Radiotherapy-MRI Development Cooperative,   the MD Anderson Head and Neck Cancer Symptom Working Group, Sanders Keith L. , Mulder Sam , Wahid Kareem A. , McDonald Brigid A. , Ahmed Sara , Salzillo Travis C. , He Renjie , Naser Mohamed A. , Dede Cem , Salama Vivian , Way Ashley , Sharafi Christina Setareh , Mohamed Abdallah S.R. , Rigert Jillian , Chambers Mark , Moreno Amy C. , Hutcheson Katherine A. , Lai Stephen Y. , Fuller Clifton D. , van Dijk Lisanne V.
Published: July 2022

Purpose

Parotid whole-gland magnetic resonance (MR) T1 intensity, thresholded at the 90th percentile (T1 P90), has been previously reported to be a candidate MR imaging biomarker (MR-IBM) for improved prediction of xerostomia development after radiotherapy. Although P90 was previously derived from the parotid glands of T1-weighted MRI, in this study, we aim to validate P90 in an external cohort using fat only images reconstructed from a T1 Dixon MRI sequence, as well as determining alternative T1 intensity thresholds for potential qualification as predictive FDA BEST biomarkers of xerostomia development 6 months after radiotherapy (Xero6m).

Methods

MR-IBMs derived from T1 Dixon intensity-normalized scans from 76 head and neck cancer (HNC) patients were extracted from pre-treatment MR images. Scans were normalized to fat tissue, and imaging characteristics were quantified. A reference model and MR-IBM models were created using multivariable logistic regression to predict Xero6m. External validation was performed using the model coefficients described in a previous study. The area under the curve (AUC) of the resulting models were compared. Stepwise forward feature selection was performed to discover additional MR-IBMs for improved predictions of xerostomia.

Results

The external validation of a previous model coefficients against our cohort showed decreased performance of the P90 MR-IBM model (AUC of 0.73 (CI 0.61-0.85)). The reference model exhibited improved performance when P90 was incorporated (AUC of 0.78 (CI 0.67-0.89)). Feature selection demonstrated the P10 MR-IBM provided performance improvements (AUC of 0.79 (CI: 0.69-0.90)).

Conclusion

Our findings validated P90 as predictive biomarker for radiation-induced xerostomia and showed MR-IBMs derived from Dixon sequences can improve Xero6m prediction when compared to the reference model. Formal biomarker qualification should be considered for T1 sequences/relaxometry via formalized approaches.
Assessment of concordance between related systematic reviews and between related guideline recommendations: protocol for a methodological survey
Authors: Agarwal Arnav , Albarqouni Loai , Badran Nour , Brax Nina , Gandhi Pooja , Pereira Tiago , Roberts Abigail , Zein Ola El , Akl Elie
Published: July 2022

Independent systematic reviewers may arrive at different conclusions when analyzing evidence addressing the same clinical questions. Similarly, independent expert panels may arrive at different recommendations addressing the same clinical topics. When faced with a multiplicity of reviews or guidelines on a given topic, users are likely to benefit from a structured approach to evaluate concordance, and to explain discordant findings and recommendations. This protocol proposes a methodological survey to evaluate the prevalence of concordance between reviews addressing similar clinical questions, and between clinical practice guidelines addressing similar topics; and to identify methodological frameworks for the evaluation of concordance between related reviews and between related guidelines.
Small gene networks can delineate immune cell states and characterize immunotherapy response in melanoma
Authors: Egan Donagh , Kreileder Martina , Nabhan Myriam , Iglesias-Martinez Luis F. , Dovedi Simon , Valge-Archer Viia , Grover Amit , Wilkinson Robert , Slidel Tim , Bendtsen Claus , Barrett Ian , Brennan Donal , Kolch Walter , Zhernovkov Vadim
Published: July 2022

Background

Single-cell sequencing studies have elucidated some of the underlying mechanisms responsible for immune checkpoint inhibitor (ICI) response, but are difficult to implement as a general strategy or in a clinical diagnostic setting. In contrast, bulk RNAseq is now routine for both research and clinical applications. Therefore, our analysis extracts small transcription factor-directed co-expression networks (regulons) from single-cell RNA-seq data and uses them to deconvolute immune functional states from bulk RNA-seq data to characterize patient responses.

Methods

Regulons were inferred in pre-treatment CD45+ cells from metastatic melanoma samples (n=19) treated with first-line ICI therapy (discovery dataset). A logistic regression-based classifier identified immune cell states associated with response, which were characterized according to differentially active, cell-state specific regulons. The complexity of these regulons was reduced and scored in bulk RNAseq melanoma samples from four independent studies (n=209, validation dataset). Patients were clustered according to their regulon scores, and the associations between cluster assignment, response, and survival were determined. Intercellular communication analysis of cell states was performed, and the resulting effector genes were analyzed by trajectory inference.

Results

Regulons preserved the information of gene expression data and accurately delineated immune cell phenotypes, despite reducing dimensionality by > 100-fold. Four cell states, termed exhausted T cells, monocyte lineage cells, memory T cells, and B cells, were associated with therapeutic responses in the discovery dataset. The cell states were characterized by seven differentially active and specific regulons that showed low specificity in non-immune cells. Four clusters with significantly different response outcomes (P <0.001) were identified in the bulk RNAseq validation cohort. An intercellular link between exhausted T cells and monocyte lineage cells was established, whereby their cell numbers were correlated, and exhausted T cells predicted prognosis as a function of monocyte lineage cell number. Analysis of ligand – receptor expression suggested that monocyte lineage cells drive exhausted T cells into terminal exhaustion through programs that regulate antigen presentation, chronic inflammation, and negative co-stimulation.

Conclusions

Regulon-based characterization of cell states provides robust and functionally informative markers that can deconvolve bulk RNA-seq data to identify ICI responders.
Perturbations of a causal synaptic molecular network in autism and schizophrenia revealed with multiplexed imaging
Authors: Falkovich Reuven , Danielson Eric W. , Perez de-Arce Karen , Wamhoff Eike C. , Cottrell Jeffrey , Sheng Morgan , Bathe Mark
Published: July 2022

The complex functions of neuronal synapses in the central nervous system depend on their tightly interacting, compartmentalized molecular network of hundreds of proteins spanning the pre- and post-synaptic sites. This biochemical system is implicated in the pathogenesis of autism spectrum disorders and schizophrenia, with identified common synaptopathologies and numerous risk genes associated with synaptic function. However, it remains unclear how the synaptic molecular network is altered in these disorders, and whether effects are common to distinct genetic perturbations. Here, we applied PRISM, a quantitative single-synapse multiplexed imaging technique, to systematically probe the effects of RNAi knockdown of 16 autism- and schizophrenia-associated genes on the simultaneous distribution of 10 synaptic proteins. This enabled the identification of novel phenotypes in synapse compositions and distributions. We applied Bayesian network inference to construct and validate a predictive model of causal hierarchical dependencies among eight proteins of the excitatory synapse. The resulting conditional dependence relationships could only be accessed via measurement which is both single-synapse and multiprotein, unique to PRISM. Finally, we show that central features of the network are similarly affected across distinct gene knockdowns. These results offer insight into the convergent molecular etiology of these debilitating, hereditary and highly polygenic disorders, as well as offering a novel, general framework for probing subcellular molecular networks.
Nonenzymatic template-directed replication using 2′-3′ cyclic nucleotides under wet-dry cycles
Authors: Dagar Shikha , Sarkar Susovan , Rajamani Sudha
Published: July 2022

‘RNA World Hypothesis’ is centred around the idea of a period in the early history of life’s origin, wherein nonenzymatic oligomerization and replication of RNA resulted in functional ribozymes. Previous studies in this endeavour have demonstrated template-directed replication using chemically modified nucleotides and primers. Nonetheless, similar studies that used non-activated nucleotides led to the formation of RNA only with abasic sites. In this study, we report template-directed replication with prebiotically relevant cyclic nucleotides, under dehydration-rehydration (DH-RH) cycles occurring at high temperature (90°C) and alkaline conditions (pH 8). 2′–3′ cyclic nucleoside monophosphates (cNMP) resulted in primer extension, while 3′–5′ cNMP failed to do so. Intact extension of up to two nucleotide additions was observed with both canonical hydroxy-terminated (OH-primer) and activated amino-terminated (NH2-primer) primers. We demonstrate primer extension reactions using both purine and pyrimidine 2′–3′ cNMPs, with higher product yield observed during cAMP additions. Further, the presence of lipid was observed to significantly enhance the extended product in cCMP reactions. In all, our study provides a proof-of-concept for nonenzymatic replication of RNA, using intrinsically activated prebiotically relevant cyclic nucleotides as monomers.
Correspondence between the layered structure of deep language models and temporal structure of natural language processing in the human brain
Authors: Goldstein Ariel , Ham Eric , Nastase Samuel A. , Zada Zaid , Grinstein-Dabus Avigail , Aubrey Bobbi , Schain Mariano , Gazula Harshvardhan , Feder Amir , Doyle Werner , Devore Sasha , Dugan Patricia , Friedman Daniel , Brenner Michael , Hassidim Avinatan , Devinsky Orrin , Flinker Adeen , Levy Omer , Hasson Uri
Published: July 2022

Deep language models (DLMs) provide a novel computational paradigm for how the brain processes natural language. Unlike symbolic, rule-based models described in psycholinguistics, DLMs encode words and their context as continuous numerical vectors. These “embeddings” are constructed by a sequence of computations organized in “layers” to ultimately capture surprisingly sophisticated representations of linguistic structures. How does this layered hierarchy map onto the human brain during natural language comprehension? In this study, we used electrocorticography (ECoG) to record neural activity in language areas along the superior temporal gyrus and inferior frontal gyrus while human participants listened to a 30-minute spoken narrative. We supplied this same narrative to a high-performing DLM (GPT2-XL) and extracted the contextual embeddings for each word in the story across all 48 layers of the model. We next trained a set of linear encoding models to predict the temporally-evolving neural activity from the embeddings at each layer. We found a striking correspondence between the layer-by-layer sequence of embeddings from GPT2-XL and the temporal sequence of neural activity in language areas. In addition, we found evidence for the gradual accumulation of recurrent information along the linguistic processing hierarchy. However, we also noticed additional neural processes in the brain, but not in DLMs, during the processing of surprising (unpredictable) words. These findings point to a connection between human language processing and DLMs where the layer-by-layer accumulation of contextual information in DLM embeddings matches the temporal dynamics of neural activity in high-order language areas.
Evidence for absence of links between striatal dopamine synthesis capacity and working memory capacity, spontaneous eye-blink rate, and trait impulsivity
Authors: van den Bosch Ruben , Hezemans Frank H. , Määttä Jessica I. , Hofmans Lieke , Papadopetraki Danae , Verkes Robbert-Jan , Marquand Andre F. , Booij Jan , Cools Roshan
Published: July 2022

Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, ‘off-the-shelf’ tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [18F]-FDOPA PET in a large sample of healthy volunteers (N=94) and assessed the correlation with simple, short tests of working memory capacity, trait impulsivity, and sEBR. We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes Factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.
Interrogating the effect of enzyme kinetics on metabolism using differentiable constraint-based models
Authors: Wilken St. Elmo , Besançon Mathieu , Kratochvíl Miroslav , Foko Kuate Chilperic Armel , Trefois Christophe , Gu Wei , Ebenhöh Oliver
Published: July 2022

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Metabolic models are typically characterized by a large number of parameters. Traditionally, metabolic control analysis is applied to differential equation-based models to investigate the sensitivity of predictions to parameters. A corresponding theory for constraint-based models is lacking, due to their formulation as optimization problems. Here, we show that optimal solutions of optimization problems can be efficiently differentiated using constrained optimization duality and implicit differentiation. We use this to calculate the sensitivities of predicted reaction fluxes and enzyme concentrations to turnover numbers in an enzyme-constrained metabolic model of Escherichia coli. The sensitivities quantitatively identify rate limiting enzymes and are mathematically precise, unlike current finite difference based approaches used for sensitivity analysis. Further, efficient differentiation of constraint-based models unlocks the ability to use gradient information for parameter estimation. We demonstrate this by improving, genome-wide, the state-of-the-art turnover number estimates for E. coli. Finally, we show that this technique can be generalized to arbitrarily complex models. By differentiating the optimal solution of a model incorporating both thermodynamic and kinetic rate equations, the effect of metabolite concentrations on biomass growth can be elucidated. We benchmark these metabolite sensitivities against a large experimental gene knockdown study, and find good alignment between the predicted sensitivities and in vivo metabolome changes. In sum, we demonstrate several applications of differentiating optimal solutions of constraint-based metabolic models, and show how it connects to classic metabolic control analysis.
Autocrine Sfrp1 inhibits lung fibroblast invasion during transition to injury induced myofibroblasts
Authors: Mayr Christoph H. , Sengupta Arunima , Ansari Meshal , Pestoni Jeanine C. , Ogar Paulina , Angelidis Ilias , Liontos Andreas , Rodriguez-Castillo Alberto , Lang Niklas J. , Strunz Maximilian , Asgharpour Sara , Porras-Gonzalez Diana , Gerckens Michael , Oehrle Bettina , Viteri-Alvarez Valeria , Fernandez Isis E. , Tallquist Michelle , Irmler Martin , Beckers Johannes , Eickelberg Oliver , Stoleriu Gabriel Mircea , Behr Jürgen , Kneidinger Nikolaus , Yildirim Ali Önder , Ahlbrecht Katrin , Morty Rory E. , Samakovlis Christos , Theis Fabian J. , Burgstaller Gerald , Schiller Herbert B.
Published: July 2022

Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Several distinct lineages of fibroblasts support homeostatic tissue niche functions, yet, specific activation states and phenotypic trajectories of fibroblasts during injury and repair have remained unclear. Here, we combined spatial transcriptomics, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21-Cre lineage positive and negative cells. Sfrp1+ cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1+ transitional fibroblasts and Cthrc1+ myofibroblasts. Tgfβ1 downregulated Sfrp1 in non-invasive transitional cells and induced their switch to an invasive Cthrc1+ myofibroblast identity. Finally, using loss of function studies we showed that autocrine Sfrp1 directly inhibits fibroblast invasion by regulating the RhoA pathway. In summary, our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies Sfrp1 as an autocrine inhibitor of fibroblast invasion during early stages of fibrogenesis.
Subcellular localization of GPCR kinases differentially modulate biased signaling at CXCR3
Authors: Gardner Julia , Eiger Dylan Scott , Hicks Chloe , Choi Issac , Pham Uyen , Rajagopal Sudarshan
Published: July 2022

Some G protein-coupled receptors (GPCRs) demonstrate biased signaling, where ligands of the same receptor differentially activate specific downstream signaling pathways over others. Ligand-specific receptor phosphorylation by GPCR kinases (GRKs) is one mechanism underlying this phenomenon. Recent evidence demonstrates that GPCRs traffic to and signal from subcellular compartments beyond the plasma membrane, a paradigm termed location bias. Here, we show that GRKs translocate to endosomes following stimulation of the chemokine receptor CXCR3 and other GPCRs. The GRK recruitment patterns at the plasma membrane and endosome are distinct and depend on the identity of the ligand used to activate the receptor. Using cells deficient of GRKs, we demonstrate that biased ligands have unique signaling profiles upon rescue of location-specific GRK isoforms. Our work highlights a role of the GRKs in location-biased GPCR signaling and demonstrates the complex interactions between ligand, GRK isoform and cellular location that contribute to biased signaling.