bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of metastatic renal cell carcinoma following prior vascular endothelial growth factor–targeted therapy: A real-world retrospective study from Taiwan
Authors: Chung Hsiao-Jen , Chang Yen-Hwa , Huang Yi-Hsiu , Lin Tzu-Ping , Wei Tzu-Chun , Lin Fang-Ju , Huang Huai-Hsuan , Wang Hui-Chuan
Published: February 2022

Background:

There are limited real-world data to guide the sequencing of targeted therapies in patients with metastatic renal cell carcinoma (mRCC). The objective of this study was to characterize real-world treatment patterns (primarily second line [2L]) after prior vascular endothelial growth factor (VEGF) targeted therapy in an unselected mRCC population from Taiwan between 2013 and 2017. Treatment-related adverse events (TRAEs) and their management were also evaluated (NCT03633579).

Methods:

This retrospective cohort study included patients who had received prior VEGF-targeted therapy and were treated at the National Taiwan University Hospital or the Taipei Veterans General Hospital between June 2013 and December 2017. Outcomes were characterized using descriptive statistics.

Results:

Overall, 27 patients were included: 22 (81.5%) male; mean standard deviation (SD) age, 63.1 (11.1) years; 18 (66.7%) initiated targeted therapy during the year immediately following mRCC diagnosis. All patients received sunitinib as their first-line (1L) targeted therapy, with a median (range) treatment duration of 10 (1.8–65.8) months. The most common reason for discontinuing 1L sunitinib was disease progression (88.9% of patients). Everolimus was the most common 2L targeted therapy, in 23 patients (85.2%); 4 patients (14.8%) received 2L axitinib. Median (range) duration of 2L therapy was 4.0 (0.1–30.5) months for everolimus and 4.2 (0.5–9.2) months for axitinib. Ten TRAEs were reported among seven patients receiving 2L everolimus: hypertension (n = 5), hand-foot syndrome (n = 2), hyperglycemia (n = 1), renal failure (n = 1), and interstitial pneumonitis (n = 1). The majority (80%) of TRAEs were managed in the outpatient setting. No TRAEs were reported in the axitinib group.

Conclusion:

Real-world management of patients with mRCC in Taiwan broadly aligned with clinical guidelines and national reimbursement policy at the time of the study. These findings may be a useful reference for assessing the implications of evolving mRCC management approaches in Taiwan.
Treatment for Children with Upper-Limb Differences in Various Parts of the World: Preliminary Findings
Authors: Hill Wendy , Hermansson Liselotte Maria
Published: February 2022

Introduction

To support clinicians who treat children with upper-limb differences, we must first understand how these children are treated around the world.

Study Design

A descriptive survey was carried out in this study.

Objectives

The aim was to describe how treatment for children with upper-limb difference is provided in different parts of the world.

Methods

A web-based survey was used to gather data. The survey was shared on the Handsmart website, through providers and members using snowball sampling.

Results

Sixty-eight respondents from 18 countries, with most being occupational therapists and prosthetists, participated. All respondents reported that they provide prosthetic treatment and most fit a passive prosthesis before 1 year of age.

Respondents from 13 countries reported having governmental funding for the provision of care for people with upper-limb loss. Intervention is guided by the presentation of the limb as well as availability of funding and other resources. In 12 countries, no treatment other than fitting of prostheses is provided for the children. The children who do not receive a prosthesis continue to see an occupational or physical therapist for other treatment (other devices, follow-up). Respondents stated that they would like to see clear treatment guidelines used by multidisciplinary teams to fit children and that treatment should include regular follow-up.

Conclusions

Children are treated differently in various parts of the world based on different funding, family support, and therapy resources. Further studies should encompass a geographically representative sample of children’s clinics.

Clinical Relevance

This study provides information regarding treatment practices for children with upper-limb loss/difference in various parts of the world; prosthetic treatment is common for children, although ages for fitting vary among clinics and countries. Results will contribute by supporting clinicians to provide better treatment for children with upper-limb loss/difference.
Reversal of Total Artificial Heart Mechanical Valve Thrombosis Using Catheter-Directed Thrombolysis
Authors: Yemul Golhar Shweta R. , Trinh Muoi A. , Anyanwu Anelechi C. , Williams Elbert , Chen Martin
Published: February 2022

Total artificial heart is associated with increased incidence of thromboembolism, which can prove to be fatal. The presence of four metallic tilting discs increases the chances of thrombus formation and sudden obstruction of the valve in a closed position resulting in severe hemodynamic collapse. Such a condition is conventionally treated by a surgical approach for device change; however, this procedure is extremely high risk and associated with complications and poor outcomes. We describe two total artificial heart patients with sudden obstruction to the filling of the right side due to fixing of the atrioventricular valve in a closed position due to a thrombus. After a quick diagnosis by rescue transesophageal echocardiography, we successfully treated these patients with catheter-directed thrombolysis with minimal adverse outcomes. We propose a carefully weighed application of this approach in hemodynamically unstable patients too tenuous for a timely surgery and with low risk for bleeding.
Prevention of pneumococcal infections in childhood: two decades of progress
Authors: Walter Emmanuel B. , Smith Michael J.
Published: February 2022

Purpose of review

This review highlights progress in combating pediatric pneumococcal disease in the era of pneumococcal conjugate vaccines (PCVs). This review is timely given the development of increased valency PCVs for potential use in children.

Recent findings

Countries implementing vaccination programs with PCVs have witnessed dramatic reductions in cases of childhood invasive pneumococcal disease (IPD). In the US, the largest decline of IPD followed the introduction of 7-valent PCV with additional decreases following the switch to 13-valent PCV (PCV13). Despite these gains, IPD still occurs in the US but at much lower rates. Likewise, pneumonia hospitalizations and office visits for otitis media have decreased. Nasopharyngeal colonization with pneumococci has persisted due to replacement by nonvaccine serotypes: colonizing non-PCV13 serotypes have less invasive potential. The PCV era has also been marked by reductions in the proportions of pneumococcus showing nonsusceptibility or resistance to some antimicrobial agents. Furthermore, PCVs have an excellent safety profile.

Despite proven safety and efficacy, childhood vaccination programs in some countries do not include PCVs, resulting in the majority of global deaths attributable to pneumococcus. Increased worldwide vaccination of children and the development of higher valency vaccines holds additional promise for further reductions in childhood IPD.
Incorporation of Telehealth Into Multidisciplinary Clinics
Authors: Gleghorn Elizabeth E. , Hilk Susan S. , Rothbaum Robert
Published: February 2022

Shelter in place orders in the coronavirus disease 2019 (COVID‐19) pandemic necessitate changes in how medical care is delivered. We describe our method for team telemedicine visits for California Children's Services, a state insurance for children requiring multidisciplinary care, to demonstrate how such visits can be efficiently conducted. Although the physical distance provides some obstacles, telemedicine visits can also improve some elements of the team visit.
Clinicopathologic Profile and Treatment Outcomes of Children With Diffuse Large B-cell Lymphomas: Experience From a Tertiary Cancer Center in India
Authors: Mande Radnyi , Roy Moulik Nirmalya , Shet Tanuja , Narula Gaurav , Prasad Maya , Dhamne Chetan , Bhat Vasudeva , Cheriyalinkal Parambil Badira , Shah Sneha , Shridhar Epari , Gujral Sumeet , Banavali Shripad
Published: February 2022

Clinicopathologic profile and outcome of 15 children (15 years or above) with diffuse large B-cell lymphoma treated with MCP-842 protocol are reported. Eleven of 15 presented with advanced (stage-III/IV) disease. Post-2 cycles of chemotherapy, complete metabolic and morphologic response was documented in 10 (66%) and rest 5 (33%) with partial response achieved complete metabolic remission by end of treatment. At a median follow-up of 44 months (range: 16 to 79 mo), the 3-year event-free survival and overall-survival were 77.1%±11.7% and 85.7%±9.4%, respectively. Though majority of our patients had advanced disease, outcome on MCP-842 protocol was satisfactory.
Assessment of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia: A Multicenter Study From Turkey
Authors: Tüfekçi Özlem , Evim Melike Sezgin , Güneş Adalet Meral , Celkan Tiraje , Karapinar Deniz Yilmaz , Kaya Zühre , Baysal Birsen , Baytan Birol , Koçak Ülker , Yilmaz Şebnem , Çinar Suzan , Ören Hale
Published: February 2022

Assestment of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) is of utmost importance both for risk classification and tailoring of the therapy. The data of pediatric ALL patients that received treatment with Berlin-Frankfurt-Münster (BFM) protocols were retrospectively collected from 5 university hospitals in Turkey. Of the 1388 patients enrolled in the study 390 were treated according to MRD-based protocols. MRD assestment was with real time quantitative polymerase chain reaction (qPCR) in 283 patients and with multiparametric flow cytometry (MFC)-MRD in 107 patients. MRD monitoring had upstaged a total of 8 patients (2%) from intermediate risk group to high-risk group. Univariate analysis revealed age 10 years or above, prednisone poor response, PCR-MRD ≥10−3 on day 33 and on day 78 as poor prognostic factors affecting event-free survival (EFS). Detection of >10% blasts on day 15 with MFC (MFC-high-risk group) was not shown to affect EFS and/or overall survival (log-rank P=0.339). Multiple logistic regression analysis revealed PCR-MRD ≥10−3 on day 78 as the only poor prognostic factor affecting EFS (odds ratio: 8.03; 95% confidence interval: 2.5-25; P=0.000). It is very important to establish the infrastructure and ensure necessary standardization for both MRD methods for optimal management of children with ALL.
Impact of Time to Diagnosis on Morbidity and Survival in Children With Malignant Central Nervous System Tumors
Authors: Ronsley Rebecca , Crowell Cameron , Irvine Mike , Kang Mehima , Goldman Ran D. , Erker Craig , Cheng Sylvia
Published: February 2022

Objective:

The aim was to determine the impact of time to diagnosis (TTD) on morbidity and mortality and to identify factors associated with overall survival (OS) in pediatric patients with malignant central nervous system (CNS) tumors.

Methods:

This is a retrospective review of all malignant CNS tumors presenting to 2 tertiary care pediatric hospitals from 2000 to 2019. Cox proportional hazard model analysis outcomes included TTD and OS as well as morbidity; stratified by tumor category, age, relapse, and presence of metastatic disease.

Results:

There were 197 children with malignant CNS tumors (mean age 8.7 y, 61% male). Tumors included medulloblastoma (N=58, 29.4%), ependymoma (N=27, 13.7%), high-grade glioma (N=42, 21.3%), germ cell tumors (N=47, 23.9%), and other embryonal tumors (N=23, 11.7%). Median TTD from symptom onset was 62 (interquartile range: 26.5 to 237.5 d) and 28% had metastatic disease. Three-year progression free survival was 55% and 3-year OS was 73.1%. Increased OS was associated with increased TTD (parameter estimate 0.12; confidence interval [CI]: 0.019-7.06; P=0.019), high-grade glioma (hazard ratio [HR]: 2.46; CI [1.03-5.86]; P=0.042), other embryonal tumor (HR: 2.84; CI [1.06-7.56]; P=0.037), relapse (HR: 10.14; CI: 4.52-22.70; P<0.001) and metastatic disease (HR: 3.25; CI: 1.51-6.96; P=0.002). Vision change (HR: 0.58; CI: 0.313-1.06; P=0.078), hearing loss (HR: 0.71; CI: 0.35-1.42; P=0.355), and cognitive impairment (HR: 0.73; CI: 0.45-1.19; P=0.205) were not associated with TTD in this model.

Conclusions:

Increased median TTD is associated with higher OS in pediatric patients treated for malignant CNS tumors. Tumor biology and treatment modality are more important factors than TTD for predicting morbidity and long-term outcomes in pediatric patients with CNS tumors.
The Public Health Role of Medical Examiner Offices During COVID-19 and Other Mass Fatality Events
Authors: Bhullar Manreet K. , Gilson Thomas P. , Lee Junghyae
Published: February 2022

The public health role of a medical examiner office (MEO) in a pandemic is largely undefined; however, death data may be useful in strategic planning. Deaths reportable to MEO are defined in statute, with discretion as to the assumption of jurisdiction. We analyzed the daily reported death numbers (DRDNs) in our jurisdiction from March 1, 2020, to March 31, 2021, and compared them with hospital admission and COVID-19 fatality data over the same period. The DRDN from an MEO is easily obtained and may be useful as a supplemental and surrogate metric in certain pandemic mass casualty decisions. Hospital admission data were analyzed in real time and with a 2-week time-shift, as deaths lag hospital admissions as a disease surveillance metric. Moderate correlation was observed between DRDN and hospital admissions (r = 0.570), and this improved to strong correlation (0.645) when the 2-week time-shift was incorporated into the analysis. Both evaluations were statistically significant (P < 0.0001). The DRDN also moderately correlated (r = 0.412) with the number of COVID-19 deaths. Because death certification and hospital diagnosis may be delayed, real-time trend recognition in a pandemic may benefit from use of DRDN from MEO.
Optimal Lung Cancer Screening Criteria Among Persons Living With HIV
Authors: Sellers Subhashini A. , Edmonds Andrew , Ramirez Catalina , Cribbs Sushma K. , Ofotokun Igho , Huang Laurence , Morris Alison , Mccormack Meredith C. , Kunisaki Ken M. , D'souza Gypsyamber , Rivera M. Patricia , Drummond M. Bradley , Adimora Adaora A.
Published: February 2022

Background:

The US Preventive Services Task Force (USPSTF) 2021 updated recommendations on lung cancer screening with chest computed tomography to apply to individuals 50–80 years of age (previously 55–80 years), with a ≥20 pack-year history (previously ≥30), whether currently smoking or quit ≤15 years ago. Despite being at higher risk for lung cancer, persons with HIV (PWH) were not well-represented in the National Lung Screening Trial, which informed the USPSTF 2013 recommendations. It is unknown or unclear how PWH are affected by the 2021 recommendations.

Setting:

This study was a retrospective analysis of PWH with and without lung cancer in the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study.

Methods:

We identified PWH, ages 40–80 years, who currently or previously smoked, with (cases) and without lung cancer (noncases). The sensitivity and specificity of the old, new, and alternative screening criteria were evaluated in each cohort.

Results:

We identified 52 women and 19 men with lung cancer and 1950 women and 1599 men without lung cancer. Only 11 women (22%) and 6 men (32%) with lung cancer met 2013 screening criteria; however, more women (22; 44%) and men (12; 63%) met 2021 criteria. Decreased age and tobacco exposure thresholds in women further increased sensitivity of the 2021 criteria.

Conclusions:

The 2021 USPSTF lung cancer screening recommendations would have resulted in more PWH with lung cancer being eligible for screening at the time of their diagnosis. Further investigation is needed to determine optimal screening criteria for PWH, particularly in women.
Prospective validation of the Rib Injury Guidelines for traumatic rib fractures
Authors: Nelson Adam , Reina Raul , Northcutt Ashley , Obaid Omar , Castanon Lourdes , Ditillo Michael , Gries Lynn , Bible Letitia , Anand Tanya , Joseph Bellal
Published: February 2022

INTRODUCTION

The Rib Injury Guidelines (RIG) were developed to guide triage of traumatic rib fracture patients to home, regular floor, or intensive care unit (ICU) and standardize care. The RIG score is based on patient history, physical examination, and imaging findings. The aim of this study was to evaluate triage effectiveness and health care resources utilization following RIG implementation.

METHODS

This is a prospective analysis at a level I trauma center from October 2017 to January 2020. Adult (18 years or older) blunt trauma patients with a diagnosis of at least one rib fracture on computed tomography imaging were included. Patients before (PRE) and after (POST) implementation of RIG were compared. In the POST group, patients were divided into RIG 1, RIG 2, and RIG 3 based on their RIG score. Outcomes were readmission for RIG 1 patients, unplanned ICU admission for RIG 2 patients, and overall ICU admission. Secondary outcomes were hospital length of stay (LOS) and mortality.

RESULTS

A total of 1,100 patients were identified (PRE, 754; POST, 346). Mean ± SD age was 56 ± 19 years, 788 (71.6%) were male, and median Injury Severity Score was 14 (range, 10–22). The most common mechanism of injury was motor vehicle collision (554 [50.3%]), 253 patients (22.9%) had ≥5 rib fractures, and 53 patients (4.8%) had a flail chest. In the POST group, 74 patients (21.1%) were RIG 1; 121 (35.2%), RIG 2; and 151 (43.7%), RIG 3. No patient in RIG 1 was readmitted following initial discharge, and two patients (1.6%) in RIG 2 had an unplanned ICU admission (both for alcohol withdrawal syndrome). Patients after implementation of RIG had shorter hospital LOS (3 [1–6] vs. 4 [1–7] days; p = 0.019) and no difference in mortality (5.8% vs. 7.7%; p = 0.252). On multivariate analysis, RIG implementation was associated with decreased ICU admission (adjusted odds ratio, 0.55 [0.36–0.82]; p = 0.004).

CONCLUSION

Rib Injury Guidelines are safe and effectively define triage of rib fracture patients with an overall reduction in ICU admissions, shorter hospital LOS, and no readmissions.

LEVEL OF EVIDENCE

Therapeutic/care management, level III.
Tactics for hemorrhagic shock: A virtual course and visual aid for improved resuscitation
Authors: Keating Jane Josephine , Silvis Jennifer , Ricaurte Daniel , Desrochers Ryan , Jacobs Lenworth , Saccomanno Fabio , Staff Ilene , Croteau Alfred , Merchant Nishant , Gates Jonathan
Published: February 2022

BACKGROUND

Our trauma performance improvement initiative recognized missed treatment opportunities for patients undergoing massive transfusion. To improve patient care, we developed a novel cognitive aid in the form of a poster entitled “TACTICS for Hemorrhagic Shock.” We hypothesized that this reference and corresponding course would improve the performance of trauma leaders caring for simulated patients requiring massive transfusion.

METHODS

First, residents and physician assistants participated in a one-on-one, socially distanced, screen-based virtual patient simulation. Next, they watched a short presentation introducing the TACTICS visual aid. They then underwent a similar second virtual simulation during which they had access to the reference. In both simulations, the participants were assessed using a scoring system developed to measure their ability to provide appropriate predetermined interventions while leading a trauma resuscitation (score range, 0–100%). Preintervention and postintervention scores were compared using a one-group pre-post within-subject design. Participants' feedback was obtained anonymously.

RESULTS

Thirty-two participants (21 residents and 11 physician assistants) completed the course. The median score for the first simulation without the use of the visual aid was 43.8% (interquartile range, 33.3.8–61.5%). Commonly missed treatments included giving tranexamic acid (success rate, 37.5%), treating hypothermia (31.3%), and reversing known anticoagulation (28.1%). All participants' performance improved using the visual aid, and the median score of the second simulation was 89.6% (interquartile range, 79.2–94.8%; p < 0.001). Ninety-two percent of survey respondents “strongly agreed” that the TACTICS visual aid would be a helpful reference during real-life trauma resuscitations.

CONCLUSION

The TACTICS visual aid is a useful tool for improving the performance of the trauma leader and is now displayed in our emergency department resuscitation rooms. This performance improvement course, the associated simulations, and visual aid are easily and virtually accessible to interested trauma programs.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Adjunctive High-Definition Transcranial Direct Current Stimulation in Brain Glutamate-Glutamine and γ-Aminobutyric Acid, Withdrawal and Craving During Early Abstinence Among Patients With Opioid Use Disorder on Buprenorphine-Naloxone
Authors: Kumar Aravind S. , Khanra Sourav , Goyal Nishant , Dharani Ramamoorthy , Roy Chandramouli
Published: February 2022

Objective

Our study aimed to (1) examine the effect of adjunctive high-definition transcranial direct current stimulation (HD-tDCS) in craving and withdrawal among patients with opioid use disorder on buprenorphine-naloxone, and (2) examine effect of HD-tDCS changes in glutamate-glutamine and γ-aminobutyric acid (GABA) at the left dorsolateral prefrontal cortex (DLPFC) among patients with opioid use disorder on buprenorphine-naloxone.

Methods

This was a pilot randomized double-blind, sham-controlled parallel-group study. A total of 28 patients on buprenorphine-naloxone (6/1.5 mg/d) were randomly allocated into 2 groups for active and sham HD-tDCS stimulation. High-definition transcranial direct current stimulation was administered twice daily for consecutive 5 days, from days 2 to 6. The Clinical Opiate Withdrawal Scale (COWS), the Desire for Drug Questionnaire (DDQ), the Obsessive-Compulsive Drug Use Scale (OCDUS), and glutamate-glutamine and GABA at DLPFC via proton magnetic resonance spectroscopy were measured at baseline and on day 7.

Results

Both active and sham groups had comparable changes in DDQ, OCDUS (except 2 subcomponents), COWS, and glutamate-glutamine and GABA at DLPFC. In the active HD-tDCS group, statistically significant reductions were observed in DDQ, OCDUS, and COWS but not in glutamate-glutamine and GABA.

Conclusions

The adjunctive active HD-tDCS group showed comparable changes in craving and withdrawal, and glutamate-glutamine and GABA at DLPFC compared with sham HD-tDCS. Craving and withdrawal but not glutamate-glutamine and GABA at DLPFC decreased significantly with adjunctive HD-tDCS. Future studies with larger sample size and online assessment of glutamate-glutamine and GABA would enhance our knowledge.
Experimental Suppression of TMS-EEG Sensory Potentials
Authors: Ross Jessica M. , Sarkar Manjima , Keller Corey J.
Published: February 2022

Background

The sensory experience of transcranial magnetic stimulation (TMS) evokes cortical responses measured in EEG that confound interpretation of TMS-evoked potentials (TEPs). Methods for sensory masking have been proposed to minimize sensory contributions to the TEP, but the most effective combination for suprathreshold TMS to dorsolateral prefrontal cortex (dlPFC) is unknown.

Objective

We applied sensory suppression techniques and quantified electrophysiology and perception from suprathreshold dlPFC TMS to identify the best combination to minimize the sensory TEP.

Methods

In 21 healthy adults, we applied single pulse TMS at 120% resting motor threshold (rMT) to the left dlPFC and compared EEG vertex N100-P200 and perception. Conditions included three protocols: No masking (no auditory masking, no foam, jittered inter-stimulus interval (ISI)), Standard masking (auditory noise, foam, jittered ISI), and our ATTENUATE protocol (auditory noise, foam, over-the-ear protection, unjittered ISI).

Results

ATTENUATE reduced vertex N100-P200 by 56%, “click” loudness perception by 50%, and scalp sensation by 36%. We show that sensory prediction, induced with predictable ISI, has a suppressive effect on vertex N100-P200, and that combining standard suppression protocols with sensory prediction provides the best N100-P200 suppression. ATTENUATE was more effective than Standard masking, which only reduced vertex N100-P200 by 22%, loudness by 27%, and scalp sensation by 24%.

Conclusions

We introduce a sensory suppression protocol superior to Standard masking and demonstrate that using an unjittered ISI can contribute to minimizing sensory confounds. ATTENUATE provides superior sensory suppression to increase TEP signal-to-noise and contributes to a growing understanding of TMS-EEG sensory neuroscience.

Highlights

ATTENUATE is a novel sensory suppression protocol for suprathreshold dlPFC TMS

ATTENUATE is superior to standard masking for minimizing sensory confounds

ATTENUATE reduced vertex N100-P200 by 56% with no effect on the early TEP

ATTENUATE reduced “click” loudness rating by 50% and scalp sensation by 36%

Individual modifications are not sufficient to reduce vertex N100-P200 or perception
Interferon regulates stem cell function at all ages by orchestrating mTOR and cell cycle
Authors: Ibañez Damian Carvajal , Skabkin Maxim , Hooli Jooa , Cerrizuela Santiago , Göpferich Manuel , Jolly Adrien , Zumwinkel Marc , Bertolini Matilde , Höfer Thomas , Kramer Guenter , Anders Simon , Telemann Aurelio , Marciniak-Czochra Anna , Martin-Villalba Ana
Published: February 2022

Stem cells show intrinsic interferon signalling, which protects them from viral infections at all ages. In the ageing brain, interferon signalling in stem cells also reduces their ability to activate. Whether these functions are linked and at what time interferons start taking on a role in stem cell functioning is unknown. Additionally, the molecular link between interferons and activation in neural stem cells and how this relates to productivity is not well understood. Here we combine single-cell transcriptomics, RiboSeq and animal models of interferon to show that this pathway is important for proper stem cell function at all ages. Interferon orchestrates cell cycle and mTOR activity to post-transcriptionally repress Sox2 and drive the exit from stem cell activation. The interferon response then decreases in the subsequent maturation states. Mathematical simulations indicate that this regulation is beneficial for the young and harmful for the old brain. Our study establishes molecular mechanisms of interferon in stem cells and interferons as genuine regulators of stem cell homeostasis and a potential therapeutic target to repair the ageing brain.
Transfer Learning for Cognitive Reserve Quantification
Authors: Zhu Xi , Liu Yi , Habeck Christian G. , Stern Yaakov , Lee Seonjoo ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2022

Cognitive reserve (CR) has been introduced to explain individual differences in susceptibility to cognitive or functional impairment in the presence of age or pathology. We developed a deep learning model to quantify the CR as residual variance in memory performance using the structural MRI data from a lifespan healthy cohort. The generalizability of the sMRI-based deep learning model was tested in two independent healthy and Alzheimer’s cohorts using transfer learning framework.

Structural MRIs were collected from three cohorts: 495 healthy adults (initially aged 20-80) from RANN, 620 healthy participants (age 36-100) from lifespan Human Connectome Project Aging (HCPA), and 941 subjects from Alzheimer’s Disease Neuroimaging Initiative (ADNI). Region of interest (ROI)-specific cortical thickness and volume measures were extracted using the Desikan-Killiany Atlas. Cognitive reserve was quantified by residuals which subtract the predicted memory from the true memory. Cascade neural network (CNN) models were used to train RANN dataset for memory prediction. Transfer learning was applied to transfer the T1 imaging-based model from source domain (using RANN) to the target domain (HCPA or ADNI).

The CNN model trained on the RANN dataset exhibited strong linear correlation between true and predicted memory based on the chosen T1 cortical thickness and volume predictors. In addition, the model generated from healthy lifespan data (RANN) was able to generalize to an independent healthy lifespan data (HCPA) and older demented participants (ADNI) across different scanner types. The estimated CR was correlated with CR proxies such education and IQ across all three datasets.

The current findings suggest that the transfer learning approach is an effective way to generalize the residual-based CR estimation. It is applicable to various diseases and may flexibly incorporate different imaging modalities such as fMRI and PET, making it a promising tool for scientific and clinical purposes.

Highlight

Quantification of cognitive reserve using brain measures for pre-symptomatic Alzheimer’s patients can be estimated by leveraging lifespan data.

Multi-center, multi-scanner, multi-sequence can affect the performance of the quantification.

Leveraging lifespan data from a single site can improve the performance.

Transfer learning allows the pre-trained network to successfully reconstruct the dataset acquired from different domains or age groups.
Analyzing the Impact of a Real-life Outbreak Simulator on Pandemic Mitigation: an Epidemiological Modeling Study
Authors: Specht Ivan , Sani Kian , Loftness Bryn C. , Hoffman Curtis , Gionet Gabrielle , Bronson Amy , Marshall John , Decker Craig , Bailey Landen , Siyanbade Tomi , Kemball Molly , Pickett Brett E. , Hanage William P. , Brown Todd , Sabeti Pardis C. , Colubri Andrés
Published: February 2022

Operation Outbreak (OO), an app-based, educational outbreak simulator, seeks to engage, educate, and empower citizens to prevent and better respond to infectious disease outbreaks. We examine the utility of OO for further understanding and mitigating the spread of communicable diseases. The OO smartphone app uses Bluetooth to spread a virtual pathogen among nearby participants’ devices to simulate an outbreak, providing an experiential learning opportunity. Deployed at many college campuses and other settings, the app collects these anonymized spatio-temporal data, including the time and duration of the contacts among participants of the simulation. Here, we report the distribution, timing, duration, and connectedness of student social contacts at two university deployments and uncover cryptic transmission pathways through individuals’ second-degree contacts. We then construct epidemiological models based on the contact networks generated by OO to predict the transmission pathways of hypothetical pathogens with varying reproductive numbers. Finally, we show that the granularity of OO data enables institutions to improve outbreak mitigation by proactively and strategically testing and/or vaccinating individuals based on individual social interaction levels.

BIGGER PICTURE

Outbreak simulation technology can greatly enhance individual and community pandemic preparedness while also helping us understand and mitigate outbreak spread. Building on an existing platform called Operation Outbreak (OO)––an app-based program that spreads a virtual pathogen via Bluetooth among participants’ smartphones––we demonstrate the power of this approach. We investigate the first- and second-degree contacts of OO participants, analyzing the differential risk associated with various local contact network structures. We use OO data to construct an epidemiological model, with which communities may predict the spread of infectious agents and assess the effectiveness of mitigation measures. Based on our findings, we advocate for the wider adoption of outbreak simulation technology to study the implications of social mixing patterns on outbreaks within close-knit communities, to aid pandemic preparedness and response.
The Public Health Impact of a US Menthol Cigarette Ban on the Non-Hispanic Black Population: A Simulation Study
Authors: Issabakhsh Mona , Meza Rafael , Li Yameng , Yuan Zhe , Sanchez-Romero Luz Maria , Levy David T.
Published: February 2022

Introduction

As the US Food and Drug Administration (FDA) evaluates implementing a ban on menthol cigarettes and cigars, it is critical to estimate the potential public health effects of such a ban. With high rates of menthol cigarette use by the non-Hispanic Black (NHB) population and important smoking-related health disparity implications, the impact of the ban on this population merits strong consideration.

Methods

We apply the previously developed Menthol Smoking and Vaping Model. A Status Quo Scenario is developed using population, smoking and vaping data specific to the NHB population. Estimates from a recent expert elicitation on behavioral impacts of a menthol cigarette ban on the NHB population are used to develop a Menthol Ban Scenario implemented in 2021. The public health impacts of the menthol ban are estimated as the difference between smoking and vaping attributable deaths (SVADs) and life years lost (LYLs) in the Status Quo and the Menthol Ban Scenarios from 2021-2060.

Results

Under the Menthol Ban Scenario, overall smoking is projected to decline by 35.1% in 2026, and by 24.0% in 2060 relative to the Status Quo Scenario. With these reductions, SVADs are estimated to fall by about 18.5% and LYLs by 22.1%, translating to 255,000 premature deaths averted, and 3.9 million life-years gained over a 40-year period.

Conclusions

A menthol cigarette ban will substantially reduce the smoking-associated health impact on the NHB population thereby reducing health disparities.
Body mass and latitude as global predictors of vertebrate populations exposure to multiple threats
Authors: Capdevila Pol , Noviello Nicola , McRae Louise , Freeman Robin , Clements Christopher
Published: February 2022

The interactive effects of multiple threats are one of the main causes of biodiversity loss, yet our understanding of what predisposes species to be impacted by multiple threats remains limited. Here we analyse a global dataset of over 7000 marine, freshwater, and terrestrial vertebrate populations, alongside trait, threat and geographical data, to identify the factors influencing the number of threats a species is subjected to at the population level. Out of a suite of predictors tested, we find that body mass and latitude both are broadly available for vertebrate species, and influence the number of threats a population is subjected to. Larger bodied species and those nearer the equator are typically affected by a higher number of threats. However, whilst this pattern broadly holds across ecosystems for most taxa, amphibians and reptiles show opposing trends. We suggest that latitude and body mass should be considered as key predictors to identify which vertebrate populations are likely to be impacted by multiple threats. These general predictors can help to better understand the impacts of the Anthropocene on global vertebrate biodiversity and design effective conservation policies.
Cell-type specific transcriptional networks in root xylem adjacent cell layers
Authors: Asensi Fabado Maria Amparo , Armstrong Emily A , Walker Liam , Perrella Giorgio , Hamilton Graham , Herzyk Pawel , Gifford Miriam L , Amtmann Anna
Published: February 2022

Transport of water, ions and signals from roots to leaves via the xylem vessels is essential for plant life and needs to be tightly regulated. The final composition of the transpiration stream before passage into the shoots is controlled by the xylem-adjacent cell layers, namely xylem parenchyma and pericycle, in the upper part of the root. To unravel regulatory networks in this strategically important location, we generated Arabidopsis lines expressing a nuclear tag under the control of the HKT1 promoter. HKT1 retrieves sodium from the xylem to prevent toxic levels in the shoot, and this function depends on its specific expression in upper root xylem-adjacent tissues. Based on FACS RNA-sequencing and INTACT ChIP-sequencing, we identified the gene repertoire that is preferentially expressed in the tagged cell types and discovered transcription factors experiencing cell-type specific loss of H3K27me3 demethylation. For one of these, ZAT6, we show that H3K27me3-demethylase REF6 is required for de-repression. Analysis of zat6 mutants revealed that ZAT6 activates a suite of cell-type specific downstream genes and restricts Na+ accumulation in the shoots. The combined Files open novel opportunities for ‘bottom-up’ causal dissection of cell-type specific regulatory networks that control root-to-shoot communication under environmental challenge.
Evolutionary quantitative proteomics of reproductive interactions in Drosophila
Authors: Garlovsky Martin D. , Ahmed-Braimah Yasir H.
Published: February 2022

Reproductive traits evolve rapidly between species. Understanding the causes and consequences of this rapid divergence requires characterization of male and female reproductive proteins and how their interaction mediates fertilisation success. Species in the Drosophila virilis clade exhibit interspecific postmating prezygotic reproductive isolation, making them ideal for studies on diversification of reproductive proteins and their role in speciation. Here we present a novel method to simultaneously identify and quantify transferred male ejaculate proteins and the female reproductive proteome using multiplexed Tandem-Mass-Tag (TMT) isobaric labelling of the lower female reproductive tract before and immediately after mating in three species of the virilis group. We identified over 200 putative male ejaculate proteins, many of which show differential abundance between species. We also identified over 2000 proteins that provide the first description of the female reproductive tract proteome outside of the D. melanogaster group. The female reproductive tract proteome shows significant divergence between species, especially female-specific serine-type endopeptidases, which showed differential abundance between species and elevated rates of molecular evolution that is similar to that of male seminal fluid proteins. We also found that only ~1/3 of male ejaculate proteins are likely produced in the accessory glands and code for a signal peptide sequence. Finally, we assessed the utility of species-specific compared to single species query databases for protein identification and quantification from multiple species’ samples. Our results show that using species-specific query databases dramatically improves protein identification and quantification.
Extrachromosomal DNA is associated with decreased immune cell infiltration and antigen presentation, represents a potential cancer immune evasion mechanism
Authors: Wu Tao , Wu Chenxu , Zhao Xiangyu , Wang Guangshuai , Ning Wei , Tao Ziyu , Chen Fuxiang , Liu Xue-Song
Published: February 2022

Extrachromosomal DNA (ecDNA) is a type of circular and tumor specific genetic element. EcDNA has been reported to display open chromatin structure, facilitate oncogene amplification and genetic material unequal segregation, and is associated with poor cancer patients’ prognosis. The ability of immune evasion is a typical feature for cancer progression, however the tumor intrinsic factors that determine immune evasion remain poorly understood. Here we show that the presence of ecDNA is associated with markers of tumor immune evasion, and obtaining ecDNA could be one of the mechanisms employed by tumor cells to escape immune surveillance. Tumors with ecDNA usually have comparable TMB and neoantigen load, however they have lower immune cell infiltration and lower cytotoxic T cell activity. The microenvironment of tumors with ecDNA shows increased immune desert, decreased immune enriched fibrotic types. Both MHC class I and class II antigen presentation genes’ expression are decreased in tumors with ecDNA, and this could be the underlying mechanism for ecDNA associated immune evasion. This study provides evidence that the presence of ecDNA is an immune escape mechanism for cancer cells.
Exploring Genomic Conservation in Actinobacteriophages with Small Genomes
Authors: Tse Vincent Y. , Liu Haoyuan , Kapinos Andrew , Torres Canela , Cayabyab Breanna Camille S. , Fett Sarah N. , Nakashima Lucy G. , Rahman Mujtahid , Vargas Aida S. , Reddi Krisanavane , Parker Jordan Moberg , Freise Amanda C.
Published: February 2022

Actinobacteriophages of a wide range of genome sizes continue to be isolated and characterized, but only a handful of these have atypically small genomes, defined in this work as genome sizes under 20,000 bp. These “small phages” are relatively rare and have received minimal study thus far. Of the actinobacteriophages published in PhagesDB.org, small phages have been isolated on Arthrobacter, Gordonia, Rhodococcus, and Microbacterium hosts. A previous study by Pope et al. showed that Gordonia small phages have similar gene products and amino acid sequences. Here, we set out to further examine relationships between small Gordonia phages as well as small phages that infect other hosts. Of the 3222 sequenced phages listed on PhagesDB, we identified 109 distinctly small phages with genome sizes under 20,000 bp. The majority of the small phages were isolated on Arthrobacter or Microbacterium hosts. Using comparative genomics, we searched for patterns of similarity among 34 cluster-representative small phages. Dot plot comparisons showed that there was more amino acid conservation than nucleotide identity amongst small phages. Gene content similarity (GCS) analysis revealed that the temperate Gordonia phages in Cluster CW share significant GCS values (over 35%) with the lytic Arthrobacter phages in Cluster AN, suggesting that some small phages have a considerable degree of genomic similarity with each other. SplitsTree analyses of shared phams (genes with substantial amino acid identity) supported the complexity of clustering criteria in small phages, given shuffling of genes across phages of different clusters and close relationships despite varied cluster membership. We observed this continuum of phage diversity through Rhodococcus phage RRH1’s closer similarity to phages in Gordonia subcluster CW1 than CW1 is to Gordonia subcluster CW3. Finally, we were able to confirm the presence of conserved phams across not only small Gordonia phages but also within small phages from different clusters and hosts. Studying these genomic trends hidden in small phages allows us to better understand and appreciate the overall diversity of phages.
Genomic neighbor typing for bacterial outbreak surveillance
Authors: Steinig Eike , Pitt Miranda , Aglua Izzard , Suttie Annika , Greenhill Andrew , Heather Christopher , Firth Cadhla , Smith Simon , Pomat William , Horwood Paul , McBryde Emma , Coin Lachlan
Published: February 2022

Genomic neighbor typing enables heuristic inference of bacterial lineages and phenotypes from nanopore sequencing data. However, small reference databases may not be sufficiently representative of the diversity of lineages and genotypes present in a collection of isolates. In this study, we explore the use of genomic neighbor typing for surveillance of community-associated Staphylococcus aureus outbreaks in Papua New Guinea (PNG) and Far North Queensland, Australia (FNQ). We developed Sketchy, an implementation of genomic neighbor typing that queries exhaustive whole genome reference databases using MinHash. Evaluations were conducted using nanopore read simulations and six species-wide reference sketches (4832 - 47616 genomes), as well as two S. aureus outbreak data sets sequenced at low depth using a sequential multiplex library protocol on the MinION (n = 160, with matching Illumina data). Heuristic inference of lineages and antimicrobial resistance profiles allowed us to conduct multiplex genotyping in situ at the Papua New Guinea Institute of Medical Research in Goroka, on low-throughput Flongle adapters and using multiple successive libraries on the same MinION flow cell (n = 24 - 48). Comparison to phylogenetically informed genomic neighbor typing with RASE on the dominant outbreak sequence type suggests slightly better performance at predicting lineage-scale genotypes using large sketch sizes, but inferior performance in resolving clade-specific genotypes (methicillin resistance). Sketchy can be used for large-scale bacterial outbreak surveillance and in challenging sequencing scenarios, but improvements to clade-specific genotype inference are needed for diagnostic applications. Sketchy is available open-source at: https://github.com/esteinig/sketchy
De Novo multi-omics pathway analysis (DMPA) designed for prior data independent inference of cell signaling pathways
Authors: Vaparanta Katri , Merilahti Johannes A. M. , Ojala Veera K. , Elenius Klaus
Published: February 2022

New tools for cell signaling pathway inference from multi-omics data that are independent of previous knowledge are needed. Here we propose a new de novo method, the de novo multi-omics pathway analysis (DMPA), to model and combine omics data into regulatory complexes and pathways. DMPA was validated with publicly available omics data and was found accurate in discovering protein-protein interactions, kinase substrate phosphosite relationships, transcription factor target gene relationships, metabolic reactions, epigenetic trait associations and signaling pathways. DMPA was benchmarked against existing module and network discovery and multi-omics integration methods and outperformed previous methods in module and signaling pathway discovery especially when applied to datasets with low sample sizes and zero-inflated data. Transcription factor, kinase, subcellular location and function prediction algorithms were devised for transcriptome, phosphoproteome and interactome regulatory complexes and pathways, respectively. To apply DMPA in a biologically relevant context, interactome, phosphoproteome, transcriptome and proteome data were collected from analyses carried out using melanoma cells to address gamma-secretase cleavage-dependent signaling characteristics of the receptor tyrosine kinase TYRO3. The pathways modeled with DMPA reflected both the predicted function and the direction of the predicted function in validation experiments.
Dynamical management of potential threats regulated by dopamine and direct- and indirect-pathway neurons in the tail of the striatum
Authors: Tsutsui-Kimura Iku , Uchida Naoshige , Watabe-Uchida Mitsuko
Published: February 2022

Avoiding potential threats before experiencing an actual outcome is critical to prevent a disaster. Here we examined roles of the tail of the striatum (TS) and its dopamine input in threat management. Mice were presented with a potential threat (a moving object) while pursuing rewards. Mice initially failed to obtain rewards, but gradually successfully obtained rewards in later trials. We show that the initial failures depended on dopamine and direct-pathway neurons in TS, and variability in failure rate across trials and individuals was positively correlated with the activity of these neurons. In contrast, indirect-pathway neurons in TS were critical for eventual improvement in reward acquisition, and their activity was positively correlated with successful reward acquisition. These results demonstrate that direct- and indirect-pathway TS neurons promote and suppress threat avoidance, respectively, at different stages, providing a mechanism for overcoming a potential threat while maintaining the threat estimates.