bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust, Universal Tree Balance Indices
Authors: Lemant Jeanne , Le Sueur Cécile , Manojlović Veselin , Noble Robert
Published: April 2022

Balance indices that quantify the symmetry of branching events and the compactness of trees are widely used to compare evolutionary processes or tree-generating algorithms. Yet, existing indices are not defined for all rooted trees, are unreliable for comparing trees with different numbers of leaves, and are sensitive to the presence or absence of rare types. The contributions of this article are twofold. First, we define a new class of robust, universal tree balance indices. These indices take a form similar to Colless’ index but can account for population sizes, are defined for trees with any degree distribution, and enable meaningful comparison of trees with different numbers of leaves. Second, we show that for bifurcating and all other full m-ary cladograms (in which every internal node has the same out-degree), one such Colless-like index is equivalent to the normalized reciprocal of Sackin’s index. Hence, we both unify and generalize the two most popular existing tree balance indices. Our indices are intrinsically normalized and can be computed in linear time. We conclude that these more widely applicable indices have the potential to supersede those in current use. [Cancer; clone tree; Colless index; Sackin index; species tree; tree balance.]
Phylogenetic Diversity Rankings in the Face of Extinctions: The Robustness of the Fair Proportion Index
Authors: Fischer Mareike , Francis Andrew , Wicke Kristina
Published: April 2022

Planning for the protection of species often involves difficult choices about which species to prioritize, given constrained resources. One way of prioritizing species is to consider their “evolutionary distinctiveness,” (ED) that is, their relative evolutionary isolation on a phylogenetic tree. Several evolutionary isolation metrics or phylogenetic diversity indices have been introduced in the literature, among them the so-called Fair Proportion (FP) index (also known as the ED score). This index apportions the total diversity of a tree among all leaves, thereby providing a simple prioritization criterion for conservation. Here, we focus on the prioritization order obtained from the FP index and analyze the effects of species extinction on this ranking. More precisely, we analyze the extent to which the ranking order may change when some species go extinct and the FP index is recomputed for the remaining taxa. We show that for each phylogenetic tree, there are edge lengths such that the extinction of one leaf per cherry completely reverses the ranking. Moreover, we show that even if only the lowest-ranked species goes extinct, the ranking order may drastically change. We end by analyzing the effects of these two extinction scenarios (extinction of the lowest-ranked species and extinction of one leaf per cherry) for a collection of empirical and simulated trees. In both cases, we can observe significant changes in the prioritization orders, highlighting the empirical relevance of our theoretical findings. [Biodiversity conservation; Fair Proportion index; phylogenetic diversity; species prioritization.]
Lateral Stress Radiographs of Lateral Compression Type 1 Pelvic Injuries, With the Injured Side Down or Up, Reliably Measure Occult Instability
Authors: Parry Joshua A. , Hadeed Michael M. , Strage Katya E. , Heare Austin , Stacey Stephen C. , Mauffrey Cyril
Published: April 2022

Objectives:

To evaluate the interobserver reliability of measured displacement and occult instability of minimally displaced lateral compression type 1 (LC1) fractures on lateral stress radiographs (LSRs) and to compare differences in displacement between LSR with the injured side down (ID) and up (IU).

Design:

Retrospective review.

Setting:

Urban Level 1 trauma center.

Patients/Participants:

Twenty-three adult patients with minimally displaced (<1 cm) LC1 injuries.

Intervention:

None.

Main Outcome Measurements:

Three orthopaedic surgeons measured the distance between the radiographic teardrops on LSR and supine anteroposterior pelvic radiographs to calculate dynamic fracture displacement. The interobserver reliability of the measured displacement, a continuous variable, was assessed by calculating the intraclass correlation coefficient. The interobserver reliability of occult instability (≥10 mm of displacement on LSR), a categorical variable, was assessed by calculating the kappa value. Matched-pairs analysis was performed to calculate the mean difference of measurements between observers and between ID and IU LSR.

Results:

The interobserver reliability of the measured displacement was excellent (intraclass correlation coefficient 0.93). The mean difference in measurements between observers ranged from −1.8 to 0.96 mm. The mean difference in the measured displacement between ID and IU LSRs for each observer ranged from −0.6 to 0.3 mm. There was 83% (19/23 cases) agreement on the presence of occult instability (≥10 mm of displacement on LSR) on both ID and IU LSRs. The interobserver reliability of occult instability was moderate (kappa 0.76).

Conclusions:

Measured fracture displacement and occult instability of minimally displaced LC1 injuries were reliably measured and identified on LSR, regardless of the laterality.
The Progressive Loss Risk Scale for Hair Restoration Surgery
Authors: Stough Dow B.
Published: April 2022

BACKGROUND

Limited information exists on the long-term risks to individuals undergoing procedures in hair restoration surgery. The short-term risks are well known and similar to other procedures in dermatologic surgery. The long-term risks of hair restoration surgery are seldom discussed between the physician and patient.

OBJECTIVE

The author sought to describe a classification system that can be used as a communication tool between physicians and patients to define the long-term risk involved with hair restoration surgery.

METHODS

The Progressive Loss (PL) Scale is an attempt at assessing the cosmesis because of future hair loss following a hair transplant procedure. The PL Risk Scale has designated 5 levels, 1 to 5, with each ascending level representing a higher level of risk. The PL Risk Scale can be assigned to an individual at the time of the assessment for hair restoration surgery.

RESULTS

Each patient can be assigned a risk level based on how future hair loss may affect the overall cosmetic result of their hair transplant. This risk is dependent on age, and specific for the area to be transplanted. The younger the age of the patient, the higher the risk. The larger the area to be transplanted, the higher the risk. It is not a static scale, because it will be affected by age, donor area, location of transplantation, and other mitigating factors.

CONCLUSION

Pattern baldness in men and women is progressive and unrelenting. The dichotomy of hair restoration surgery is that a satisfactory short-term outcome can evolve to disappointing results because of progressive hair loss. The PL Risk Scale can be assigned to every individual undergoing a hair restoration procedure. This scale assignment will convey to the patient their lifetime risk associated with any given surgical hair restoration procedure for that age and the specific area to be restored.
Contralateral Limb Pain Is Prevalent, Persistent, and Impacts Quality of Life of Veterans with Unilateral Upper-Limb Amputation
Authors: Resnik Linda , Borgia Matthew , Clark Melissa A.
Published: April 2022

Introduction

Individuals with upper-limb amputation (ULA) have increased risk for contralateral limb pain (CLP), and further study of CLP in ULA is needed. Study objectives were to: (1) describe CLP frequency, intensity, and 1-year change; (2) identify factors associated with CLP; and (3) quantify associations between CLP, health-related quality of life (HRQoL), and disability (QuickDASH).

Methods

A total of 776 veterans with unilateral ULA were surveyed at baseline, and 562 were surveyed again at 1 year. Participants reported CLP frequency and intensity and nonamputated limb conditions. Multivariable models examined factors associated with CLP, as well as associations between CLP intensity and HRQOL (physical component score and mental component score) and disability (QuickDASH).

Results

Contralateral limb pain prevalence was 72.7% (baseline) and 71.6% (follow-up); 59.8% had persistent pain. Contralateral limb conditions and neck and residual limb pain were associated with higher odds of CLP. Black race (vs White), back pain (vs without), and age 45 to 65 years (vs 18–45 years) were associated with greater CLP intensity. Female sex (vs male) and use of cosmetic prostheses (vs body-powered) were associated with lower intensity. The mental component scores were 2.7 and 6.6 points lower for moderate and severe CLP, respectively; the physical component scores were 4.2 and 8.4 points lower for moderate and severe CLP; and QuickDASH scores were 9.4 and 20.7 point higher for moderate and severe CLP, compared with none to mild pain.

Conclusions

Findings suggest that overreliance on the nonamputated limb, leading to CLP, occurs regardless of amputation level or prosthesis use. Further research is needed to understand whether disparities in pain treatment exist by race. Contralateral limb pain is prevalent and persistent in veterans with ULA. Moderate to severe CLP is associated with worse HRQOL and greater disability. Efforts are needed to prevent and treat ULA CLP pain.

Clinical Relevance

Clinicians caring for persons with unilateral ULA should evaluate the contralateral upper limb and refer patients to appropriate therapies to address painful conditions. Persons with ULA should be educated about the risks of development of CLP and be provided with strategies to minimize overuse when possible.
Upregulated NORAD is implicated in apoptosis, inflammation, and oxidative stress in ulcerative colitis through the nuclear factor-κappaB signaling
Authors: Lei Na , Kong Pengfei , Chen Simin , Wang Qiuxiao , Tang Xuegui , Liu Fang
Published: April 2022

Background

Ulcerative colitis (UC) is a chronic inflammatory disease that affects the colon. It has been discovered that long non-coding RNA activated by DNA damage (NORAD) is upregulated in UC patient-derived serums, but its functional mechanism in UC has not been disclosed.

Methods

Relative levels of NORAD in colonic mucosal tissues and TNF-α-stimulated human normal colonic mucosal cells (FHCs) were detected. Functional experiments were executed to evaluate the effects of NORAD silencing on TNF-α-induced FHC proliferation, apoptosis, inflammation, and oxidative stress. The molecular mechanism related to NORAD was predicted by starBase and confirmed by dual-luciferase reporter and RIP assays.

Results

Our data exhibited higher levels of NORAD in UC patient-derived colonic mucosal tissues and TNF-α-stimulated FHCs. Functional experiments presented that NORAD inhibition impaired TNF-α-induced FHC apoptosis, inflammation, and oxidative stress. NORAD acted as a miR-552-3p sponge, and miR-552-3p silencing weakened NORAD inhibition-mediated effects on TNF-α-induced FHC apoptosis, inflammation, and oxidative stress. Myeloid differentiation primary response gene 88 (MYD88) was verified as a miR-552-3p target, and MYD88 overexpression whittled miR-552-3p mimic-mediated inhibition on TNF-α-induced FHC apoptosis, inflammation, and oxidative stress. Notably, TNF-α-induced NORAD regulated the nuclear factor-κappaB (NF-κB) signaling via the miR-552-3p/MYD88 axis.

Conclusion

NORAD participates in TNF-α-induced FHC apoptosis, inflammation, and oxidative stress via the NF-κB signaling via the miR-552-3p/MYD88 axis, offering new insights into the pathogenesis of UC.
Left ventricular strain predicts subclinical atherosclerosis in nonadvanced nonalcoholic fatty liver disease patients
Authors: Sonaglioni Andrea , Cerini Federica , Nicolosi Gian Luigi , Lombardo Michele , Rumi Maria Grazia , Viganò Mauro
Published: April 2022

Objectives

The association between nonalcoholic fatty liver disease (NAFLD) and carotid atherosclerosis is still controversial. The present study was designed to assess the relationship between left ventricular systolic mechanics, noninvasively assessed by two-dimensional (2D) speckle-tracking echocardiography (STE) and common carotid artery (CCA) intima-media thickness (IMT), in patients with nonadvanced NAFLD.

Methods

All consecutive NAFLD patients diagnosed with liver stiffness measurement (LSM) <12.5 kPa on transient elastography between September 2021 and December 2021 were prospectively enrolled. All participants underwent blood tests, transient elastography, 2D transthoracic echocardiography (TTE) implemented with 2D-STE analysis of left ventricular (LV) global longitudinal strain (GLS) and finally carotid ultrasonography. Main independent predictors of subclinical atherosclerosis, defined as CCA-IMT >0. 9 mm, were evaluated.

Results

A total of 92 NAFLD patients (54.0 ± 11.1 years, 50% males) were prospectively analyzed. Mean LSM was 6.2 ± 2.4 kPa. FibroScan results revealed that 76.1% of patients had F0–F1, 5.4% F2 and 18.5% F3 liver fibrosis. Despite normal biventricular systolic function on 2D-TTE, LV-GLS was reduced (less negative than −20%) in 64.1% of patients. However, 62.0% of NAFLD patients were found with CCA-IMT >0. 9 mm. Age [odds ratio (OR),1.19; 95% confidence interval (CI), 1.05–1.36], hypertension (OR, 3.73; 95% CI, 1.53–9.11), LSM (OR, 4.83; 95% CI, 2.43–9.59), LV-GLS (OR, 0.49; 95% CI, 0.36–0.68) and statin therapy (OR, 0.10; 95% CI, 0.02–0.60) were independently associated with subclinical atherosclerosis. Age ≥51 years, LSM ≥5.5 kPa and LV-GLS less negative than −20% were the best cutoff values for predicting subclinical atherosclerosis.

Conclusions

Subclinical myocardial dysfunction and subclinical atherosclerosis are simultaneously present in patients with nonadvanced NAFLD.
The predictive value of procalcitonin combined with C-reactive protein and D dimer in moderately severe and severe acute pancreatitis
Authors: He QiYong , Ding Jian , He ShanShan , Yu YunWen , Chen XiaoPing , Li Dan , Chen FengLin
Published: April 2022

Objective

The objective of this study is to investigate the predictive value of a parametric model constructed by using procalcitonin, C-reactive protein (CRP) and D dimer within 48 h after admission in moderately severe and severe acute pancreatitis.

Methods

A total of 238 patients were enrolled, of which 170 patients were moderately severe and severe acute pancreatitis (MSAP+SAP). The concentrations of procalcitonin, CRP and D dimer within 48 h after admission were obtained. The predictive value of the parametric model, modified computed tomography severity index (MCTSI), bedside index for severity in acute pancreatitis (BISAP), Ranson score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, modified Marshall score and systemic inflammatory response syndrome (SIRS) score of all patients was calculated and compared.

Results

The area under receiver operator characteristic curve, sensitivity, specificity, Youden index and critical value of the parametric model for predicting MSAP+SAP were 0.853 (95% CI, 0.804–0.903), 84.71%, 70.59%, 55.30% and 0.2833, respectively. The sensitivity of the parametric model was higher than that of MCTSI (84.00%), Ranson score (73.53%), BISAP (56.47%), APACHE II score (27.65%), modified Marshall score (17.06%) and SIRS score (78.24%); the specificity of it were higher than that of MCTSI (52.94%) and Ranson score (67.65%), but lower than BISAP (73.53%), APACHE II score (76.47%), modified Marshall score (100%)and SIRS score (100.00%).

Conclusion

The parametric model constructed by using procalcitonin 48 h, CRP 48 h and D dimer 48 h can be regarded as an evaluation model for predicting moderately severe and severe acute pancreatitis.
NSAIDs are not enough – a double blinded randomized controlled trial on the impact of intensive hydration for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis
Authors: Boal Carvalho Pedro , Magalhães Joana , Dias de Castro Francisca , Cúrdia Gonçalves Tiago , Monteiro Sara , Xavier Sofia , Rosa Bruno , Cotter José
Published: April 2022

Background

Pancreatitis is the most common complication following endoscopic retrograde cholangiopancreatography (ERCP). In patients receiving NSAID prophylaxis, we aimed to assess whether periprocedural intensive hydration (IH) resulted in a lower incidence of PEP when compared to standard hydration (SH).

Material and Methods

Prospective, single-center, double-blinded randomized controlled trial, with inclusion of consecutive patients submitted to inaugural ERCP between January 2015 and December 2018. Patients were randomized on admission, in a 1:1 ratio, to either SH–Ringer’s Lactate (RL) at a rate of 1.5 mL/kg/h during and for 8 h following the procedure, or IH–RL at a rate of 3 mL/kg/h during and for 8 h following the procedure, with an additional bolus of 20 mL/kg at the end of the procedure. PEP incidence and severity were assessed according to the Atlanta Guidelines.

Results

A total of 155 patients were randomized (83 to IH, 72 to SH). PEP was observed in 8,4% (n = 13) of the patients, and was significantly less frequent in IH patients when compared to SH (3,6% vs 13,9%, P = 0,021; relative risk 0.233 [95% IC, 0.061–0.881]); five patients in the SH group developed moderate to severe PEP, in contrast to 0 patients in the IH group (6.9% vs 0.0%, P = 0,020).

Conclusions

Intensive hydration significantly decreased the risk of post-ERCP pancreatitis by four-fold. Moreover, no cases of moderate or severe pancreatitis were observed in patients submitted to this intervention. Associated with nonsteroidal anti-inflammatory drugs, intensive hydration could constitute a new standard of care for patients undergoing ERCP.
Evaluating the Impact of a Regional Student-Led Physiotherapy Clinic Model to Improve Self-Reported Function in Community-Dwelling Adults With Neurological Diagnoses
Authors: Hams Andrea , Bell Neil , Jones Taryn
Published: April 2022

Background and Purpose:

Neurological conditions are a major cause of health morbidity that negatively impacts function and quality of life (QoL). Despite this burden, community services are disproportionally scarce. Student-led physiotherapy services (SLSs) are a model that can increase community access to health care while providing authentic clinical experiences for students. SLSs consistently demonstrate high client satisfaction; however, limited evaluation of the impact of this model on the client's clinical outcomes exists. Therefore the aim of this project was to evaluate the impact of a physiotherapy student-led community-based rehabilitation service.

Methods:

The SLS operated 4 days a week over a 15-week period. Forty-two community-dwelling clients (mean age 74 years) with a neurological diagnosis were included. During initial consultation, participants completed basic demographics, up to 3 Patient-Specific Functional Scales (PSFSs) and a QoL questionnaire (World Health Organization Quality of Life-Brief Questionnaire [WHOQOL-BREF]). At discharge, participants completed the WHOQOL-BREF, PSFS, and a patient experience survey. Risk event data were also collected.

Results:

Over half of the PSFS items targeted mobility (55%). There was a significant improvement (P < 0.05) in median change (quartiles) for pre-/post-PSFS scores for clients whose primary condition was balance 1.0 (0.0-3.0), cerebrovascular accident 1.0 (2.0-3.0) or multiple Sclerosis 1.0 (1.0-2.0), and mean (SD) WHOQOL-BREF scores for Physical Health (12.2 ± 1.5 to 13.1 ± 1.3) and Social Relationships (12.7 ± 2.7 to 16.6 ± 3.3). Patient experience survey results indicated that clients had confidence and trust in students. No adverse events were reported.

Discussion and Conclusions:

The SLS model provides a strategy to increase access to health care and clinical placement capacity. Findings demonstrated improved self-rated function, QoL, and positive patient experience for community-dwelling clients with nonacute neurological diagnoses.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A380).
Case Report: Topical Netarsudil in the Treatment of a Neurotrophic Corneal Ulcer
Authors: Bronner Aaron William
Published: April 2022

SIGNIFICANCE

Rho-associated kinase inhibitors have been used in glaucoma management for reducing intraocular pressure. Their role in treating corneal endothelial damage and promoting corneal epithelial healing has also been reported. Presented is a case report demonstrating healing of a previously nonresponsive neurotrophic ulcer with addition of the Rho-associated kinase inhibitor, netarsudil.

PURPOSE

Early in vitro–based research on corneal application of Rho-associated kinase inhibitors has shown these molecules to be beneficial to corneal epithelial wound healing. The presented case supports their use in epithelial disease. It is the author's hope that this will inspire further investigation.

CASE REPORT

Presented here is a case report describing the use of netarsudil, a Rho-associated kinase inhibitor in the management of a neurotrophic corneal ulcer that was nonresponsive to frontline therapy. The application of netarsudil was followed by rapid healing of the defect, although a concomitant increase in mucous production was also noted.

CONCLUSIONS

This case supports the use of netarsudil as an agonist of epithelial healing, although further research is needed.
Transcranial Doppler Ultrasonography in Children With Acute Liver Failure and Severe Hepatic Encephalopathy
Authors: Cousin Vladimir L. , Charbel Ramy , Ghali Narjess , Marais Clémence , Tissières Pierre
Published: April 2022

OBJECTIVES:

To report our single-center use of transcranial Doppler (TCD) for noninvasive neuromonitoring in pediatric patients with acute liver failure (ALF).

DESIGN:

Retrospective cohort from January 2016 to June 2019.

SETTING:

PICU in Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), a national referral center for pediatric liver transplantation.

PATIENTS:

Pediatric patients with severe ALF (prothrombin time < 30% and Hepatic Encephalopathy score ≥ 3), on continuous venovenous high-flow hemofiltration.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Ten children were identified, six were transplanted (1/6 died) and four were not (3/4 died). TCD was performed several times per patient and the evolution of cerebral perfusion parameters was followed. Of interest, zero of six patients who survived lost end-diastolic velocity (EDV), whereas four of four patients who died did (difference, 100%; 95% CI, 37–100%; χ2, 9; degrees of freedom, 1; p = 0.0027). We failed to identify an association between pulsatility index (PI) or EDV, and severity of hepatic encephalopathy.

CONCLUSIONS:

TCD was a noninvasive and bedside available tool to detect and screen for presence of abnormal cerebral flow in children with ALF, according to age-related reference values. TCD detected reduced EDV and elevated PI in children with ALF awaiting transplant who died compared with those who survived.
Symptomatic Cervical Spinal Cord Injury Without Accompanying Intracranial Injury Because of Child Abuse
Authors: Feldman Kenneth W. , Wright Jason N. , Menashe Sarah J. , Otjen Jeffrey P. , Pidaparti Vaidehi
Published: April 2022

Although spinal ligamentous injuries and extra-axial hemorrhages are known to commonly accompany abusive head trauma (AHT), symptomatic and radiological apparent cervical spinal cord injuries are rare. Of the 16 previously reported cases, 3 such cord injuries lacked the accompanying intracranial injuries of AHT. We report an additional child who developed symptomatic central cervical cord syndrome, with accompanying cervical imaging findings, but no intracranial AHT injuries. The mechanism of trauma for this child and the other children without intracranial injury remains unclear. However, 1 additional reported child sustained similar injuries when she was held by her head and shaken. It is likely that as cervical magnetic resonance imaging becomes more common in AHT, more cases will be recognized.
“Parenteral” Diarrhea Associated With Pediatric Urinary Tract Infections
Authors: Mellick Larry B. , Murray Caleb , Kalra Sarathi
Published: April 2022

Objectives

The association of noninfectious diarrhea with extraintestinal infections such as otitis media, pneumonia, or febrile urinary tract infections (UTIs) is commonly known as parenteral diarrhea. Although this association has been described for over a century and parenteral diarrhea is mentioned in current reference literature, available evidence for this association seems to be limited. The primary research question was to determine if there is an association between UTIs and reports of diarrhea.

Methods

A retrospective chart review was performed using the medical records from October 1, 2017, to March 29, 2019 at our tertiary pediatric medical center. We searched for all cases of afebrile and febrile UTIs evaluated in the pediatric emergency department or admitted directly to the hospital for treatment. All children younger than 5 years were eligible for inclusion. Exclusion criteria included children with recent urological procedures, known urinary tract disease, immune suppression, sepsis, or known gastrointestinal diseases. The medical records of each of the pediatric patients with culture-positive UTIs were reviewed for reports of concurrent diarrhea or diarrhea-like illness. In addition, using a comparative quantitative design, we performed a retrospective chart review of all children younger than 5 years with 1 of 2 noninfectious chief complaints, head trauma, and extremity fractures, presenting during the same period to assess the background rate of reported diarrhea.

This research project received the approval of the University of South Alabama's Institutional Review Board.

Results

A total of 236 children with a culture-positive UTI presented to our pediatric medical center from October 1, 2017 to March 29, 2019. Reports of diarrhea were documented in the medical record for 44 of the 236 UTIs (18.6%). Escherichia coli was the predominant infectious agent in 32 of the 44 children (72.7%) with culture-positive UTIs and diarrhea. Of the 368 comparison group patients who visited the pediatric emergency department for a noninfectious complaint, diarrhea was reported in 2 patients (0.01%).

Conclusions

Our retrospective review of pediatric patients younger than 5 years with culture-proven UTIs found an association of reported diarrhea. It is our opinion based on our single-center retrospective chart review that the current available evidence suggests an association between UTIs and extraintestinal diarrhea. Future prospective studies are recommended to confirm this association.
Effective Transcranial Direct Current Stimulation Parameters for the Modulation of Eating Behavior: A Systematic Literature Review and Meta-Analysis
Authors: Beaumont Jordan D. , Smith Natalie C. , Starr David , Davis Danielle , Dalton Michelle , Nowicky Alexander , Russell Mark , Barwood Martin J.
Published: April 2022

Objective

This study aimed to consider the effect of differing transcranial direct current stimulation (tDCS) parameters on eating-related measures and how issues with experimental design (e.g., inadequate blinding) or parameters variation may drive equivocal effects.

Methods

Literature searches were conducted across MEDLINE, PsycINFO, Scopus, and Science Direct. Studies using conventional sham-controlled tDCS to modify eating-related measures in adult human participants were included. A total of 1135 articles were identified and screened by two independent authors. Study quality was assessed using the Risk of Bias tool. Random-effects meta-analyses were performed, with subgroup analyses to determine differences between parameter sets.

Results

We identified 28 eligible studies; 7 showed low risk of bias, with the remaining studies showing bias arising from issues implementing or reporting blinding protocols. Large variation in applied parameters was found, including montage, current intensity and density, participant and researcher blinding, and the use of online or offline tasks. The application of differing parameters seemed to alter the effects of tDCS on eating-related measures, particularly for current density (g = −0.25 to 0.31), and when comparing single-session (g = −0.08 to 0.01) versus multisession protocols (g = −0.34 to −0.29). Some parameters result in null effects.

Conclusions

The absence of tDCS-mediated change in eating-related measures may be driven by variation in applied parameters. Consistent application of parameters that seem to be effective for modulating eating behavior is important for identifying the potential impact of tDCS. Using the findings of this review, we propose a series of parameters that researchers should apply in their work.
Brief Report: Validation of the D:A:D Chronic Kidney Disease Risk Score Incorporating Proteinuria in People Living With HIV in Harare, Zimbabwe
Authors: Anderson Matthew A. , Chimbetete Cleophas , Shamu Tinei , Dahwa Rumbizai , Gracey David M.
Published: April 2022

Objective:

We sought to validate the D:A:D risk score for chronic kidney disease (CKD) in people living with HIV in a cohort from Harare, Zimbabwe. In addition, we aimed to evaluate proteinuria as a predictive variable in the risk score model, being the first study to do so.

Design:

Data from people living with HIV attending a clinic in Harare were evaluated. Those with a baseline estimated the glomerular filtration rate >60 mL/min/1.73 m2, and at least 2 subsequent estimated glomerular filtration rate measurements were included. A modified version of the D:A:D risk score model was applied to categorize participants as “low,” “medium,” and “high-risk” of progression to CKD. Potential predictors of renal impairment were assessed by logistic regression in univariate and multivariate models. Proteinuria was evaluated in a nested model using D:A:D risk categories.

Results:

Two thousand seven hundred ninety-three participants were included. Forty participants (1.4% of the cohort) progressed to CKD during the median follow-up time of 4.2 years. Progression rates were 1%, 3%, and 12% in the low, medium, and high-risk groups, respectively. Proteinuria data were available for 2251 participants. The presence of proteinuria was strongly associated with progression to CKD [(OR 7.8, 95% CI: 3.9 to 15.7), and its inclusion in the risk score improved the discrimination of the model with the c-statistic increasing from 0.658 to 0.853].

Conclusion:

A modified version of the D:A:D CKD risk score performed well in predicting CKD events among this sub-Saharan African cohort of people living with HIV. Inclusion of proteinuria into the risk score model significantly improved predictability.
Noninvasive Diagnosis of Acute Rejection in Renal Transplant Patients Using Mass Spectrometric Analysis of Urine Samples: A Multicenter Diagnostic Phase III Trial
Authors: Gwinner Wilfried , Karch Annika , Braesen Jan H. , Khalifa Abedalrazag A. , Metzger Jochen , Naesens Maarten , Van Loon Elisabet , Anglicheau Dany , Marquet Pierre , Budde Klemens , Matz Mareen , Arns Wolfgang , Fischereder Michael , Habicht Antje , Eisenberger Ute , Mühlfeld Anja , Busch Martin , Wiesener Michael , Scheffner Irina , Koch Armin
Published: April 2022

Background.

Timely recognition and treatment of acute kidney graft rejection is important to prevent premature graft failure. A predefined urinary marker set for acute T cell–mediated rejection (TCMR) containing 14 peptides was tested for this purpose in a multicenter in-place validation study.

Methods.

Three hundred twenty-nine prospectively collected and 306 archived urine samples from 11 transplant centers in Germany, France, and Belgium were examined. Samples were taken immediately before a biopsy, performed for graft dysfunction within the first transplant year. Primary outcomes were sensitivity and specificity of the marker set for the diagnosis of biopsy-proven acute TCMR, with prespecified thresholds of 83% for sensitivity and 70% for specificity.

Results.

Eighty-two patients (13%) had acute TCMR grade I–III. In relation to the biopsy diagnosis of TCMR, the sensitivity of the urine test was 0.66 (95% confidence interval, 0.56-0.76) and the specificity 0.47 (95% confidence interval, 0.43-0.51), with an area under the curve (AUC) of 0.60. The different TCMR grades I–III were not reflected by the marker set, and borderline TCMR was not specifically detected. Secondary independent masked assessment of biopsies consented by 2 pathologists revealed an interobserver kappa value of 0.49 for diagnosing TCMR, compared with the local center’s diagnosis. Using this consensus diagnosis, the AUC of the urine test was 0.63 (sensitivity 0.73, specificity 0.45). Post hoc optimization of the marker set improved the diagnostic performance in the study cohort (AUC 0.67) and in an independent patient cohort (AUC 0.69).

Conclusions.

This study illustrates the difficulty of proteomics-based diagnosis of TCMR and highlights the need for rigorous independent in-place validation and optimization of diagnostic biomarkers.
Suppressor genetics reveals novel inter-domain crosstalk within the multidrug transporter Mdr1 protein
Authors: Sharma Suman , Banerjee Atanu , Moreno Alexis , Falson Pierre , Prasad Rajendra
Published: April 2022

The Multidrug resistance-1 protein (Mdr1p) of Candida albicans is a crucial drug/H+ antiporter within the Major Facilitator Superfamily of proteins involved in the efflux of a broad spectrum of structurally diverse xenobiotic compounds. As a member of the DHA1 subfamily, Mdr1p consists of 12 transmembrane helices (TMHs), divided equally into two Transmembrane Domains (TMDs). How the pseudo-symmetrically positioned TMHs, and the TMDs they compose, communicate with each other remains poorly characterized. In that direction, the recovery of spontaneous chromosomal mutants that negatively affect the primary mutant phenotype can provide essential inter-domain communication insights. For this purpose, in the current study we have performed a suppressor screen for a critically transport deficient mutant G230A, located within TMH-4 of Mdr1p, predicted towards the intracellular space. The recovered suppressor (P528H), that restores the transport capacity of this initially drug susceptible mutant, map to TMH-12, very close to the extracellular space. Since the mutant and suppressor sites occupy the N-domain and C-domain, respectively, and locate at a pseudo-symmetrical position, these results hint to a novel pattern of crosstalk. Additionally, the recovered suppressor mutation restores wild type phenotypes for all tested xenobiotic substrates except cycloheximide, thus implying substrate selectivity. Furthermore, the molecular modeling and docking results suggest a novel compensatory mechanism which is independent of drug binding. Altogether, the present study is a first attempt to gain insights into the transport mechanism of drug/H+ antiporter using the suppressor genetics approach.
Phylogenetic-informed graph deep learning to classify dynamic transmission clusters in infectious disease epidemics
Authors: Sun Chaoyue , Li Yanjun , Marini Simone , Riva Alberto , Wu Dapeng O. , Salemi Marco , Magalis Brittany Rife
Published: April 2022

In the midst of an outbreak, identification of groups of individuals that represent risk for transmission of the pathogen under investigation is critical to public health efforts. Several approaches exist that utilize the evolutionary information from pathogen genomic data derived from infected individuals to distinguish these groups from the background population, comprised of primarily randomly sampled individuals with undetermined epidemiological linkage. These methods are, however, limited in their ability to characterize the dynamics of these groups, or clusters of transmission. Dynamic transmission patterns within these clusters, whether it be the result of changes at the level of the virus (e.g., infectivity) or host (e.g., vaccination implementation), are critical in strategizing public health interventions, particularly when resources are limited. Phylogenetic trees are widely used not only in the detection of transmission clusters, but the topological shape of the branches within can be useful sources of information regarding the dynamics of the represented population. We evaluate the limitation of existing tree shape statistics when dealing with smaller sub-trees containing transmission clusters and offer instead a phylogeny-based deep learning system –DeepDynaTree– for classification of transmission cluster. Comprehensive experiments carried out on a variety of simulated epidemic growth models indicate that this graph deep learning approach is effective in predicting cluster dynamics (balanced accuracy of 0.826 vs. 0.533 and Brier score of 0.234 vs. 0.466 in independent test set). Our deployment model in DeepDynaTree incorporates a primal-dual graph neural network principle using output from phylogenetic-based cluster identification tools (available fromhttps://github.com/salemilab/DeepDynaTree).
Candidate genes associated with neurological manifestations of COVID-19: Meta-analysis using multiple computational approaches
Authors: Hazra Suvojit , Chaudhuri Alok Ghosh , Tiwary Basant K. , Chakrabarti Nilkanta
Published: April 2022

COVID-19 develops certain neurological symptoms, the molecular pathophysiology of which is obscure. In the present study, two networks were constructed and their hub-bottleneck and driver nodes were evaluated to consider them as ‘target genes’ followed by identifying ‘candidate genes’ and their associations with neurological phenotypes of COVID-19. A tripartite network was first constructed using literature-based neurological symptoms of COVID-19 as input. The target genes evaluated therefrom were then used as query genes to identify the co-expressed genes from the RNA-sequence data of the frontal cortex of COVID-19 patients using pair-wise mutual information to genes. A ‘combined gene network’ (CGN) was constructed with 189 genes selected from TN and 225 genes co-expressed in COVID-19. Total 44 ‘target genes’ evaluated from both networks and their connecting genes in respective networks were analyzed functionally by measuring pair-wise ‘semantic similarity scores’ (SSS) and finding Enrichr annotation terms against a set of genes. A new integrated ‘weighted harmonic mean score’ was formulated using SSS and STRING-based ‘combined score’ to select 21 gene-pairs among ‘target genes’ that provided 21 ‘candidate genes’ with their properties as ‘indispensable driver nodes’ of CGN. Finally, six pairs providing seven prevalent candidate genes (ADAM10, ADAM17, AKT1, CTNNB1, ESR1, PIK3CA, FGFR1) exhibited direct linkage with the neurological phenotypes under tumour/cancer, cellular signalling, neurodegeneration and neurodevelopmental diseases. The other phenotypes under behaviour/cognitive and motor dysfunctions showed indirect associations with the former genes through other candidate genes. The pathophysiology of ‘prevalent candidate genes’ has been discussed for better interpretation of neurological manifestation in COVID-19.
A discovery pipeline for identification and in vivo validation of drugs that alter T cell/ dendritic cell interaction
Authors: Scales Hannah E. , Keijzer Chantal , Evertsson Emma , Garside Paul , Delaney Stephen , Brewer James M.
Published: April 2022

The interaction between T cells and dendritic cells (DC) is central to determining whether or not an adaptive immune response develops. Autoimmune diseases like rheumatoid arthritis result from inappropriate activation of self-antigen specific T cells, therefore targeting the interaction between T cells and DCs is of considerable therapeutic interest. Here, we describe the development and validation of a drug development platform that includes a high-throughput image-based screening assay and a complementary in vivo model. The in vitro assay directly measures the ability of compounds to influence the interaction of T cells with DC, both negatively and positively. While the in vivo model allows the validation of hit molecules directly in the lymph nodes of intact animals. Using this pipeline, we identify a new function for the protein kinase inhibitor AS703569 by inhibiting T cell/ DC interactions in vitro and in vivo.
UBC9 and EME1 sumoylation foster ribosomal DNA damage repair in CPT response
Authors: Nagamalleswari Easa , Bakshi Karishma , Breucker Jan , Gschweitl Michaela , González-Prieto Román , Eisenhardt Nathalie , Fatouros Chronis , Chaugule Viduth K , Vertegaal Alfred C.O. , Pichler Andrea
Published: April 2022

UBC9 sumoylation (S*UBC9) in mammals contributes to SUMO target discrimination, biochemically1. Here, we present biological insights by characterizing a sumoylation mimetic UBC9-fusion (mCS~UBC9) in comparison to its wild-type (mCUBC9). We observe that sumoylation promotes UBC9’s stability, nuclear localization and is beneficial for cell survival. We identified EME1, the regulatory subunit of the structure-specific endonuclease EME1-MUS81, as S*UBC9 substrate and demonstrate EME1 and UBC9 sumoylation being advantageous for survival upon Camptothecin (CPT) exposure. Moreover, mCS~UBC9 expression enhances double-strand breaks (DSBs) and replication upon CPT treatment, features assigned to the EME1-MUS81 complex2. EME1 and mCS~UBC9 co-localize in nucleolar repair-condensates, that enlarge and round when exposed to the drug. Together, these findings imply that S*UBC9-induced EME1 sumoylation improves ribosomal rDNA repair, which might prevent dangerous second template switches in highly repetitive ribosomal chromatin and allow the converging replication fork to complete DNA replication. Finally, we discuss implications of these findings for anti-cancer therapy.
Influence of RNA circularity on Target RNA-Directed MicroRNA Degradation
Authors: Wightman Federico Fuchs , Lukin Jerónimo , Giusti Sebastián , Soutschek Michael , Bragado Laureano , Pozzi Berta , González Paula , Fededa Juan P. , Schratt Gerhard , Fujiwara Rina , Wilusz Jeremy E. , Refojo Damián , de la Mata Manuel
Published: April 2022

A subset of circular RNAs (circRNAs) and linear RNAs have been proposed to “sponge” or block microRNA activity. Additionally, certain RNAs induce microRNA destruction through the process of Target RNA-Directed MicroRNA Degradation (TDMD), but whether both linear and circular transcripts are equivalent in driving TDMD is unknown. Here we study whether circular/linear topology of endogenous and artificial RNA targets affects TDMD. Consistent with previous knowledge thatCdr1as (ciRS-7)circular RNA protects miR-7 from Cyrano-mediated TDMD, we demonstrate that depletion ofCdr1asreduces miR-7 abundance. In contrast, overexpression of an artificial linear version ofCdr1asdrives miR-7 degradation. Using plasmids that express a circRNA with minimal co-expressed cognate linear RNA, we show differential effects on TDMD that cannot be attributed to the nucleotide sequence, as the TDMD properties of a sequence often differ between its circular and linear forms. By analysing RNA sequencing data of a neuron differentiation system, we further detect potential effects of circRNAs on microRNA stability. Our results support the view that RNA circularity influences TDMD, either enhancing or inhibiting it on specific microRNAs.
The specific roles of renal macrophages in monitoring and clearing off intratubular particles
Authors: He Jian , Cao Yangyang , Zhu Qian , Wang Xinge , Cheng Guo , Wang Qiang , Han Fei , Shi Peng , Shen Xiao Z
Published: April 2022

During the filtrate of the glomerulus flows though the renal tubular system, a variety of microscopic sediment particles, including mineral crystals resulting from urine concentration, are generated. Dislodging these particles in the intratubular compartment is critical to ensure free flow of filtrate and the final formation of urine. However, the underlying mechanism for the clearance is unclear. Here, using high-resolution microscopy, we uncovered that the juxtatubular macrophages in the medulla constitutively formed transepithelial protrusions and were “sampling” urine contents. These behaviors were strengthened in the development of nephrolithiasis. In particular, the juxtatubular macrophages were efficient in sequestering and phagocytosing intraluminal sediment particles, and occasionally making transmigration to the tubule lumen to escort the excretion of urine particles. Specific depletion of renal macrophages precipitated kidney stone formation and aggravated the accompanied inflammation upon hyperoxaluria challenge. Thus, renal macrophages undertake a specific role in maintaining the tubular system unobstructed.
Preclinical evaluation of CDK4 phosphorylation predicts high sensitivity of malignant pleural mesotheliomas to CDK4/6 inhibition
Authors: Paternot Sabine , Raspé Eric , Meiller Clément , Tarabichi Maxime , Assié Jean-Baptiste , Libert Frederick , Remmelink Myriam , Bisteau Xavier , Pauwels Patrick , Blum Yuna , Le Stang Nolwenn , Tabone-Eglinger Séverine , Galateau-Sallé Françoise , Blanquart Christophe , Van Meerbeeck Jan P. , Berghmans Thierry , Jean Didier , Roger Pierre P.
Published: April 2022

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in a panel of 28 MPM cell lines, including 19 patient-derived cell lines, using a variety of approaches including RNA-sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 23 MPM cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with the high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, and also (unexpectedly) cyclin E1 over-expression in the presence of wild-type RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was also irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPM tumors indicating their intrinsic sensitivity to CDK4/6 inhibitors. The absence of this phosphorylation in some highly proliferative MPM tumors was linked to partial deletions of RB1, leading to very high p16 (CDKN2A) expression. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment, in monotherapy or combination therapy.