bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of remote peer support on stigma in patients after breast cancer surgery during the COVID-19 pandemic
Authors: Liang Dandan , Jia Ruiying , Yu Jingfen , Wu Zhen , Chen Chaoran , Lu Guangli
Published: June 2021

Background:

Patients after breast cancer surgery have a high sense of stigma due to the formation of surgical scars, loss of breast shape or other reasons, leading to anxiety, depression, and other adverse mental health problems, thus reducing their quality of life. Remote peer support intervention based on telephone, internet or email is low-cost and easy to spread, and protects patients’ privacy, solves the barriers to access that many patients face when attending face-to-face programs. Therefore, remote peer support may be an effective way to reduce stigma and improve mental health in patients after breast cancer surgery during the coronavirus disease 2019 (COVID-19) pandemic.

Methods:

Eight databases (PubMed, Embase, Cochrane Library, CNKI, PsycNET, MEDLINE, Psychology & Behavioral Sciences Collection and Web of Science) will be used to select eligible studies that were published from inception to May, 2021. The eligible studies will be screened, extracted and then the methodological quality will be evaluated independently by 2 reviewers. Review manager software version 5.3 software and Stata version 14.0 software will be used for meta-analysis.

Results:

The results of this study will show the effect of remote peer support on stigma, depression and anxiety in patients after breast cancer surgery during the COVID-19 pandemic and will be submitted to a peer-reviewed journal for publication.

Conclusion:

The results of this study will provide evidence for the effectiveness of remote peer support in patients after breast cancer surgery during the COVID-19 pandemic.

PROSPERO registration number:

CRD42021255971.
Comparison of endoscopically determined gross tumor volume and metabolic tumor volume in esophageal cancer
Authors: Lee Tae Hoon , Ryoo Hyun Gee , Lee Reeree , Paeng Jin Chul , Chung Hyunsoo , Kim Hak Jae
Published: June 2021

The purpose of this study is to compare the longitudinal location of endoscopically-defined gross tumor volume (GTV) and positron emission tomography-based metabolic tumor volume (MTV) of esophageal cancer.

A retrospective review of medical records was performed of the nine patients who underwent endoscopic placement of fiducial markers for radiotherapy of esophageal squamous cell carcinoma. Endoscopic hemoclips were used as the fiducial markers, and GTV was newly delineated solely based on the locations of the fiducial markers. The standardized uptake value (SUV) threshold corresponding to the superior and inferior borders of GTV was defined as the highest threshold that made MTV reach each border of GTV.

The median fixed relative and absolute thresholds were 32% and 3.8, respectively. The coefficient of variation of the threshold values was 0.781 for the fixed relative threshold method and 0.400 for the fixed absolute threshold method, indicating more consistent results from the fixed absolute threshold method. All but two GTV borders were included in MTV with a SUV threshold of 2.5. Esophageal tumors with a maximum SUV > 20 tended to have closer threshold values corresponding to the GTV borders to 2.5 (median 2.8 vs 3.6, P = .069).

The fixed absolute threshold method was suitable for determining the MTV threshold for esophageal lesions. A SUV of 2.5 was appropriate for esophageal tumors with a maximum SUV > 20. Endoscopic hemoclips were stable enough for using as the fiducial marker.
Does a combination treatment of repetitive transcranial magnetic stimulation and occupational therapy improve upper limb muscle paralysis equally in patients with chronic stroke caused by cerebral hemorrhage and infarction?
Authors: Tatsuno Hisashi , Hamaguchi Toyohiro , Sasanuma Jinichi , Kakita Kiyohito , Okamoto Takatsugu , Shimizu Masato , Nakaya Naoki , Abo Masahiro
Published: June 2021

The clinical presentation of stroke is usually more severe in patients with intracerebral hemorrhage (ICH) than in those with cerebral infarction (CI); recovery of stroke-related muscle paralysis is influenced and limited by the type of stroke. To date, many patients have been treated by neurorehabilitation; however, the changes in the recovery of motor paralysis depending on the type of stroke, ICH or CI, have not been established. This study aimed to determine this difference in improvement of upper extremity paralysis using 2-week in-hospital NovEl intervention Using Repetitive transcranial magnetic stimulation combined with Occupational therapy (NEURO).

We scrutinized the medical records of all patients with poststroke (ICH or CI) upper extremity muscle paralysis using Fugl-Meyer assessments (FMAs) who had been admitted to 6 hospitals between March 2010 and December 2018 for rehabilitation treatment. This was a multiinstitutional, open-label, retrospective cohort study without control patients. We evaluated the effects of NEURO on patients with CI and ICH by dividing them into 2 groups according to the type of stroke, after adjustment for age, sex, dominant hand, affected hand side, time since stroke, and prediction of recovery capacity in the upper extremity.

The study included 1716 (CI [n = 876] and ICH [n = 840]) patients who had undergone at least 2 FMAs and had experienced stroke at least 6 months before. The type of stroke had no effect on the outcomes (changes in the FMA-upper extremity score, F
[4,14.0] = 2.05, P = .09, partial η2 = 0.01). Patients from all 5 groups equally benefited from the treatment (improvement in FMA scores) according to the sensitivity analysis-stratified analysis (F = 0.08 to 1.94, P > .16, partial η2 < 0.001).

We conclude that NEURO can be recommended for chronic stroke patients irrespective of the type of stroke.
Evaluation of efficacy and safety of combined rosuvastatin and atorvastatin in treating with coronary heart disease
Authors: Li Ke , Liu Meng-Meng , Yang Xin , Chen Li , Geng Hui , Luo Wei , Ma Jie
Published: June 2021

Background:

Globally, coronary heart disease (CHD) is a primary cause of morbidity leading to disabilities and mortality. Modern clinical practice adopts several pharmacological methods to treat CHD. Angina pectoris refers to sever chest pain due to CHD, it has a profound impact on the wellbeing of patients. Moreover, angina pectoris is a crucial prognosis predictor. The aim of the current study is to evaluate the effectiveness and safeness of using combined rosuvastatin and atorvastatin to treat CHD patients.

Methods:

A systematic literature search for articles will be conducted on several electronic databases from their inception to May 2021. The search will include all randomized controlled trials examining the use of rosuvastatin in combination with atorvastatin to treat CHD patients. The databases are as follows: MEDLINE, Web of Science, the Cochrane Library, WanFang database, China National Knowledge Infrastructure, and EMBASE. A couple of authors will independently assess the eligibility, extract study data, and assess the possibility of bias. Moreover, depending on the type of data and heterogeneity of the included studies, either the Mantel–Haensel fixed-effect model or the DerSimonian-Laird random-effect model will be used to estimate the relative risk, mean differences, or standardized mean differences and 95% confidence intervals. All differences in opinion shall be decided by involving an additional author in the discussion. Lastly, the RevMan software (version: 5.3) will be used to perform sensitivity analysis, data synthesis, and risk of bias assessment.

Results:

The effectiveness and security of using rosuvastatin in combination with atorvastatin to treat CHD patients will be systematically evaluated.

Conclusion:

This study will provide evidence to evaluate the efficacy and security of using a combination of rosuvastatin and atorvastatin to treat CHD patients.

Ethics and dissemination:

Ethical approval will not be required since it is based on already published data.

Registration number:

DOI 10.17605/OSF.IO/VYBDR (https://osf.io/vybdr/).
A new optical coherence tomography method for subfoveal choroidal thickness measurement
Authors: Kang Kyung Tae , Jang Ji Hye , Kim Yu Cheol
Published: June 2021

Several macular pathologies are associated with choroidal vascular supply and thus require choroidal thickness evaluation. However, there is no standard subfoveal choroidal thickness (SFCT) measurement method. This study investigated a new method of SFCT measurement, using optical coherence tomography.

This is a single-center observational study. Eighty-two senior medical students participated as observers and independently measured the SFCT on 5 standard optical coherence tomography images of healthy adults in a tertiary care setting. They used 3 different methods: the observer's own method, the conventional method, perpendicular to the retinal pigment epithelium, and the new method, along a virtual line connecting the umbo with the most elevated point of the ellipsoid. Additionally, the SFCT angle—the angle between the measurement line and the vertical line of the image—was measured and compared between methods. The intraclass correlation coefficient was used to determine interpersonal variability.

The intraclass correlation coefficients for SFCT, measured using methods 1, 2, and 3, were 0.853, 0.880, and 0.896, respectively (P < .001 for all). Method 3 was the highest. The intraclass correlation coefficients of the SFCT angles were 0.647, 0.842, and 0.307, respectively (P < .001 for all).

The new method showed the lowest interpersonal variability and could therefore be a reliable standard for SFCT measurement, even in foveae with a steep slope on optical coherence tomography.

Trial registration: Not applicable.
Improving work-life balance among administrative officers in Catholic primary schools
Authors: Iremeka Felicia Ukamaka , Ede Moses Onyemaechi , Amaeze Fidelis Eze , Okeke Chinedu Ifedi , Ilechukwu Leonard Chidi , Ukaigwe Patricia Chinelo , Wagbara Chinyere Dorathy , Ajuzie Henry D. , Isilebo Nwamara Chidiebere , Ede Augustina Obioma , Ekesionye Ngozi E. , Okeke Polycarp , Okoronkwo Okereke Lawrence , Okengwu Mary Chinyere , Chigbu Baptista , Ejionueme Lambert Kenechukwu , Agu Patricia U. , Ezeaku Felicia , Aneke Mary
Published: June 2021

Objective:

Work-life balance (WLB) is an essential precursor of workers’ mental health. The theory of rational emotive behaviour therapy proposes that an imbalance in work and family life may result from people's dysfunctional perceptions of their work and other aspects of their personal life. Also, the constructive philosophies of rational emotive behavior therapy are said to be congruent with most religious belief systems of Christian clients. Therefore, our research examined the efficacy of Christian religious rational emotive behaviour therapy (CRREBT) on WLB among administrative officers in Catholic primary schools.

Methods:

This is a group randomized trial involving 162 administrative officers from Catholic primary schools in Southeast Nigeria. The treatment process involved an 8-session CRREBT programme.

Results:

The scores for WLB of the administrative officers enrolled in the CRREBT programme were significantly improved compared to those in the control group at the end of the study. At the follow-up phase, the CRREBT programme proved to be effective over a 3-month period.

Conclusion:

CRREBT is an effective therapeutic strategy for managing WLB among Catholic school administrative officers.
Efficacy of erythropoietin alone in treatment of neonates with hypoxic-ischemic encephalopathy
Authors: Yang Guang , Xue Zhimin , Zhao Yuan
Published: June 2021

Background:

Multiple clinical trials have demonstrated the safety and efficacy of erythropoietin in improving neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy (HIE). It is undoubtedly urgent to include only randomized controlled trials (RCTs) for more standardized systematic reviews and meta-analyses. The purpose of this study is to examine whether erythropoietin reduces the risk of death and improve neurodevelopmental disorders in infants with HIE.

Methods:

The electronic databases of Cochrane Library, EMBASE, PubMed, and Web of Science were searched from the inception to June 2021 using the following key terms: “erythropoietin,” “hypoxic-ischemic encephalopathy,” and “prospective,” for all relevant RCTs. Only English publications were included. The primary outcome was mortality rate. Secondary outcomes included neurodevelopmental disorders, brain injury, and cognitive impairment. The Cochrane risk of bias tool was independently used to evaluate the risk of bias of included RCTs by 2 reviewers.

Results:

We hypothesized that group with erythropoietin would provide better therapeutic benefits compared with control group.

OSF registration number:

10.17605/OSF.IO/FERUS.
Combined exercise and nutrition intervention for spinal sarcopenia
Authors: Lee Sang Yoon , Park Jinhee , Kim Dong Hyun , Lim Jae-Young
Published: June 2021

Introduction:

Spinal sarcopenia is a multifactorial disorder associated with the atrophy of and fatty changes to the paraspinal muscles. We previously developed the concept of spinal sarcopenia in community-dwelling older adults and investigated the association between conventional sarcopenic indices and spinal sarcopenia. However, interventional studies of spinal sarcopenia are lacking. This pilot study will aim to evaluate the effectiveness of a combined exercise and nutrition intervention for treating spinal sarcopenia.

Methods and analysis:

This open-label single-arm prospective study will include 35 community-dwelling older women who were diagnosed with spinal sarcopenia in our previous cohort study. The 12-week combined intervention will consist of back extensor strengthening exercise and nutritional supplementation. The primary outcome of this study will be isometric back extensor strength after the 12-week intervention. All functional and radiographic outcomes will be measured at 0, 12, and 24 weeks post-intervention. The data will be analyzed using the intention-to-treat principle.
Effects of an Avocado-based Mediterranean Diet on Serum Lipids for Secondary Prevention after Ischemic Stroke Trial (ADD-SPISE)
Authors: Olavarría Verónica V. , Campodónico Paola , Vollrath Valeska , von Geldern Paula , Velásquez Carolina , Pavez Patricia , Valente Barbara , Donoso Pamela , Ginesta Alexandra , Cavada Gabriel , Mazzon Enrico , Navia Víctor , Guzmán Matías , Brinck Pablo , Lavados Pablo M.
Published: June 2021

Background:

A poor or unhealthy diet is responsible for an important fraction of ischemic stroke risk. Adherence to dietary patterns, such as the Mediterranean diet, rich in monounsaturated fatty acids mainly from olive oil, is associated with a lower stroke risk. Furthermore, lowering low-density cholesterol (LDL-C) levels decreases stroke recurrence. Interestingly, Avocado-substituted diets, which are also rich in monounsaturated fatty acids, significantly decrease LDL cholesterol levels. This study aims to evaluate whether a Mediterranean diet based on Avocados reduces LDL-C compared to a low-fat high-complex carbohydrate diet after 3 months of the intervention in patients who had a recent acute ischemic stroke. The trial will also assess safety and feasibility.

Patients and methods:

Prospective, randomized open-label, blinded outcome assessment clinical trial. Participants are patients within a month of being admitted with an ischemic stroke, who consent and fulfil the eligibility criteria. Patients are randomly assigned to either diet intervention in a 1:1 ratio on top of the usual secondary prevention treatment. The intervention diet is:

The main efficacy outcome is a reduction in plasma LDL-C levels at 3 months of the dietary intervention. Secondary outcomes include changes in the levels of serum lipid profile and serum inflammation markers, safety, and feasibility. A sample size of 200 patients was estimated to provide 80% power and 5% level of significance (10% loss and 5% crossover) to detect a minimum difference of 4.6 mg/dL in LDL-C after 3 months of intervention.

Conclusion:

We hypothesize that an Avocado-based Mediterranean diet will further reduce the levels of LDL-cholesterol at 3 months compared to the control diet, and that the intervention is safe and feasible.

Registration:

The study is registered under ADDSPISE at www.clinicaltrials.gov. Identifier NCT03524742. Protocol ID CAS-605 version 3.0 (May 2nd, 2019).
Reduction of patient waiting time by the preparation and administration of trastuzumab and pertuzumab in a single infusion bag: a 1-year review, retrospective, single institution experience in a French cancer center
Authors: Deppenweiler Marine , Teytaud Manon , Stein Philippe , Donamaria Catherine , Lortal Barbara
Published: June 2021

In France, over the past few years, the number of patients treated with chemotherapy (conventional and/or with targeted therapy) has steadily increased with a large proportion of patients treated for breast cancer (around 40%), and a constant paramedical staff in day care unit (DCU). Of the time spent in DCU, the waiting time is estimated at 50 minutes. Reducing waiting times, if not eliminating them, seems necessary since it is this unproductive time that generates the most dissatisfaction. One way to reduce the waiting time is to reduce the infusion time for chemotherapy. A new schedule of preparation and administration of trastuzumab and pertuzumab in the same infusion bag has been used in our health-care establishment for maintenance doses only (from cycle 2) that represents approximately 800 preparations per year. The administration time of the bag combining trastuzumab and pertuzumab is 30 minutes instead of 60 minutes when the products are administered separately. The time required to complete each step has been estimated from the computerized pharmaceutical validation process in the Centralized Cytotoxic Reconstitution Unit to the disconnection carried out by the nurse in DCU. Co-administration of these products reduces the average total wait time of patients at DCU by 40 minutes. This timesaving is significant and essential for the satisfaction of patients treated in DCU. The financial benefit linked to a saving in consumables is minimal, of the order of € 4.1 per preparation, or a saving of € 3,280 per year.
Uterine Inflammatory Myofibroblastic Neoplasms With Aggressive Behavior, Including an Epithelioid Inflammatory Myofibroblastic Sarcoma
Authors: Collins Katrina , Ramalingam Preetha , Euscher Elizabeth D. , Reques Llanos Armando , García Angel , Malpica Anais
Published: June 2021

The experience with uterine inflammatory myofibroblastic neoplasms with an unfavorable outcome is limited. We present the clinicopathologic features of 9 such cases, including 8 inflammatory myofibroblastic tumors (IMTs) and 1 epithelioid inflammatory myofibroblastic sarcoma (EIMS). Median patient age for the IMT group was 50.5 years; the patient with EIMS was 43 years old. Patients presented with abnormal uterine bleeding, presumed fibroids, pelvic pain, arthralgia and low-grade fever, as well as an incidental finding. Median tumor size for the IMTs was 8.5 cm. The borders were either infiltrative or well-circumscribed. Histologically, IMTs were purely fascicular or myxoid or showed predominance of one or the other pattern. Seven tumors were spindled, and 1 was both spindled and epithelioid. Tumors had variable nuclear atypia, ranging from grade 1 to 3. All tumors had an inflammatory infiltrate-predominantly lymphocytic, majority had necrosis (62.5%) and none had lymphovascular invasion. 7/8 (87.5%) tumors were positive for ALK-1 by immunohistochemistry (IHC). One tumor was negative for ALK-1 by IHC but was positive for ALK fusion by fluorescence in situ hybridization and had TNS1-ALK fusion by next-generation sequencing (NGS). Three other tumors with NGS testing showed one of the following ALK-fusion partners: FN1, DCTN1, and IGFBP5. The EIMS had infiltrative borders, myxoid and hyalinized patterns, epithelioid cells, and no lymphovascular invasion. This tumor was ALK-1 positive by IHC, had ALK rearrangement by fluorescence in situ hybridization and RANBP2-ALK fusion by NGS. Extrauterine disease at time of diagnosis was noted in 2/8 (25%) of IMTs, and in the single case of EIMS. Seven patients had surgery as primary treatment, 1 patient had neoadjuvant chemotherapy and 1 patient declined treatment. Patients with recurrence were treated with a combination of chemotherapy, targeted therapy, radiotherapy or hormonal therapy. Most patients (71.4%) recurred within 24 months (mos). Two thirds of patients were alive with disease at last follow up (mean 43.6 mos). The patient with EIMS was alive with disease at 22 mos. IMT referral cases were initially diagnosed as smooth muscle tumors in 87.5% of cases; while the EIMS was diagnosed as high-grade endometrial stromal sarcoma. Lack of consideration of IMT in the differential diagnosis of smooth muscle tumors with myxoid features can result in misdiagnosis and under-utilization of targeted therapy in these patients.
Brief Report: Subclinical Carotid Artery Atherosclerosis Is Associated With Increased Expression of Peripheral Blood IL-32 Isoforms Among Women Living With HIV
Authors: El-Far Mohamed , Hanna David B. , Durand Madeleine , Larouche-Anctil Etienne , Sylla Mohamed , Chartrand-Lefebvre Carl , Cloutier Guy , Goulet Jean Philippe , Kassaye Seble , Karim Roksana , Kizer Jorge R. , French Audrey L. , Gange Stephen J. , Lazar Jason M. , Hodis Howard N. , Routy Jean-Pierre , Ancuta Petronela , Chomont Nicolas , Landay Alan L. , Kaplan Robert C. , Tremblay Cécile L.
Published: June 2021

Background:

Persistent inflammation in HIV infection is associated with elevated cardiovascular disease (CVD) risk, even with viral suppression. Identification of novel surrogate biomarkers can enhance CVD risk stratification and suggest novel therapies. We investigated the potential of interleukin 32 (IL-32), a proinflammatory multi-isoform cytokine, as a biomarker for subclinical carotid artery atherosclerosis in virologically suppressed women living with HIV (WLWH).

Methods and Results:

Nested within the Women's Interagency HIV Study, we conducted a cross-sectional comparison of IL-32 between 399 WLWH and 100 women without HIV, followed by a case–control study of 72 WLWH (36 carotid artery plaque cases vs. 36 age-matched controls without plaque). Plasma IL-32 protein was measured by ELISA, and mRNA of IL-32 isoforms (IL-32α, β, γ, D, ε, and θ) was quantified by reverse transcription polymerase chain reaction from peripheral blood mononuclear cells. Plasma IL-32 protein levels were higher in WLWH compared with women without HIV (P = 0.02). Among WLWH, although plasma IL-32 levels did not differ significantly between plaque cases and controls, expression of IL-32 isoforms α, β, and ε mRNA was significantly higher in peripheral blood mononuclear cells from cases (P = 0.01, P = 0.005, and P = 0.018, respectively). Upregulation of IL-32β and IL-32ε among WLWH with carotid artery plaque persisted after adjustment for age, race/ethnicity, smoking, systolic blood pressure, body mass index, and history of hepatitis C virus (P = 0.04 and P = 0.045); the adjusted association for IL-32α was marginally significant (P = 0.07).

Conclusions:

IL-32 isoforms should be studied further as potential CVD biomarkers. This is of particular interest in WLWH by virtue of altered IL-32 levels in this population.
Nationwide utilization of cardiopulmonary bypass in cardiothoracic trauma: A retrospective analysis of the National Trauma Data Bank
Authors: Johnson Benjamin P. , Hojman Horacio M. , Mahoney Eric J. , Detelich Danielle , Karamchandani Manish , Ricard Caroline , Breeze Janis L. , Bugaev Nikolay
Published: June 2021

BACKGROUND

The American College of Surgeons Committee on Trauma requires that all level I trauma centers have cardiopulmonary bypass (CPB) capabilities immediately available. Despite this mandate, there are limited data on the utilization and clinical outcomes among trauma patients requiring CPB in the management of injuries. The aim of this study was to evaluate the current use of CPB in the care of trauma patients.

METHODS

This is a retrospective analysis of the National Trauma Data Bank from 2010 to 2015. Adult patients sustaining cardiothoracic injuries who underwent surgical repair within the first 24 hours of admission were included. Propensity score matching was used to compare outcomes (in-hospital mortality, hospital length of stay (LOS), intensive care unit LOS, and complications) between patients who underwent CPB within the first 24 hours of admission and those with similar injuries who did not receive CPB.

RESULTS

A total of 28,481 patients who met the inclusion criteria were identified, of whom 319 underwent CPB. Three-hundred three CPB patients were matched to 895 comparison patients who did not undergo CPB. Overall in-hospital mortality was 35%. Patients who were not treated with CPB had a significantly higher in-hospital mortality compared with those treated with CBP (odds ratio, 1.57; 95% confidence interval, 1.16–2.12; p = 0.003); however, complications were significantly lower in those who did not receive CPB (odds ratio, 0.63; 95% confidence interval, 0.47–0.86; p = 0.003). Hospital LOS (non-CPB: mean, 13.4 ± 16.3 days; CPB: mean, 14.7 ± 15.1 days; p = 0.23) and intensive care unit LOS (non-CPB: mean, 9.9 ± 10.7 days; CPB: mean, 10.1 ± 9.7 days; p = 0.08) did not differ significantly between groups.

CONCLUSION

The use of CPB in the initial management of select cardiothoracic injuries is associated with a survival benefit. Further investigation is required to delineate which specific injuries would benefit the most from the use of CPB.

LEVEL OF EVIDENCE

Therapeutic, level IV.
Review article: History of venous trauma
Authors: Feliciano David V. , Kochuba Matthew P. , Rozycki Grace F.
Published: June 2021

This is a literature review on the history of venous trauma since the 1800s, especially that to the common femoral, femoral and popliteal veins, with focus on the early 1900s, World War I, World War II, Korean War, Vietnam War, and then civilian and military reviews (1960–2020). In the latter two groups, tables were used to summarize the following: incidence of venous repair versus ligation, management of popliteal venous injuries, patency of venous repairs when assessed <30 days from operation, patency of venous repairs when assessed >30 days from operation, clinical assessment (edema or not) after ligation versus repair, incidence of deep venous thrombosis after ligation versus repair, and incidence of pulmonary embolism after ligation versus repair.

There is a lack of the following in the literature on the management of venous injuries over the past 80 years: standard definition of magnitude of venous injury in operative reports, accepted indications for venous repair, standard postoperative management, and timing and mode of early and later postoperative assessment.

Multiple factors have entered into the decision on venous ligation versus repair after trauma for the past 60 years, but a surgeon’s training and local management protocols have the most influence in both civilian and military centers. Ligation of venous injuries, particularly those in the lower extremities, is well tolerated in civilian trauma, although there is the usual lack of short- and long-term follow-up as noted in many of the articles reviewed.

LEVEL OF EVIDENCE

Review article, levels IV and V.
Machine Learning Prediction of Parkinson’s Disease Onset and Subtype Using Germline Variants
Authors: Dennis Saya R , Simuni Tanya , Luo Yuan
Published: June 2021

Abstract

Parkinson’s Disease is the second most common neurodegenerative disorder in the United States, and is characterized by a largely irreversible worsening of motor and non-motor symptoms as the disease progresses. A prominent characteristic of the disease is its high heterogeneity in manifestation as well as the progression rate. For sporadic Parkinson’s Disease, which comprises 90% of all diagnoses, the relationship between the patient genome and disease onset or progression subtype remains largely elusive. Machine learning algorithms are increasingly adopted to study the genomics of diseases due to their ability to capture patterns within the vast feature space of the human genome that might be contributing to the phenotype of interest. In our study, we develop two machine learning models that predict the onset as well as the progression subtype of Parkinson’s Disease based on subjects’ germline mutations. Our best models achieved an ROC of 0.77 and 0.61 for disease onset and subtype prediction, respectively. To the best of our knowledge, our models present state-of-the-art prediction performances of PD onset and subtype solely based on the subjects’ germline variants. The genes with high importance in our best-performing models were enriched for several canonical pathways related to signaling, immune system, and protein modifications, all of which have been previously associated with PD symptoms or pathogenesis. These high-importance gene sets provide us with promising candidate genes for future biomedical and clinical research.
Non-replication of structural brain changes from Mindfulness-Based Stress Reduction: Two combined randomized controlled trials
Authors: Kral Tammi RA , Davis Kaley , Korponay Cole , Hirshberg Matthew J. , Hoel Rachel , Tello Lawrence Y , Goldman Robin I , Rosenkranz Melissa A , Lutz Antoine , Davidson Richard J
Published: June 2021

Studies purporting to show changes in brain structure following the popular, eight-week Mindfulness-Based Stress Reduction (MBSR) course are widely referenced despite major methodological limitations. Here, we present findings from a large, combined dataset of two, three-arm randomized controlled trials with active and waitlist (WL) control groups. Meditation-naive participants (n=218) completed structural MRI scans during two visits: baseline and post-intervention period. After baseline, participants were randomly assigned to WL (n=70), an 8-week MBSR program (n=75), or a validated, matched active control (n=73). We assessed changes in gray matter volume, gray matter density, and cortical thickness. In the largest and most rigorously controlled study to date, we failed to replicate prior findings and found no evidence that MBSR produced neuroplastic changes compared to either control group, at either the whole-brain level or in regions of interest drawn from prior MBSR studies.
Integrative genomic and epigenomic analyses identified IRAK1 as a novel target for chronic inflammation-driven prostate tumorigenesis
Authors: Oseni Saheed Oluwasina , Adebayo Olayinka , Adebayo Adeyinka , Kwakye Alexander , Pavlovic Mirjana , Asghar Waseem , Hartmann James , Fields Gregg B. , Kumi-Diaka James
Published: June 2021

The impacts of many inflammatory genes in prostate tumorigenesis remain understudied despite the increasing evidence that associates chronic inflammation with prostate cancer (PCa) initiation, progression, and therapy resistance. The overarching goal of this study was to identify dysregulated inflammatory genes that correlate with PCa progression and decipher their molecular mechanisms as well as clinical significance in PCa using integrative genomics, transcriptomics, and epigenomics approach. Our Weighted Gene Co-expression Analysis (WGCNA) and multivariate analysis identified 10 inflammatory genes: IRAK1, PPIL5/LRR1, HMGB3, HMGB2, TRAIP, IL1F5/IL36RN, ILF2, TRIM59, NFKBIL2/TONSL, and TRAF7 that were significantly associated with PCa progression. We explored the potentials of IRAK1 and other inflammatory genes as diagnostic and/or prognostic biomarkers by performing both KM survival and AUROC curve analyses. Our results indicate the clinical significance of these inflammatory genes in predicting the development and progression of PCa. IRAK1 was found to be overexpressed and hypomethylated in most PCa samples. A significantly high percentage of castration-resistant PCa (CRPC) and neuroendocrine PCa (NEPC) samples display copy number variations, especially amplification of the IRAK1 gene compared to the indolent prostate adenocarcinoma (PRAD) samples. Furthermore, we identified missense and frameshift mutations of IRAK1 in a few PRAD samples with potential functional implications. In conclusion, the results from this study suggest that IRAK1 dysregulation may be an important contributor to chronic prostatitis (inflammation) and PCa progression.
scanMiR: a biochemically-based toolkit for versatile and efficient microRNA target prediction
Authors: Soutschek Michael , Gross Fridolin , Schratt Gerhard , Germain Pierre-Luc
Published: June 2021

microRNAs are important post-transcriptional regulators of gene expression, but the identification of functionally relevant targets is still challenging. Recent research has shown improved prediction of microRNA-mediated repression using a biochemical model combined with empirically-derived k-mer affinity predictions. Here, we translate this approach into a flexible and user-friendly bioconductor package, scanMiR, also available through a web interface. Using lightweight linear models, scanMiR efficiently scans for binding sites, estimates their affinity, and predicts aggregated transcript repression. Moreover, flexible 3’-supplementary alignment enables the prediction of unconventional interactions, such as bindings potentially leading to target-directed microRNA degradation (TDMD) or slicing. We showcase scanMiR through a systematic scan for such unconventional sites on neuronal transcripts, including lncRNAs and circRNAs.
Effect of knee joint loading on chondrocyte mechano-vulnerability and severity of post-traumatic osteoarthritis induced by ACL-injury in mice
Authors: Kotelsky Alexander , Elahi Anissa , Can Nejat Yigit , Proctor Ashley , Mannava Sandeep , Pröschel Christoph , Lee Whasil
Published: June 2021

Objective

The objective of this study is to understand the role of altered in vivo mechanical environments in knee joints post anterior cruciate ligament (ACL)-injury in chondrocyte vulnerability against mechanical stimuli and in the progression of post-traumatic osteoarthritis (PT-OA).

Methods

Differential in vivo mechanical environments were induced by unilateral ACL-injury (uni-ACL-I) and bilateral ACL-injury (bi-ACL-I) in 8-week-old female C57BL/6 mice. The gait parameters, the mechano-vulnerability of in situ chondrocytes, Young’s moduli of cartilage extracellular matrix (ECM), and the histological assessment of OA severity (OARSI score) were compared between control and experimental groups at 0∼8-weeks post-ACL-injury.

Results

We found that bi-ACL-I mice experience higher joint-loading on their both injured limbs, but uni-ACL-I mice balance their joint-loading between injured and uninjured hind limbs resulting in a reduced joint-loading during gait. We also found that at 4- and 8-week post-injury the higher weight-bearing hind limbs (i.e., bi-ACL-I) had the increased area of chondrocyte death induced by impact loading and higher OARSI score than the lower weight-bearing limbs (uni-ACL-I). Additionally, we found that at 8-weeks post-injury the ECM became stiffer in bi-ACL-I joints and softer in uni-ACL-I joints.

Conclusions

Our results show that ACL-injured limbs with lower in vivo joint-loading develops PT-OA significantly slower than injured limbs with higher joint-loading during gait. Our data also indicate that articular chondrocytes in severe PT-OA are more fragile from mechanical impacts than chondrocytes in healthy or mild PT-OA. Thus, preserving physiologic joint-loads on injured joints will reduce chondrocyte death post-injury and may delay PT-OA progression.
Reciprocal EGFR signaling in the Anchor Cell ensures precise inter-organ connection during C. elegans vulval morphogenesis
Authors: Spiri Silvan , Berger Simon , Mereu Louisa , DeMello Andrew , Hajnal Alex
Published: June 2021

During C. elegans vulval development, the uterine anchor cell (AC) first secretes an epidermal growth factor (EGF) to specify the vulval cell fates and then invades into the underlying vulval epithelium. Thereby, the AC establishes direct contact with the invaginating 1° vulF cells and attaches the developing uterus to the vulva. The signals involved and the exact sequence of events joining these two organs are not fully understood.

Using a conditional let-23 egf receptor (EGFR) allele along with novel microfluidic short- and long-term imaging methods, we discovered a specific function of the EGFR in the AC during vulval lumen morphogenesis. Tissue-specific inactivation of let-23 in the AC resulted in imprecise alignment of the AC with the 1° vulval cells, delayed AC invasion and disorganized adherens junctions at the newly forming contact site between the AC and the dorsal vulF toroid. We propose that EGFR signaling, activated by a reciprocal EGF cue from the 1° vulval cells, positions the AC at the vulval midline, guides it during invasion and assembles a cytoskeletal scaffold organizing the adherens junctions that connect the developing uterus to the dorsal vulF toroid. EGFR signaling in the AC thus ensures the precise alignment of the two developing organs.
The Myogenesis Program Drives Clonal Selection and Drug Resistance in Rhabdomyosarcoma
Authors: Patel Anand G. , Chen Xiang , Huang Xin , Clay Michael R. , Komorova Natalia , Krasin Matthew J. , Pappo Alberto , Tillman Heather , Orr Brent A. , McEvoy Justina , Gordon Brittney , Blankenship Kaley , Reilly Colleen , Zhou Xin , Norrie Jackie L. , Karlstrom Asa , Yu Jiyang , Wodarz Dominik , Stewart Elizabeth , Dyer Michael A.
Published: June 2021

Rhabdomyosarcoma (RMS) is a pediatric cancer with features of skeletal muscle; patients with unresectable or metastatic RMS fare poorly due to high rates of disease recurrence. Here, we use single cell and single nucleus RNA-sequencing to show that RMS tumors recapitulate the spectrum of embryonal myogenesis. Using matched patient samples from a clinical trial and orthotopic patient-derived xenografts (O-PDXs), we show chemotherapy eliminates the most proliferative component with features of myoblasts; after treatment, the quiescent immature population with features of paraxial mesoderm expands to reconstitute the developmental hierarchy of the original tumor. We discovered that this paraxial mesoderm population is dependent on EGFR signaling and is sensitive to EGFR inhibitors. Taken together, this data serves as a proof-of-concept that targeting each developmental state in RMS is an effective strategy for improving outcomes by preventing disease recurrence.
Reorganization of the Mitochondria-Organelle Interactome during Postnatal Development in Skeletal Muscle
Authors: Kim Yuho , Lindberg Eric , Bleck Christopher K. E. , Glancy Brian
Published: June 2021

Cellular development requires the integrated assembly of intracellular structures into functionally specialized regions supporting overall cellular performance. However, it remains unclear how coordination of organelle interactions contributes to development of functional specificity across cell types. Here, we utilize a subcellular connectomics approach to define the cell-scale reorganization of the mitochondria-organelle interactome across postnatal development in skeletal muscle. We show that while mitochondrial networks are disorganized and loosely associated with the contractile apparatus at birth, contact sites among mitochondria, lipid droplets, and the sarcoplasmic reticulum are highly abundant in neonatal muscles. The maturation process is characterized by a transition to highly organized mitochondrial networks wrapped tightly around the muscle sarcomere but also to less frequent interactions with both lipid droplets and the sarcoplasmic reticulum. These data demonstrate a developmental redesign reflecting a functional shift from muscle cell assembly supported by inter-organelle communication toward a muscle fiber highly specialized for contractile function.
The E3 ligase Thin controls homeostatic plasticity through neurotransmitter release repression
Authors: Baccino-Calace Martin , Schmidt Katharina , Müller Martin
Published: June 2021

Synaptic proteins and synaptic transmission are under homeostatic control, but the relationship between these two processes remains enigmatic. Here, we systematically investigated the role of E3 ligases, key regulators of protein degradation-mediated proteostasis, in presynaptic homeostatic plasticity (PHP). An electrophysiology-based genetic screen of 157 E3 ligase-encoding genes at the Drosophila neuromuscular junction identified thin, an ortholog of human tripartite motif-containing 32 (TRIM32), a gene implicated in several neural disorders, including Autism Spectrum Disorder and schizophrenia. We demonstrate that thin functions presynaptically during rapid and sustained PHP. Presynaptic thin negatively regulates neurotransmitter release under baseline conditions by limiting the number of release-ready vesicles, independent of gross morphological defects. We provide genetic evidence that thin controls release through dysbindin, a schizophrenia-susceptibility gene required for PHP. Thin and Dysbindin localize in close proximity within presynaptic boutons, and Thin degrades Dysbindin in vitro. Thus, the E3 ligase Thin links protein degradation-dependent proteostasis of Dysbindin to homeostatic regulation of neurotransmitter release.
Physiologically distinct neurons within the ventrolateral periaqueductal gray are not defined by mu-opioid receptor expression but are differentially activated by persistent inflammation
Authors: McPherson Kylie B. , Bouchet Courtney A. , Ingram Susan L.
Published: June 2021

The ventrolateral periaqueductal gray (vlPAG) is a key structure within the descending pain modulatory pathway and an important target for opioid-induced analgesia. This area contains heterogeneous neurons with respect to neurotransmitter and receptor expression so it is difficult to define vlPAG neurons that contribute to pain and analgesia. Characterization of intrinsic membrane properties of 371 vlPAG neurons from female and male Long-Evans rats identified 4 neuron types with distinct intrinsic firing patterns: Phasic, Tonic, Onset, and Random. Phasic and Tonic neurons comprise the majority of the neurons sampled. Mu-opioid receptor (MOR) expression was determined by the ability of the selective MOR agonist DAMGO to activate G protein-coupled inwardly-rectifying potassium channel (GIRK) currents. Opioid-sensitive and -insensitive neurons were observed within each neuron type in naïve rats and in rats pretreated with Complete Freund’s adjuvant in a hindpaw to produce persistent inflammation. The presence of low threshold spikes (LTS) did not correlate with MOR-mediated GIRK currents indicating that MOR expression alone does not define a physiologically distinct neuron type in the vlPAG. MOR activation inhibited firing in nearly all spontaneously active neurons, both in naïve and persistent inflammation conditions. CFA-induced inflammation increased Fos expression at both acute (2 h) and persistent inflammation (5-7 d) time points. However, persistent, but not acute, inflammation selectively enhanced spontaneous firing and lowered firing thresholds of Phasic neurons which was maintained in the absence of synaptic inputs. Taken together, persistent inflammation selectively activates Phasic neurons, of which only a subset was opioid-sensitive.

Significance statement

Intrinsic membrane properties define separate vlPAG neurons types that are functionally important. Persistent, and not acute, inflammation selectively activates Phasic firing vlPAG neurons that are not defined by MOR expression. Although the vlPAG is known to contribute to the descending inhibition of pain, the activation of a single physiologically-defined neuron type in the presence of inflammation may represent a mechanism by which the vlPAG participates in descending facilitation of pain.
In silico Computed Clusters of Prostate Luminal Progenitors Match FACS-Enriched LSCmed cells
Authors: Lombardi Emilia Puig , Baures Manon , Dariane Charles , Guidotti Jacques-Emmanuel , Goffin Vincent
Published: June 2021

Several groups recently published single-cell (sc) expression atlases of the adult mouse prostate cells based on RNA sequencing (scRNA-seq) data. All studies identified one computerized cluster of non-secretory luminal progenitor cells enriched in luminal and stemness-related gene transcripts. The actual correspondence between these luminal progenitor cell clusters has not been investigated. In addition, the presence of Krt4 (encoding cytokeratin 4) in these in silico-identified luminal progenitors suggested the overlap with FACS-enriched LSCmed luminal progenitor cells earlier identified as a stem-like, castration-tolerant and tumor-initiating cell population. Here, we used a unified bioinformatics pipeline to re-analyze published prostate scRNA-seq datasets and perform various pan-transcriptomic comparisons including the LSCmed cell signature. Our study demonstrates that i) the mouse prostate luminal progenitor cell clusters identified in the different scRNA-seq studies largely overlap and can be defined by a common 15-gene signature including Krt4, ii) mouse LSCmed cells match both mouse and human luminal progenitors identified by scRNA-seq analysis. Bridging these in silico-identified and ex vivo-characterized prostate luminal progenitor subsets should benefit our understanding of their actual involvement in prostate diseases.
Low cost, medium throughput depletion-binding assay for screening S-domain-receptor ligand interactions using in planta protein expression
Authors: Shu Lin-Jie , Schäffer Milena , Eschrig Sabine , Ranf Stefanie
Published: June 2021

Background

Plant cell-surface receptors sense various ligands to regulate physiological processes. Matching ligand-receptor pairs requires evidence of their direct interaction and is often a bottleneck in functional receptor studies. The S-domain-type (SD) pattern recognition receptor LORE senses medium chain-3-hydroxy fatty acids (mc-3-OH-FAs) such as 3-hydroxy decanoic acid (3-OH-C10:0) via its extracellular domain (ECD) They are perceived as signals of danger from Gram-negative bacteria and activate immune responses in Arabidopsis thaliana. LORE is found in low levels in planta and is poorly expressed in heterologous systems. Furthermore, chemical modifications of the mc-3-OH-FA ligand affect its biological activity. Taken together, this makes LORE-mc-3-OH-FA binding studies particularly challenging.

Results

To investigate the LORE-mc-3-OH-FA interaction, we have developed a sensitive assay system based on protein expression in planta. The ECDs of LORE and other proteins of interest were transiently expressed as soluble, apoplastic mCherry fusion proteins in Nicotiana benthamiana and collected in apoplastic washing fluids. Protein-ligand complexes and unbound ligand were separated according to their molecular weight. In a two-step procedure, we first investigated whether the ECD-mCherry fusion protein depletes 3-OH-C10:0 from the low molecular weight fraction (step ‘depletion’). Subsequently, protein-bound 3-OH-C10:0 retained in the high molecular weight fraction in the depletion step is released and detected (step ‘binding’). Both the unbound and the released 3-OH-C10:0 ligand are detected by a sensitive bioassay using LORE loss- and gain-of-function Arabidopsis plants. Using the depletion-binding assay, we show that the ECD of AtLORE and its ortholog from Capsella rubella, CrubLORE, bind 3-OH-C10:0. The ECD of AtSD1-23, the closest paralog of AtLORE, and mCherry did not bind 3-OH-C10:0 and are suitable negative controls.

Conclusion

The depletion-binding assay is a simple method for reliably detecting interactions between plant-expressed SD-type receptor ectodomains and mc-3-OH-FAs. It does not require special equipment or expensive consumables and is suitable for medium throughput screening. The assay is very flexible and can be easily adapted to investigate ligand interactions of other extracellular receptor domains.