bluuebunny/crossref_metadata_2025 huggingface dataset:
Energy Balance Dynamics: Exercise, Appetite, Diet, and Weight Control
Authors: Esquivel Monica Kazlausky
Published: February 2021

Individuals seeking to achieve weight loss are encouraged to achieve a negative energy balance, essentially eat less and move more. The complex relationship between energy expenditure and intake is often overlooked, leaving individuals and practitioners underwhelmed by the results of weight loss efforts. Independently, physical activity and diet interventions can yield modest weight loss and when combined have synergistic effects that promote sustained weight loss. Although physical activity benefits appetite suppression, reduces food rewards, and can be considered a gateway to healthy eating, high levels of daily activity are needed to induce weight loss. Diet is an important component to achieving weight loss, and high-protein diets have the potential for supporting weight loss as well. This column will be focused on the benefits of physical activity in reducing body weight, more specifically, the interdependent relationship between dietary intake and physical activity in achieving weight reduction.
Chronic kidney disease, pregnancy and haemodialysis: Case reports from a single centre in Kenya and literature review
Authors: Kabinga Samuel K , Otieno Jackline , Ngige John , Mcligeyo Seth O
Published: February 2021

Chronic kidney disease (CKD) and end stage kidney disease are prevalent even in women of reproductive age. These are known to reduce fertility and successful pregnancy. There are chances of conception even in advanced CKD, though laden with complications. We present two cases of women who conceived in advanced CKD and were on haemodialysis in a tertiary hospital in Kenya, and review of literature.
Extensive cerebellar involvement and cognitive impairment in COVID-19-associated acute necrotizing encephalopathy
Authors: Ciolac Dumitru , Crivorucica Igor , Zota Eremei , Gorincioi Nadejda , Efremova Daniela , Manea Diana , Crivorucica Veaceslav , Ciocanu Mihail , Groppa Stanislav A.
Published: February 2021

Neurological complications of the newly appeared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly recognized. Here, we report a case of a young male presenting with a clinical and neuroimaging scenario of an acute necrotizing encephalopathy related to the coronavirus disease 2019 (COVID-19). This case is notable by its distinct pattern of magnetic resonance imaging findings of an extensive involvement of the cerebellum, and emergence of cognitive and behavioral impairment.
The critical role of health promotion for effective universal health coverage
Authors: Shilton Trevor , Barry Margaret M.
Published: February 2021

The Political Declaration from the United Nations High-Level Meeting on Universal Health Coverage: Moving Together to Build a Healthier World (2019) provided important reaffirmation of health as a precondition for sustainable development and equity, as well as of the role for primary care as a cornerstone of universal health coverage. Health promotion, prevention and sustainable healthcare go hand in glove. Health promotion can enable more effective use of health resources by reducing demand for expensive health services and reducing hospital admissions. Promoting mental and physical health, and addressing health literacy and the social determinants of health, enables governments and departments of health to (i) empower citizens and communities to take control of their health, and (ii) better support innovative and financially sustainable healthcare. Without the bedrock underpinning of effective health promotion, treasuries and health systems will struggle to meet the rising costs and burden of ill health.
Traumatic Obturator Internus and Quadratus Femoris Injury in a Pediatric Patient: A Case Report
Authors: Reintgen Christian , Bruner Michelle , Smith M. Seth , Moser Michael
Published: February 2021

We present the case of a 11-year-old White female patient with a traumatic quadratus femoris and obturator internus tear after a sprint while at school. She felt immediate pain, swelling, and point tenderness in her posterosuperior thigh with a severely antalgic gait. Magnetic resonance imaging demonstrated a quadratus femoris tear, obturator internus tear, and ischial spine avulsion fracture. Although a less common etiology for acute hip pain in the pediatric population, traumatic injury to the short external rotators should not be excluded. The prognosis is favorable with a full return to previous activities expected using an appropriate rehabilitation program.
Medical Tent Usage From Bank of America Chicago Marathon 2015-2017
Authors: Parker Brendan , Thaker Poonam , Chan Shu , Chiampas George
Published: February 2021

Background:

As mass participation events continue to increase in popularity, the need for medical care continues to increase. Our objective was to evaluate the course medical tent usage throughout the Bank of America Chicago Marathon course. Our second objective was to evaluate emergency medical services (EMS) utilization during the event.

Hypothesis:

We hypothesize that as the race progresses, medical tents will see more participants and EMS will have an increase in utilization.

Level of Evidence:

Level 4.

Methods:

This study was a retrospective analysis of data collected by the medical staff from 2015 to 2017. Documented patient encounters were analyzed from each course medical tent. Twenty medical tents were spaced roughly 1.2 miles apart depending on location and ease of EMS access to the medical tent location.

Results:

From 2015 to 2017, the course medical tents saw 2973 patients, with a 96.3% discharge rate. The data showed a linear increase of 5.69 patients seen per mile until mile 20 (linear regression P < 0.01). After mile 20, the number of patients seen per mile was about the same. The data also showed an increase in EMS utilization every 5 miles as the race progressed ( P = 0.04) and an increase in ratio of patients transported to the hospital compared with patients transferred to the main medical tents up to mile 20 ( P = 0.02).

Conclusion:

Course medical tents saw a statistically significant linear increase in patients per mile until mile 20. Total EMS utilization showed a statistically significant increase in usage as the race progressed and a statistically significant increase in ratio of transports to transfers as the race progressed until mile 20.

Clinical Relevance:

This study has the potential to influence medical tent and EMS placement for endurance events with increasing patient encounters and hospital transports as the mileage of the endurance event increases.
Dictators Differ From Democratically Elected Leaders in Facial Warmth
Authors: Giacomin Miranda , Mulligan Alexander , Rule Nicholas O.
Published: February 2021

Despite the many important considerations relevant to selecting a leader, facial appearance carries surprising sway. Following numerous studies documenting the role of facial appearance in government elections, we investigated differences in perceptions of dictators versus democratically elected leaders. Participants in Study 1 successfully classified pictures of 160 world leaders as democrats or dictators significantly better than chance. Probing what distinguished them, separate participants rated the affect, attractiveness, competence, dominance, facial maturity, likability, and trustworthiness of the leaders’ faces in Study 2. Relating these perceptions to the categorizations made by participants in Study 1 showed that democratically elected leaders looked significantly more attractive and warmer (an average of likability and trustworthiness) than dictators did. Leaders’ facial appearance could therefore contribute to their success within their respective political systems.
Long-term survival in a cat with tonsillar squamous cell carcinoma treated with surgery and chemotherapy
Authors: Treggiari Elisabetta , Romanelli Giorgio , Ferro Silvia , Roccabianca Paola
Published: February 2021

Case summary

A 13-year-old neutered female domestic shorthair cat was presented for further investigation of a right-sided cervical mass. Oral cavity examination revealed a unilateral, right tonsillar mass. Following a contrast-enhanced CT scan of head, thorax and abdomen, which showed no clear evidence of distant metastasis, cytology of the cervical mass was consistent with a metastatic retropharyngeal lymph node, and the patient underwent tonsillectomy and lymphadenectomy. The tumour was histopathologically confirmed to be a well-differentiated squamous cell carcinoma with lymph node metastasis, and sequential chemotherapy treatments with carboplatin were administered. The cat underwent a second surgery to treat local recurrence and chemotherapy was continued. Subsequently, multiple lymphadenectomies to remove additional metastatic lymph nodes were performed, followed by adjuvant treatment with doxorubicin. Restaging procedures, performed every 3-6 months did not document any local recurrence nor any local or distant metastasis. The patient was euthanased after developing neoplastic pleural effusion 965 days following tonsillectomy.

Relevance and novel information

Tonsillar tumours are rare in cats, but clinical presentation can be similar to that in dogs. Treatment with surgery and chemotherapy, and more importantly multiple lymphadenectomies, may delay the onset of distant metastasis and it should be considered in similar cases to possibly prolong survival.
A Racism Burnout: My Life as a Black Academic
Authors: Hawkins Darnell F.
Published: February 2021

The author explores within the context of academia the interpersonal and structural dynamics that underpin the systemic racism to which the Black Lives Matter movement responds.
Behavioral Drivers of Performance in Public-Sector Organizations: A Literature Review
Authors: Asif Aymen , Rathore Kashif
Published: February 2021

The main purpose of the article is to review performance management in the public sector through internal management of public employees by a micro-level approach to enhance the delivery of services by public-sector organizations. The study systematically analyses all the previous research that impacts public organizations through the behavior of public administrators. It aims to demonstrate that the behavioral aspect of public employees is as important as measurement aspects. The research methodology was based on a comprehensive and traditional literature review established on previous research studies. The literature surveyed in this article consists of peer-reviewed articles and research papers based on highly scientific databases. Thus, research finding uncovered that: leadership capacity along with management behavior toward the employee and integration of commitment-based Human Resource Management practices that build long-term commitment in which employees feel obliged toward their organizations, plays a major role in improving the performance of public-sector organizations, which in turn help in increasing the performance of the government.
Gold and Government Bonds as Safe-Haven Assets Against Stock Market Turbulence in China
Authors: Huang Wei , Chang Meng-Shiuh
Published: February 2021

We examine whether gold and China’s government bonds are safe-haven assets against the turbulence of the Shanghai Stock Exchange Composite Index by employing vine copula models during the 2003 to 2015 period. We find that either bonds or gold can be a weak safe haven but only gold can be a strong safe haven. Our simultaneous analysis advises against a joint safe-haven strategy of gold and bonds, given the high- to low-tail correlation. This result highlights an investment strategy of using a single safe-haven asset against the Chinese stock market turbulences.
A Case Report of Loperamide-Induced Ventricular Storm
Authors: De Vera Jerome , Kim Hyungjin Ben , Sakr Antoine E.
Published: February 2021

Loperamide is an easily accessible antidiarrheal medication. Unlike other medications in its class, loperamide is unique in that it causes euphoria at supratherapeutic levels due to its effect on opioid receptors. Unfortunately, with its growing abuse potential also comes increasing reports of cardiotoxicity including prolonged QT, torsades de pointes, and sudden cardiac death. We report a case of a 29-year-old female who presented with unstable arrhythmia that further progressed into electrical storm in the setting of loperamide toxicity. Due to its growing popularity and availability, it is important for clinicians to understand loperamide’s mechanisms for causing toxicity as well as how to appropriately treat its complications.
Book review: Lily Halder, Bhanga Berar Panchali
Authors: Mukherjee Sipra
Published: February 2021

Lily Halder, Bhanga Berar Panchali, Parampara, 2019, ₹350.00, 335 pp. (Paperback), ISBN: 978-93-88341-02-8.
Getting Started Creating Data Dictionaries: How to Create a Shareable Data Set
Authors: Buchanan Erin M. , Crain Sarah E. , Cunningham Ari L. , Johnson Hannah R. , Stash Hannah , Papadatou-Pastou Marietta , Isager Peder M. , Carlsson Rickard , Aczel Balazs
Published: February 2021

As researchers embrace open and transparent data sharing, they will need to provide information about their data that effectively helps others understand their data sets’ contents. Without proper documentation, data stored in online repositories such as OSF will often be rendered unfindable and unreadable by other researchers and indexing search engines. Data dictionaries and codebooks provide a wealth of information about variables, data collection, and other important facets of a data set. This information, called metadata, provides key insights into how the data might be further used in research and facilitates search-engine indexing to reach a broader audience of interested parties. This Tutorial first explains terminology and standards relevant to data dictionaries and codebooks. Accompanying information on OSF presents a guided workflow of the entire process from source data (e.g., survey answers on Qualtrics) to an openly shared data set accompanied by a data dictionary or codebook that follows an agreed-upon standard. Finally, we discuss freely available Web applications to assist this process of ensuring that psychology data are findable, accessible, interoperable, and reusable.
Tensile and fatigue properties of fiber-reinforced metal matrix composites Cf/5056Al
Authors: Ba Ying , Sun Shu
Published: February 2021

Fiber-reinforced metal matrix composites have mechanical properties highly dependent on directions, possessing high strength and fatigue resistance in fiber longitudinal direction achieved by weak interface bonding. However, the disadvantage of weak interface combination is the reduction of transversal performances. In this article, tensile and fatigue properties of carbon fiber-reinforced 5056 aluminum alloy matrix (Cf/5056Al) composite under the condition of medium-strength interface combination are carried out. The fatigue damage mechanisms of Cf/5056Al composite under tension–tension and tension–compression loads are not the same, but the fatigue life curves are close, which may be the result of the medium-strength interface combination.
Evaluation of the Clinical Role of Strain Elastography in Patients Diagnosed With Congenital Torticollis
Authors: Özkan Elif Özyazici , Ozkan Mehmet Burak , İsik İshak Abdurrahman
Published: February 2021

Objective:

The objective of this study was to determine the elasticity of sternocleidomastoid muscle (SCM) in patients with congenital muscular torticollis (CMT).

Methods:

In all, 41 patients and 22 controls were included in the study, and the elasticity of the patients’ SCM was measured. Echogenicity, thickness, and strain values of the SCM were also obtained.

Results:

The thickness and strain values of the SCM were higher in the patient group than in the control group ( P = .02 and P = .15). For median values, there was no difference in echogenicity and strain. In the strain elastography evaluation of the receiver operating curve (ROC) for muscle echogenicity in the isoechoic muscle group, the specificity and sensitivity were determined to be 100% and 22%, respectively, for the area under the curve (AOC) value of 0.558 (95% confidence interval [CI], 0.424–0.6686), and the cutoff value was <1.4. In the hyperechoic muscle group, the ROC for AUC values was found to be 0.542 (95% CI, 0.411–0.6686), and the cutoff value was >1.4 with 100% sensitivity and 20.75 specificity.

Conclusions:

The strain elastography technique can be used in the diagnosis of CMT.
The Function and Autophagy Regulation of PLEKHA8 in T Cell Acute Lymphoblastic Leukemia
Authors: Yuan Tian , Shi Ce , Tian Chen , You M. James
Published: February 2021

Introduction:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Over the past 20 years, several oncogenic drivers and crucial signaling pathways have been unraveled in this disease. However, most T-ALL patients are still treated with high dose multiagent chemotherapy due to limited targeted treatment. To further investigate the pathogenesis and develop the new therapeutic targets of T-ALL, we previously developed a mouse genetic model of T-ALL that is deficient forPtentumor suppressor gene. We identified PLEKHA8, a Golgi protein, is highly expressed in thePtenconditional knockout mouse T-ALL. We have verified the high expression of PLEKHA8 in patients' T-ALL samples. PLEKHA8 has the pleckstrin homology (PH) domain binding to phosphatidylinositol 4-monophosphate (PI4P) at the Golgi, is important in lipid metabolism and transport. The Golgi complex regulates the production and delivery of proteins and lipids, and is a site of lipid metabolism needed for autophagy, in particular PI(4)P. We hypothesized that PLEKHA8 affects the cell function and plays a role in the autophagy of human T-ALL via lipid metabolism.

Methods:PLEKHA8 was knocked down in T-ALL cell lines using a lentivirus-based vector with shRNAs to assess its effect on cell function. CCK8 assay was employed to detect the cell proliferation. Cell cycle was analyzed using 5-bromo-2'-deoxyuridine (BrdU) and flow cytometry. Autophagy proteins were monitored by western blot. PI(4)P was tested by confocal fluorescence microscopy.

Results:T-ALL cells underwent lower cell proliferation and sub-G1 cell accumulation after knocking down PLEKHA8 gene by using shRNA systems. The autophagy marker LC3, Beclin 1 and ATG 5 were markedly increased while P62 decreased after the downregulation PLEKHA8 in T-ALL cells. In addition, PLEKHA8 knocking down in T-ALL cells led to the accumulation of PI(4)P in cytoplasm as observed by confocal fluorescence microscopy.

Conclusion:Our data indicate that PLEKHA8 facilitates cell growth in T-ALL cells. Decreased expression of PLEKHA8 inhibits cell proliferation and accumulate sub-G1 phase of T-ALL cells. Decreased PLEKHA8 expression increases the autophagy of T-ALL cells, which could be based on the PI(4)P pathway of autophagy. Our studies provide a new insight into the pathogenesis and potential targeted therapy of T-ALL.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of New Anti-CD20 Monoclonal Antibodies Versus Rituximab for Induction Therapy of CD20+ B-Cell Non-Hodgkin Lymphomas: A Systematic Review and Meta-Analysis
Authors: Luo Chengxin , Li Xi , Xu Shuangnian , Chen Jieping
Published: February 2021

Rituximab combined with chemotherapy is the first-line induction therapy of CD20positive B-cell non-Hodgkin lymphomas (CD20+ B-NHL). Recently new anti-CD20 monoclonal antibodies (mAbs) have been developed, but their efficacy and safety compared with rituximab are still controversial. We aimed to assess the efficacy and safety of new anti-CD20 mAbs compared with rituximab in the induction therapy of CD20+ B-NHL with a systematic review and meta-analysis. We searched MEDLINE, Embase, and Cochrane Library for eligible randomised controlled trials (RCTs) that compared new anti-CD20 mAbs with rituximab in induction therapy of B-NHL. The primary outcomes are progression-free survival (PFS) and overall survival (OS), additional outcomes include event-free survival (EFS), disease-free survival (DFS), overall response rate (ORR), complete response rate (CRR) and incidences of adverse events (AEs). Time-to-event data were pooled as hazard ratios (HRs) using the generic inverse-variance method and dichotomous outcomes were pooled as odds ratios (ORs) using the Mantel-Haenszel method with their respective 95% confidence interval (CI). Eleven RCTs comprising 5,261 patients with CD20+ B-NHL were included. Compared with rituximab, obinutuzumab significantly prolonged PFS (HR 0.84, 95% CI 0.73-0.96, P = 0.01), had no improvement on OS, ORR, and CRR, but increased the incidences of serious AEs (OR 1.29, 95%CI 1.13-1.48, P < 0.001). Ofatumumab was inferior to rituximab in consideration of ORR (OR 0.73, 95% CI 0.55-0.96, P = 0.02), and had no significant differences with rituximab in regard to PFS, OS and CRR. 131I-tositumomab yield similar PFS, OS, ORR and CRR with rituximab. 90Y-ibritumomab tiuxetan increased ORR (OR 3.07, 95%CI 1.47-6.43, P = 0.003), but did not improve PFS, DFS, OS and CRR compared with rituximab. In conclusion, compared with rituximab in induction therapy of CD20+ B-NHL, obinutuzumab can significantly improves PFS but with higher incidence of AEs, ofatumumab decrease ORR, 90Y-ibritumomab tiuxetan increase ORR.

Disclosures

No relevant conflicts of interest to declare.
Elucidating Barriers to Advance Care Planning in Malignant Hematology Clinics: A Single Centre Experience in Ontario, Canada
Authors: Motalo Oksana , Hillis Christopher M.
Published: February 2021

Introduction: Advance care planning (ACP) is a patient-centered process with clear benefits for patients. Despite the widespread recognition of ACP as an integral part of quality cancer care,compliance with ACP provision remains suboptimal especially in malignant hematology. Many barriers to end-of-life discussions among hematologists have been identified in the literature. This study aims to describe a baseline rate of ACP with hematology outpatients at the end-of-life and the local barriers to ACP, which could inform future quality improvement (QI) initiatives in this area.

Setting/participants: Malignant hematologists (n = 10), hematology fellows (n=2), and hematology clinic nurses (n=4) of the Juravinski Cancer Centre (JCC) in Hamilton, Ontario, Canada participated in this study.

Methods: A retrospective chart audit was undertaken to establish the baseline rate of ACP for the target population at our centre. Subsequently, key stakeholder interviews were held with our local multiple myeloma (MM) specialists to document barriers to ACP from their perspectives. The emerging themes were synthesized using a Fishbone diagram and validated by the JCC hematology clinic staff through multivoting.

Results: The baseline rate of ACP with hematology outpatients at the end-of-life at our centre is 40%. The are three main local barriers to ACP with the target population: 1) lack of patient initiative; 2) time/scheduling constraints; and 3) competing priorities.

Discussion: Patients who participate in ACP are much more likely to have their end-of-life wishes followed than those who do not. Malignant hematology patients are at the greatest risk of not having ACP discussions with their clinicians due to several patient, provider, and system barriers. Patient- and system-level barriers have been identified as the most prevalent at the JCC, necessitating a tailored QI initiative to achieve the standard of care.

Disclosures

Hillis: Roche: Honoraria.
Loss of the DNA Fork Remodeling Protein Smarcal1 Impairs the Replication Stress Response in Proliferating Hematopoietic Cells
Authors: Kushinsky Saul , Puccetti Matthew V , Adams Clare M , Eischen Christine M
Published: February 2021

Rapidly proliferating hematopoietic cells are particularly prone to threats to genomic integrity through replication stress. The response to replication stress involves complex molecular machinery to prevent replication fork collapse, avoid accumulation of DNA damage, and ensure the completion of DNA synthesis. Smarcal1, a DNA remodeling enzyme, has been linked to the replication stress response through stabilization, repair, and restart of stalled DNA replication forks. In humans, complete loss of function of Smarcal1 leads to the pleiotropic disorder Schimke immuno-osseous dysplasia (SIOD), which is characterized, in part, by a severe lymphoid immunodeficiency that leaves patients susceptible to opportunistic infections. Currently, the mechanisms driving the clinical immunodeficient phenotype of SIOD and the in vivo functions of Smarcal1 in hematopoietic cells remain largely unexplored. We evaluated the contribution of Smarcal1 to normal and stressed/emergency hematopoiesis, using a Smarcal1 knockout mouse model and hematopoietic cell replication stresses such as low-dose radiation, 5-fluorouracil, bone marrow transplantation, and oncogene- driven proliferation. We determined that, while loss of Smarcal1 does not affect hematopoietic stem and progenitor cells (HSPCs) or mature hematopoietic cell populations at a normal "resting" state, Smarcal1 is required in these cells undergoing proliferative stress. Following DNA replication stress, we detected defects in multiple Smarcal1-deficient hematopoietic cell populations. We also observed that loss of Smarcal1 led to significantly increased levels of replication stress, DNA damage, and apoptosis in proliferating cells. Through bone marrow transplantation, we determined that the deficiencies observed were not due to a defect in the bone marrow environment or an inability of the HSPCs to home to the bone marrow. Thus, our results reveal that Smarcal1 is critical to maintaining hematopoietic cell survival and function under conditions of DNA replication stress. Our data also suggest that the immunodeficiency of patients with Smarcal1 mutations may be due to an inability of hematopoietic cells, especially HSPCs, to properly respond to replication stress and proliferate. Since wild-type bone marrow is able to fully reconstitute and function in a Smarcal1-deficient environment, bone marrow transplantation may be an effective therapy for immunodeficient SIOD patients.

Disclosures

Eischen: AbbVie Inc.: Research Funding.
Cellular Fibronectin Promotes Deep Vein Thrombosis in Obese Mice
Authors: Dhanesha Nirav , Jain Manish , Doddapattar Prakash , Undas Anetta , Chauhan Anil K
Published: February 2021

Objective: Obesity is a significant risk factor for deep vein thrombosis (DVT). The mechanisms of increased DVT in preexisting comorbid condition of obesity remain poorly understood. Cellular fibronectin containing extra domain A (Fn-EDA), an endogenous ligand for toll-like-receptor 4 (TLR4), is known to contribute to thrombo-inflammation in the experimental models. However, the role of Fn-EDA in modulation of venous thrombosis in context of obesity is not elucidated yet.

Approach and Results: We found that cellular Fn-EDA levels were significantly elevated in plasma of venous thromboembolism (VTE) patients that positively correlated with body mass index (BMI). To investigate whether Fn-EDA promotes venous thrombosis in obese condition, WT and Fn-EDA-/- mice were either fed a control or high-fat diet (HF-diet) for 12-weeks. DVT was induced by inferior vena cava stenosis and evaluated after 48 hours. We found that HF diet-fed WT mice exhibited increased DVT susceptibility compared with control diet-fed WT mice. In contrast, HF-fed Fn-EDA-/- mice exhibited significantly reduced thrombus weight and decreased incidence (%) of DVT compared with HF-fed WT mice that was concomitant with improved blood flow, reduced neutrophil content and citrullinated histone H3-positive cells (a marker of NETosis) in IVC thrombus. Exogenous Fn-EDA potentiated NETosis in neutrophils stimulated with thrombin-activated platelets via TLR4. Genetic deletion of TLR4 in Fn-EDAfl/fl mice, which constitutively express Fn-EDA, reduced DVT compared with Fn-EDAfl/fl mice.

Conclusion: These results demonstrate a previously unknown role of Fn-EDA in the modulation of DVT, which may be an important mechanism promoting DVT in the setting of obesity.

Figure

Disclosures

No relevant conflicts of interest to declare.
Aberrant rRNA 2'-O-Methylation Causes Bone Marrow Failure and Defective Immune Function
Authors: Nachmani Daphna , Mendez Lourdes M. , Pandolfi Pier Paolo
Published: February 2021

RNA modifications are emerging as key determinants of development and disease. Understanding the mechanisms regulating their functional impact is crucial to uncovering their relevance for disease pathology. The NPM1 gene is frequently a target of genetic alteration in hematological tumors, particularly of the myeloid lineage. While extensively studied, the mechanisms by which NPM1 exert its impact on HSPCs are still not fully elucidated. Recently, we have identified NPM1 as an essential regulator of rRNA 2'-O-methylation (2'OMe). We found that NPM1, through its RNA-binding activity, binds C/D box small nucleolar RNAs (snoRNAs) in the nucleolus, to regulate rRNA 2'OMe, and thereby controls translation. Additionally, we identified NPM1 germ-line mutations in dyskeratosis congenita patients presenting with BMF. Characterization of these mutations found them as selectively deficient in snoRNA binding, and thus their expression led to reduce 2'OMe levels and aberrant translation in patient cells. To causally link reduced 2'OMe to dyskeratosis congenita manifestation, we generated mice harboring a dyskeratosis congenita germ-line NPM1 mutation. The KI mice phenocopy both hematological and non-hematological DC features, thus casually linking mutated NPM1 and reduced 2'OMe to bone marrow failure. Currently, we are taking advantage of our Npm1-mutated mouse model to explore the role of 2'OMe in mature immune cell function. We find that aberrant 2'OMe in mature macrophages (due to Npm1 mutation) does not affect their maturation, however, it leads to altered functions. Specifically, we find that Npm1-mutated macrophages, with reduced 2'OMe, display reduced production of reactive oxygen species, chemotactic properties and phagocytic capacity. These studies demonstrate a role for Npm1 and 2'OMe in adult immune cells, and reveal the importance of translation regulation in both hematopoietic stem cells and mature macrophage function.

Figure

Disclosures

No relevant conflicts of interest to declare.
Modified Beac Conditioning Regimen with Idarubicin Followed By Autologous Hematopoietic Stem Cell Transplantation Is Safe and Effective for Invasive B-Cell Non-Hodgkin's Lymphoma Patients
Authors: Tian Chen
Published: February 2021

High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) is still a consolidation treatment choice for relapsed/refractory (R/R) B-cell Non-Hodgkin's lymphoma (NHL) patients and some aggressive B-cell NHL as frontline therapy. Due to the shortage of carmustine, we switched to idarubicin-substituted BEAC (IEAC). We compared the outcomes of 72 B-cell NHL patients treated with IEAC or BEAC regimens followed by ASCT. The median time to neutrophil and platelet reconstitution showed no difference between IEAC and BEAC groups. IEAC regimen was well tolerated without increase of adverse events. Transplant-related mortality didn't occur. The overall survival (OS) and progression-free survival (PFS) of IEAC group were a little longer than that of BEAC group. 2-year OS and PFS rate were higher in IEAC group compared to BEAC group. Multivariate analysis showed that AnnArbor staging, IPI score, lactate dehydrogenase (LDH) level, remission of disease, modified regimen were related with the prognosis. In conclusion, IEAC regimen was well tolerated and replacement with idarubicin could effectively prolong the survival of patients.

Disclosures

No relevant conflicts of interest to declare.
Protein expression profiling suggests relevance of noncanonical pathways in isolated pulmonary embolism
Authors: Ten Cate Vincent , Prochaska Jürgen H. , Schulz Andreas , Koeck Thomas , Pallares Robles Alejandro , Lenz Michael , Eggebrecht Lisa , Rapp Steffen , Panova-Noeva Marina , Ghofrani H. Ardeschir , Meyer F. Joachim , Espinola-Klein Christine , Lackner Karl J. , Michal Matthias , Schuster Alexander K. , Strauch Konstantin , Zink Alexander M. , Laux Volker , Heitmeier Stefan , Konstantinides Stavros V. , Münzel Thomas , Andrade-Navarro Miguel A. , Leineweber Kirsten , Wild Philipp S.
Published: February 2021

Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism Project, a multicenter prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n = 96) against those of patients with DVT-associated PE (n = 276) or isolated DVT (n = 160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of 5 proteins: interferon-γ, glial cell line–derived neurotrophic growth factor, polypeptide N-acetylgalactosaminyltransferase 3, peptidyl arginine deiminase type-2, and interleukin-15 receptor subunit α. These proteins were orthogonally validated using cis protein quantitative trait loci. External replication in an independent population-based cohort (n = 5778) further validated the proteomic results and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years; interquartile range: 1.6-4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate noncanonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.
Redefining outcomes in immune TTP: an international working group consensus report
Authors: Cuker Adam , Cataland Spero R. , Coppo Paul , de la Rubia Javier , Friedman Kenneth D. , George James N. , Knoebl Paul N. , Kremer Hovinga Johanna A. , Lӓmmle Bernhard , Matsumoto Masanori , Pavenski Katerina , Peyvandi Flora , Sakai Kazuya , Sarode Ravi , Thomas Mari R. , Tomiyama Yoshiaki , Veyradier Agnès , Westwood John-Paul , Scully Marie
Published: February 2021

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti–von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.
Boolean implication analysis unveils candidate universal relationships in microbiome data
Authors: Vo Daniella , Singh Shayal Charisma , Safa Sara , Sahoo Debashis
Published: February 2021

Background

Microbiomes consist of bacteria, viruses, and other microorganisms, and are responsible for many different functions in both organisms and the environment. Past analyses of microbiomes focused on using correlation to determine linear relationships between microbes and diseases. Weak correlations due to nonlinearity between microbe pairs may cause researchers to overlook critical components of the data. With the abundance of available microbiome, we need a method that comprehensively studies microbiomes and how they are related to each other.

Results

We collected publicly available datasets from human, environment, and animal samples to determine both symmetric and asymmetric Boolean implication relationships between a pair of microbes. We then found relationships that are potentially invariants, meaning they will hold in any microbe community. In other words, if we determine there is a relationship between two microbes, we expect the relationship to hold in almost all contexts. We discovered that around 330,000 pairs of microbes universally exhibit the same relationship in almost all the datasets we studied, thus making them good candidates for invariants. Our results also confirm known biological properties and seem promising in terms of disease diagnosis.

Conclusions

Since the relationships are likely universal, we expect them to hold in clinical settings, as well as general populations. If these strong invariants are present in disease settings, it may provide insight into prognostic, predictive, or therapeutic properties of clinically relevant diseases. For example, our results indicate that there is a difference in the microbe distributions between patients who have or do not have IBD, eczema and psoriasis. These new analyses may improve disease diagnosis and drug development in terms of accuracy and efficiency.
Methodological approaches to imputing early-pregnancy weight based on weight measures collected during pregnancy
Authors: Yang Jiaxi , Wang Dongqing , Darling Anne Marie , Liu Enju , Perumal Nandita , Fawzi Wafaie W. , Wang Molin
Published: February 2021

Background

Early pregnancy weights are needed to quantify gestational weight gain accurately. Different methods have been used in previous studies to impute early-pregnancy weights. However, no studies have systematically compared imputed weight accuracy across different imputation techniques. This study aimed to compare four methodological approaches to imputing early-pregnancy weight, using repeated measures of pregnancy weights collected from two pregnancy cohorts in Tanzania.

Methods

The mean gestational ages at enrollment were 17.8 weeks for Study I and 10.0 weeks for Study II. Given the gestational age distributions at enrollment, early-pregnancy weights were extrapolated for Study I and interpolated for Study II. The four imputation approaches included: (i) simple imputation based on the nearest measure, (ii) simple arithmetic imputation based on the nearest two measures, (iii) mixed-effects models, and (iv) marginal models with generalized estimating equations. For the mixed-effects model and the marginal model with generalized estimating equation methods, imputation accuracy was further compared across varying degrees of model flexibility by fitting splines and polynomial terms. Additional analyses included dropping third-trimester weights, adding covariate to the models, and log-transforming weight before imputation. Mean absolute error was used to quantify imputation accuracy.

Results

Study I included 1472 women with 6272 weight measures; Study II included 2131 individuals with 11,775 weight measures. Among the four imputation approaches, mixed-effects models had the highest accuracy (smallest mean absolute error: 1.99 kg and 1.60 kg for Studies I and II, respectively), while the other three approaches showed similar degrees of accuracy. Depending on the underlying data structure, allowing appropriate degree of model flexibility and dropping remote pregnancy weight measures may further improve the imputation performance.

Conclusions

Mixed-effects models had superior performance in imputing early-pregnancy weight compared to other commonly used strategies.
Age-related impairment of navigation and strategy in virtual star maze
Authors: Zhang Jia-Xin , Wang Lin , Hou Hai-Yan , Yue Chun-Lin , Wang Liang , Li Hui-Jie
Published: February 2021

Background

Although it is well known that aging impairs navigation performance, the underlying mechanisms remain largely unknown. Egocentric strategy requires navigators to remember a series of body-turns without relying on the relationship between environmental cues. Previous study suggested that the egocentric strategy, compared with non-egocentric strategy, was relatively unimpaired during aging. In this study, we aimed to examine strategy use during virtual navigation task and the underlying cognitive supporting mechanisms in older adults.

Methods

Thirty young adults and thirty-one older adults were recruited from the local community. This study adapted star maze paradigm using non-immersive virtual environment. Participants moved freely in a star maze with adequate landmarks, and were requested to find a fixed destination. After 9 learning trials, participants were probed in the same virtual star maze but with no salient landmarks. Participants were classified as egocentric or non-egocentric strategy group according to their response in the probe trial.

Results

The results revealed that older adults adopting egocentric strategy completed the navigation task as accurate as young adults, whereas older adults using non-egocentric strategy completed the navigation task with more detours and lower accuracy. The relatively well-maintained egocentric strategy in older adults was related to better visuo-spatial ability.

Conclusions

Visuo-spatial ability might play an important role in navigation accuracy and navigation strategy of older adults. This study demonstrated the potential value of the virtual star maze in evaluating navigation strategy and visuo-spatial ability in older adults.
Care homes, their communities, and resilience in the face of the COVID-19 pandemic: interim findings from a qualitative study
Authors: Marshall Fiona , Gordon Adam , Gladman John R. F. , Bishop Simon
Published: February 2021

Background

From late February 2020, English care homes rapidly adapted their practices in response to the COVID-19 pandemic. In addition to accommodating new guidelines and policies, staff had to adjust to rapid reconfiguration of services external to the home that they would normally depend upon for support. This study examined the complex interdependencies of support as staff responded to COVID-19. The aim was to inform more effective responses to the ongoing pandemic, and to improve understanding of how to work with care home staff and organisations after the pandemic has passed.

Methods

Ten managers of registered care homes in the East Midlands of England were interviewed by videoconference or phone about their experiences of the crisis from a structured organisational perspective. Analysis used an adapted organisational framework analysis approach with a focus on social ties and interdependencies between organisations and individuals.

Results

Three key groups of interdependencies were identified: care processes and practice; resources; and governance. Care home staff had to deliver care in innovative ways, making high stakes decisions in circumstances defined by: fluid ties to organisations outside the care home; multiple, sometimes conflicting, sources of expertise and information; and a sense of deprioritisation by authorities. Organisational responses to the pandemic by central government resulted in resource constraints and additional work, and sometimes impaired the ability of staff and managers to make decisions. Local communities, including businesses, third-sector organisations and individuals, were key in helping care homes overcome challenges. Care homes, rather than competing, were found to work together to provide mutual support. Resilience in the system was a consequence of dedicated and resourceful staff using existing local networks, or forging new ones, to overcome barriers to care.

Conclusions

This study identified how interdependency between care home organisations, the surrounding community, and key statutory and non-statutory organisations beyond their locality, shaped decision making and care delivery during the pandemic. Recognising these interdependencies, and the expertise shown by care home managers and staff as they navigate them, is key to providing effective healthcare in care homes as the pandemic progresses, and as the sector recovers afterwards.
Associations between post-stroke motor and cognitive function: a cross-sectional study
Authors: Einstad Marte Stine , Saltvedt Ingvild , Lydersen Stian , Ursin Marie H. , Munthe-Kaas Ragnhild , Ihle-Hansen Hege , Knapskog Anne-Brita , Askim Torunn , Beyer Mona K. , Næss Halvor , Seljeseth Yngve M. , Ellekjær Hanne , Thingstad Pernille
Published: February 2021

Background

Motor and cognitive impairments are frequently observed following stroke, but are often managed as distinct entities, and there is little evidence regarding how they are related. The aim of this study was to describe the prevalence of concurrent motor and cognitive impairments 3 months after stroke and to examine how motor performance was associated with memory, executive function and global cognition.

Methods

The Norwegian Cognitive Impairment After Stroke (Nor-COAST) study is a prospective multicentre cohort study including patients hospitalized with acute stroke between May 2015 and March 2017. The National Institutes of Health Stroke Scale (NIHSS) was used to measure stroke severity at admission. Level of disability was assessed by the Modified Rankin Scale (mRS). Motor and cognitive functions were assessed 3 months post-stroke using the Montreal Cognitive Assessment (MoCA), Trail Making Test Part B (TMT-B), 10-Word List Recall (10WLR), Short Physical Performance Battery (SPPB), dual-task cost (DTC) and grip strength (Jamar®). Cut-offs were set according to current recommendations. Associations were examined using linear regression with cognitive tests as dependent variables and motor domains as covariates, adjusted for age, sex, education and stroke severity.

Results

Of 567 participants included, 242 (43%) were women, mean (SD) age was 72.2 (11.7) years, 416 (75%) had an NIHSS score ≤ 4 and 475 (84%) had an mRS score of ≤2. Prevalence of concurrent motor and cognitive impairment ranged from 9.5% for DTC and 10WLR to 22.9% for grip strength and TMT-B. SPPB was associated with MoCA (regression coefficient B = 0.465, 95%CI [0.352, 0.578]), TMT-B (B = -9.494, 95%CI [− 11.726, − 7.925]) and 10WLR (B = 0.132, 95%CI [0.054, 0.211]). Grip strength was associated with MoCA (B = 0.075, 95%CI [0.039, 0.112]), TMT-B (B = -1.972, 95%CI [− 2.672, − 1.272]) and 10WLR (B = 0.041, 95%CI [0.016, 0.066]). Higher DTC was associated with more time needed to complete TMT-B (B = 0.475, 95%CI [0.075, 0.875]) but not with MoCA or 10WLR.

Conclusion

Three months after suffering mainly minor strokes, 30–40% of participants had motor or cognitive impairments, while 20% had concurrent impairments. Motor performance was associated with memory, executive function and global cognition. The identification of concurrent impairments could be relevant for preventing functional decline.

Trial registration

ClinicalTrials.gov Identifier: NCT02650531.