bluuebunny/crossref_metadata_2025 huggingface dataset:
OTME-6. Deep sequencing reveals heterogeneity of brain metastasis-associated macrophages and microglia and uncovers their cell type-specific functions within the tumor microenvironment
Authors: Schulz Michael , Alekseeva Tijna , Anthes Julian , Macas Jandranka , Michels Birgitta , Möckl Aylin , Niesel Katja , Salamero-Boix Anna , Stein Stefan , Farin Henner , Plate Karl H , Reiss Yvonne , Rödel Franz , Sevenich Lisa
Published: July 2021

Macrophages represent a highly plastic cell type,indispensable for tissue and organ homeostasis, as well as innate immunity. Basic and translational research attributed tumor-promoting functions to macrophages, and their presence is often associated to poor patient prognosis and therapy resistance. While brain-resident macrophages, the so-called microglia (MG), represent the major immune cell type in the parenchyma under normal conditions, primary and metastatic brain tumors induce the recruitment of different immune cell types from the periphery, including monocyte-derived macrophages (MDM). Controversy remained about the redundancy of disease-associated molecular signatures and functions. The identification of markers that reliably distinguish brain-resident from blood-borne tumor-associated macrophages (TAMs) allowed the interrogation of molecular traits of different TAM populations in mouse and human brain tumors.

Using RNA-Seq, we demonstrated that TAMs rapidly acquire disease-associated transcriptional programs upon initial tumor infiltration, while gene expression remained stable during different stages of BrM progression. Across different BrM models, disease-associated transcriptional changes revealed lineage-specific, non-redundant functions of TAM populations, which was further reflected by cell type-specific occupation of different niches within the BrM microenvironment. Furthermore, we observed dose- and cell type-specific immune modulatory effects of whole brain radiotherapy on myeloid cells in BrM leading to a transient loss of disease-associated transcriptional programs predominately in blood-borne myeloid populations. This effect can at least in part be attributed to a replenishment of the recruited macrophage pool. This observation was further supported by scRNA-Seq analyses revealing higher heterogeneity of TAM-MDM compared to TAM-MG under treatment-naïve conditions and in response to radiotherapy.

Together, our results point towards the phenotypic plasticity of TAMs, especially MDMs, and the contribution of each compartment in instigating cancer-associated inflammation or the establishment of an immuno-suppressive TME. While TAM-MG exert functions related to pro-inflammatory responses, TAM-MDM are rather involved in tissue repair and regulation of adaptive immune cell functions.
OTME-20. Chitinase-3-like-1(CHI3L1) Protein Complexes Regulate the immunosuppressive Microenvironment in Glioblastoma
Authors: Chen Apeng , Jiang Yinan , Li Zhengwei , Xiao Xiangwei , Yimlamai Dean , Pollack Ian , Camacho Carlos , Hu Baoli
Published: July 2021

Glioblastoma (GBM) is the most common and highly malignant brain tumor in adults. Despite advances in multimodal treatment, GBM remains largely incurable. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Based on unbiased approaches, we found that Chitinase-3-like-1 (CHI3L1), also known as human homolog YKL-40, is highly expressed in GBM, which is regulated by the CHI3L1-PI3K/AKT/mTOR signaling in a positive feedback loop. Gain- and loss-function studies reveal that CHI3L1 plays a predominant role in regulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Using the liquid chromatography-mass spectrometry and orthogonal structure-based screening, we found that Galectin-3 binding protein (Gal3BP) and its binding partner, Galectin-3 (Gal3), can interact competitively with the same binding motif on CHI3L1, leading to selective migration of M2-like versus M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Mechanistically, the CHI3L1-Gal3 protein complex governs a transcriptional program of NFκB/CEBPβ to control the protumor phenotype of BMDMs, leading to inhibition of T cell infiltration and activation in the GBM TME. However, Gal3BP can reverse CHI3L1-Gal3 induced signaling pathway activation and subsequent protumor phenotype in TAMs. Based on protein binding motifs, a newly developed Gal3BP mimetic peptide can attenuate immune suppression and tumor progression in the syngeneic GBM mouse models, including decreasing M2-like TAMs and increasing M1-like TAMs and T cell infiltration. Together, these results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.
LDIP cooperates with SEIPIN and LDAP to facilitate lipid droplet biogenesis in Arabidopsis
Authors: Pyc Michal , Gidda Satinder K. , Seay Damien , Esnay Nicolas , Kretzschmar Franziska K. , Cai Yingqi , Doner Nathan M. , Greer Michael S. , Hull J. Joe , Coulon Denis , Bréhélin Claire , Yurchenko Olga , de Vries Jan , Valerius Oliver , Braus Gerhard H. , Ischebeck Till , Chapman Kent D. , Dyer John M. , Mullen Robert T.
Published: July 2021

Cytoplasmic lipid droplets (LDs) are evolutionarily conserved organelles that store neutral lipids and play critical roles in plant growth, development, and stress responses. However, the molecular mechanisms underlying their biogenesis at the endoplasmic reticulum (ER) remain obscure. Here we show that a recently identified protein termed LD-associated protein [LDAP]-interacting protein (LDIP) works together with both endoplasmic reticulum-localized SEIPIN and the LD-coat protein LDAP to facilitate LD formation in Arabidopsis thaliana. Heterologous expression in insect cells demonstrated that LDAP is required for the targeting of LDIP to the LD surface, and both proteins are required for the production of normal numbers and sizes of LDs in plant cells. LDIP also interacts with SEIPIN via a conserved hydrophobic helix in SEIPIN and LDIP functions together with SEIPIN to modulate LD numbers and sizes in plants. Further, the co-expression of both proteins is required to restore normal LD production in SEIPIN-deficient yeast cells. These data, combined with the analogous function of LDIP to a mammalian protein called LD Assembly Factor 1, are discussed in the context of a new model for LD biogenesis in plant cells with evolutionary connections to LD biogenesis in other eukaryotes.
’t Hooft expansion of multi-boundary correlators in 2D topological gravity
Authors: Okuyama Kazumi , Sakai Kazuhiro
Published: July 2021

We study multi-boundary correlators of Witten–Kontsevich topological gravity in two dimensions. We present a method of computing an open string like expansion, which we call the ’t Hooft expansion, of the $n$-boundary correlator for any $n$ up to any order by directly solving the Korteweg–De Vries equation. We first explain how to compute the ’t Hooft expansion of the one-boundary correlator. The algorithm is very similar to that for the genus expansion of the open free energy. We next show that the ’t Hooft expansion of correlators with more than one boundary can be computed algebraically from the correlators with a lower number of boundaries. We explicitly compute the ’t Hooft expansion of the $n$-boundary correlators for $n=1, 2, 3$. Our results reproduce previously obtained results for Jackiw–Teitelboim gravity and also the ’t Hooft expansion of the exact result of the three-boundary correlator which we calculate independently in the Airy case.
Functional Reach Test, Single-Leg Stance Test, and Tinetti Performance-Oriented Mobility Assessment for the Prediction of Falls in Older Adults: A Systematic Review
Authors: Omaña Humberto , Bezaire Kari , Brady Kyla , Davies Jayme , Louwagie Nancy , Power Sean , Santin Sydney , Hunter Susan W
Published: July 2021

Objective

The authors sought to systematically review the existing literature on the falls-related diagnostic test properties of the Functional Reach Test (FRT), single-leg stance test (SLST), and Tinetti Performance-Oriented Mobility Assessment (POMA) in older adults across settings and patient populations.

Methods

The PubMed, EMBASE, and CINAHL databases were searched (inception–July 2020). Inclusion criteria were participants aged 60 years or more, prospectively recorded falls, and the reporting of falls-related predictive validity. Manuscripts not published in English were excluded. Methodological quality of reporting was assessed using the Tooth Scale.

Results

Of 1071 studies reviewed, 21 met the inclusion criteria (12 POMA, 8 FRT, 6 SLST). Seven studies (58.3%) used a modified version of the POMA, and 3 (37.5%) used a modified FRT. For the outcome of any fall, the respective ranges of sensitivity and specificity were 0.076 to 0.615 and 0.695 to 0.97 for the POMA, 0.27 to 0.70 and 0.52 to 0.83 for the modified POMA, 0.73 and 0.88 for the FRT, 0.47 to 0.682 and 0.59 to 0.788 for the modified FRT, and 0.51 and 0.61 for the SLST in community-dwelling older adults. For the SLST, the sensitivity and specificity for recurrent falls in the community-dwelling setting were 0.33 and 0.712, respectively.

Conclusion

All the clinical tests of balance demonstrated an overall low diagnostic accuracy and a consistent inability to correctly identify fallers. None of these tests individually are able to predict future falls in older adults. Future research should develop a better understanding of the role that clinical tests of balance play in the comprehensive assessment of falls risk in older adults.

Impact

Neither the FRT, SLST, nor POMA alone shows consistent evidence of being able to correctly identify fallers across fall types, settings, or older adult subpopulations. These clinical tests of balance cannot substitute a comprehensive falls risk assessment and thus should be incorporated in practice solely to identify and track balance impairment in older adults.
Medication decision-making and adherence in lupus: patient–physician discordance and the impact of previous ‘adverse medical experiences’
Authors: Sloan Melanie , Lever Elliott , Gordon Caroline , Harwood Rupert , Georgopoulou Sofia , Naughton Felix , Wincup Chris , Sutton Stephen , D’Cruz David
Published: July 2021

Objectives

Medication adherence is critical in the successful management of lupus. There is very limited existing literature on reasons why non-adherence is not reported. This study explores the impact of current and previous medical experiences on patient satisfaction, adherence and reporting of non-adherence.

Methods

Mixed methodology involved thematic analysis of in-depth interviews (n = 23) to further explore the statistically analysed quantitative survey findings (n = 186).

Results

This study identified five themes: (i) physician-patient discordance and a ‘hierarchy of evidence’ in medication decisions; (ii) the association of adherence with satisfaction with care; (iii) the persisting impact of past adverse medical experiences (AMEs); (iv) the dynamic balance of patient-physician control; and (v) holistic care, beyond a purely medication-based focus. Improving quality of life (43% of participants) and a supportive medical relationship (24%) were the main reasons for adherence. Patient-priorities and self-reported symptoms were perceived as less important to physicians than organ-protection and blood results. Non-reporters of non-adherence, non-adherers and those with past AMEs (e.g. psychosomatic misdiagnoses) had statistically significant lower satisfaction with care. The importance of listening to patients was a key component of every theme, and associated with patient satisfaction and adherence. The mean rating for rheumatologist’s listening skills was 2.88 for non-adherers compared with 3.53 for other participants (mean difference 0.65, P = 0.003).

Conclusion

Patients would like more weight and discussion given to self-reported symptoms and quality of life in medication decisions. Greater understanding and interventions are required to alleviate the persisting impact of past AMEs on some patients’ wellbeing, behaviour and current medical relationships.
Species Tree Inference Methods Intended to Deal with Incomplete Lineage Sorting Are Robust to the Presence of Paralogs
Authors: Yan Zhi , Smith Megan L , Du Peng , Hahn Matthew W , Nakhleh Luay
Published: July 2021

Many recent phylogenetic methods have focused on accurately inferring species trees when there is gene tree discordance due to incomplete lineage sorting (ILS). For almost all of these methods, and for phylogenetic methods in general, the data for each locus are assumed to consist of orthologous, single-copy sequences. Loci that are present in more than a single copy in any of the studied genomes are excluded from the data. These steps greatly reduce the number of loci available for analysis. The question we seek to answer in this study is: what happens if one runs such species tree inference methods on data where paralogy is present, in addition to or without ILS being present? Through simulation studies and analyses of two large biological data sets, we show that running such methods on data with paralogs can still provide accurate results. We use multiple different methods, some of which are based directly on the multispecies coalescent model, and some of which have been proven to be statistically consistent under it. We also treat the paralogous loci in multiple ways: from explicitly denoting them as paralogs, to randomly selecting one copy per species. In all cases, the inferred species trees are as accurate as equivalent analyses using single-copy orthologs. Our results have significant implications for the use of ILS-aware phylogenomic analyses, demonstrating that they do not have to be restricted to single-copy loci. This will greatly increase the amount of data that can be used for phylogenetic inference.[Gene duplication and loss; incomplete lineage sorting; multispecies coalescent; orthology; paralogy.]
Types, Evidence, and Resources of Interventions Focused on Improving the Psychosocial Well-being of Parents of Premature/Sick Infants
Authors: Thomson Gill , Feeley Claire
Published: July 2021

Background:

Parents of infants born premature and/or sick and who require neonatal care are at risk of poor mental health. Currently, there is no comprehensive knowledge about interventions (ie, types, evidence, resources) that have been exclusively designed to improve the psychosocial well-being of this population group.

Purpose:

To undertake a systematic scoping review of interventions focused on improving the psychosocial well-being of parents of sick/premature infants who required neonatal care to identify the (a) types of interventions, (b) evidence of the interventions, and (c) level of resources required to deliver the interventions.

Search Strategy:

e searched 7 databases (MEDLINE, CINAHL, PsycINFO, Cochrane, EMBASE, Web of Science, and Global Index), reviewed references, and followed up key authors.

Results:

From 10,516 hits, 38 articles met the inclusion criteria (36 different studies/interventions). Studies included creative oriented (n = 11), group/peer support (n = 4), relaxation/mindfulness (n = 3), spiritual/religious (n = 4), psychotherapeutic-based (n = 11), and “other” (n = 3) (eg, sleep, acupuncture). Most had been undertaken in high-income settings with mothers and required varying levels of resources within and between the different intervention types. While some interventions were effective, there was high heterogeneity with similar interventions using different designs, protocols, and outcomes. Most intervention types included studies that highlighted what parents valued (eg, self-care, relaxation, social opportunities).

Implications for Research:

Evidence highlights a wide range of potential interventions for nursing and other specialist staff to consider and offers insights into potential mechanisms of effectiveness to underpin future intervention design.
Is a Right Angle the Right Angle? Normal Coronal Radiographic Alignment in the Pediatric Finger Phalanges
Authors: Krueger Andrew , Qudsi Rameez , Eckstein Kendra , Cornwall Roger
Published: July 2021

Background:

Quantifying pediatric phalanx fracture displacement requires understanding the normal radiographic alignment of pediatric phalanges, which has never been assessed in the coronal plane, although prior studies have assumed the articular surfaces and physes to be perpendicular to the diaphyses. This study tests the hypothesis that these relationships are not uniformly perpendicular and instead vary by digit and age.

Methods:

Normal hand bone age radiographs were retrospectively reviewed from 40 males and 40 females 2 to 18 years old. For each finger proximal phalanx (P1) and middle phalanx (P2), 2 raters each measured twice the angle between the diaphysis and distal articular surface (D-DA), diaphysis and physis (D-P, when physis present), and diaphysis and proximal articular surface (D-PA). Intra-rater and inter-rater reliability were calculated with intraclass correlation coefficients. 95% confidence intervals were calculated for each angle for each digit, phalanx, age group, and sex to determine which angles ~90 degrees. Variability among ages and sex was assessed with analysis of variance.

Results:

Intra-rater and inter-rater intraclass correlation coefficients were >0.90, except in P2 ∠D-DA in children under 8 years old with unossified P2 condyles. Overall, only 173 (47.8%) of 362 confidence intervals included 90 degrees. Three angles of the small finger (P1 ∠D-DA, P2 ∠D-P, P2 ∠D-PA) never ~90 degrees at any age or sex, with an average 10 degrees ulnar tilt of the small finger proximal interphalangeal joint. Of the 24 angles across digits and phalanges, 10 varied significantly with age, especially in the index and middle finger P1 where initially wedge-shaped epiphyses progressively became more symmetric with age.

Conclusions:

The coronal radiographic angles between the phalangeal diaphyses and articular surfaces or physes differ from 90 degrees more than half the time in pediatric fingers, and nearly half the angles vary by age. These findings demonstrate that the articular surfaces and physes of the pediatric finger phalanges are not uniformly perpendicular to the diaphyses, underscoring the need to consider the variability among digits, phalanges, ages and subjects.

Level of Evidence:

Level IV.
Navigated Transsacral Screw Fixation for the Treatment of Bilateral Sacral Insufficiency Fractures
Authors: Balling Horst
Published: July 2021

Nondisplaced and minimally displaced sacral insufficiency fractures are increasingly being recognized as a cause of immobilizing low back pain in the elderly. These insufficiency fractures are most accurately diagnosed by visualizing sacral bone marrow edema on magnetic resonance imaging, which is the radiologic imaging modality with the highest sensitivity for identifying these fractures. Successful treatment options range from nonsurgical (eg, bed rest, pain medication, mobilization, antiosteoporotic medication, low-intensity-pulsed ultrasound, etc.) to surgical management (ie, sacroplasty and/or osteosynthesis with iliosacral screws or lumbosacral hinge fixation with or without application of reinforcing bone cement). The appropriate surgical treatment for frail subjects requires a less-invasive technique that establishes full weight-bearing stability for successful early remobilization of affected elderly and multimorbid individuals. Iliosacral screw osteosynthesis with a single C-arm is a common surgical technique for stabilizing the posterior pelvic ring after traumatic instabilities or fractures of the sacrum. Bilateral injuries are generally addressed from both sides of the pelvis. This article describes the surgical technique of 3D image-guided transsacral screw fixation for unilateral and bilateral nondisplaced sacral insufficiency fractures in the elderly using a single-sided approach, and specifies the associated preoperative and postoperative management. The procedure is illustrated in an instructional video that demonstrates step-by-step, how the navigated surgical procedure is performed.
Influence of Vascular Anatomy on the Radiologic Outcomes in Oblique Lateral Interbody Fusion at L5–S1
Authors: Chung Nam-Su , Lee Han-Dong , Chung Hee-Woong , Jeon Chang-Hoon
Published: July 2021

Study Design:

This was a retrospective study.

Objective:

The objective of this study was to evaluate whether the anatomy of the left common iliac vein (LCIV) affects the radiologic outcomes in oblique lateral interbody fusion (OLIF) at L5–S1.

Summary of Background Data:

Upward mobilization and retraction of the LCIV is an essential technique in OLIF at L5–S1. However, mobilization of the LCIV is sometimes difficult and may affect the surgical outcomes in OLIF at L5–S1.

Methods:

This study involved 52 consecutive patients who underwent OLIF at L5–S1 and had >1-year regular follow-up. The configuration of LCIV on preoperative axial magnetic resonance images of the lumbar spine was categorized into 3 types according to the difficulty of mobilization: type I (no requirement for mobilization), type II (potentially easy mobilization), and type III (potentially difficult mobilization). Radiologic parameters included anterior/posterior disk heights (ADH/PDH), disk angle (DA), cage migration, cage subsidence, cage position, and fusion rate at L5–S1. Intraoperative/perioperative events associated with OLIF at L5–S1 were reviewed. Radiologic outcomes among the LCIV types were compared.

Results:

There were 19 men and 33 women with a mean age of 62.8±9.7 years. The mean follow-up duration was 24.8±15.5 months. The LCIV anatomy was type I in 25 (48.1%) patients, type II in 14 (26.9%), and type III in 13 (25.0%). The mean ADH increased from 7.0±4.7 to 16.9±4.1 mm at the last follow-up (P<0.001), and the mean PDH increased from 2.7±1.7 to 4.9±1.6 mm (P<0.001). The mean DA increased from 5.4±5.4 to 16.9±6.5 degrees (P<0.001). There were no significant differences in ADH, PDH, and DA at the last follow-up among the LCIV types. Two (3.8%) major and 2 (3.8%) minor LCIV injuries were identified, all of which had a type III LCIV.

Conclusions:

OLIF at L5–S1 showed favorable radiologic outcomes regardless of the LCIV anatomy. However, type III LCIV patients had a high rate of intraoperative vascular injury.
Current treatment options for nodular lymphocyte-predominant Hodgkin lymphoma
Authors: Eichenauer Dennis A. , Engert Andreas
Published: July 2021

Purpose of review

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B cell-derived malignancy. This review aims at providing an overview of recent developments in the management of NLPHL.

Recent findings

Patients with stage IA NLPHL without risk factors have excellent outcomes. The 8-year progression-free survival (PFS) is roughly 90% and the 8-year overall survival (OS) close to 100% after limited-field radiotherapy (RT) alone. Individuals presenting with early stages other than stage IA without risk factors and intermediate stages have 10-year PFS rates in excess of 70% and 10-year OS rates exceeding 90% when treated with 2 and 4 cycles of ABVD, respectively, followed by consolidation RT. In advanced NLPHL, different protocols such as BEACOPP, ABVD, and R-CHOP have been evaluated retrospectively. However, the optimal approach is undefined. Patients with relapsed NLPHL mostly receive single-agent anti-CD20 antibody treatment or conventional chemotherapy. High-dose chemotherapy and autologous stem cell transplantation are restricted to high-risk patients. NLPHL recurrence is salvaged successfully in the majority of cases.

Patients with NLPHL have a very good prognosis. Treatment differs from classical Hodgkin lymphoma in some situations.
Lithium chloride prevents glucocorticoid-induced osteonecrosis of femoral heads and strengthens mesenchymal stem cell activity in rats
Authors: Zhang Yue-Lei , Zhu Zhen-Zhong , Zhang Le-Cheng , Wang Gang
Published: July 2021

Background:

Accumulating evidence suggests that lithium influences mesenchymal stem cell (MSC) proliferation and osteogenic differentiation. As decreased bone formation in femoral heads is induced by glucocorticoids (GCs), we hypothesized that lithium has a protective effect on GC-induced osteonecrosis of femoral heads (ONFH).

Methods:

A rat ONFH model was induced by methylprednisolone (MP) and the effect of lithium chloride on the models was evaluated. Micro-computed tomography (CT)-based angiography and bone scanning were performed to analyze the vessels and bone structure in the femoral heads. Hematoxylin and eosin and immunohistochemical staining were performed to evaluate the trabecular structure and osteocalcin (OCN) expression, respectively. Bone marrow-derived MSCs were isolated from the models, and their proliferative and osteogenic ability was evaluated. Western blotting and quantitative real-time polymerase chain reaction were performed to detect osteogenic-related proteins including Runx2, alkaline phosphatase, and Collagen I.

Results:

Micro-CT analysis showed a high degree of osteonecrotic changes in the rats that received only MP injection. Treatment with lithium reduced this significantly in rats that received lithium (MP + Li group); while 18/20 of the femoral heads in the MP showed severe osteonecrosis, only 5/20 in the MP + Li showed mild osteonecrotic changes. The MP + Li group also displayed a higher vessel volume than the MP group (0.2193 mm3
vs. 0.0811 mm3, P < 0.05), shown by micro-CT-based angiography. Furthermore, histological analysis showed better trabecular structures and more OCN expression in the femoral heads of the MP + Li group compared with the MP group. The ex vivo investigation indicated higher proliferative and osteogenic ability and upregulated osteogenic-related proteins in MSCs extracted from rats in the MP + Li group than that in the MP group.

Conclusions:

We concluded that lithium chloride has a significant protective effect on GC-induced ONFH in rats and that lithium also enhances MSC proliferation and osteogenic differentiation in rats after GC administration.
Cholesterol Paradigm and Beyond in Atherosclerotic Cardiovascular Disease: Cholesterol, Sterol Regulatory Element-Binding Protein, Inflammation, and Vascular Cell Mobilization in Vasculopathy
Authors: Zhou Ruihai , Stouffer George A. , Frishman William H.
Published: July 2021

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). How cholesterol and its carrier lipoproteins are involved in ASCVD is still under extensive investigation. Satins are thus far the best-proven class of cholesterol-lowering medications to improve the clinical outcomes of ASCVD. Statins specifically inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase of the mevalonate pathway for cholesterol biosynthesis. The widely accepted theory is that statins inhibit the hepatic cholesterol synthesis causing upregulation of hepatocyte low-density lipoprotein (LDL) receptor; receptor-mediated LDL uptake and metabolism in the liver results in reduction of circulating LDL cholesterol, which subsequently reduces vascular deposition and retention of cholesterol or LDL in atherogenesis. Nevertheless, cholesterol biosynthesis is ubiquitous, also in extrahepatic cells including those in vascular wall, under tight regulation by sterol regulatory element-binding protein (SREBP), the master gene transcription factor governing cholesterol biosynthesis. Studies have shown that SREBP can be upregulated in vascular wall subject to injury or stent implantation. SREBP can be activated by proinflammatory and mitogenic factors in vascular cells, leading to hyperactive mevalonate pathway, which promotes vascular cell mobilization, further proinflammatory and mitogenic factor release from vascular cells, and vascular inflammation. In this article, we review the cellular cholesterol homeostasis regulation by SREBP and SREBP-mediated vascular hyperactive cholesterol biosynthesis, we term vascular hypercholesterolism, in the pathogenesis of ASCVD and vasculopathy. SREBP functions as a platform bridging cholesterol, inflammation, and vascular cell mobilization in ASCVD pathogenesis. Targeting vascular hypercholesterolism could open a new avenue in fighting against ASCVD.
Simultaneous Measurement of 11 Antibiotics for Use in the Intensive Care Unit by Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry
Authors: Woksepp Hanna , Karlsson Louise , Ärlemalm Andreas , Hällgren Anita , Schön Thomas , Carlsson Björn
Published: July 2021

Background:

Recent studies indicate that a high proportion of patients in the intensive care unit fail to attain adequate antibiotic levels. Thus, there is a need to monitor the antibiotic concentration to ensure effective treatment. In this article, the authors aimed to develop an ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of antimicrobials to assess individualized therapeutic drug monitoring.

Methods:

A UHPLC-MS/MS method with 11 antibiotics (ciprofloxacin, moxifloxacin, benzylpenicillin, levofloxacin, linezolid, rifampicin, meropenem, cloxacillin, cefotaxime, clindamycin, and piperacillin) was developed. Chromatographic separation was performed using a Kinetex Biphenyl reversed-phase column, with gradient elution using 0.1% formic acid and methanol with 0.1% formic acid. Sample preparation was performed using methanol protein precipitation. The total run time was 5 minutes.

Results:

For all analytes, the interassay inaccuracies for calibrators were ≤5%. The interday inaccuracies for the quality controls (QCs) were ≤5% for all analytes. The interassay precision for calibration standards ranged between 1.42% and 6.11%. The interassay imprecision for QCs of all antibiotics and concentrations ranged between 3.60% and 16.1%. Interassay inaccuracy and imprecision for the QCs and calibration standards were ≤15% for all drugs, except benzylpenicillin.

Conclusions:

A rapid UHPLC-MS/MS method was developed for the simultaneous quantification of 11 different antibiotics. Minimal sample preparation was required to ensure a rapid turnaround time. The method was applied to clinical samples collected from 4 intensive care units.
Dose Assessment for Technologically Enhanced Naturally Occurring Radioactive Materials Disposal in Landfills
Authors: Caffrey Emily A. , Rood Arthur S. , Grogan Helen A. , Till John E. , Herman Kurt
Published: July 2021

Technologically enhanced naturally occurring radioactive material (TENORM) is gaining notoriety in the public sector, as the oil and gas industry looks for disposal locations for its slightly radioactive waste streams. Due in part to both the lack of federal regulations on the disposal of TENORM and the lack of permitted landfills that are designated for TENORM waste, occasionally it ends up being unknowingly placed in municipal landfills. It was alleged that a municipal landfill in Kentucky accepted 1.05 × 106 kg of TENORM over approximately 8 mo starting in July 2015. This matter is still in litigation, and many facts, including whether the material in question actually constituted TENORM, are still in dispute. The authors had no means available to independently verify the actual composition of the material. Therefore, for purposes of this article only, we assume that the material in question did constitute TENORM. This qualification allows us to evaluate potential doses while respecting the litigation process. Doses from the disposals and for two remediation alternatives, (1) closure-in-place and monitoring and (2) excavation and redisposition of waste, were evaluated, taking into consideration the landfill construction, local geology and hydrology, meteorology, background radiation, population distribution, and current and future land uses. This study outlines appropriate methods for calculating doses to potential receptors for a variety of exposure pathways that are broadly applicable to municipal or chemical/hazardous waste landfills. As this study demonstrates, doses to landfill workers and members of the public are low, both during the disposal and for the remediation alternatives evaluated, and well below regulatory limits. Removal of the materials does not reduce present day doses, and it presents other risks that outweigh any benefit from the long-term dose reduction.
Estimated Prevalence of Keratoconus in the United States From a Large Vision Insurance Database
Authors: Munir Saleha Z. , Munir Wuqaas M. , Albrecht Jennifer
Published: July 2021

Purpose:

To estimate the prevalence of keratoconus in the United States using a large vision insurance database.

Methods:

We used data from the 2016 vision service plan (VSP) Global claims database to estimate the prevalence of keratoconus among enrollees by state. The VSP Global database includes cross-sectional de-identified claims data summarized by state of residence in predefined age and gender groups. Crude values of prevalence of keratoconus are provided in the VSP Global database. The open-source software package qGIS version 3.12 was used as the geographic information system for geospatial analysis.

Results:

The prevalence of keratoconus among VSP enrollees in the United States was estimated to be 0.15% with 95% confidence interval (CI) (0.15%, 0.15%). The prevalence of keratoconus was highest in Western states and among male population. The highest prevalence of keratoconus was in Colorado (0.51%; 95% CI 0.49%–0.52%), with particularly high prevalence for men in the age groups 18 to 39 years (0.90%; 95% CI 0.84%–0.95%) and 40 to 64 years (0.90%; 95% CI 0.85%–0.95%).

Conclusion:

The average prevalence of keratoconus in the United States in 2016 may be higher than previously reported. Living in Western states and male sex were associated with high prevalence.
Voluntary exercise blocks ongoing pain and diminishes bone remodeling while sparing protective mechanical pain in a rat model of advanced osteoarthritis pain
Authors: Townsend Kaylee , Imbert Ian , Eaton Victoria , Stevenson Glenn W. , King Tamara
Published: July 2021

Exercise is the most common treatment recommended by healthcare providers for the treatment of musculoskeletal pain. We examined whether voluntary running wheel exercise improves pain and bone remodeling in rats with monosodium iodoacetate–induced unilateral knee joint pain. During acquisition of wheel running before osteoarthritis (OA) treatment, rats separated into 2 groups characterized by either high or low levels of voluntary wheel running as indicated by distance and peak speed. After the induction of knee joint OA, all rats showed diminished voluntary wheel running throughout the study. Voluntary wheel running failed to alter evoked nociceptive responses evaluated as weight asymmetry or hind paw tactile thresholds at any timepoint of the study. By contrast, relief of ongoing pain was demonstrated by conditioned place preference produced by lidocaine injection into the monosodium iodoacetate–treated knee in high but not low-running rats. Both high and low voluntary runners showed diminished trabecular bone loss compared with sedentary controls. These observations indicate that both high-intensity and low-intensity exercise is beneficial in protecting against bone remodeling in advanced OA. The data suggest that similar to clinical observation, bone remodeling does not correlate with pain. In addition, these results suggest that higher intensity exercise may relieve persistent ongoing OA pain while maintaining movement-evoked nociception. The relief of ongoing pain can potentially offer significant improvement in quality of life, whereas preservation of responses to movement-evoked pain may be especially important in protecting the joint from damage because of overuse.
Impact of Level of Pediatric Amputation on Selection of Prosthetic Component Options
Authors: Nemade Amit , Miller Freeman , Thacker Mihir , Oleas-Santillan Geovanny , Rogers Kenneth J.
Published: July 2021

Introduction

Amputation is one of the oldest surgeries known to the human race. The principles of amputation in children are different than in adults. Common indications for amputation include congenital, traumatic, infection, malignancy, vascular, and other pathology. Improper prosthetic fitting or inability to use the most modern available prosthesis can lead to dissatisfaction and compromised high-level function. The aim of this study was to assess residual limbs for compatibility to fit the most modern prosthetic components.

Methods

This study is a retrospective review of medical records of patients who underwent amputation between the pelvis and midfoot before 18 years of age. Age, sex, etiology, and level of amputation were recorded. A senior certified prosthetist graded the limbs based on limitations the residual limb imposed on options for the highest functioning modern prosthetic components.

Results

Sixty-one patients were identified (35 male, 26 female) with a mean age at assessment of 17.35 years (range, 1.86–35.35 years). Congenital causes and tumors were the most common etiology. Amputations around the ankle were most common (25), followed by transtibial (20). There were 59% grade 1 limbs with no restrictions to component options, 28% grade 2 with moderate restrictions, and 13% grade 3 or severely limited component options due to the residual limb. Most grade 1 residual limbs were transtibial or proximal. Amputations distal to transtibial were of all grades.

Conclusions

The choices for optimal high-level prosthetic components are much less limited for transtibial amputation than more distal amputations leading to potentially less high-level prosthetic function. Managing the residual limb length and prosthetic fitting ability is an important element in pediatric amputations if the goal is to fit mature young adults with the highest functioning level prosthetic components.
Plasma Cell Vulvitis: A Systematic Review
Authors: Krapf Jill M. , Cavallo Kathryn , Saleeb Monica , Goldstein Andrew T.
Published: July 2021

Objective

This systematic review aimed to present the available literature on plasma cell vulvitis (PCV), a relatively uncommon form of inflammatory vulvovaginal dermatitis.

Materials and Methods

A literature search was performed in PubMed, Science Direct, and Google Scholar using the following key words: “plasma cell vulvitis,” “Zoon vulvitis,” and “vulvitis circumscripta plasmacellularis.” Specific variables were assessed in each article, including patient age, menopausal status, comorbidities, presenting symptoms, symptom duration, histological description, treatment, and treatment response.

Results

Thirty-nine articles met inclusion criteria, including 38 case reports and 1 observational study, with a total of 96 cases of PCV reported. The mean age of diagnosis was 52.9 years, with an age range of 8–76 years. Most common presenting symptoms included pruritis and vaginal discomfort, with average duration of symptoms 28.2 months (range = 2 months to 10 years). All reports demonstrated subepithelial plasma cell infiltrate on histology. Five percent of PCV cases reported concomitant autoimmune conditions and 6% sexually transmitted infections. Most common treatment modalities included topical corticosteroids (n = 41), tacrolimus (n = 6), and imiquimod (n = 6). In 53 reported outcomes, 88.7% of patients had resolution of symptoms with treatment.

Conclusions

Clinical research is needed to better determine the diagnostic criteria and to assess the efficacy of treatment options for PCV.
Influence of Cochlear Implant Use on Perceived Listening Effort in Adult and Pediatric Cases of Unilateral and Asymmetric Hearing Loss
Authors: Lopez Erin M. , Dillon Margaret T. , Park Lisa R. , Rooth Meredith A. , Richter Margaret E. , Thompson Nicholas J. , O’Connell Brendan P. , Pillsbury Harold C. , Brown Kevin D.
Published: July 2021

Objective:

Assess the influence of cochlear implant (CI) use on the perceived listening effort of adult and pediatric subjects with unilateral hearing loss (UHL) or asymmetric hearing loss (AHL).

Study design:

Prospective cohort.

Setting:

Tertiary referral center.

Patients:

Adults and children with UHL or AHL.

Intervention:

Cochlear implantation. Subjects received their CI as part of a clinical trial assessing the effectiveness of cochlear implantation in cases of UHL and AHL.

Main outcome measures:

Responses to the Listening Effort pragmatic subscale on the Speech, Spatial, and Qualities of Hearing Scale (SSQ) or SSQ for Children with Impaired Hearing (SSQ-C) were compared over the study period. Subjects or their parents completed the questionnaires preoperatively and at predetermined postactivation intervals. For the adult subjects, responses were compared to word recognition in quiet and sentence recognition in noise.

Results:

Forty adult subjects (n = 20 UHL, n = 20 AHL) and 16 pediatric subjects with UHL enrolled and underwent cochlear implantation. Subjects in all three groups reported a significant reduction in perceived listening effort within the initial months of CI use (p < 0.001; η
2 ≥ 0.351). The perceived benefit was significantly correlated with speech recognition in noise for the adult subjects with UHL at the 12-month interval (r
(20) = .59, p = 0.006).

Conclusions:

Adult and pediatric CI recipients with UHL or AHL report a reduction in listening effort with CI use as compared to their preoperative experiences. Use of the SSQ and SSQ-C Listening Effort pragmatic subscale may provide additional information about a CI recipient's experience beyond the abilities measured in the sound booth.
Novel Web-Based Music Re-Engineering Software for Enhancement of Music Enjoyment Among Cochlear Implantees
Authors: Hwa Tiffany Peng , Tian Lisa Likun , Caruana Francesco , Chun Michael , Mancuso Dean , Cellum Ilana P. , Lalwani Anil K.
Published: July 2021

Objectives:

Cochlear implant (CI) listeners experience diminished music perception and enjoyment from a variety of patient-related and implant-related factors. We investigate the hypothesis that patient-directed music re-engineering may enhance music enjoyment with CI.

Study Design:

Prospective cohort study.

Setting:

Academic cochlear implant center.

Subjects and Methods:

A multidisciplinary team of neurotologists, audiologists, and a sound/audio engineer collaborated with a web developer to create a music re-engineering application. Experienced adult CI listeners rated original excerpts from five major genres of music on enjoyment using a visual analog scale (VAS). Subjects were then allowed to re-engineer the original by adjusting treble frequencies, bass frequencies, percussion emphasis, and reverberation and again rated on enjoyment.

Results:

Total of 46 subjects, with a mean age of 57.6 years (SD = 16; range, 18–90) participated in the study. User-mixed audio was rated higher across all measures of enjoyment than original recordings (mean difference +0.92; p < 0.05, CI [0.22, 1.62]), an effect that was seen across all genres except for country music. Subjects preferred louder bass frequencies (mean difference +7.1 dB; p < 0.01, CI [2.15, 24.3]) and more reverberation (mean difference +6.6 ms; p < 0.01, CI [2.85, 10.7]). Re-engineered music increased enjoyment in 57%, and 79% reported an interest in being able to mix music of their own choosing.

Conclusion:

User-directed music re-engineering increases music enjoyment for CI listeners. The cochlear implantee preferred heightened bass, reverberation, and treble across musical genres. These findings support the implementation of patient-directed music re-engineering to enhance music enjoyment with technology that is readily available today.
Improved Time in Therapeutic Range with International Normalized Ratio Remote Monitoring for Patients with Left Ventricular Assist Devices
Authors: Nguyen Vi N. , Stevens Craig A. , Brambatti Michela , Smith Monica , Braun Oscar O. , Mariski Mark , Pretorius Victor G. , Adler Eric D. , Feist Ashley A.
Published: July 2021

Despite advances in therapy, bleeding and thromboembolic events are frequent complications in patients with left ventricular assist device (LVAD) support. Maintaining warfarin in therapeutic range has been shown to be more challenging in this patient population compared to other indications. Patients with LVADs on warfarin typically are within goal international normalized ratio (INR) range 36–57% of the time, compared to about 65% for other indications. The goal of this study was to evaluate if an INR remote monitoring system along with the implementation of a standardized warfarin management protocol improves warfarin time in therapeutic range (TTR) for patients with LVADs. This single-center, retrospective, observational study included 78 patients with LVADs that were followed at our academic center from January 2015 to October 2017. In October 2016, we updated our warfarin management protocol and implemented a remote monitoring system with patients’ weekly INR results monitored. The primary objective of the study was to determine the difference between TTRs in remote monitoring versus standard monitoring. We found that the average TTR was significantly higher in the remote monitoring group compared to the standard monitoring cohort (61.1% vs. 40.0%, p < 0.005). However, bleeding, thrombotic incidence, and hospital readmission rates were similar between the two patient cohorts. Remote monitoring improved warfarin TTR significantly in this study and may have the potential to improve anticoagulation-related outcomes in patients with LVADs.
Immune thrombocytopenia: options and new perspectives
Authors: Caserta Santino , Zaccuri Anna Maria , Innao Vanessa , Musolino Caterina , Allegra Alessandro
Published: July 2021

Immune thrombocytopenia is a haematological, autoimmune disorder characterized by elevated platelet demolition due to the presence of antiplatelet autoantibodies derived from B cells and to an irregular, deficient process of platelets production in bone marrow. In this review, after a brief presentation of ‘old’ strategies used nowadays yet, we focused on new drugs used in the treatment of immune thrombocytopenia and their mechanism of action and posology, basing on the last scientific literature. The observation that CoViD-19 can be associated with immune thrombocytopenia is also put in evidence. Particular attention will be dedicated on the concept that the ideal treatment should represent a solution not only for the failure of normal processes of production and survival of platelets, but also it should improve quality of life of patients, with minimum adverse events. Anyway, despite enormous advances of the last years, further investigations are necessary in order to define scrupulously long-term efficacy of new molecules proposed.
Update on the management of penile and meatal strictures
Authors: Vetterlein Malte W. , Fisch Margit M. , Zumstein Valentin
Published: July 2021

Purpose of review

Treatment of penile and distal urethral strictures including the fossa navicularis and the meatus remains challenging due to their adverse etiology and lack of ventral tissue support. In this contemporary review, we summarize the available evidence and recent advancements in reconstructive techniques.

Recent findings

Over the last years, several refinements of already established techniques have been added to the reconstructive armamentarium in the management of penile urethral strictures. These include the single-stage combination of flap and graft, the additional use of tissue glue, or an optimized single-stage tubularization using a free graft.

There is a shift toward an increased use of single-stage procedures even in complex strictures of the penile and distal urethra. This is reflected by advancements and refinements in operative techniques. Nonetheless, staged urethroplasty remains a cornerstone of curative management in such patients with durable success rates. Future research should focus on identifying distinct patient and stricture characteristics to determine the individual therapeutic approach with optimal functional outcomes.