bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone Conduction Vibration Vestibular Evoked Myogenic Potential (VEMP) Testing: Reliability in Children, Adolescents, and Young Adults
Authors: Greenwalt Nicole, L. , Patterson Jessie N. , Rodriguez Amanda I. , Fitzpatrick Denis , Gordon Katherine R. , Janky Kristen L. 
Published: July 2020

Objectives:
Bone conduction vibration (BCV) vestibular evoked myogenic potentials (VEMP) are clinically desirable in children for multiple reasons. However, no accepted standard exists for stimulus type and the reliability of BCV devices has not been investigated in children. The objective of the current study was to determine which BCV VEMP method (B-71, impulse hammer, or Mini-shaker) yields the highest response rates and reliability in a group of adults, adolescents, and children. It was hypothesized that the Mini-shaker would yield the highest response rates and reliability because it provides frequency specificity, higher output levels without distortion, and the most consistent force output as compared to the impulse hammer and B-71.

Design:
Participants included 10 child (ages 5 to 10), 11 adolescent (ages 11 to 18), and 11 young adult (ages 23 to 39) normal controls. Cervical VEMP (cVEMP) and ocular VEMP (oVEMP) were measured in response to suprathreshold air-conducted, 500 Hz tone bursts and 3 types of BCV (B-71, impulse hammer, and Mini-shaker) across 2 test sessions to assess reliability.

Results:
For cVEMP, response rates were 100% for all methods in all groups with the exception of the adult group in response to the impulse hammer (95%). For oVEMP, response rates varied by group and BCV method. For cVEMP, reliability was highest in adults using the Mini-shaker, in adolescents using the impulse hammer, and in children using the B-71. For oVEMP, reliability was highest in adults using the Mini-shaker, in adolescents using the Mini-shaker or impulse hammer, and in children using the impulse hammer. Age positively correlated with air-conducted oVEMP amplitude, but not cVEMP amplitude or cVEMP corrected amplitude. Age negatively correlated with all BCV VEMP amplitudes with the exception of cVEMP corrected amplitude in response to the Mini-shaker.

Conclusions:
All BCV methods resulted in consistent cVEMP responses (response rates 95 to 100%) with at least moderate reliability (intraclass correlation coefficient ≥ 0.5) for all groups. Similarly, all BCV methods resulted in consistent oVEMP responses (89 to 100%) with at least moderate reliability (intraclass correlation coefficient ≥ 0.5) except for the B-71 in adults.
Intercalary Allograft Reconstruction of the Proximal Tibia With and Without a Free Fibula Flap in Pediatric Patients
Authors: Misaghi Amirhossein , Jackson Taylor J. , Stans Anthony A. , Shaughnessy William J. , Rose Peter S. , Moran Steven L. , Houdek Matthew T. 
Published: July 2020

Background:
Limb salvage of the proximal tibia can be difficult due to the growth potential of and functional demands of the pediatric patients. Multiple reconstruction techniques exist, however, the ideal form of reconstruction is yet to be elucidated. The purpose of the current study is to evaluate outcomes in patients with an intercalary resection of the proximal tibia reconstructed with an allograft with or without a free vascularized fibula flap (FVF).

Methods:
Seventeen pediatric patients (9 males, 8 females) underwent lower extremity limb salvage with the use of intercalary cadaveric allograft at a mean age of 12±4 years. The most common diagnoses were osteosarcoma (n=6) and Ewing sarcoma (n=6). Patients were reconstructed with an allograft alone (n=6) or supplemented with an FVF (n=11).

Results:
All surviving patients had at least 2 years of clinical follow-up, with the mean follow-up of 12±7 years. The mean time to union of the allograft was 11±4 months, with 6 patients requiring additional bone grafting. There was no difference in the need for an additional bone graft (odds ratio=1.14, P=1.0) between patients with an FVF and those without. Four patients underwent an amputation, all with an allograft alone, due to disease recurrence (n=2) and due to infection (n=2). As such, there was a higher 10-year overall limb-salvage rate when the allograft was combined with an FVF compared with an allograft alone (100% vs. 33%, P=0.001). At last follow-up, the mean Mankin and Musculoskeletal Tumor Society rating was 86%, with a higher mean score in patients reconstructed with an FVF (94% vs. 70%, P=0.002).

Conclusion:
Use of an intercalary allograft supplemented with an FVF to reconstruct the proximal tibia provides a durable means of reconstruction with an excellent functional outcome following oncologic proximal tibia resection in a pediatric population.

Level of Evidence:
Level III—therapeutic level.
Association Between the Serum Carnitine Level and Ammonia and Valproic Acid Levels in Patients with Bipolar Disorder
Authors: Yokoyama Saaya , Yasui-Furukori Norio , Nakagami Taku , Miyazaki Kensuke , Ishioka Masamichi , Tarakita Natsumi , Kubo Kazutoshi , Sugawara Norio , Shimoda Kazutaka 
Published: July 2020

Purpose:
Valproic acid (VPA) is not only an antiepileptic drug but also a mood stabilizer for patients with bipolar disorder. Long-term VPA therapy can cause carnitine deficiency, which may result in an increase in the blood ammonia level, in patients with epilepsy. However, information about this effect in patients with bipolar disorder is limited. The aim of this study was to investigate the associations between the serum VPA level and the carnitine and ammonia levels in psychiatric adult patients with epilepsy.

Methods:
The subjects were 182 consecutive Japanese adult patients (mean age 54.3 ± 19.5 years) diagnosed with bipolar disorder and treated with VPA. The serum VPA level, carnitine fraction, and plasma ammonia level were measured. Furthermore, the free carnitine and acylcarnitine fractions were measured using an enzyme cycling method.

Results:
Sixty-nine patients (38%) had a low free carnitine level. There were significant differences in sex, height, VPA dose, serum VPA level, total carnitine level, acylcarnitine level, and acylcarnitine/free carnitine ratio between patients with a low free carnitine level and those with a normal range of free carnitine. The simple and multiple regression analyses revealed that the VPA dose and the serum VPA level were inversely and significantly correlated with the free carnitine level. The plasma ammonia level was correlated with the VPA dose, serum VPA level, and acylcarnitine level but not with the free carnitine level.

Conclusions:
These findings suggest that carnitine deficiency is associated with the VPA dose and the serum VPA level in patients with bipolar disorder. However, it is unlikely that carnitine deficiency is associated with hyperammonemia in patients with bipolar disorder.
Neurotoxicity Despite a Renal Function-Adjusted Cefepime Regimen: A Case Study
Authors: Engalenc Xavier , Monchaud Caroline , Tafzi Naïma , Woillard Jean-Baptiste 
Published: July 2020

Abstract:
An 83-year-old man, presenting decreased renal function (estimated glomerular filtration rate 21 mL/min/1.73 m2), was treated for a bone and joint infection (on a trans-metatarsal right foot amputation) caused by Klebsiella Pneumonia sensitive to cefepime. The starting dose (1 g bid) was based on recommendations for patients presenting severe infections. One week after treatment initiation, the patient developed neurotoxicity, exhibiting extremely high plasma cefepime concentrations. Based on TDM, the dose was reduced by 8 times the original dose. This case report highlights the importance of therapeutic drug monitoring for cefepime, especially in patients presenting altered renal functions, as typical recommendations are estimated for standard patients.
Differences in Theophylline Clearance Between Patients With Chronic Hepatitis and Those With Liver Cirrhosis
Authors: Kurata Yasuo , Muraki Shota , Kashihara Yushi , Hirota Takeshi , Araki Hiroshi , Ieiri Ichiro 
Published: July 2020

Background:
Theophylline, a xanthine derivative drug, is used for the treatment of respiratory diseases, such as asthma, and is primarily eliminated by hepatic metabolism. There is marked interindividual variability in theophylline clearance. Therefore, the aim of this study was to evaluate the influence of chronic hepatitis (CH), liver cirrhosis (LC), and other covariates on theophylline clearance by population pharmacokinetic (PPK) analysis.

Methods:
The authors retrospectively obtained 496 trough concentrations of theophylline at steady state from 226 adult patients with bronchial asthma. The liver functions of the patients were classified into 3 categories: normal hepatic function, CH, and LC. The PPK analysis was performed using the NONMEM program. CH, LC, age, smoking status, coadministration of clarithromycin (CAM), and sex were considered as covariates that affected theophylline clearance.

Results:
Theophylline clearance (CL/F per kg) was significantly influenced by CH, LC, smoking, and CAM. The final model of theophylline clearance was as follows: CL/F (L/h·kg−1) = 0.0484 × 1.40SMK × 0.861CAM × 0.889CH × 0.557LC. Smoking is a well-known factor that markedly enhances CL/F through the induction of CYP1A enzymes, whereas CAM has been reported to inhibit CYP3A4. The final model for hepatic function showed that CL/F in CH and LC patients was 0.043 and 0.027 L/h/kg, respectively, and it was lower than that in patients with normal hepatic function. As theophylline clearance depends on intrinsic hepatic clearance, lower CL/F in patients with LC than in those with CH may be due to a decrease in the metabolic enzymatic capability of LC patients.

Conclusions:
Differences exist in theophylline clearance between CH and LC patients as per the PPK analysis.
Impact of Education-based HEART Score Pathway on Coronary Computed Tomography Angiography Utilization and Yield in the Emergency Department
Authors: Shrestha Pragati , Morley Eric J. , Thode Henry C. , Schweitzer Mark E. , Singer Adam J. 
Published: July 2020

Objective:
There is a growing consensus to reduce unnecessary testing among low-risk chest pain patients. The objective of this study was to evaluate the impact of implementing an education-based HEART score pathway in the emergency department on coronary computed tomography angiography (CCTA) utilization and yield.

Methods:
A retrospective before and after intervention study was conducted at a single site. Adult emergency department patients undergoing CCTA for suspected acute coronary syndrome were included. Primary outcomes were CCTA utilization and yield. Utilization was defined as the percentage of patients evaluated with CCTA and yield was calculated as the percentage of patients with a diagnosis of obstructive coronary artery disease, defined as ≥50% stenosis in any one coronary artery due to atherosclerosis.

Results:
1540 patients undergoing CCTAs were included. CCTA utilization before and after were 2.2% [95% confidence interval (CI) 2.0–2.3] and 2.0% (95% CI 1.9–2.2), respectively; mean difference 0.1% (95% CI −0.1 to 0.3; P = 0.21). The mean age was 53 years (SD = 11) and females were 52%. Of 1477 patients included in CCTA yield analysis, patients diagnosed with obstructive coronary artery disease before and after were 15.0% (95% CI 12.6–17.7) and 16.2% (95% CI 13.6–19.1), respectively; mean difference 1.2% (95% CI −2.6 to 5.1; P = 0.53).

Conclusions:
There was no significant change in the CCTA utilization or yield after the implementation of an education-based HEART pathway in a large academic center. Our findings suggest adopting a more comprehensive approach for deploying such evidence-based protocols to increase institutional compliance.
A longitudinal examination of the interpersonal fear avoidance model of pain: the role of intolerance of uncertainty
Authors: Neville Alexandra , Kopala-Sibley Daniel C. , Soltani Sabine , Asmundson Gordon J.G. , Jordan Abbie , Carleton R. Nicholas , Yeates Keith Owen , Schulte Fiona , Noel Melanie 
Published: July 2020

Abstract
Youth with chronic pain and their parents face uncertainty regarding their diagnosis, treatment, and prognosis. Given the uncertain nature of chronic pain and high comorbidity of anxiety among youth, intolerance of uncertainty (IU) may be critical to the experience of pediatric chronic pain. This study longitudinally examined major tenets of the Interpersonal Fear Avoidance Model of Pain and included parent and youth IU as key factors in the model. Participants included 152 youth with chronic pain (Mage = 14.23 years; 72% female) and their parents (93% female). At baseline, parents and youth reported on their IU and catastrophic thinking about youth pain; youth reported on their fear of pain, pain intensity, and pain interference; and parents reported on their protective responses to child pain. Youth reported on their pain interference 3 months later. Cross-lagged panel models, controlling for baseline pain interference, showed that greater parent IU predicted greater parent pain catastrophizing, which, in turn, predicted greater parent protectiveness, greater youth fear of pain, and subsequently greater youth 3-month pain interference. Youth IU had a significant indirect effect on 3-month pain interference through youth pain catastrophizing and fear of pain. The results suggest that parent and youth IU contribute to increases in youth pain interference over time through increased pain catastrophizing, parent protectiveness, and youth fear of pain. Thus, parent and youth IU play important roles as risk factors in the maintenance of pediatric chronic pain over time and may be important targets for intervention.
Netrin-1 receptor DCC is required for the contralateral topography of lamina I anterolateral system neurons
Authors: Bourojeni Farin B. , Zeilhofer Hanns Ulrich , Kania Artur 
Published: July 2020

Abstract
Anterolateral system (AS) neurons relay nociceptive information from the spinal cord to the brain, protecting the body from harm by evoking a variety of behaviours and autonomic responses. The developmental programs that guide the connectivity of AS neurons remain poorly understood. Spinofugal axons cross the spinal midline in response to Netrin-1 signalling through its receptor deleted in colorectal carcinoma (DCC); however, the relevance of this canonical pathway to AS neuron development has only been demonstrated recently. Here, we disrupted Netrin-1:DCC signalling developmentally in AS neurons and assessed the consequences on the path finding of the different classes of spinofugal neurons. Many lamina I AS neurons normally innervate the lateral parabrachial nucleus and periaqueductal gray on the contralateral side. The loss of DCC in the developing spinal cord resulted in increased frequency of ipsilateral projection of spinoparabrachial and spinoperiaqueductal gray neurons. Given that contralateral spinofugal projections are largely associated with somatotopic representation of the body, changes in the laterality of AS spinofugal projections may contribute to reduced precision in pain localization observed in mice and humans carrying Dcc mutations.
Activation of the Notch signaling pathway in the anterior cingulate cortex is involved in the pathological process of neuropathic pain
Authors: Duan Haifeng , Shen Fengyan , Li Li , Tu Zhiyi , Chen Ping , Chen Pei , Wang Zhiru , Liang Weimin , Wang Yingwei 
Published: July 2020

Abstract
Plastic changes in the anterior cingulate cortex (ACC) are critical in pain hypersensitivity caused by peripheral nerves injury. The Notch signaling pathway has been shown to regulate synaptic differentiation and transmission. Therefore, this study was to investigate the function of the Notch signaling pathway in the ACC during nociceptive transmission induced by neuropathic pain. We adopted Western blotting, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) microinjections, RNA interference targeting Notch1, Hairy and enhancer of split (Hes) 1 or Hes5, electrophysiological recordings, and behavioral tests to verify the link between Notch signaling in ACC and neuropathic pain with adult male Sprague-Dawley rats. Levels of the Notch intracellular domain were increased in ACC on day 7 after chronic constriction injury surgery or spared nerve injury. Meanwhile, the mRNA level of the downstream effector of Notch signaling Hes1 was increased, whereas the level of Hes5 mRNA did not change. Microinjection of DAPT, a γ-secretase (a key enzyme involved in Notch pathway) inhibitor, into ACC significantly reversed neuropathic pain behaviors. Intra-ACC injection of short hairpin RNA-Notch reduced Notch intracellular domain expression and decreased the potentiation of synaptic transmission in the ACC. Moreover, pain perceptions were also alleviated in rats subjected to chronic constriction injury or spared nerve injury. This process was mainly mediated by the downstream effector Hes1, but not Hes5. Based on these results, the activation of the Notch/Hes1 signaling pathway in the ACC participates in the development of neuropathic pain, indicating that the Notch pathway may be a new therapeutic target for treating chronic pain.
Modality-specific facilitation of noninjurious sharp mechanical pain by topical capsaicin
Authors: Shabes Polina , C. Rosenberger Daniela , Henrich Florian , Greffrath Wolfgang , Treede Rolf-Detlef , Baumgärtner Ulf , Magerl Walter 
Published: July 2020

Abstract
We had previously shown that a “blunt blade” stimulator can mimic the noninjurious strain phase of incisional pain, but not its sustained duration. Here, we tested whether acute sensitization of the skin with topical capsaicin can add the sustained phase to this noninvasive surrogate model of intraoperative pain. Altogether, 110 healthy volunteers (55 male and 55 female; 26 ± 5 years) participated in several experiments using the “blunt blade” (0.25 × 4 mm) on normal skin (n = 36) and on skin pretreated by a high-concentration capsaicin patch (8%, Qutenza; n = 36). These data were compared with an experimental incision (n = 40) using quantitative and qualitative pain ratings by numerical rating scale and SES Pain Perception Scale descriptors. Capsaicin sensitization increased blade-induced pain magnitude and duration significantly (both P < 0.05), but it failed to fully match the sustained duration of incisional pain. In normal skin, the SES pattern of pain qualities elicited by the blade matched incision in pain magnitude and pattern of pain descriptors. In capsaicin-treated skin, the blade acquired a significant facilitation only of the perceived heat pain component (P < 0.001), but not of mechanical pain components. Thus, capsaicin morphed the descriptor pattern of the blade to become more capsaicin-like, which is probably explained best by peripheral sensitization of the TRPV1 receptor. Quantitative sensory testing in capsaicin-sensitized skin revealed hyperalgesia to heat and pressure stimuli, and loss of cold and cold pain sensitivity. These findings support our hypothesis that the blade models the early tissue-strain-related mechanical pain phase of surgical incisions.
Burden of idiopathic pulmonary fibrosis on patients’ emotional well being and quality of life: a literature review
Authors: Antoniou Katerina , Kamekis Apostolos , Symvoulakis Emmanouil K. , Kokosi Maria , Swigris Jeffrey J. 
Published: July 2020

Purpose of review
To present an overview of the impact of idiopathic pulmonary fibrosis (IPF) on patients’ emotional well being and quality of life (QoL).

Recent findings
IPF is an interstitial lung disease which causes irreversible, progressive lung scarring in a pathological pattern of usual interstitial pneumonia. The incidence of IPF is increasing at a global level, subjecting an increasing number of people to its high morbidity and risk of mortality. Diagnosis is based on a multidisciplinary team approach and the exclusion of other interstitial lung diseases. Two novel antifibrotic treatments, pirfenidone and nintedanib, were recently approved by regulatory agencies around the globe, thus providing many IPF patients with treatment options for the first time. Several other drugs have entered the investigational pipeline, including many in early-phase or late-phase clinical trials. Given the incurable and progressive nature of IPF, even with antifibrotic therapy, depression and anxiety are common among patients; these and burdensome symptoms of breathlessness, cough and fatigue are factors that impact patients’ emotional well being and QoL. In addition to even more effective drugs, there is a need for psychosocial interventions and mental health support strategies focused on improving patients’ QoL so they are better equipped to live with this devastating condition.

Summary
The current article highlights the effects of IPF on patients’ emotional well being and QoL and offers suggestions for strategies to help patients with IPF live as well as possible in their daily lives.
LDL-cholesterol reduction in chronic kidney disease: options beyond statins
Authors: Goonasekera Michelle A. , Mafham Marion M. , Haynes Richard J. 
Published: July 2020

Purpose of review
Individuals with chronic kidney disease (CKD) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) events. LDL cholesterol (LDL-C) is a key modifiable cause of ASCVD and lowering LDL-C with statins reduces the risk of ASCVD events in a wide range of populations, including those with CKD. This review considers the utility of recently developed nonstatin LDL-C-lowering therapies in CKD.

Recent findings
The cholesterol absorption inhibitor, ezetimibe, reduces LDL-C by 15–20% and is well tolerated in CKD. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin kexin type 9 (PCSK9) reduce LDL-C by 50–60% and reduce the risk of ASCVD events. However, these agents require self-administration by subcutaneous injection every 2–4 weeks. The PCSK9 synthesis inhibitor, inclisiran, is administered approximately 6 monthly and may be more suitable for widespread use, although outcome trials are awaited. These PCSK9 targeting therapies require no dose adjustment in CKD and have no drug interactions.

Summary
Statins and ezetimibe are safe and reduce ASCVD risk in CKD populations. PCSK9 targeting agents may be useful in high-risk CKD patients, including those with prior ASCVD.
Iron deficiency and iron therapy in heart failure and chronic kidney disease
Authors: Walther Carl P. , Triozzi Jefferson L. , Deswal Anita 
Published: July 2020

Purpose of review
Iron deficiency is common and associated with adverse outcomes in heart failure, regardless of anemia. Iron deficiency, absolute and functional, with and without anemia, is associated with adverse outcomes in chronic kidney disease (CKD). Heart failure and CKD frequently occur together. Intravenous iron therapy has been shown to reduce heart failure symptoms and improve physical function in heart failure with reduced ejection fraction with iron deficiency. In CKD, intravenous or oral iron therapy are often used for management of anemia, along with erythropoiesis stimulating agents, yet the risks and benefits of intravenous iron use is controversial. In this review, we survey available evidence and ongoing studies of iron deficiency and iron supplementation in heart failure, and integrate with recent evidence on effectiveness and safety of intravenous iron therapy in CKD.

Recent findings
Intravenous iron therapy improves heart failure symptoms and physical function in heart failure with reduced ejection fraction and iron deficiency, regardless of anemia, and may reduce heart failure hospitalizations and cardiovascular mortality. Sustained intravenous iron therapy regardless of hemoglobin level in selected patients with end-stage kidney disease receiving hemodialysis improves outcomes, and does not appear to cause infectious complications.

Summary
Iron therapy has important effects in heart failure and CKD, and appears safe in the short term. Ongoing trials will provide additional important information.