bluuebunny/crossref_metadata_2025 huggingface dataset:
Types of Pain and Pain Assessment
Authors: Bachtold Sabina , Collantes Enrique , Ganty Praveen , Kamel Yehia , Jirikowski Gustav , Ravindran Deepak , Rudiger Jan , Tameem Alifia , Tanner John
Published: June 2022

This chapter describes the features of acute and chronic pain, including the transition from acute to chronic pain. The principles and importance of history taking, physical examination and flags in pain medicine are outlined as well. It also discusses how to assess pain in children and the elderly, including the challenges in these patient groups and pain assessment tools. Furthermore, tools for the measurement of pain are included and explained in detail. This chapter also includes mental health examination and an example of a pain clinic letter. The SOCRATES-mnemonic is described as a tool for patient referrals to a chronic pain service. Furthermore, the context of Waddell signs is explained.
Pain Pathways
Authors: Collantes Enrique , Jirikowski Gustav , Pais Paolo , Ravindran Deepak , Rudiger Jan , Stasiowska Maria
Published: June 2022

This chapter describes the physiology of pain. It includes the anatomy of the peripheral and central nervous systems, and the ascending and descending pain pathways and describes the process of peripheral and central sensitization. Furthermore, the gate control theory is explained, as well as the pathophysiology of nociceptive, neuropathic, and visceral pain.
Neurotransmitters and Receptors
Authors: Mottaleb Ramy , Mulla Nofil , Stasiowska Maria , Wong Matthew
Published: June 2022

This chapter describes the molecular basis of neurotransmitters and opioid and non-opioid receptors involved in the transmission of noxious stimuli. It also covers the mechanism of action of treatments that are used in pain management.
Neurobiology of Pain
Authors: Fitzmaurice Bethany , Jayaseelan Senthil , Jirikowski Gustav , Kapur Sandeep , Mittal Manish
Published: June 2022

This chapter includes a range of key tosympathepics on the neurobiology of pain, including genetic associations and patterns of pain conditions, and the relationship between gender and pain. Furthermore, the relationship between the immune system, glial cells, and the pathophysiology of pain is discussed. The neurobiological and physiological changes in response to substance abuse are described, as well as the effect of stress on pain, and vice versa. Finally, the development of aberrant drug behaviours, such as dependence, tolerance, addiction, and pseudotolerance, that occur in patients is also discussed.
Local Anaesthetics
Authors: Collantes Enrique , Poply Kavita , Rudiger Jan
Published: June 2022

This chapter provides an overview of local anaesthetics (classification, mechanism of action, physiochemical characteristics, pharmacokinetics, and pharmacodynamics). It gives a detailed description of commonly used local anaesthetics in pain management, including Ametop®, Emla®, lidocaine, bupivacaine, and cocaine. It also discusses the use of mexiletine in chronic pain. Finally, this chapter describes the presentation and management of local anaesthetic toxicity.
Non-steroidal Anti-inflammatory Drugs and Paracetamol
Authors: Keogh Peter
Published: June 2022

This chapter provides an overview of the role of non-steroidal anti-inflammatory drugs (NSAIDs) in pain management. It describes the differences between non-selective NSAIDs and cyclo-oxygenase 2 inhibitors. It gives a detailed description of commonly used NSAIDs such as diclofenac, ibuprofen, and naproxen. This chapter also includes a detailed description of paracetamol, with different proposed mechanisms of action.
Clinical Pharmacology
Authors: Bachtold Sabina , Balasubramanian Shyam , Guru Rahul , Howells Katharine , Jack James , Kapur Sandeep , Rudiger Jan
Published: June 2022

This chapter provides an overview of the general principles and miscellaneous topics of clinical pharmacology that are relevant to pain medicine. This involves the World Health Organization (WHO) analgesic ladder which is mainly used for acute and cancer pain. Placebo and nocebo effects and their effect on clinical outcomes and treatment in pain medicine, as well as the principles of pre-emptive and preventative analgesia in acute pain, are described.

Screening tools and management principles for patients with a substance use disorder are also included. Last, but not least, serotonin syndrome and its presentation are explained.
Overview of Interventions
Authors: Al-Kaisy Adnan , Braude Simon , Collantes Enrique , Gulati Sumit , Puttapa Ashok , Rudiger Jan , Sharon Haggai , Tameem Alifia
Published: June 2022

This chapter provides an overview of the role of interventional pain management to reduce patients’ pain levels, and improve their mobility, activity levels, sleep, and quality of life. The key principles to be considered before, during, and after a pain intervention are described. The role of fluoroscopy, ultrasound, and computed tomography guidance to perform interventions is outlined. The factors that play a role in increasing the likelihood of complications from pain interventions (radiation safety/health care professionals/equipment/patient-related) and considerations to implement in daily practice to prevent patient harm are discussed. Furthermore, the role of chemical neurolysis, radiofrequency denervation, and pulsed radiofrequency treatment in interventional pain medicine is described.
Thorax and Abdomen
Authors: Beard Laura , Dorgham Mohamed , Guru Rahul , Stangoe Doug , Tameem Alifia
Published: June 2022

This chapter provides an overview of commonly performed thoracic and abdominal interventions for the management of acute, chronic, and cancer pain. It includes thoracic medial branch blocks and their radiofrequency denervation, intercostal and thoracic paravertebral blocks, and abdominal plane blocks. This chapter also includes the analgesic management of patients with rib fractures. For each procedure, the relevant anatomy, indications, contraindications, patient positioning, technique, and possible complications are outlined.
Lumbar and Pelvis
Authors: Bhayani Sadiq , Kamel Yehia , Raithatha Bhavesh , Rudiger Jan , Smith Thomas E
Published: June 2022

This chapter provides an overview of commonly performed spinal interventions for the management of acute, chronic, and cancer pain, such as caudal epidural, coccygeal nerve, ganglion impar, and piriformis block. Lumbar facet joint/medial branch nerve blocks and sacroiliac joint injections and subsequent radiofrequency denervation of the sacroiliac joint are also described.
Autonomic Nervous System
Authors: Fritz Ann-Katrin , Guru Rahul , Jirikowski Gustav , Raithatha Bhavesh , Ramani Subramanian , Rudiger Jan
Published: June 2022

This chapter provides an overview of the anatomy of the autonomic nervous system and the role of the sympathetic and parasympathetic nervous systems in pain physiology. The autonomic interventions at the cervical, thoraco-abdominal, and lumbo-sacral levels are discussed in the topics on stellate ganglion block, coeliac plexus and splanchnic nerve blocks including radiofrequency denervation, lumbar sympathetic block and sympathectomy, and hypogastric plexus block. For each procedure, the relevant anatomy, indications, contraindications, patient positioning, technique, and possible complications are outlined.
Spinal Cord and Neuromodulation
Authors: Das Sangeeta , Jirikowski Gustav , Kamel Yehia , Malik Deepak , Mittal Manish , Ng Yin Yee , Palmisani Stefano , Pang David , Rudiger Jan , Thottungal Athmaja
Published: June 2022

This chapter provides an overview of the anatomy and function of the spinal cord, dorsal root ganglion, and vertebral bodies. The role of discography, including benefits and risks, in pain medicine is discussed. Procedures used for the management of radicular and non-radicular spinal pain are described such as epidurals (cervical, thoracic, lumbar), epiduroscopy, and epidurolysis. Simple and advanced neuromodulation techniques used in pain management are explained, Therefore, transcutaneous electrical nerve stimulation and more complex procedures such as cordotomy, intrathecal drug delivery systems, and spinal cord stimulation are described, including indications, contraindications and associated complications.
Musculoskeletal Pain Conditions
Authors: Bodycombe Owen , Collantes Enrique , Dorgham Mohamed , Fitzmaurice Bethany , Guru Rahul , Kamel Yehia , Kapur Sandeep , Mulla Nofil , Pais Paolo , Pitchiah Arumugam , Ramaswamy Shankar , Rudiger Jan , Smith Thomas E , Thottungal Athmaja , Wong Ivan
Published: June 2022

This chapter provides an overview of a range of musculoskeletal conditions, which can lead to chronic pain states. The incidence, relevant anatomy, pathophysiology, aetiology, diagnosis, treatment, and other key information are covered for the following conditions. The topics included are as follows: osteoarthritis; cervicogenic headache; neck pain; whiplash; shoulder pain; carpal tunnel syndrome; low back pain; lumbo-sacral transitional vertebrae; failed back surgery syndrome; spondylosis; sacroiliac joint pain; coccygodynia; piriformis syndrome; greater trochanteric pain syndrome; and plantar fasciitis.
Rheumatological Conditions
Authors: Griffith Sian
Published: June 2022

This chapter provides an overview of rheumatological conditions that are relevant to pain medicine or can be associated with chronic pain. Common rheumatological conditions are included, such as ankylosing spondylitis, gout, hypermobility, rheumatoid arthritis, osteoporosis, and systemic lupus erythematosus. It also describes the importance of biomarkers and investigations which are used for the diagnosis and the ongoing management of rheumatological conditions. The osteoporosis topic outlines the importance of bone density measurements, and it explains the treatment of vertebral fractures at an earlier and later stage. Incidence, pathophysiology, aetiology, diagnosis, and treatment are included for common rheumatological conditions in pain medicine.
Visceral Pain Conditions
Authors: Collantes Enrique , Pais Paolo , Rudiger Jan , Thottungal Athmaja
Published: June 2022

This chapter provides an overview of visceral pain conditions which are common in pain medicine. Abdominal pain, pelvic pain, vulvodynia, and proctalgia, as well as chronic pancreatitis and their complex underlying causes are listed. Key features in the assessment and management of visceral pain are outlined, and the role of gender and old age in visceral pain is described. Refractory angina pectoris is described as a separate topic. Definition, incidence, pathophysiology, aetiology, risk factors, diagnosis, and treatment are included for each condition.
Other Pain Conditions
Authors: Collantes Enrique , Gubbay Anthony , Gulati Sumit , Harper Sarah , Lwin Tommy , Mulla Nofil , Pais Paolo , Pang David , Ramaswamy Shankar , Rudiger Jan , Tambirajoo Kantaruby , Winter Victoria , Wong Ivan
Published: June 2022

This chapter describes presentations in pain medicine which are caused by a mixture of nociceptive, neuropathic, and visceral mechanisms. These include acute pain in surgical and non-surgical patients, chronic post-surgical pain, erythromelalgia, headaches, human immunodeficiency virus, orofacial pain, the specifics of paediatric pain and pain in the elderly, pain related to sickle cell disease, and vascular insufficiency pain.
Cancer and Pain
Authors: Chmiel Kasia , Choudhari Mahesh , Dumitrescu Alix , Kamel Yehia , Puttapa Ashok , Tameem Alifia
Published: June 2022

This chapter provides an overview of the management of cancer pain. Cancer pain can be generated by different mechanisms and can have various forms of presentation such as neuropathic, somatic, visceral and/or localized pain. The psychological impact of this disease is very significant and the importance of assessment and management of this component has been discussed in this chapter. Furthermore, the treatment options for analgesia, medication in the form of opioids and adjuvants, neurolytic interventions as well as the importance of intrathecal drug delivery systems are covered, including the impact of radiotherapy and chemotherapy on cancer pain. Finally the surgical procedures, which help in palliative care, have also been considered.
Psychology and Pain
Authors: Bachtold Sabina , Burrow Caroline , Guru Rahul , LeMarchand Karen
Published: June 2022

Adverse psychological impact of chronic pain is well established, and a multidisciplinary approach, addressing the physical, psychological (psychiatric or psychological), and social contributors to pain, disability, and distress, should be incorporated. To help with psychometric assessment of the impact of chronic pain and opioid/drug misuse, this chapter includes the description of many screening tools and questionnaires, which also help to identify the affective component of pain. The disorders discussed here are fear avoidance behaviour, catastrophizing and pain behaviours, depression, anxiety, stress and suicide, personality disorders, post-traumatic stress disorder, somatic symptom disorder, and compensation issues. This chapter covers the various psychologically based treatment approaches, such as cognitive behavioural therapy (CBT), acceptance and commitment therapy (ACT), mindfulness, hypnotic therapy, and neurolinguistic programming (NLP), which can be offered to patients, as well as the rehabilitative pain management programme.
Evolution of miRNA-Binding Sites and Regulatory Networks in Cichlids
Authors: Mehta Tarang K , Penso-Dolfin Luca , Nash Will , Roy Sushmita , Di-Palma Federica , Haerty Wilfried
Published: June 2022

The divergence of regulatory regions and gene regulatory network (GRN) rewiring is a key driver of cichlid phenotypic diversity. However, the contribution of miRNA-binding site turnover has yet to be linked to GRN evolution across cichlids. Here, we extend our previous studies by analyzing the selective constraints driving evolution of miRNA and transcription factor (TF)–binding sites of target genes, to infer instances of cichlid GRN rewiring associated with regulatory binding site turnover. Comparative analyses identified increased species-specific networks that are functionally associated to traits of cichlid phenotypic diversity. The evolutionary rewiring is associated with differential models of miRNA- and TF-binding site turnover, driven by a high proportion of fast-evolving polymorphic sites in adaptive trait genes compared with subsets of random genes. Positive selection acting upon discrete mutations in these regulatory regions is likely to be an important mechanism in rewiring GRNs in rapidly radiating cichlids. Regulatory variants of functionally associated miRNA- and TF-binding sites of visual opsin genes differentially segregate according to phylogeny and ecology of Lake Malawi species, identifying both rewired, for example, clade-specific and conserved network motifs of adaptive trait associated GRNs. Our approach revealed several novel candidate regulators, regulatory regions, and three-node motifs across cichlid genomes with previously reported associations to known adaptive evolutionary traits.
Comprehensive Genomic Profiling of 274 Thymic Epithelial Tumors Unveils Oncogenic Pathways and Predictive Biomarkers
Authors: Girard Nicolas , Basse Clémence , Schrock Alexa , Ramkissoon Shakti , Killian Keith , Ross Jeffrey S
Published: June 2022

Background

Thymic malignancies represent a heterogeneous group of rare thoracic cancers, which are classified according to the World Health Organization histopathologic classification, that distinguishes thymomas from thymic carcinomas. Data regarding the biology of those tumors are limited in the literature, and the vast majority have been obtained using surgical specimens from early-stage disease. Meanwhile, treatment of advanced, refractory thymic tumors currently relies on chemotherapy, with limited efficacy. Comprehensive genomic profiling (CGP) of advanced, refractory tumors would open some opportunities for innovative treatments.

Patients and Methods

A total of 90 and 174 consecutive patients with thymoma or thymic carcinoma, respectively, for whom formalin-fixed, paraffin-embedded specimens from recurrent, refractory tumor were sequenced, were included. Sequencing was performed using hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >500× for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer.

Results

Thymomas featured a low frequency of genomic alterations (average of 1.8/tumor), and low levels of TMB. The genomic alterations identified in more than 10% of cases were in the CDKN2A/B and TP53 genes. Amplification in the NTRK1 gene was found in an unresectable, stage III, type B3 thymoma. Thymic carcinomas featured a significantly higher frequency of alterations at 4.0/tumor (P < .0001). Clinically relevant genomic alterations were observed in the CDKN2A, KIT, and PTEN/PI3K/MTOR pathways. Elevated TMB in thymic carcinomas was uncommon with only 6% of cases featuring ≥10 mutations/Mb.

Conclusions

Our cohort is the largest available so far, reporting on CGP of thymic epithelial tumors in the setting of advanced disease. The identification of clinically relevant genomic alterations in the KIT, PI3K, CDKN2A/B, or NTRK genes provides a strong rationale for potential precision medicine approaches using targeted agents. A subset of thymic carcinomas show high tumor mutation burden, what may be a predictor of efficacy of immune checkpoint inhibitors.
Paws on the Street: Neighborhood-Level Concentration of Households with Dogs and Urban Crime
Authors: Pinchak Nicolo P , Browning Christopher R , Boettner Bethany , Calder Catherine A , Tarrence Jake
Published: June 2022

The formative work of Jane Jacobs underscores the combination of “eyes on the street” and trust between residents in deterring crime. Nevertheless, little research has assessed the effects of residential street monitoring on crime due partly to a lack of data measuring this process. We argue that neighborhood-level rates of households with dogs captures part of the residential street monitoring process core to Jacobs’ hypotheses and test whether this measure is inversely associated with property and violent crime rates. Data from a large-scale marketing survey of Columbus, OH, USA residents (2013; n = 43,078) are used to measure census block group-level (n = 595) rates of households with dogs. Data from the Adolescent Health and Development in Context study are used to measure neighborhood-level rates of trust. Consistent with Jacobs’ hypotheses, results indicate that neighborhood concentration of households with dogs is inversely associated with robbery, homicide, and, to a less consistent degree, aggravated assault rates within neighborhoods high in trust. In contrast, results for property crime suggest that the inverse association of dog concentration is independent of levels of neighborhood trust. These associations are observed net of controls for neighborhood sociodemographic characteristics, temporally lagged crime, and spatial lags of trust and dog concentration. This study offers suggestive evidence of crime deterrent benefits of local street monitoring and dog presence and calls attention to the contribution of pets to other facets of neighborhood social organization.
Gender Inequality in Lifetime Earnings
Authors: de Castro Galvao Juliana
Published: June 2022

Although vast, most research on gender earnings gaps uses cross-sectional data for year-round full-time workers; therefore, little is known about the dynamics of gender inequality in lifetime earnings. To address this lacuna, this article analyzes data from the Panel Study of Income Dynamics from 1968 to 2017, to investigate the extent, trends and explanations of gender inequality in lifetime earnings both within and across five birth cohorts born between 1930 and 1979. I find that the lifetime gap sharply declined until the 1960s birth cohort, with little change thereafter. Unpacking trends throughout the lifecycle shows that this stalled gender convergence is driven by increasing gender earnings inequality throughout the prime working years of those born in the 1960s and 1970s. Decomposition of the lifetime earnings gap further reveals that gender differences in the number of hours worked throughout one’s working life is a more important factor for younger rather than older generations—despite gender convergence in lifetime labor force attachment across cohorts. On the other hand, gender inequality in stop-outs during early career has become a less relevant factor in explaining earnings differences for younger generations. These findings draw attention to the value of examining gender inequality as a cumulative long-term process.
Sarcopenia, body composition and factors associated with variceal gastrointestinal bleeding and splenectomy in hepatosplenic schistosomiasis mansoni
Authors: Barbosa Fernanda A , Nardelli Mateus J , Cançado Guilherme G L , Silva Catherine F , Osório Fernanda M F , Melo Rodolfo F Q , Taranto Daniela O L , Ferrari Teresa C A , Couto Claudia A , Faria Luciana C
Published: June 2022

Background

Sarcopenia is a common complication of cirrhosis and an important predictor of morbimortality. We aimed to determine the prevalence of sarcopenia and its associated factors in hepatosplenic schistosomiasis (HSS) as well as to evaluate whether muscle mass and function are associated with variceal upper gastrointestinal bleeding (VUGIB) and previous splenectomy in subjects without other liver diseases.

Methods

We conducted a cross-sectional study including adults with HSS who underwent clinical, biochemical, anthropometric, muscle strength and physical performance evaluations and were submitted to bioelectrical impedance analysis and abdominal ultrasound. Sarcopenia was diagnosed according to the 2019 European consensus criteria.

Results

A total of 66 patients with HSS (62.1% male; mean age 48.8±8.6 y) were included. Overall, six subjects (9.1%) were diagnosed with probable sarcopenia and none had confirmed sarcopenia. Fat-free body mass index (BMI) was independently associated with VUGIB (odds ratio 0.701 [95% confidence interval 0.51 to 0.96]; p=0.025). Compared with patients who did not undergo surgery, individuals who underwent esophagogastric devascularization combined with splenectomy (EGDS) had higher serum lipid levels, fat percentage and frequency of metabolic syndrome, with lower skeletal muscle mass index and hand grip strength.

Conclusions

HSS mansoni seems not to cause sarcopenia. However, a lower fat-free BMI was associated with previous VUGIB and the subgroup of patients who underwent EGDS presented higher lipid levels, fat percentage and frequency of metabolic syndrome and lower muscle mass and function.
Diagnostic Guide for Alternaria Leaf Spot on Sugar Beet, Red Beet, and Chard
Authors: Cortes Sarah Crizon , Hanson Linda , Miles Laura , Willbur Jaime , Naegele Rachel
Published: June 2022

Alternaria leaf spot, caused by Alternaria spp., is a common foliar disease of sugar beet and other Beta vulgaris crop types. Known to be present in the United States since at least the 1950s, this disease has been found in all major sugar beet growing regions of the United States as well being reported as present everywhere beets are grown. Alternaria leaf spot symptoms are similar to several other common foliar diseases of beets including Cercospora leaf spot and the early stages of Phoma leaf spot. Symptoms and signs of this disease in the field do not provide enough information to help distinguish between diseases unless the viewer is readily familiar with the pathogen, especially when viewed with the unaided eye. Alternaria cultures can be identified to species using colony and conidial morphology on select culture media or using molecular markers. While not as common as Cercospora leaf spot, Alternaria leaf spot can result in significant reductions in yield and quality when not managed.
Nephrin expression in human epidermal keratinocytes and its implication in poor wound closure
Authors: Kim Ji Young , Lee Eun Jung , Seo Jimyung , Lee Yangsin , Ahn Yuri , Park Sujin , Bae Yu Jeong , Lee Jinu , Lim Beom Jin , Kim Doyoung , Cho Jin Won , Oh Sang Ho
Published: June 2022

Nephrin is a type‐1 transmembrane protein and a component of the slit diaphragm renal‐filtration barrier. It has several functions in actin remodeling and cell–cell adhesion. Nephrin is principally located in the kidney glomerulus, but several studies have reported that nephrin is found in the pancreas, brain, and placenta. However, nephrin expression and its role in human skin have not yet been reported. First, using single‐cell RNA sequencing, immunohistochemistry, and immuno‐electron microscopy, nephrin expression was confirmed in human‐skin epidermal keratinocytes. Nephrin expression colocalized with the expression of zonula occludens‐1 in keratinocytes and was closely related to keratinocyte cell density, proliferation, and migration. High glucose treatment decreased nephrin expression and compromised keratinocyte cell migration without yes‐associated protein nuclear entry. This reduced cell migration under high glucose conditions was improved in nephrin‐overexpressing keratinocytes. Nephrin was highly expressed on the margins of re‐epithelized epidermis based on in vivo mice and ex vivo human skin wound models. The results demonstrate that nephrin is expressed in human‐skin keratinocytes and functions in cell adhesion, proliferation, and migration. In conclusion, this study suggests that nephrin may have a variety of physiological roles in human skin.
Global analyses of mRNA expression in human sensory neurons reveal eIF5A as a conserved target for inflammatory pain
Authors: Chase Rebecca , de la Peña June Bryan , Smith Patrick R. , Lawson Jennifer , Lou Tzu‐Fang , Stanowick Alexander D. , Black Bryan J. , Campbell Zachary T.
Published: June 2022

Nociceptors are a type of sensory neuron that are integral to most forms of pain. Targeted disruption of nociceptor sensitization affords unique opportunities to prevent pain. An emerging model for nociceptors are sensory neurons derived from human stem cells. Here, we subjected five groups to high‐throughput sequencing: human induced pluripotent stem cells (hiPSCs) prior to differentiation, mature hiPSC‐derived sensory neurons, mature co‐cultures containing hiPSC‐derived astrocytes and sensory neurons, mouse dorsal root ganglion (DRG) tissues, and mouse DRG cultures. Co‐culture of nociceptors and astrocytes promotes expression of transcripts enriched in DRG tissues. Comparisons of the hiPSC models to tissue samples reveal that many key transcripts linked to pain are present. Markers indicative of a range of neuronal subtypes present in the DRG were detected in mature hiPSCs. Intriguingly, translation factors were maintained at consistently high expression levels across species and culture systems. As a proof of concept for the utility of this resource, we validated expression of eukaryotic initiation factor 5A (eIF5A) in DRG tissues and hiPSC samples. eIF5A is subject to a unique posttranslational hypusine modification required for its activity. Inhibition of hypusine biosynthesis prevented hyperalgesic priming by inflammatory mediators in vivo and diminished hiPSC activity in vitro. Collectively, our results illuminate the transcriptomes of hiPSC sensory neuron models. We provide a demonstration for this resource through our investigation of eIF5A. Our findings reveal hypusine as a potential target for inflammation associated pain in males.
The Impact of Isolated Versus Multiple Osteochondromas: Analysis of the CoULD Registry
Authors: Wessel Lauren E. , Goldfarb Charles A. , Vuillermin Carley , Hutchinson Douglas T. , Bohn Deborah , Steinman Suzanne , Wall Lindley B. ,   CoULD Study Group
Published: June 2022

Purpose:

The burden of upper extremity (UE) osteochondromas on function and self-perception among pediatric patients is unclear. The purpose of our study was to study the impact of osteochondromas in comparison to population norms and to evaluate solitary versus multiple osteochondromas on subjective UE function as measured by patient rated outcomes.

Methods:

We utilized the CoULD (Congenital Upper Limb Differences) Registry to review all pediatric patients presenting with osteochondromas between January 2014 and February 2021. Demographic information was collected and patients were classified as having either single or multiple osteochondromas. Patient-Reported Outcome Measurement Information System (PROMIS) and Pediatric Outcomes Data Collection Instrument (PODCI) tools were utilized for assessment. Scores for PODCI subscales of UE function, Pain/comfort, and Happiness and PROMIS domains of UE Function, Pain, Depression, Anxiety, and Peer Relations were reviewed. Differences between groups were analyzed using the Studentttest.

Results:

Ninety-nine patients met inclusion criteria for the study with an average age of presentation of 9.3 years and 61 patients (62%) were male. Overall, patients demonstrated worse UE Function as well as greater Anxiety and Depression in comparison to the population normals on PROMIS assessment. Patients also demonstrated worse patient and parent reported PODCI UE, Sports and Physical Functioning, Pain/Comfort and Global Functioning scores compared with population norms but demonstrated better than average happiness scores. Patients with multiple osteochondromas demonstrated greater PROMIS pain interference and more disability in PODCI Sports and Physical Functioning, Pain/Comfort and Global Functioning compared with those with solitary osteochondromas.

Conclusion:

Patients with UE osteochondromas have worse overall function in comparison to population norms, exceeding established minimally clinically important difference values. In addition, patients with multiple osteochondromas reported more pain and poorer physical function than those with solitary osteochondromas. Physicians should be alert to the physical and psychosocial burden of this disease.

Level of Evidence:

Level II—prognostic.
Selection of Comparator Group in Observational Drug Safety Studies: Alternatives to the Active Comparator New User Design
Authors: Wintzell Viktor , Svanström Henrik , Pasternak Björn
Published: June 2022

A valid study design is essential when assessing the safety of drugs based on observational data. The comparator group is a key element of the design and can greatly influence the results. The active comparator new user design is a go-to design in observational drug safety research where a target trial of initiation of a study drug versus usual care is emulated. A comparison with another treatment that targets similar patients as the study drug and has no effect on the outcome has great potential to reduce bias. However, the active comparator new user design can be difficult to implement because no suitable comparator drug is available or because it requires extensive exclusion of study drug initiators. In this analysis, we evaluated alternative study designs that can be used in drug safety assessments when the active comparator new user design is not optimal. Using target trial emulation as a common framework, we defined and evaluated the following designs: traditional no use, no-use episodes, active comparator new user, prevalent new user, generalized prevalent new user, and hierarchical prevalent new user. We showed that all designs can be implemented by using sequential cohorts and simply altering the patient selection criteria, i.e., identifying increasingly restrictive cohorts. In this way, all designs are nested in each other and the differences between them can be demonstrated clearly. We concluded that many study-specific factors need to be considered when choosing a design, including indication, available comparator drugs, treatment patterns, potential effect modification, and sample size.
Abuse Potential of Lemborexant, a Dual Orexin Receptor Antagonist, Compared With Zolpidem and Suvorexant in Recreational Sedative Users
Authors: Landry Ishani , Hall Nancy , Aluri Jagadeesh , Filippov Gleb , Reyderman Larisa , Setnik Beatrice , Henningfield Jack , Moline Margaret
Published: June 2022

Background

Lemborexant (LEM) is a dual orexin receptor antagonist approved for the treatment of insomnia in adults in multiple countries including the the United States, Japan, Canada, Australia and several Asian countries.

Procedures

This was a randomized, single-dose, single-center, double-blind, active-control, 6-way crossover study to evaluate LEM abuse potential. The study assessed oral doses of LEM 10 mg (LEM10), 20 mg (LEM20), and 30 mg (LEM30) compared with placebo (PBO), zolpidem (ZOL) immediate release 30 mg, and suvorexant (SUV) 40 mg. Subjects were healthy, nondependent, recreational sedative users able to discriminate/like the effects of both SUV and ZOL from PBO during a qualification phase.

Results

Abuse potential endpoints were analyzed in qualified subjects who received and completed all treatments (n = 32). On the “at this moment” drug-liking visual analog scale (VAS), mean maximum (peak) effect (primary endpoint) values were 78.4, 80.5, and 83.6 for LEM10, LEM20, and LEM30, respectively, which were all significantly greater than PBO (57.8; all P > 0.05) but not different from SUV (76.1) or ZOL (78.3). Similarly, for secondary endpoints overall drug-liking VAS and take-drug-again VAS, mean maximum (peak) effect values for all LEM doses were significantly greater than PBO (P > 0.05) but not different compared with ZOL or SUV.

Conclusions

For all doses, LEM demonstrated abuse potential versus PBO and appeared to have a similar abuse potential profile to ZOL and SUV in this study population. Lemborexant was well tolerated. Lemborexant has been placed in Schedule IV, the same drug schedule as ZOL and SUV.
Pandemic response: The identification of alternative clinical hours to ensure advanced practice nursing students meet program requirements
Authors: Bricker Christina , Canale Michelle , Hay Brittany , Taylor Tracey , Maguire Denise , Remo Elizabeth , Smith Sharlene , Johansson Marcia , Morgan Hailey
Published: June 2022

The coronavirus (COVID-19) pandemic resulted in the abrupt withdrawal of clinical sites for advanced practice nursing students which worsened an already challenging placement process. Few studies to date have analyzed the use of alternative clinical practice experiences used to facilitate the completion of program requirements by advanced practice nursing students beyond direct hour requirements. The faculty team from one university decided to track and analyze their use of alternative clinical practice experiences for advanced practice nursing students actively enrolled during the first semester of the pandemic. The team collated student alternative hour entries within the clinical courses for review and statistical analysis. Data included input from advanced practice nursing students in family, pediatric primary care, adult gerontology primary care, adult gerontology acute care nurse practitioner concentrations, and nursing education, doctor of nursing practice, and nurse anesthesia programs. A total of 569 advanced practice nursing students participated in 15 distinct alternative clinical activities. There was a significant effect of students' program concentration on total number of virtual case study hours logged, F(6, 562) = 9.45, p < .0001, and a significant effect of students' program concentration on total number of continuing education hours logged, F(6, 562) = 7.79, p < .0001. Results can inform the use of concentration-specific alternative activities for advanced practice nursing students to address gaps in clinical experiences.
Accuracy and Interrater Reliability of Point-of-Care Ultrasonography Image Interpretation for Intussusception
Authors: Bergmann Kelly R. , Khant Marshal , Lammers Shea , Arroyo Alexander C. , Avendano Pablo , Chaudoin Lindsey , Cohen Stephanie G. , Deanehan J. Kate , Kornblith Aaron E. , Lam Samuel H. F. , Lin-Martore Margaret , Malia Laurie , Pade Kathryn H. , Park Daniel B. , Sivitz Adam , Shahar-Nissan Keren , Snelling Peter J. , Tessaro Mark O. , Thomas-Mohtat Rosemary , Whitcomb Valerie , Yock-Corrales Adriana , Walsh Paige , Watson Dave , Madhok Manu ,   In Collaboration with the P2Network Intussusception Study Group
Published: June 2022

Objectives

The aim of this study was to determine the accuracy and interrater reliability of (1) point-of-care ultrasound (POCUS) image interpretation for identification of intussusception and (2) reliability of secondary signs associated with intussusception among experts compared with novice POCUS reviewers.

Methods

We conducted a planned secondary analysis of a prospective, convenience sample of children aged 3 months to 6 years who were evaluated with POCUS for intussusception across 17 international pediatric emergency departments between October 2018 and December 2020. A random sample of 100 POCUS examinations was reviewed by novice and expert POCUS reviewers. The primary outcome was identification of the presence or absence of intussusception. Secondary outcomes included intussusception size and the presence of trapped free fluid or echogenic foci. Accuracy was summarized using sensitivity and specificity, which were estimated via generalized mixed effects logistic regression. Interrater reliability was summarized via Light's κ statistics with bootstrapped standard errors (SEs). Accuracy and reliability of expert and novice POCUS reviewers were compared.

Results

Eighteen expert and 16 novice POCUS reviewers completed the reviews. The average expert sensitivity was 94.5% (95% confidence interval [CI], 88.6–97.5), and the specificity was 94.3% (95% CI, 90.3–96.7), significantly higher than the average novice sensitivity of 84.7% (95% CI, 74.3–91.4) and specificity of 80.4% (95% CI, 72.4, 86.7). κ was significantly greater for expert (0.679, SE 0.039) compared with novice POCUS reviewers (0.424, SE 0.044; difference 0.256, SE 0.033). For our secondary outcome measure of intussusception size, κ was significantly greater for experts (0.661, SE 0.038) compared with novices (0.397, SE 0.041; difference 0.264, SE 0.029). Interrater reliability was weak for expert and minimal for novice reviewers regarding the detection of trapped free fluid and echogenic foci.

Conclusions

Expert POCUS reviewers demonstrate high accuracy and moderate interrater reliability when identifying intussusception via image interpretation and perform better than novice reviewers.
Recipient Selection Criteria for Facial Transplantation
Authors: Parker Augustus , Chaya Bachar F. , Rodriguez-Colon Ricardo , Hao Yvonne , Kurian Keerthi , Trilles Jorge , Boczar Daniel , Brydges Hilliard , Rodriguez Eduardo D.
Published: June 2022

Background

Recipient selection is an important determinant of surgical outcomes in facial transplantation (FT). Appropriately, each FT program develops their own guidelines for recipient selection criteria. Currently, there is no resource to simultaneously assess and identify similarities and differences between these guidelines. Such information could be useful in distinguishing areas of FT that are well understood from those that could benefit from further exploration.

Methods

We performed a systematic review of the scientific literature from inception to June 18, 2021, using Pubmed, Embase, Cochrane Library, and Scopus to identify articles pertaining to recipient selection criteria. Clinical trials were identified through the Clinicaltrials.gov registry. United States and international program websites were reviewed for patient-facing information.

Results

Our systematic review yielded 90 suitable articles, 8 clinical trials, and 7 program websites containing the recipient selection criteria of 24 different FT programs. The most reported on recipient criteria were age, positive human immunodeficiency viral status (HIV+), positive hepatitis C viral status, psychosocial stability, and medical compliance. Other criteria were rarely addressed, such as blindness and recipient immune status.

Conclusions

Guidelines among different face transplant programs are changing over time. We found consensus on certain recipient selection criteria, but the majority remain program or surgeon dependent, emphasizing that FT is still an evolving procedure. Although most programs reported on their recipient selection criteria, the rationale was often missing. Further discussion about recipient selection criteria and the reasoning behind employing or changing them will help advance the field.
Validation of a Mobile, Sensor-based Neurobehavioral Assessment With Digital Signal Processing and Machine-learning Analytics
Authors: Sloane Kelly L. , Mefford Joel A. , Zhao Zilong , Xu Man , Zhou Guifeng , Fabian Rachel , Wright Amy E. , Glenn Shenly
Published: June 2022

Background:

The Miro Health Mobile Assessment Platform consists of self-administered neurobehavioral and cognitive assessments that measure behaviors typically measured by specialized clinicians.

Objective:

To evaluate the Miro Health Mobile Assessment Platform’s concurrent validity, test–retest reliability, and mild cognitive impairment (MCI) classification performance.

Method:

Sixty study participants were evaluated with Miro Health version V.2. Healthy controls (HC), amnestic MCI (aMCI), and nonamnestic MCI (naMCI) ages 64–85 were evaluated with version V.3. Additional participants were recruited at Johns Hopkins Hospital to represent clinic patients, with wider ranges of age and diagnosis. In all, 90 HC, 21 aMCI, 17 naMCI, and 15 other cases were evaluated with V.3. Concurrent validity of the Miro Health variables and legacy neuropsychological test scores was assessed with Spearman correlations. Reliability was quantified with the scores’ intraclass correlations. A machine-learning algorithm combined Miro Health variable scores into a Risk score to differentiate HC from MCI or MCI subtypes.

Results:

In HC, correlations of Miro Health variables with legacy test scores ranged 0.27–0.68. Test–retest reliabilities ranged 0.25–0.79, with minimal learning effects. The Risk score differentiated individuals with aMCI from HC with an area under the receiver operator curve (AUROC) of 0.97; naMCI from HC with an AUROC of 0.80; combined MCI from HC with an AUROC of 0.89; and aMCI from naMCI with an AUROC of 0.83.

Conclusion:

The Miro Health Mobile Assessment Platform provides valid and reliable assessment of neurobehavioral and cognitive status, effectively distinguishes between HC and MCI, and differentiates aMCI from naMCI.
Complex subsets but redundant clonality after B cells egress from spontaneous germinal centers
Authors: Castrillon Carlos , Simoni Lea , van den Broek Theo , van der Poel Cees , Akama-Garren Elliot H. , Ma Minghe , Carroll Michael C.
Published: June 2022

Affinity matured self-reactive antibodies are found in autoimmune diseases like systemic lupus erythematous. Here we used fate-mapping reporter mice and single cell transcriptomics coupled to antibody repertoire analysis to characterize the post-germinal center (GC) B cell compartment in a new mouse model of autoimmunity. Antibody secreting cells (ASCs) and memory B cells (MemBs) from spontaneous GCs grouped into multiple subclusters. ASCs matured into two terminal clusters, with distinct secretion, antibody repertoire and metabolic profiles. MemBs contained FCRL5+ and CD23+ subsets, with different in vivo localization in the spleen. GC-derived FCRL5+ MemBs share transcriptomic and repertoire properties with atypical B cells found in aging and infection and localize to the marginal zone, suggesting a similar contribution to recall responses. While transcriptomically diverse, ASC and MemB subsets maintained an underlying clonal redundancy. Therefore, self-reactive clones could escape subset-targeting therapy by perpetuation of self-reactivity in distinct subsets.
A gut commensal protist protects against virus-mediated loss of oral tolerance
Authors: Siller Magdalena , Zeng Yanlin , Sanchez Luzmariel Medina , Brigleb Pamela H. , Sangani Kishan A. , Rana Mohit , Van Der Kraak Lauren , Pandey Surya P. , Bender Mackenzie J. , Fitzgerald Britney , Hedden Lee , Fiske Kay , Taylor Gwen M. , Rahman Syed A , Galipeau Heather J. , Mullet Steven J. , Wendell Stacy G. , Watkins Simon C. , Bercik Premysl , Das Jishnu , Meisel Marlies , Jabri Bana , Dermody Terence S. , Verdú Elena F. , Hinterleitner Reinhard
Published: June 2022

Loss of oral tolerance (LOT) to gluten, characterized by a T helper 1 (Th1) gluten-specific immune response, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. We hypothesized that certain gut microbes have the capacity to protect against virus-mediated LOT. By using our previously defined reovirus-mediated LOT CeD model, we discovered that the gut colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus-mediated LOT by suppressing the reovirus-induced proinflammatory program of dietary-antigen-presenting CD103+ dendritic cells. Importantly, T. arnold did not affect antiviral host immunity, suggesting that T. arnold-mediated protection against T1L-induced LOT is not attributable to differences in antiviral host responses. Additionally, using gnotobiotic mice, we found that Tritrichomonas arnold colonization is sufficient to protect against reovirus-mediated LOT in the absence of the microbiota. Mechanistically, we show that Tritrichomonas arnold colonization restrains reovirus-induced inflammatory responses in dendritic cells and thus limit their ability to promote Th1 immune responses ex vivo. Finally, our studies using human stool samples support a role for Tritrichomonas sp. colonization in protecting against development of CeD. This study will motivate the design of effective therapies to prevent LOT to gluten in at-risk individuals and to reinstate tolerance to gluten in CeD patients.

One Sentence Summary

Tritrichomonas arnold protects against virus-mediated loss of oral tolerance to gluten and is underrepresented in celiac disease patients.
Factors associated with the uptake of Intermittent Preventive Treatment (IPTp-SP) for malaria in pregnancy: further analysis of the 2018 Nigeria Demographic and Health Survey
Authors: Kalu Godwin Okeke , Francis Joel M , Ibisomi Latifat , Chirwa Tobias , Kagura Juliana
Published: June 2022

Pregnancy-associated malaria is preventable and curable with intermittent preventive treatment with Sulfodoxine-Pyrimethamine (IPTp-SP). However, despite the effectiveness of IPTp-SP against malaria in pregnancy, the uptake among pregnant women in Nigeria remains very low. Thus, this study aimed to establish the factors associated with the uptake of at least one dose and optimal doses of IPTp-SP among pregnant women aged 15 to 49 years living in Nigeria in 2018. The study included 12,742 women aged 15 to 49 years with live births two years before or during the 2018 Nigeria Demographic Health Survey (NDHS) in the analysis. Descriptive analysis was carried out to determine the prevalence of IPTp-SP uptake. Multivariable logistic regression was used to establish the factors associated with receiving IPTp-SP during pregnancy, adjusting for possible confounding factors. Given the complex survey design, all analyses adjusted for sampling weight, stratification and clustering. The p-value of <0.05 was considered significant. In 2018, the prevalence of at least one dose of IPTp-SP was 63.6% (95% CI:62.0–65.1), and optimal doses of IPTp-SP were 16.8% (95% CI:15.8–17.8) during pregnancy. After the multivariable analysis, age group, region, frequency of ANC visits, belief in IPTp-SP effectiveness, and morbidity caused by malaria predicted the uptake of at least one IPTp-SP dose. Similar maternal characteristics, including household wealth index, spouse’s educational level and media exposure, were significantly associated with taking optimal IPTp-SP doses. For instance, women in the wealthiest households whose husbands had secondary education predicted a four-fold increase in uptake of at least one IPTp-SP dose (aOR:4.17; 95% CI:1.11–8.85).

The low prevalence and regional variations of IPTp-SP uptake in the study area imply that most pregnant women in Nigeria are at substantial risk of pregnancy-associated malaria. Therefore, stakeholders should explore context-specific strategies to improve the IPTp-SP coverage across the regions in Nigeria.