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Pain is a common problem among children, particularly those with pediatric chronic diseases. Multifaceted assessment of pain can improve communication about pain and help clinicians characterize, differentiate, and treat a patient's unique experience of pain. Pain quality is an important domain of pain, describing the subjective sensory experiences associated with pain as well as the affective experiences of pain. The aim of the current study was to quantitatively evaluate the measurement properties of the 59 Patient-Reported Outcomes Measurement Information System pediatric pain quality candidate items developed as part of the National Institutes of Health's Patient-Reported Outcomes Measurement Information System initiative with input from children and adolescents with chronic pain. Participants included N = 448 pediatric patients between 8 and 18 years of age with chronic health conditions with a prominent component of chronic or recurrent pain, including juvenile fibromyalgia, juvenile idiopathic arthritis, and sickle cell disease. A confirmatory factor analysis revealed a unidimensional model fit the data best, with 56 of the 59 items demonstrating good psychometric properties for inclusion in the final measure. In addition, a consensus-building method was used to establish 2 versions of a short form measure-one with 8 items focused primarily on the sensory pain qualities and one with 8 items focused on affective pain qualities. The final measure shows good reliability and validity, and is recommended for use in research and clinical care with pediatric populations.

Purpose. To study and analyze in a comparative order the influence of factors of the controlled pulse process of electrode wire supply on some basic mechanical characteristics of seams and welded rollers in the processes of welding and surfacing of nickel-containing steels. Methods of research. The study the mechanical characteristics of seams and welded rollers was carried out using modern laboratory equipment and appropriate techniques. This made it possible to determine how the pulse feed parameters affect the strength characteristics of the weld and near the weld zone over the entire cross-sectional area of the weld or weld layer. Detailed characteristics of feed pulses were determined using a welding process analyzer to obtain oscillograms of power parameters of arc combustion with their analysis, including determining the stability of the arc process for different types of pulses. Important for the improvement of welding results is the controlled nature of the electrode metal transfer synchronous with the pulsed movement of the electrode. It is noted that the energy consumption of the arc process during the pulse supply of the electrode wire with an indication of its reduction compared to traditional welding. Experimental work was performed using a special electrode wire, which is usually used for welding and surfacing of nickel-containing steels. These processes were carried out in a protective environment of CO2 in automatic mode. Results. Due to the fact that the strength characteristics of the weld are among the most important, attention is paid to their definition and analysis. The strength characteristics depend on many parameters, in particular the thermal characteristics of the process, the structure of the weld metal, the presence of non-metallic inclusions and so on. All these factors were studied with the help of appropriate instruments, and on the basis of numerous comparative photos of microstructures on sections of the cross section. The analysis of the sections revealed the types of microstructures obtained, the presence of inclusions and more. It is determined, in particular, that the structure of weld metal in pulsed electrode wire welding differs significantly from the structure of traditional welding in reducing inclusions, finer grains, etc., which improves the mechanical properties of the weld and seam area. Scientific novelty. Based on a series of experimental studies, the use of pulse algorithms for the movement of the electrode wire with certain parameters in automatic mode for welding and surfacing of nickel-containing steels to improve the mechanical properties of seams and welded rollers. Practical value. It is determined that the method of pulse welding of electrode wire to the controlled variant, including nickel-containing steels is effective and can be widely used in industry using specially designed equipment that provides a suitable process with stronger characteristics.

Nearshore sandbars are common features along sandy coasts. However, identifying sandbars within a beach profile traditionally requires a large historical dataset or subjective input from an observer. Several existing methodologies rely on reference profiles, which is problematic for new study sites with limited data sets and for nourished beaches that have drastic fluctuations in the cross-shore. This novel technique is suitable for beaches where a reference profile does not exist, as it identifies morphological sandbar features by a quantitative automated process. The technique identifies sandbars with a minimum steepness of 2% grade and a minimum height of 0.2 m. The morphological boundaries of sandbars were previously not well-defined, especially the seaward limit of the sandbar, contributing to difficulty in comparing surveys and sandbar morphologies. This technique standardizes the definitions of the bar limits mathematically via standard MATLAB functions, thus removing subjectivity and allowing results to be replicated. Bar identification is focused on the beach profile below the mean high water line, not cross on-shore positions, making the technique appropriate for nourished shorelines as well as those with large seasonal fluctuations. The automated technique was tested on 840 profiles collected near a recently completed beach nourishment project in Long Branch, NJ, USA. Results indicate success in identifying prominent sandbars within the test data set.

Vibrio cholerae is the causative agent of cholera, a significant diarrheal disease affecting millions of people worldwide. Increasing evidence suggests that the environmental facets of the V. cholerae life cycle involve symbiotic associations with aquatic arthropods, which may facilitate its environmental persistence and dissemination.

Adolescence is a sensitive period for both brain development and the emergence of chronic pain particularly in females. However, the brain mechanisms supporting pain perception during adolescence remain unclear. This study compares perceptual and brain responses to pain in female adolescents and adults to characterize pain processing in the developing brain. Thirty adolescent (ages 13-17 years) and 30 adult (ages 35-55 years) females underwent a functional magnetic resonance imaging scan involving acute pain. Participants received 12 ten-second noxious pressure stimuli that were applied to the left thumbnail at 2.5 and 4 kg/cm 2 , and rated pain intensity and unpleasantness on a visual analogue scale. We found a significant group-by-stimulus intensity interaction on pain ratings. Compared with adults, adolescents reported greater pain intensity and unpleasantness in response to 2.5 kg/cm 2 but not 4 kg/cm 2 . Adolescents showed greater medial-lateral prefrontal cortex and supramarginal gyrus activation in response to 2.5 kg/cm 2 and greater medial prefrontal cortex and rostral anterior cingulate responses to 4 kg/cm 2 . Adolescents showed greater pain-evoked responses in the neurologic pain signature and greater activation in the default mode and ventral attention networks. Also, the amygdala and associated regions played a stronger role in predicting pain intensity in adolescents, and activity in default mode and ventral attention regions more strongly mediated the relationship between stimulus intensity and pain ratings. This study provides first evidence of greater low-pain sensitivity and pain-evoked brain responses in female adolescents (vs adult women) in regions important for nociceptive, affective, and cognitive processing, which may be associated with differences in peripheral nociception.

Актуальність. Переломи ліктьового відростка найчастіше зустрічаються у людей молодого, працездатного віку. Згідно з літературними даними та власними дослідженнями, рівень ускладнень і незадовільних результатів залишається високим і становить 18,5–45,6 %. Мета. Дослідження результатів лікування переломів ліктьового відростка за методикою блокованого металоостеосинтезу порівняно з традиційним металоостеосинтезом за Weber. Матеріали та методи. В дослідженні було проаналізовано клінічні результати лікування переломів ліктьового відростка після металоостеосинтезу інтрамедулярним блокуючим гвинтом (n = 34) порівняно з результатами лікування за методикою Weber (n = 35). Стан пацієнта та динаміку відновлення функції кінцівки визначали за шкалами Mayo та DASH у період 5 днів — 6 місяців після операції. Результати. При оцінці за шкалою Mayo статистично вірогідно результати лікування блокуючим гвинтом кращі, відмінний результат досягнуто в 33 (97 %) випадків, та в 1 хворого отримано добрий результат. У контрольній групі відмінний результат досягнуто у 16 (45 %), добрий результат — також у 16 (45 %) хворих, у 2 (7 %) — задовільний та в 1 (3 %) пацієнта — незадовільний результат. За шкалою DASH в основній групі відзначено втрату працездатності від 3,53 до 0,8 бала. В контрольній групі ці показники становлять від 12,3 до 6,9 бала. Різниця статистично вірогідна в усі періоди спостереження. Наведено клінічні випадки. Висновки. Аналіз результатів лікування переломів ліктьового відростка за методикою блокуючого гвинта порівняно з методикою напруженого металоостеосинтезу спицями Кіршнера та дротяним серкляжем вказує на статистично вірогідно кращі результати лікування блокуючим гвинтом.

Мета дослідження. Метою дослідження є вивчення напружено-деформованого стану в ділянці перелому ліктьового відростка при металоостеосинтезі блокованим гвинтом порівняно з методикою Weber. Матеріали і методи. Проведено математичне моделювання напружено-деформованого стану на скінченно-елементних моделях при металоостеосинтезі за Weber та металоостеосинтезі блокованим гвинтом. Моделювання виконували за допомогою системи автоматизованого проектування SolidWorks. Розрахунки напружено-деформованого стану моделей виконували за допомогою програмного комплексу CosmosM. Моделі досліджували під впливом трьох видів навантаження: вигин, розтягнення, кручення. Результати. При дослідженні напружено-деформованого стану моделі металоостеосинтезу спицями та дротяним серкляжем ліктьової кістки з переломом ліктьового відростка встановлено, що основне навантаження бере на себе саме металоконструкція. Щодо кісткової тканини, то найбільш навантаженим виявляється ліктьовий відросток. Величини напружень, що виникають у кістковій тканині в зоні перелому та в діафізі ліктьової кістки, практично не відрізняються. Використання блокованого гвинта для металоостеосинтезу ліктьової кістки змінює загальну картину розподілу напружень у системі «кістка — імплантат». Так, напруження в металевій конструкції в зоні перелому розподіляються більш рівномірно з невеликим перевищенням із боку проксимального відділу ліктьової кістки. Максимальні величини напружень у кістковій тканині виявляються на ліктьовому відростку. У діафізі та в проксимальному відділі ліктьової кістки рівень зусиль значно нижчий. Висновки. Отримані результати вказують, що в моделях із металоостеосинтезом блокованим гвинтом рівень максимальних напружень, що виникають у ліктьовому відростку та на імплантаті, у зоні перелому виявляється нижчим, ніж при використанні методики Weber.

Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1–infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase–p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1 + cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4 + T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.

Introduction Nonionizing radiation (NIR) is considered “possibly carcinogenic to humans,” and therefore, exposure of young military personnel raises concerns regarding increased risk for cancer. The aim of our study was to compare the cancer incidence in exposed and nonexposed populations in order to gain better understanding of their risk. Materials and Methods A longitudinal retrospective cohort study, between 2009 and 2018, was conducted. Israel Defense Forces (IDF) aerial defense units service members, with NIR exposure (range of 2-300 GHz, below the International Commission of Non-Ionizing Radiation Protection guidelines), were compared with a similar sociodemographic group of service members without NIR exposure. Both groups were followed for cancer incidence (all-cause and specific malignancies). Kaplan–Meier analysis of cancer-free survival and univariate and multivariable logistic regressions for possible confounders and risk factors were performed. This analysis was repeated on a matched 1:1 control group. Results Exposure and comparison groups included 3,825 and 11,049 individuals, respectively. Forty-one cases diagnosed with cancer were identified during the follow-up time (mean 4.8 [±2.7] years), 13 (0.34%) of which were reported in the exposure group, and 28 (0.25%) were reported in the comparison group. The odds ratio (OR) for cancer incidence in the exposure vs. control groups was 1.34 (95%CI, 0.70-2.60), P-value = 0.3807. The results remained unchanged after adjustment for sex, age at enrollment, service length, socioeconomic status, and military occupation (adjOR = 1.38 [95%CI, 0.67-2.82], P = 0.3818). Conclusions Our study did not find an increased short-term risk for cancer in young adults exposed to NIR radiation as compared with unexposed young adults.

Background: Joint hypermobility (JH) is a common clinical finding amongst hereditary connective tissue disorders that is observed in pediatric rheumatological settings, and often associated with chronic pain. JH may also contribute to deficits in physical functioning and physical activity, but previous findings have been inconsistent. It is possible that physical activity impairment in JH may be due to chronic aberrant movement patterns subsequent to increased joint laxity. Method: As part of a larger randomized pilot trial of juvenile onset fibromyalgia (JFM), asecondary analysis was conducted to explore whether adolescents with JFM and JH differed from non-JH peers in terms of pain, daily functioning, and movement biomechanics during a moderately vigorous functional task. Results: Thirteen adolescents (36.1%) from the larger sample of adolescents with JFM (N=36) met criteria for JH. Those with JH exhibited poorer overall functioning but there were no differences in pain. Those with JH exhibited decreased hip flexion and frontal plane hip moment (e.g., resistance to dynamic valgus) during the landing phase (early stance) and greater hip and knee transverse plane moments during the propulsion phase (late stance) of the drop vertical jump task (DVJ). No other differences in lower extremity biomechanics were observed between study groups. Conclusions: There were small but notable differences in biomechanics between patients with JFM who also had JH versus those without JH during a landing and jumping task (e.g., DVJ). These differences may indicate decreased joint stiffness during landing, associated with increased joint laxity and decreased joint stability, which may put them at greater risk for injury. Further study is warranted to examine whether these biomechanical differences in patients with JFM and JH affect their response to typical physical therapy or exercise recommendations.

New graduate nurses often lack professional confidence to voice safety concerns. An evidence review was conducted to determine how participating in a mentorship program impacts the development of assertive communication during the first year of practice. Evidence indicates that providing a supportive environment, with physical and emotional access to mentors, should be used to increase new graduate nurses' self-perceived ability and willingness to voice safety concerns.

The rotating components of a gas turbine engine are typically designed around a perfectly straight centerline. In spite of advanced manufacturing technology and the conviction of the human eye, straightness is virtually impossible to achieve during manufacturing and assembly. High-tech metrology can quantify ever so slight centerline deviations along the unconstrained rotor assembly which are called bends. Related phenomena are rotor bow and thermal bow, the latter of which is normally due to asymmetric cooling after engine shutdown. Yet, bent and bowed rotors differ from one another in that bends are permanent deviations from the centerline of the unconstrained rotor, whereas rotor bow is temporary, typically elastic, and observed in the mounted, and therefore constrained, rotor assembly. Greater complexity is introduced with the realization that a bent rotor can additionally be subject to rotor bow. The presence of bends leads to force and moment distributions along the rotating structure that can have significant dynamic implications for even very small bends. In opposition to unbalance loads, which increase with rotor speed, the rotating excitation of a bent rotor remains constant. The equations of motion (EOM) of a bent rotor are very well defined in the literature by Refs [1, 2]. However, the analysis is usually confined to simplified cases where said centerline deviations at the bearing supports are zero. For realistic rotor applications, this is not the case and an additional static analysis is required to obtain the proper dynamic load distribution along the rotor. In this paper, the finite element method (FEM) is used to analyze bent rotors within an MSC NASTRAN v2021 work-flow that can address rotor models of any complexity. The proposed approach can also account for static, compliant, and greatly featured support structures that communicate with the rotor model via its common, and potentially misaligned, bearing supports. Angular and lateral offsets are explored in three different scenarios of two rotor configurations: Scenarios 1 and 2 introduce a simply bent rotor, along which synchronous force and moment distributions are computed (due to its intrinsic deviations) to subsequently excite the bent rotor dynamically. While Scenario 1 requires an initial static analysis with enforced displacements to accomplish this task, the equivalent dynamic excitation of Scenario 2 can be computed directly due to perfect bearing alignment. In Scenario 3, the complexity of the rotor bend is increased to four angular kinks and four lateral offsets to suggest the deployment of this method in combination with hightech metrology equipment that can produce a large number of such measurements via automated probing or scanning technologies. In a final step, the bent rotor is augmented with unbalances and compared to its nominal counterpart to deliver the motivation for this method and its value to the turbomachinery community. All results of Scenarios 1, 2, and 3 are verified against an experimentally validated transfer matrix method (TMM).

Juvenile fibromyalgia is a common referral in pediatric rheumatology settings. Providing a clear diagnosis and explanation of altered pain processing offers reassurance that pain has a biologic basis and the symptoms are part of a recognized pain syndrome. Physicians should acknowledge the impact of chronic pain and associated symptoms on patient's lives and take time to understand contributing factors including stress, mood, inactivity, and lifestyle factors. The optimal treatment for juvenile fibromyalgia is multidisciplinary, focusing on education about juvenile fibromyalgia, along with physical therapy, cognitive behavioral therapy, sleep hygiene, healthy lifestyle habits, and medications for symptom management as appropriate.

Detection of hazardous gases may be lethal in minute doses, requiring a sensitive detection system. A timely warning, preferably before the gas exceeds a critical threshold, depends on the capability to map the gas concentration inside a complex structure. This requires constant spatial monitoring of gas concentrations at several locations. This letter presents a generic pooling approach for spatial gas concentration mapping using a single detector. It is based on gas sampling from several locations simultaneously at predetermined mixing ratios. The gas concentration at each sampling point is computed using a repetitious scheme based on the sensor readings and the known mixing ratios.

Juvenile Fibromyalgia (JFM) is a complex chronic pain condition that remains poorly understood. The study aimed to expand the clinical characterization of JFM in a large representative sample of adolescents with JFM and identify psychological factors that predict pain interference.Participants were 203 adolescents (12-17 years) who completed baseline assessments for the multi-site Fibromyalgia Integrative Training for Teens (FIT Teens) randomized control trial. Participants completed the Pain and Symptom Assessment Tool (PSAT), which includes a Widespread Pain Index (WPI, 0-18 pain locations) and Symptom Severity checklist of associated somatic symptoms (SS; 0-12) based on the 2010 ACR criteria for Fibromyalgia. Participants also completed self-report measures of pain intensity, functional impairment, and psychological functioning.Participants endorsed a median of 11 painful body sites (WPI) and had a median SS score of 9. Fatigue and nonrestorative sleep were prominent features and rated as moderate to severe by 85% of participants. Additionally, neurologic, autonomic, gastroenterological, and psychological symptoms were frequently endorsed. WPI was significantly correlated with pain intensity and catastrophizing, while SS scores were associated with pain intensity and all domains of physical and psychological functioning. Depressive symptoms, fatigue, and pain catastrophizing predicted severity of pain impairment.JFM is characterized by chronic widespread pain with fatigue, nonrestorative sleep, and other somatic symptoms. However, how diffusely pain is distributed appears less important to clinical outcomes and impairment than other somatic and psychological factors highlighting the need for a broader approach to the assessment and treatment of JFM.

Zoledronic acid (Zol) is a potent bisphosphonate that inhibits the differentiation of monocytes into osteoclasts. It is often used in combination with dexamethasone (Dex), a glucocorticoid that promotes the resolution of inflammation, to treat malignant diseases, such as multiple myeloma. This treatment can result in bone pathologies, namely medication related osteonecrosis of the jaw, with a poor understanding of the molecular mechanism on monocyte differentiation. IFN-β is a pro-resolving cytokine well-known as an osteoclast differentiation inhibitor. Here, we explored whether Zol and/or Dex regulate macrophage osteoclastic differentiation via IFN-β. RAW 264.7 and peritoneal macrophages were treated with Zol and/or Dex for 4–24 h, and IFN-β secretion was examined by ELISA, while the IFN stimulated gene (ISG) 15 expression was evaluated by Western blotting. RANKL-induced osteoclastogenesis of RAW 264.7 cells was determined by TRAP staining following treatment with Zol+Dex or IFN-β and anti-IFN-β antibodies. We found only the combination of Zol and Dex increased IFN-β secretion by RAW 264.7 macrophages at 4 h and, correspondingly, ISG15 expression in these cells at 24 h. Moreover, Zol+Dex blocked osteoclast differentiation to a similar extent as recombinant IFN-β. Neutralizing anti-IFN-β antibodies reversed the effect of Zol+Dex on ISG15 expression and partially recovered osteoclastic differentiation induced by each drug alone or in combination. Finally, we found Zol+Dex also induced IFN-β expression in peritoneal resolution phase macrophages, suggesting these drugs might be used to enhance the resolution of acute inflammation. Altogether, our findings suggest Zol+Dex block the differentiation of osteoclasts through the expression of IFN-β. Revealing the molecular pathway behind this regulation may lead to the development of IFN-β-based therapy to inhibit osteoclastogenesis in multiple myeloma patients.

Objectives A university-based randomized clinical study evaluated the 5-year performance of chairside-fabricated zirconia-reinforced lithium silicate (ZLS)-ceramic partial crowns. Material and methods Forty-five patients were restored with 61 chairside-fabricated ZLS-restorations (Cerec SW 4.2, Dentsply Sirona, Germany; Vita Suprinity, Vita Zahnfabrik, Germany). Deviating from the manufacturers’ recommendations, restorations with reduced minimum material thicknesses (MMT) were fabricated: group 1, MMT = 0.5–0.74 mm (n = 31); group 2, MMT = 0.75–1.0 mm (n = 30). For luting, a self-adhesive cement (SAC) or a total-etch technique with a composite cement (TEC) was applied. Statistical evaluation was performed by time-to-event analysis (Kaplan–Meier). Possible covariates of the survival (SVR) and success rates (SCR), evaluated in a Cox regression model, were MMT, restoration position (premolar/molar), and cementation technique (SAC vs. TEC). Results Forty patients (54 restorations, premolars, n = 23; molars, n = 31) participated in the 5-year follow-up. Five losses due to ceramic fractures occurred in group 1 (n = 28) (SVR: 83.0% [95% confidence interval (CI): 0.71–0.96]). Group 2 (n = 26) showed no losses (SVR: 100%). The success rate for partial crowns placed on premolars was 100% and 69% (95% CI: 0.54–0.84) for molar restorations. Recementation was required in 4 restorations with SAC (SCR: 86% [95% CI: 0.73–0.99]; SCR-DC: 100%). Restorations in group 2 showed a significantly reduced risk of material fracture hazard ratio (HR) = 0.09, p = 0.0292) compared with the restorations in group 1. Molar partial crowns showed an increased risk for a clinical intervention (HR = 5.26, p = 0.0222) compared to premolar restorations. Conclusions Material thickness and position of the restoration are risk factors influencing the survival and success rate of ZLS-ceramic partial crowns. Clinical relevance Observation of an MMT of at least 0.75–1.0 mm for ZLS-ceramics is essential to avoid material-related fractures. Clinical trial registration: German Clinical Trails Register (trial number: DRKS00005611)

National Science Foundation funded project 1612485 from the University of Florida http://uftidess.wordpress.com https://nsf.gov/awardsearch/showAward?AWD_ID=1612485&HistoricalAwards=false

SummaryProductively and latently HIV-infected cells are the source of virus that respectively establishes and sustains systemic infections and the reservoir in which HIV persists and rebounds when anti-retroviral therapy (ART) is interrupted. While infected activated CD4+T cells are thought to be the principal source of HIV production, and reversion of activated infected cells to a resting state as the major pathway to establishment of the latently infected cell reservoir, we now show that in the earliest stages of detectable HIV infection in the lymphoid tissue reservoir, infection of resting CD4+T cells establishes the first populations of both productively and latently infected cells. We further show that the early infection of resting T cells reflects their predominance in lymphoid tissues and the expression of pTEFb in vivo in resting T cells to support their infection. The immediate establishment of productively and latently infected cell populations enable HIV to propagate and persist, and generates reservoirs from which infection can rebound despite instituting ART at the earliest stage of detectable infection.

Identification of particulate matter and liquid spills contaminations is essential for many applications, such as forensics, agriculture, security, and environmental protection. For example, toxic industrial compounds deposition in the form of aerosols, or other residual contaminations, pose a secondary, long-lasting health concern due to resuspension and secondary evaporation. This chapter explores several approaches for employing diffuse reflectance spectroscopy in the mid-IR and SWIR to identify particles and films of materials in field conditions. Since the behavior of thin films and particles is more complex compared to absorption spectroscopy of pure compounds, due to the interactions with background materials, the use of physical models combined with statistically-based algorithms for material classification, provides a reliable and practical solution and will be presented.

ObjectiveJuvenile fibromyalgia (JFM) is a chronic widespread pain condition that primarily affects adolescent girls. Previous studies have found increased sensitivity to noxious pressure in adolescents with JFM. However, the underlying changes in brain systems remain unclear. The aim of this study was to characterize pain-evoked brain responses and identify brain mediators of pain hypersensitivity in adolescent girls with JFM.MethodsThirty-three adolescent girls with JFM and thirty-three healthy adolescent girls underwent functional MRI scans involving noxious pressure applied to the left thumbnail at an intensity of 2.5 or 4 kg/cm2 and rated pain intensity and unpleasantness on a computerized visual analogue scale. We conducted standard general linear model analyses and exploratory whole-brain mediation analyses, and computed pain-evoked brain responses within seven major cortical networks.ResultsThe JFM group reported significantly greater pain intensity and unpleasantness than the control group in response to noxious pressure stimuli at both intensities (p2 (Z>3.1, cluster-corrected p2, and greater primary sensorimotor cortex activation in response to 4kg/cm2 mediated the between-group differences in pain intensity ratings (pConclusionWe found heightened sensitivity to noxious pressure stimuli and augmented pain-evoked sensorimotor cortex responses in adolescent girls with JFM, which could reflect central sensitization or amplified nociceptive input.

Background: Joint hypermobility (JH) is a common clinical finding amongst hereditary connective tissue disorders that is observed in pediatric rheumatological settings, and often associated with chronic pain. JH may also contribute to deficits in physical functioning and physical activity, but previous findings have been inconsistent. It is possible that physical activity impairment in JH may be due to chronic aberrant movement patterns subsequent to increased joint laxity. Within a larger study of juvenile onset fibromyalgia (JFM), a secondary analysis was conducted to explore whether adolescents with JFM and JH differed from non-JH peers in terms of pain, daily functioning, and movement biomechanics during a moderately vigorous functional task. Findings: Thirteen adolescents (36.1%) from the larger sample of adolescents with JFM (N=36) met criteria for JH. Those with JH exhibited poorer overall functioning but there were no differences in pain. Those with JH exhibited decreased hip flexion and frontal plane hip moment (e.g., resistance to dynamic valgus) during the landing phase (early stance) and greater hip and knee transverse plane moments during the propulsion phase (late stance) of the drop vertical jump task (DVJ). No other differences in lower extremity biomechanics were observed between study groups. Conclusions: There were small but notable differences in biomechanics between patients with JFM who also had JH versus those without JH during a landing and jumping task (e.g., DVJ). These differences may indicate decreased joint stiffness during landing, associated with increased joint laxity and decreased joint stability, which may put them at greater risk for injury. Further study is warranted to examine whether these biomechanical differences in patients with JFM and JH affect their response to typical physical therapy or exercise recommendations.

During the design phase of a rotor system, the identification of whirl type carries much significance. Forward whirl (FW) critical speeds reveal themselves by harmonic peaks during spin-up. Backward whirl (BW) modes are dynamically quiet, but produce cyclic stresses and therefore contribute to material fatigue. The realization, that FW and BW can occur simultaneously in so-called mixed whirl (MW) modes, demands greater investigative scrutiny from the design team. While pure FW or BW modes can be identified by one pair of proximity probes at any single rotor location, many measurements along the rotor axis are needed to either rule out or confirm MW. Since there are practical and economic limits to the number of measurement locations and experiments, the purpose of this paper is to deliver guiding analytic insight. The proposed approach is to overcome experimental limitations by using a finite element (FE) model of the rotor system, compute its nodal whirl distributions from each of its complex-valued eigenvectors, and map the resulting whirl quantities back onto all FE grids. This delivers insightful surface and volume diagnostics to augment experimental rotor validation. Exercising this technique on simplified example models reveals unexpected insight in that FW and BW modes influence one another and become mixed across a greater rotor speed range than anticipated. Therefore, MW turns from an elusive phenomenon into a common occurrence throughout the Campbell diagram, to a point where it becomes increasingly challenging to discern pure FW and BW mode shapes — particularly, at higher modal frequencies. The most surprising and truly unexpected conclusion of this work is that all of the FW/BW pairs considered here do not intersect but veer upon closer investigation. And, as FW transforms into BW and vice versa during the veering transition in the Campbell diagram, their stability maps and root loci accentuate this shift by indicating that stability is traded between them. A mode’s ability to transition from one whirl type to another is significant from the practical design and simulation perspectives, in that engineering responsibility is shared between accurate predictions and appropriate design. As shown in this work, both numerical and eigenvector-based tracking algorithms favor intersection over veering at low rotor speed resolution and can produce believable but incorrect answers.

Background: One cause for the failure of checkpoint inhibitors is the immunosuppressive nature of the tumor microenvironment. LILRB1 (ILT2) and LILRB2 (ILT4) are ITIM-containing inhibitory receptors that recognize HLA Class 1 and nonclassical ligands (e.g., HLA-A, HLA-G, etc.). LILRB1 is expressed on myeloid cells and subsets of B, NK, and T cells, while LILRB2 expression is mostly restricted to myeloid cells. Interaction of LILRB1 and LILRB2 receptors with HLA ligands promotes an inhibitory milieu that prevents T cells from attacking cancer cells. The distinct pattern of expression and function of these lymphoid and myeloid checkpoints suggests complementary targeting approaches for cancer immunotherapy. Dual blockade of LILRB1 and LILRB2 receptors by a single antibody that restores both innate and adaptive immune responses is a promising strategy to enhance efficacy of checkpoint inhibitors. Methods: Dual LILRB1 and LILRB2 targeting antibodies were cloned from B cells derived from rabbits immunized with human LILRB2 recombinant protein, and subsequently humanized. Antibodies were evaluated for binding to human LILRB1 and LILRB2 proteins. Dual targeting antibodies were evaluated in a panel of functional and phenotypic assays. Selected antibodies were further tested for efficacy in a humanized NSG-SGM3 tumor model. Results: Dual antibodies were selected based on binding to recombinant human LILRB1 and LILRB2 protein, as well as blocking of HLA-G binding. These antibodies demonstrated binding to cells expressing LILRB1 and LILRB2, with no appreciable binding to other family members. Lead antibodies demonstrated activity in functional cell-based assays modeling LILRB1- or LILRB2-mediated immunosuppression. Dual antibodies also enhanced IFN-γ production by LPS-stimulated human PBMC. Selected clones restored T-cell function from M2c macrophage-mediated suppression in coculture with CD8+ T cell, and enhanced the tumoricidal activity of NK cells. Importantly, the lead antibody demonstrated in vivo efficacy with significant tumor growth inhibition and tumor regression in an SK-MEL-5 tumor model in humanized NSG-SGM3 mice. Conclusions: We have identified dual antagonist antibodies targeting both LILRB1 and LILRB2 antibodies that restore both innate and adaptive immune responses. Additionally, dual antibodies restored CD8+ T cell activation from macrophage-mediated suppression and enhanced NK cell cytotoxic activity. These data provide a strong rationale for further development of dual antibodies as an anti-cancer immunotherapy. Citation Format: Meghan Zuck, Myriam Bouchlaka, Huyen Dinh, Kevin Green, Francisco Zapata, Ramya Chandrasekaran, Tatyana Pisarenko, Lauren Loh, Gajendra S. Naika, Meilyn Sylvestre, Jacob Heit, Raymond Fox, Darbie Whitman, Tom Graddis, Kamal D. Puri, Peter Probst. Discovery and preclinical characterization of dual antagonist antibodies targeting both LILRB1 and LILRB2 that enhance innate and adaptive anti-cancer immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6376.

The goal of the current study was to enhance the measurement of the pediatric chronic pain experience through a methodologically rigorous approach. This paper outlines the development and initial validation of a pain intensity measure for pediatric patients with chronic pain using Patient-Reported Outcomes Measurement Information System methodology. Measure development incorporated feedback from children with painful conditions. Based on input from pediatric participants and content experts, 4 candidate items assessing pain intensity were included for large scale testing. Children completed self-report items pertaining to their pain experience that were developed as part of a larger pool of new candidate Patient-Reported Outcomes Measurement Information System pediatric pain domain items as well as measures of pain interference, depressive symptoms, fatigue, pain behavior, pain intensity, and pain catastrophizing. The final sample for the large scale testing included N = 442 pediatric patients between the ages 8 to 18 years (Mean age = 13.54, Standard Deviation = 2.78; 71.27% female) experiencing chronic pain. Psychometric analysis resulted in a final measure that included 3 items with evidence of reliability (Cronbach alpha = .82) and convergent validity. The Likert format of the response options may be preferable to the traditional numeric rating scale for use in pediatric populations who experience chronic pain based on patients' feedback, which was directly utilized in designing the scale. Further, the inclusion of fewer and clinically meaningful response options should reduce ambiguity for young respondents. PERSPECTIVE: We have developed and evaluated a clinically sensitive and psychometrically precise 3-item pain intensity measure with Likert-type responses for self-report use among children and adolescents ages 8 to 18 years with chronic pain. Development of the item content and response options included input from children and adolescents with chronic pain. The development of pain intensity items with pediatric appropriate language, and labeled, fewer response options to yield maximal clinically meaningful information improves the precision of pain intensity measurement in children.

Objective School anxiety is a prevalent mental health concern that drives school-related disability among youth with chronic pain. The only available measure of school anxiety—the School Anxiety Inventory, Short Version (SAI-SV)—lacks content specificity for measuring school anxiety in pediatric pain populations. We aimed to refine the SAI-SV by obtaining qualitative data about unique school situations that are anxiety-provoking for youth with pain and characterizing the nature of symptoms experienced in these situations. Methods Adolescents with chronic pain (n = 16) completed a semistructured interview focused on experiences with anxiety in school-related academic and social contexts. We employed thematic analysis to extend the empirical understanding of school anxiety from the perspective of patients suffering from pain and to generate new item content. The content was refined with iterative feedback from a separate group of adolescents with chronic pain (n = 5) and a team of expert pain psychologists (n = 3). Results We identified six themes within the data and generated new items designed to capture anxiety related to negative interactions with teachers and peers, falling behind with schoolwork, and struggles with concentration and fatigue. Participants and experts rated new item content as highly relevant for use among youth with pain. The updated item bank was named the School Anxiety Inventory for Chronic Pain. Conclusions Future research is needed to complete the psychometric evaluation of the item bank and finalize items to be included in a measure that can be used in research and clinical settings. Implications for treating school-related anxiety among youth with pain are also discussed.

Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with bromodomain (BD) and extraterminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single-cell RNA-Seq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bD-selective BET, or selective BET isoform targeting in CD4+ T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA, but lesser induction of fully elongated and tat-rev RNA compared with T cell activation-positive controls. IAPi+BETi resulted in HIV protein induction in bulk cultures of CD4+ T cells using an ultrasensitive p24 assay, but did not result in enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. This study defines HIV transcriptional elongation and splicing as important barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their BDs in HIV latency, and provides a rationale for exploration of IAPi+BETi in animal models of HIV latency.

ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of mitochondria to initiate caspase activation. ARTS induces apoptosis by specifically binding XIAP and allowing de-repression of active caspases required for Mitochondrial Outer Membrane Permeabilzation (MOMP). Moreover, ARTS promotes apoptosis by inducing ubiquitin-mediated degradation of both major anti-apoptotic proteins XIAP and Bcl-2. In the resolution phase of inflammation, the infiltrating leukocytes, which execute the acute innate response, undergo apoptosis and are subsequently cleared by phagocytic macrophages (i.e. efferocytosis). In this course, macrophages undergo reprogramming from inflammatory, to anti-inflammatory, and eventually to resolving macrophages that leave the injury sites. Since engulfment of apoptotic leukocytes is a key signaling step in macrophage reprogramming and resolution of inflammation, we hypothesized that a failed apoptosis in leukocytes in vivo would result in an impaired resolution process. To test this hypothesis, we utilized the Sept4/ARTS-/- mice, which exhibit resistance to apoptosis in many cell types. During zymosan A-induced peritonitis, Sept4/ARTS-/- mice exhibited impaired resolution of inflammation, characterized by reduced neutrophil apoptosis, macrophage efferocytosis and expression of pro-resolving mediators. This was associated with increased pro-inflammatory cytokines and reduced anti-inflammatory cytokines, secreted by resolution-phase macrophages. Moreover, ARTS overexpression in leukocytes in vitro promoted an anti-inflammatory behavior. Overall, our results suggest that ARTS is a key master-regulator necessary for neutrophil apoptosis, macrophage efferocytosis and reprogramming to the pro-resolving phenotype during the resolution of inflammation.

Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.

Transcatheter mitral valve repair using the MitraClip (Abbott Vascular, Santa Clara, CA) is a reasonable option for the treatment of patients with severe symptomatic degenerative mitral regurgitation (MR) who are at prohibitive surgical risk. The occurrence of recurrent severe MR after initial successful MitraClip repair is uncommon. Data are sparse on the management of recurrent severe MR after initial successful repair using the MitraClip. We describe a successful case of redo MitraClip repair for late recurrent severe MR secondary to progressive degenerative mitral valve disease after a successful initial MitraClip procedure and review the literature. Résumé: La réparation transcathéter de la valve mitrale au moyen d’un dispositif MitraClip (Abbott Vascular, Santa Clara, CA) constitue une bonne option pour le traitement de l’insuffisance mitrale (IM) dégénérative symptomatique grave lorsque la chirurgie représente un risque prohibitif pour le patient. Il est rare qu’une IM grave récurrente survienne après l’implantation réussie d’un dispositif MitraClip. On dispose de très peu de données sur la prise en charge de l’IM grave récurrente après une première réparation au moyen d’un dispositif MitraClip. Nous présentons le cas d’une seconde réparation au moyen d’un dispositif MitraClip pour remédier à une IM grave récurrente tardive secondaire à une atteinte dégénérative évolutive de la valve mitrale survenue après une première intervention efficace au moyen d’un dispositif MitraClip, et nous passons en revue les publications portant sur cette question.

Transcatheter mitral valve repair using the MitraClip (Abbott Vascular, Santa Clara, CA) is a reasonable option for the treatment of patients with severe symptomatic degenerative mitral regurgitation (MR) who are at prohibitive surgical risk. The occurrence of recurrent severe MR after initial successful MitraClip repair is uncommon. Data are sparse on the management of recurrent severe MR after initial successful repair using the MitraClip. We describe a successful case of redo MitraClip repair for late recurrent severe MR secondary to progressive degenerative mitral valve disease after a successful initial MitraClip procedure and review the literature.

Background and Purpose— Clinical deficits from ischemic stroke are more severe in women, but the pathophysiological basis of this sex difference is unknown. Sex differences in core and penumbral volumes and their relation to outcome were assessed in this substudy of the DEFUSE 3 clinical trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke). Methods— DEFUSE 3 randomized patients to thrombectomy or medical management who presented 6 to 16 hours from last known well with proximal middle cerebral artery or internal carotid artery occlusion and had target core and perfusion mismatch volumes on computed tomography or magnetic resonance imaging. Using univariate and adjusted regression models, the effect of sex was assessed on prerandomization measures of core, perfusion, and mismatch volumes and hypoperfusion intensity ratio, and on core volume growth using 24-hour scans. Results— All patients were included in the analysis (n=182) with 90 men and 92 women. There was no sex difference in the site of baseline arterial occlusion. Adjusted by age, baseline National Institutes of Health Stroke Scale, baseline modified Rankin Scale score, time to randomization, and imaging modality, women had smaller core, hypoperfusion, and penumbral volumes than men. Median (interquartile range) volumes for core were 8.0 mL (1.9–18.4) in women versus 12.6 mL (2.7–29.6) in men, for T max >6 seconds 89.0 mL (63.8–131.7) versus 133.9 mL (87.0–175.4), and for mismatch 82.1mL (53.8–112.8) versus 108.2 (64.1–149.2). The hypoperfusion intensity ratio was lower in women, 0.31 (0.15–0.46) versus 0.39 (0.26–0.57), P =0.006, indicating better collateral circulation, which was consistent with the observed slower ischemic core growth than men within the medical group ( P =0.003). Conclusions— In the large vessel ischemic stroke cohort selected for DEFUSE 3, women had imaging evidence of better collateral circulation, smaller baseline core volumes, and slower ischemic core growth. These observations suggest sex differences in hemodynamic and temporal features of anterior circulation large artery occlusions. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02586415.

Supplemental Digital Content is available in the text, Background: A declining selenium (Se) status constitutes a characteristic of critical illness and may affect disease course and survival. The dynamics of trauma-induced changes in biomarkers of Se status are poorly characterized, and an association with multiple organ failure (MOF) and mortality can be hypothesized. It was the aim of this study to investigate Se and selenoprotein P (SELENOP) concentrations in major trauma patients during the early posttraumatic period. Patients and Methods: Twenty-four patients after major trauma (ISS ≥16) were included at our level one trauma center. Se supplementation ever during the 90-day observation period was defined as an exclusion criterion. Serum samples were drawn within less than 60 min after trauma, and after 6 h, 12 h, 24 h, 48 h, and 72 h. Serum Se was analyzed by X-ray fluorescence and SELENOP concentrations by ELISA. The data were correlated to clinical parameters, occurrence of MOF defined by MOF and APACHE II score, lung injury defined by Horowitz index and clinical outcome (90-days survival). Results: Serum Se and SELENOP concentrations of the trauma patients were significantly below the average of healthy European subjects (mean ±SD; Se, 41.2±8.1 vs. 84.7±23.3 μg/L, P

Ian Boggero,1,2 Cecelia Valrie,3,4 Krystal Morgan,5 Nao Hagiwara,3 Susmita Kashikar-Zuck,2,6 Christopher King2,6 1Department of Oral Health Science, Division of Orofacial Pain, University of Kentucky College of Dentistry, Lexington, KY, USA; 2Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 3Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA; 4Institute for Inclusion, Inquiry, and Innovation, Virginia Commonwealth University, Richmond, VA, USA; 5Division of Transplant, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 6Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USACorrespondence: Ian Boggero, 740 S Limestone, Lexington, KY, 40536, USA, Tel +859-562-3291, Email ian.boggero@uky.eduContext: General fatigue, sleep-related fatigue, and cognitive fatigue are prevalent and disruptive in adults with chronic musculoskeletal (MSK) pain, but little is known about these fatigue subtypes in pediatric musculoskeletal pain.Objective: To compare fatigue and its subtypes between adolescents with chronic MSK pain and pain-free controls and to test if fatigue subtypes were associated with concurrent pain and its impact (pain intensity, number of pain sites, pain interference, and functional disability) or experimental pain (intensity and tolerance) in adolescents with chronic MSK pain. Finally, we sought to explore adolescents’ qualitative characterizations of their fatigue.Methods: Adolescents with chronic MSK pain (12– 17 y.o., n = 26) and pain-free controls (n = 26) completed validated self-report measures of fatigue, pain, and functional disability, underwent an experimental pain tolerance task (cold water immersion of the hand), and provided qualitative descriptions of their fatigue (pain group only).Results: Adolescents with chronic MSK pain reported significantly greater general, sleep-related, and cognitive fatigue than pain-free controls (all p’s < 0.001). In adolescents with chronic MSK pain, fatigue subtypes were associated with clinical pain and pain impact (r’s = 0.43– 0.84) but not experimental pain measures (p’s > 0.05). Adolescents with chronic MSK pain qualitatively described the negative implications of the different fatigue subtypes, particularly when perceived as long-lasting.Conclusion: This preliminary study suggests that fatigue subtypes are prevalent and impactful in pediatric patients with chronic MSK pain. When planning multi-disciplinary treatment for pediatric MSK pain, providers should recognize fatigue as another disabling symptom.Keywords: disability, fatigue, pediatric, musculoskeletal pain, widespread bodily pain

Blocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. However, the lack of well-defined features within vaccine-elicited antibody responses that correlate with protection represents a major roadblock to improving on current generation vaccines. We vaccinated mice (BALB/cJ and C57BL/6J) with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated vaccine-elicited humoral immunity and identified immunological factors associated with protection after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice. In contrast, all C57BL/6J mice were infected similar to controls. Protection was mediated by antibodies and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer CSP-specific germinal center experienced B cells and class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that the development of protective antibody responses in BALB/cJ mice in response to vaccination with PyCSP was associated with increased germinal center activity and somatic mutation compared to C57BL/6J mice, highlighting the key role B cell maturation may have in the development of vaccine-elicited protective antibodies against CSP.