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BACKGROUND There are limited qualitative data describing general pediatric hospitalizations through the caregivers’ lens, and most focus on one particular challenge or time during the hospitalization. This qualitative study aimed to address a gap in the description of the breadth and depth of personal challenges caregivers may face during the entire hospitalization, irrespective of severity of patient illness or diagnosis, and explored caregiver-suggested interventions. METHODS Caregivers of pediatric patients on the hospitalist service at a Pacific Northwest children’s hospital were interviewed to explore their hospitalization experience and solicit feedback for potential interventions. Content was coded iteratively using a framework analysis until thematic saturation was met. Findings were triangulated through 2 focus groups, 1 with parent advisors and the other with hospital physicians and nurses. RESULTS Among 14 caregivers (7 each of readmitted and newly admitted patients) and focus group participants, emergent domains on difficulties faced with their child’s hospitalization were anchored on physiologic (sleep, personal hygiene, and food), psychosocial (feelings of isolation, mental stress), and communication challenges (information flow between families and the medical teams). Caregivers recognized that addressing physiologic and psychosocial needs better enabled them to advocate for their child and suggested interventions to ameliorate hospital challenges. CONCLUSIONS Addressing physiologic and psychosocial needs may reduce barriers to caregivers optimally caring and advocating for their child. Downstream consequences of unaddressed caregiver challenges should be explored in relation to participation in hospital care and confidence in shared decision-making, both vital components for optimization of family-centered care.

To identify variability in reported hearing outcomes for intratympanic (IT) steroid treatment of idiopathic sudden sensorineural hearing loss (ISSNHL) by comparing outcomes using the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guideline with other published criteria.Retrospective chart review.Tertiary otology practice.Patients with ISSNHL treated with IT steroid between April 2003 and December 2020.IT steroid injection and audiometric evaluation.1) Rates of full, partial, or no recovery using the AAO-HNS guideline versus other reported criteria, and 2) correlation analyses of demographic and clinical variables with response to IT steroid.Using AAO-HNS reporting criteria, full recovery of the pure-tone average was noted in 25.68% of patients. Applying eight other published outcomes criteria to this patient cohort classified full recovery in 14.87 to 40.54% of patients. Similarly, AAO-HNS criteria classified "no recovery" in 51.35% of our patients, whereas applying the other reported criteria showed an average rate of 62.16% no recovery and as high as 82.43% of patients without recovery. Younger age ( p = 0.003; effect size, 0.924) and IT injection within a week of onset ( p0.001; effect size, 1.099) positively correlated with full recovery. There was no impact of prior or concurrent oral steroids, or number of steroid injections on outcome.Great variability exists in the literature for assessment of IT steroid outcomes in ISSNHL. Standard reporting of outcomes as per the AAO-HNS SSNHL guideline is recommended to consistently characterize IT steroid efficacy and allow comparison across studies.

To characterize the degree to which individual coping strategies may influence speech perception after cochlear implantation.Retrospective cohort study.Tertiary referral center.Adult, postlingually deaf cochlear implant recipients.The Coping Orientation to Problems Experience inventory, a validated, multidimensional self-reported coping scale, was administered preoperatively.Speech perception was measured using consonant-nucleus-consonant (CNC) phoneme and word scores, AzBio sentence accuracy in quiet and noise, and Hearing in Noise Test sentences in quiet preoperatively and at 1, 3, and 6 months postoperatively. Quality of life was measured with the Hearing Implant Sound Quality Index and the Nijmegen Cochlear Implant Questionnaire.Thirty-six patients were included in this study. Mean age at surgery was 70.7 ± 11.4 years. Acceptance was associated with a decreased AzBio in noise score in the 6 months after CI (regression coefficient b = -0.05; 95% confidence interval [CI], -0.07 to -0.03; p0.01). Denial was associated with a decreased AzBio in quiet score (b = -0.05; 95% CI, -0.09 to -0.01; p0.05), whereas humor was associated with an increased AzBio in quiet score (b = 0.02; 95% CI, 0.01 to 0.04; p0.05). Humor was also associated with an increased Hearing in Noise Test score (b = 0.05; 95% CI, 0.02 to 0.07; p0.05). Denial was associated with decreased CNC word (b = -0.04; 95% CI, -0.06 to -0.02; p0.01) and phoneme (b = -0.04; 95% CI, -0.07 to -0.02; p0.01) scores, whereas substance use was associated with increased CNC word (b = 0.03; 95% CI, 0.01 to 0.05, p0.01) and phoneme (b = 0.04; 95% CI, 0.02 to 0.06; p0.01) scores. Scores on self-reported quality of life measures were not significantly correlated with coping strategies.A variety of adaptive and maladaptive coping strategies are used by postlingually deaf adult cochlear implant users. Denial and acceptance may be more predictive of poor speech performance, whereas humor and substance use may be more predictive of improved speech performance.

OBJECTIVE Our aim was to understand the breadth of the hospital-to-home experience from the caregiver perspective using a mixed method approach. METHODS Caregivers of children who experienced an inpatient admission (N = 184) completed a hospital-to-home transition questionnaire after discharge. Twenty-six closed-ended survey items captured child’s hospitalization, discharge, and postdischarge experiences and were analyzed using descriptive statistics. Four additional free-response items allowed caregivers to expand on specific challenges or issues. A conventional content analysis coding framework was applied to the free responses. RESULTS Ninety-one percent of caregivers reported satisfaction with the hospital experience and 88% reported they understood how to manage their child’s health after discharge. A majority of survey respondents (74%) provided answers to 1 or more of the qualitative free-response items. In the predischarge period, qualitative responses centered on concerns related to finances or available resources and support, communication, hospital environment, and the discharge process. Responses for the postdischarge time period centered on family well-being (child health, other family member health), finances (bills, cost of missed work), and medical follow-up (supplies, appointments, instruction). CONCLUSIONS Caregivers were generally satisfied with their hospital experience; however, incorporating survey items specifically related to family stressors either through closed- or open-ended questions gave a richer context for caregiver-identified concerns. Basing future quality improvement efforts on supporting caregiver needs and identifying stressors before discharge may make for a more robust and successful transition to home.

OBJECTIVES. To compare intraoperative intracochlear electrocochleography (ECochG) with hearing preservation outcomes in cochlear implant (CI) subjects. DESIGN. Intraoperative electrocochleography was performed in adult CI subjects who were recipients of Advanced Bionics’ Bionics LLC precurved HiFocus(™) MidScala or straight HiFocus(™) SlimJ electrode arrays. ECochG responses were recorded from the most apical electrode contact during insertion. No changes to the insertions were made due to ECochG monitoring. No information about insertion resistance was collected. ECochG drops were estimated as the change in amplitude from peak (defined as maximum amplitude response) to drop (largest drop) point after the peak during insertion was measured following the peak response. .Audiometric thresholds from each subject were obtained before and approximately one month after CI surgery. The change in pure tone average (PTA) for frequencies between 125 Hz and 500 Hz was measured after surgery. No post-operative CT scans were collected as part of this study. RESULTS. A total of 68 subjects from 5 surgical centers participated in the study. The study sample included 30 MidScala and 38 SlimJ electrodes implanted by approximately 20 surgeons who contributed to the study. Although a wide range of results were observed, there was a moderate positive correlation (Pearson Correlation coefficient r = 0.56, p < 0.01) between the size of the ECochG drop and the magnitude of PTA change. This trend was present for both the MidScala and SlimJ arrays. The SlimJ and MidScala arrays produced significantly different hearing loss after surgery. CONCLUSION. Large ECochG amplitude drops observed during electrode insertion indicated poorer hearing preservation. Although the outcomes were variable, this information may be helpful to guide surgical decision-making when contemplating full electrode insertion and the likelihood of hearing preservation.

PEGylation is a promising approach to address the central challenge of applying biologics, i.e., lack of protein stability in the demanding environment of the human body. Wider application is hindered by lack of atomic level understanding of protein-PEG interactions, preventing design of conjugates with predicted properties. We deployed an integrative structural and biophysical approach to address this critical challenge with the PEGylated carbohydrate recognition domain of human galectin-3 (Gal3C), a lectin essential for cell adhesion and potential biologic. PEGylation dramatically increased Gal3C thermal stability, forming a stable intermediate and redirecting its unfolding pathway. Structural details revealed by NMR pointed to a potential role of PEG localization facilitated by charged residues. Replacing these residues subtly altered the protein-PEG interface and thermal unfolding behavior, providing insight into rationally designing conjugates while preserving PEGylation benefits.

OBJECTIVE: To identify demographic and clinical features impacting initial treatment pathway for vestibular schwannoma. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care academic medical center. PATIENTS: Patients diagnosed with vestibular schwannoma between 2009 and 2019. INTERVENTIONS: Observation, stereotactic radiosurgery, or microsurgical resection. MAIN OUTCOME MEASURES: χ(2) Test, one-way analysis of variance, and multivariate logistic regression were used to correlate demographic and clinical factors with initial treatment pathway for 197 newly diagnosed vestibular schwannoma patients. RESULTS: Among 197 patients, 93 (47%) were initially treated with observation, 60 (30%) with stereotactic radiation (Gamma Knife) and 44 (22%) with surgical resection. Age univariately had no statistically significant impact on initial pathway, but those undergoing surgery trended toward a younger demographic (49.1 yr [surgery] versus 57.2 yr [observation] versus 59.0 yr [Gamma Knife]). Men were more likely to be initially observed than women (p = 0.04). Patients initially observed were more likely to have a lower Koos classification (p < 0.001) and have better tumor-ear hearing (p = 0.03). Only 34.4% of patients living outside the local geographic region were initially observed compared with 53.0% living locally (p = 0.055). Surgeon correlated with initial treatment (p = 0.04) but did not maintain significance when adjusting for hearing level or tumor size. A multiple linear regression model found age, maximum tumor diameter, and Koos class to correlate with initial treatment pathway (p < 0.0001, r(2) = 0.42). CONCLUSION: Initial treatment pathway for newly diagnosed vestibular schwannoma is impacted by demographic factors such as age, sex, and geographic proximity to the medical center. Clinical features including hearing level and tumor size also correlated with initial treatment modality.

To evaluate the utility of intracochlear electrocochleography (ECochG) monitoring during cochlear implant (CI) surgery on postoperative hearing preservation.Prospective, randomized clinical trial.Ten high-volume, tertiary care CI centers.Adult patients with sensorineural hearing loss meeting the CI criteria who selected an Advanced Bionics CI.Patients were randomized to CI surgery either with audible ECochG monitoring available to the surgeon during electrode insertion or without ECochG monitoring. Hearing preservation was determined by comparing preoperative unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to postoperative LF-PTA at CI activation. Pre- and post-CI computed tomography was used to determine electrode scalar location and electrode translocation.Eighty-five adult CI candidates were enrolled. The mean (standard deviation [SD]) unaided preoperative LF-PTA across the sample was 54 (17) dB HL. For the whole sample, hearing preservation was "good" (i.e., LF-PTA change 0-15 dB) in 34.5%, "fair" (i.e., LF-PTA change15-29 dB) in 22.5%, and "poor" (i.e., LF-PTA change ≥30 dB) in 43%. For patients randomized to ECochG "on," mean (SD) LF-PTA change was 27 (20) dB compared with 27 (23) dB for patients randomized to ECochG "off" ( p = 0.89). Seven percent of patients, all of whom were randomized to ECochG off, showed electrode translocation from the scala tympani into the scala vestibuli.Although intracochlear ECochG during CI surgery has important prognostic utility, our data did not show significantly better hearing preservation in patients randomized to ECochG "on" compared with ECochG "off."

BACKGROUND Periacetabular osteotomy (PAO) increases acetabular coverage of the femoral head and medializes the hip's center, restoring normal joint biomechanics. Past studies have reported data regarding the degree of medialization achieved by PAO, but measurement of medialization has never been validated through a comparison of imaging modalities or measurement techniques. The ilioischial line appears to be altered by PAO and may be better visualized at the level of the inferior one-third of the femoral head, thus, an alternative method of measuring medialization that begins at the inferior one-third of the femoral head may be beneficial. QUESTIONS/PURPOSES (1) What is the true amount and variability of medialization of the hip's center that is achieved with PAO? (2) Which radiographic factors (such as lateral center-edge angle [LCEA] and acetabular inclination [AI]) correlate with the degree of medialization achieved? (3) Does measurement of medialization on plain radiographs at the center of the femoral head (traditional method) or inferior one-third of the femoral head (alternative method) better correlate with true medialization? (4) Are intraoperative fluoroscopy images different than postoperative radiographs for measuring hip medialization? METHODS We performed a retrospective study using a previously established cohort of patients who underwent low-dose CT after PAO. Inclusion criteria for this study included PAO as indicated for symptomatic acetabular dysplasia, preoperative CT scan, and follow-up between 9 months and 5 years. A total of 333 patients who underwent PAO from February 2009 to July 2018 met these criteria. Additionally, only patients who were between 16 and 50 years old at the time of surgery were included. Exclusion criteria included prior ipsilateral surgery, femoroacetabular impingement (FAI), pregnancy, neuromuscular disorder, Perthes-like deformity, inadequate preoperative CT, and inability to participate. Thirty-nine hips in 39 patients were included in the final study group; 87% (34 of 39) were in female patients and 13% (5 of 39 hips) were in male patients. The median (range) age at the time of surgery was 27 years (16 to 49). Low-dose CT images were obtained preoperatively and at the time of enrollment postoperatively; we also obtained preoperative and postoperative radiographs and intraoperative fluoroscopic images. The LCEA and AI were assessed on plain radiographs. Hip medialization was assessed on all imaging modalities by an independent, blinded assessor. On plain radiographs, the traditional and alternative methods of measuring hip medialization were used. Subgroups of good and fair radiographs, which were determined by the amount of pelvic rotation that was visible, were used for subgroup analyses. To answer our first question, medialization of all hips was assessed via measurements made on three-dimensional (3-D) CT hip reconstruction models. For our second question, Pearson correlation coefficients, one-way ANOVA, and the Student t-test were calculated to assess the correlation between radiographic parameters (such as LCEA and AI) and the amount of medialization achieved. For our third question, statistical analyses were performed that included a linear regression analysis to determine the correlation between the two radiographic methods of measuring medialization and the true medialization on CT using Pearson correlation coefficients, as well as 95% confidence intervals and standard error of the estimate. For our fourth question, Pearson correlation coefficients were calculated to determine whether using intraoperative fluoroscopy to make medialization measurements differs from measurements made on radiographs. RESULTS The true amount of medialization of the hip center achieved by PAO in our study as assessed by reference-standard CT measurements was 4 ± 3 mm; 46% (18 of 39 hips) were medialized 0 to 5 mm, 36% (14 hips) were medialized 5 to 10 mm, and 5% (2 hips) were medialized greater than 10 mm. Thirteen percent (5 hips) were lateralized (medialized < 0 mm). There were small differences in medialization between LCEA subgroups (6 ± 3 mm for an LCEA of ≤ 15°, 4 ± 4 mm for an LCEA between 15° and 20°, and 2 ± 3 mm for an LCEA of 20° to 25° [p = 0.04]). Hips with AI ≥ 15° (6 ± 3 mm) achieved greater amounts of medialization than did hips with AI of < 15° (2 ± 3 mm; p < 0.001). Measurement of medialization on plain radiographs at the center of the femoral head (traditional method) had a weaker correlation than using the inferior one-third of the femoral head (alternative method) when compared with CT scan measurements, which were used as the reference standard. The traditional method was not correlated across all radiographs or only good radiographs (r = 0.16 [95% CI -0.17 to 0.45]; p = 0.34 and r = 0.26 [95% CI -0.06 to 0.53]; p = 0.30), whereas the alternative method had strong and very strong correlations when assessed across all radiographs and only good radiographs, respectively (r = 0.71 [95% CI 0.51 to 0.84]; p < 0.001 and r = 0.80 [95% CI 0.64 to 0.89]; p < 0.001). Measurements of hip medialization made on intraoperative fluoroscopic images were not found to be different than measurements made on postoperative radiographs (r = 0.85; p < 0.001 across all hips and r = 0.90; p < 0.001 across only good radiographs). CONCLUSION Using measurements made on preoperative and postoperative CT, the current study demonstrates a mean true medialization achieved by PAO of 4 mm but with substantial variability. The traditional method of measuring medialization at the center of the femoral head may not be accurate; the alternate method of measuring medialization at the lower one-third of the femoral head is a superior way of assessing the hip center's location. We suggest transitioning to using this alternative method to obtain the best clinical and research data, with the realization that both methods using plain radiography appear to underestimate the true amount of medialization achieved with PAO. Lastly, this study provides evidence that the hip center's location and medialization can be accurately assessed intraoperatively using fluoroscopy. LEVEL OF EVIDENCE Level III, diagnostic study.

OBJECTIVE: To compare 3D hip kinematics during single leg squat (SLsquat) and step down, between patients with hip-related groin pain (HRGP) and asymptomatic participants. To assess relationships among hip kinematics, muscle strength and bony morphology. DESIGN: Controlled laboratory cross-sectional study. METHODS: 40 patients with HRGP and 40 matched, asymptomatic participants, 18–40 years. Hand-held dynamometry was used to assess hip abductor and external rotator strength. An 8-camera motion analysis system was used to quantify 3D kinematics during SLSquat and step down. MRI was used to quantify bony morphology. Independent t-tests and Mann-Whitney U tests were used to assess between-group differences. Pearson coefficient correlations were used to assess relationships. RESULTS: Patients with HRGP had smaller peak hip flexion angles, smaller knee flexion angles and lesser squat depth compared to asymptomatic participants during SLSquat. Among patients with HRGP, smaller hip flexion angles during SLSquat were associated with hip abductor weakness (r=.47, P =

Developmental dysplasia of the hip (DDH) causes hip instability and early-onset osteoarthritis. The focus on pathomechanics in DDH has centered on the shallow acetabulum, however there is growing awareness of the role of femoral deformities in joint damage. The objective of this study was to determine the influence of femoral version (FV) on the muscle and joint reaction forces (JRFs) of dysplastic hips during gait. Magnetic resonance images, in-vivo gait data, and musculoskeletal models were used to calculate JRFs and simulate changes due to varying FV deformities. Rotation about the long axis of the femur was added in the musculoskeletal models to simulate FV values from -5° (relative retroversion) to + 35° (increased anteversion). In our simulations, FV deformities caused the largest changes to the anteroposterior and resultant JRFs. From a normal FV of 15°, a 15° increase in femoral anteversion caused JRFs to be less posterior in early stance (Δ = 0.43 ± 0.22 xbodyweight) and more anterior in late stance (Δ = 0.60 ± 14 xbodyweight). Relative retroversion caused anteroposterior changes that were similar to anteversion in early stance but opposite in late stance. Resultant JRFs experienced the largest changes during late stance where anteversion raised the peak by 0.48 ± 0.15 xbodyweight and relative retroversion lowered the peak by 0.32 ± 0.30 xbodyweight. Increasing anteversion increased hip flexor and abductor muscle forces, which caused the changes in JRFs. Identifying how FV deformities influence hip joint loading can elucidate their role in the mechanisms of hip degeneration in patients with DDH.

The survival rate for metastatic osteosarcoma has not improved for several decades, since the introduction and refinement of chemotherapy as a treatment in addition to surgery. Over two thirds of metastatic osteosarcoma patients, many of whom are children or adolescents, fail to exhibit durable responses and succumb to their disease. Concerted efforts have been made to increase survival rates through identification of candidate therapies via animal studies and early phase trials of novel treatments, but unfortunately, this work has produced negligible improvements to the survival rate for metastatic osteosarcoma patients. This review summarizes data from clinical trials of metastatic osteosarcoma therapies as well as pre-clinical studies that report efficacy of novel drugs against metastatic osteosarcoma in vivo. Considerations regarding the design of animal studies and clinical trials to improve survival outcomes for metastatic osteosarcoma patients are also discussed.

The TB Portals program is an international collaboration for the collection and dissemination of tuberculosis data from patient cases focused on drug resistance. The central database is a patient-oriented resource containing both patient and pathogen clinical and genomic information. Herein we provide a summary of the pathogen genomic data available through the TB Portals and show one potential application by examining patterns of genomic pairwise distances. Distributions of pairwise distances highlight overall patterns of genome variability within and between Mycobacterium tuberculosis phylogenomic lineages. Closely related isolates (based on whole-genome pairwise distances and time between sample collection dates) from different countries were identified as potential evidence of international transmission of drug-resistant tuberculosis. These high-level views of genomic relatedness provide information that can stimulate hypotheses for further and more detailed research.

Background: The combination of neuromuscular impairments plus psychosocial aspects of chronic kidney disease (CKD) may predispose these patients to greater risk for experiencing increased levels of fatigability. There has been extensive clinical and scientific interest in the problem of fatigue in CKD and end-stage kidney disease (ESKD) patients, whereas less attention has been directed to understanding fatigability. Accordingly, the primary purposes of this review are to (1) discuss fatigue and fatigability and their potential interactions in patients with CKD and ESKD, (2) provide evidence for increased fatigability in CKD and ESKD patients, (3) examine how commonly experienced neuromuscular impairments in CKD and ESKD patients may contribute to the severity of performance fatigability, and (4) highlight preliminary evidence on the effects of exercise as a potential clinical treatment for targeting fatigability in this population. Summary: Fatigue is broadly defined as a multidimensional construct encompassing a subjective lack of physical and/or mental energy that is perceived by the individual to interfere with usual or desired activities. In contrast, fatigability is conceptualized within the context of physical activity and is quantified as the interactions between reductions in objective measures of performance (i.e., performance fatigability) and perceptual adjustments regulating activity performance (i.e., perceived fatigability). We propose herein a conceptual model to extend current understandings of fatigability by considering the interactions among fatigue, perceived fatigability, and performance fatigability. Neuromuscular impairments reported in patients with CKD and ESKD, including reductions in force capacity, skeletal muscle atrophy, mitochondrial dysfunction, abnormal skeletal muscle excitability, and neurological complications, may each contribute to the greater performance fatigability observed in these patients. Key Messages: Considering the interactions among fatigue, perceived fatigability, and performance fatigability provides a novel conceptual framework to advance the understanding of fatigability in CKD and ESKD patients. Measures of fatigability may provide valuable clinical insights into the overall health status of CKD and ESKD patients. Existing data suggest that CKD and ESKD patients are at greater risk of experiencing increased fatigability, partly due to neuromuscular impairments associated with reduced kidney function. Further investigations are warranted to determine the potential clinical role fatigability measures can play in monitoring the health of CKD and ESKD patients, and in identifying potential treatments targeting fatigability in this patient population.

Hips with developmental dysplasia (DDH) are at a heightened risk of premature hip osteoarthritis, which is often expedited by mechanically induced articular tissue damage. A prevalent form of damage in DDH is labral tears caused by abnormal loading at the shallow acetabular edge. Although the majority of reported DDH-related labral tears occur in the antero-superior acetabulum, posterior labral tears are prevalent in individuals whose lifestyle involves frequent high hip flexion tasks such as squatting. To better understand region-specific risks for chondrolabral damage during high hip flexion, we used image-based musculoskeletal models to compare acetabular edge loading (AEL) during double-legged squat between hips with symptomatic DDH (n = 10) and healthy controls (n = 10). Compared to controls, hips with DDH had higher instantaneous posterior AEL at the lowest point of squat (2.6 vs. 1.8 ×BW, p ≤ 0.04), and higher accumulative loading across the duration of the squatting motion (2.6 vs. 1.9 ×BW*s, p ≤ 0.04). Elevated posterior AEL coincided with increased net hip extension moments and posterior joint reaction forces, and was correlated with the severity of DDH acetabular deformity. Our findings suggest that posterior AEL is elevated in hips with symptomatic DDH during double-legged squat, which may contribute to chondrolabral damage in individuals who often perform such high hip flexion tasks. Clinical evaluation of DDH should consider patient-specific anatomy and lifestyle factors when establishing diagnoses and planning personalized treatment.

OBJECTIVES:Although health systems are increasingly moving toward addressing social determinants of health, social risk screening for hospitalized children is largely unexplored. We sought to determine if inpatient screening was feasible and describe the prevalence of social risk among children and caregivers, with special attention given to children with chronic conditions.METHODS:Caregivers of pediatric patients on the hospitalist service at a children’s hospital in the Pacific Northwest completed a social risk survey in 2017. This survey was used to capture items related to caregiver demographics; socioeconomic, psychosocial, and household risks; and adverse childhood experiences (ACEs). Charts were reviewed for child demographics and medical complexity. Results were tabulated as frequency distributions, and analyses compared the association of risk factors with a child’s medical complexity by using χ2 tests.RESULTS:A total of 265 out of 304 (87%) caregivers consented to participate. One in 3 families endorsed markers of financial stress (eg, difficulty paying for food, rent, or utilities). Forty percent experienced medical bill or insurance troubles. Caregiver mental health concerns were prevalent, affecting over one-third of all respondents. ACEs were also common, with 38% of children having at least 1 ACE. The presence of any ACE was more likely for children with chronic conditions than those without.CONCLUSIONS:We found that social risk screening in the inpatient setting was feasible; social risk was uniformly common and did not disproportionately affect those with chronic diseases. Knowing the prevalence of social risk may assist in appropriate alignment of interventions tiered by social complexity.

HYPOTHESIS Objective physiologic changes measured using electrocochleography at the round window (ECOG) are observable during endolymphatic sac decompression and shunt surgery (ELS). BACKGROUND Limited effective treatment options are available to patients with Meniere's disease (MD) who have failed conservative management, experience persistent vertigo symptoms, and have substantial residual hearing. ELS is a feasible therapeutic option for these patients. However, the efficacy of this procedure has been questioned, and objective measures assessing inner ear physiologic alterations are lacking. METHODS ECOG was measured in patients with MD undergoing ELS. Stimuli consisted of tone bursts (250, 500, 1000, 2000, 4000 Hz) and 100 μs broadband clicks at various intensities (60-90 dB nHL). Cochlear microphonic (CM), summation potential (SP), compound action potential (AP), SP:AP ratio, and CM harmonic distortions were measured. RESULTS ECOG was completed in 18 patients. The mean SP magnitude at 500 Hz changed significantly from -7.1 μV before to -5.1 μV after ELS (p

Objectives/hypothesis To compare the identification of safety-relevant environmental sounds between experienced cochlear implant (CI) users and CI candidates. Study design Cross-sectional. Methods A sample of 19 adult, postlingually deaf CI candidates (CI-Cs), 47 experienced CI users (CI-Es), and a control group of 37 age-matched normal-hearing adults were assessed using the Familiar Environmental Sounds Test-Identification (FEST-I). A subset of 11 sounds relevant for safety were selected for analysis in the current study. Results Analysis of safety-relevant sound identification accuracy revealed no significant difference in safety-relevant environmental sound identification skills between CI-E and CI-C participants, with average scores of 68.1% and 67.9%, respectively. Both performed substantially lower than age-matched normal hearing adults (95.1%). A significant moderate negative correlation (-0.4) was found between safety-relevant sound accuracy and chronological age only in one group, the CI-E group (r = -0.4, P Conclusions These findings fail to demonstrate superior performance in safety-relevant environmental sound identification among CI-Es compared with CI-Cs. Although preliminary, these findings suggest that identification of safety-relevant sounds is a significant area of weakness for both CI-Es and CI-Cs, both of whom may benefit from rehabilitation. Level of evidence 4 Laryngoscope, 130:1547-1551, 2020.

Cells are dynamic structures that must respond to complex physical and chemical signals from their surrounding environment. The cytoskeleton is a key mediator of a cell's response to the signals of both the extracellular matrix and other cells present in the local microenvironment and allows it to tune its own mechanical properties in response to these cues. A growing body of evidence suggests that altered cellular viscoelasticity is a strong indicator of disease state; including cancer, laminopathy (genetic disorders of the nuclear lamina), infection, and aging. Here, we review recent work on the characterization of cell mechanics in disease and discuss the implications of altered viscoelasticity in regulation of immune responses. Finally, we provide an overview of techniques for measuring the mechanical properties of cells deeply embedded within tissues.

The International Association for Research on Cancer (IARC) has classified “welding fume” as Group 1 carcinogen[1] with the lung as the target organ. While there are Occupational Exposure Limits (O...

Introduction Youth with type 1 diabetes (T1D) experiencing self-management difficulties are at risk of irreversible long-term health problems and consume a disproportionate amount of health care resources. Behavioral health interventions for this population have shown limited long-term effects, perhaps because of limited research on and intervention in relevant environments. To effectively intervene, providers must first thoroughly understand how risk factors interact with various contexts (e.g., school, home, hospital) to determine opportunities for the development of relevant interventions. Method This review utilized an ecological systems framework to examine the state of the literature with regard to risk factors for poor T1D outcomes and associated intervention. Results This review identified that, whereas risk factors in some systems (e.g., individual, family) have received disproportionate scrutiny, other environments and contexts (e.g., school, medical system) have been relatively neglected by researchers. Similarly, interventions that target understudied environments are lacking, and the majority of rigorously studied interventions only target a single context. Perhaps this accounts for the lack of interventions shown to have a long-term impact on glycemic control. Discussion Our review demonstrates that researchers and funding agencies should prioritize efforts that (a) examine the influence of underexamined environments (e.g., primary care clinics, schools) and interactions (e.g., health care provider to parent, school nurse to youth) on T1D outcomes, (b) place increased emphasis on inclusion of understudied populations (e.g., families of minority racial/ethnic backgrounds), and (c) develop and evaluate interventions that specifically are tailored for these settings, interactions, and populations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Developmental dysplasia of the hip (DDH) is strongly associated with increased risk for hip osteoarthritis. Skeletal deformities undeniably contribute to detrimental biomechanical loading in dysplastic hips, but cannot explain all types of damage and symptoms that patients with DDH experience. Characterizing the geometry and function of the muscles spanning the hip is a logical next step in our progression of knowledge about DDH pathomechanics. In this study, we compared skeletal geometry, muscle volumes, intramuscular fatty infiltration, moment arms, and isometric strength in patients with DDH (N=20) to healthy controls (N=15). Femoral coverage was significantly less in patients (p

Osteosarcoma is the most common form of primary bone cancer and frequently metastasizes to the lungs. Current therapies fail to successfully treat over two thirds of patients with metastatic osteosarcoma, so there is an urgent imperative to develop therapies that effectively target established metastases. Smac mimetics are drugs that work by inhibiting the pro-survival activity of IAP proteins such as cIAP1 and cIAP2, which can be overexpressed in osteosarcomas. In vitro, osteosarcoma cells are sensitive to a range of Smac mimetics in combination with TNFα. This sensitivity has also been demonstrated in vivo using the Smac mimetic LCL161, which inhibited the growth of subcutaneous and intramuscular osteosarcomas. Here, we evaluated the efficacy of LCL161 using mice bearing osteosarcoma metastases without the presence of a primary tumor, modeling the scenario in which a patient's primary tumor had been surgically removed. We demonstrated the ability of LCL161 as a single agent and in combination with doxorubicin to inhibit the growth of, and in some cases eliminate, established pulmonary osteosarcoma metastases in vivo. Resected lung metastases from treated and untreated mice remained sensitive to LCL161 in combination with TNFα ex vivo. This suggested that there was little to no acquired resistance to LCL161 treatment in surviving osteosarcoma cells and implied that tumor microenvironmental factors underlie the observed variation in responses to LCL161.

Objective The aim of this study was to assess the cost-effectiveness of pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) for the treatment of advanced gastric cancer. Methods A Partitioned Survival Model followed by state transition Markov model was developed to estimate the costs and effectiveness of the use of PIPAC C/D versus palliative chemotherapy in the UK. The intervention was assessed at two different levels of care, including upfront therapy (PIPAC C/D plus Oxaliplatin in combination with Capecitabine (XELOX) chemotherapy versus first-line chemotherapy alone) and second-line therapy (PIPAC C/D alone versus second-line chemotherapy (ramucirumab monotherapy)). Data from multiple sources, including published literature and UK-based databases, were used to inform the economic model. Results For the upfront therapy analysis, the estimated total costs in the intervention and comparator arms were £32,606 (SD: £3877) and £17,844 (SD: £920), respectively. PIPAC C/D plus XELOX led to an increase of 0.46 in quality-adjusted life-years (QALYs) gained. The incremental cost per QALY gained was £31,868. For the second-line therapy analysis, the use of PIPAC C/D led to an increase of 0.19 in QALYs and a £21,474 reduction in costs, meaning the intervention was a dominant strategy. Conclusions The cost-effectiveness results for the upfront therapy analysis indicate that PIPAC C/D plus chemotherapy is a cost-effective strategy. Additionally, PIPAC C/D alone as a second-line therapy has the potential to reduce costs and improve clinical outcomes for patients with advanced gastric cancer with peritoneal metastasis.

Objective To compare muscle ultrasound (MUS) parameters in patients with juvenile JDM and healthy controls, and examine their association with JDM disease activity measures and MRI. Methods MUS of the right mid-rectus femoris was performed in 21 patients with JDM meeting probable or definite Bohan and Peter criteria and 28 demographically matched healthy control subjects. MUS parameters were quantitated by digital image processing and correlated with JDM disease activity measures and semi-quantitative thigh MRI short tau inversion recovery (STIR) and T1 scores. Results Rectus femoris MUS echogenicity was increased (median 47.8 vs 38.5, P = 0.002) in patients with JDM compared with controls. Rectus femoris MUS echogenicity correlated with Physician Global Activity (PGA), Manual Muscle Testing (MMT), and Childhood Myositis Assessment Scale (CMAS) (rs 0.4–0.54). Some MUS parameters correlated with functional quantitative measures of muscle strength: resting RF area on MUS strongly correlated with knee extension quantitative muscle testing (rs 0.76), and contracted area correlated with proximal MMT, knee extension quantitative muscle testing, and CMAS (rs 0.71–0.80). MUS echogenicity correlated with both STIR and T1 MRI (rs 0.43), and T1 MRI correlated inversely with RF contracted area (rs -0.49) on MUS. There were differences in pre- and post-exercise vascular power and colour Doppler on MUS in patients with JDM vs controls, with the percentage change of post-exercise vascular power Doppler lower in JDM compared with controls (7.1% vs 100.0%). Conclusions These data suggest MUS may be a valuable imaging modality to assess JDM disease activity and damage.

T cells discriminate between healthy and infected cells with remarkable sensitivity when mounting an immune response, which is hypothesized to depend on T cells combining stimuli from multiple antigen‐presenting cell interactions into a more potent response. To quantify the capacity for T cells to accomplish this, we have developed an antigen receptor that is optically tunable within cell conjugates, providing control over the duration, and intensity of intracellular T‐cell signaling. We observe limited persistence within the T‐cell intracellular network on disruption of receptor input, with signals dissipating entirely in ~15 min, and directly show sustained proximal receptor signaling is required to maintain gene transcription. T cells thus primarily accumulate the outputs of gene expression rather than integrate discrete intracellular signals. Engineering optical control in a clinically relevant chimeric antigen receptor (CAR), we show that this limited signal persistence can be exploited to increase CAR‐T cell activation threefold using pulsatile stimulation. Our results are likely to apply more generally to the signaling dynamics of other cellular networks., An optically controllable chimeric antigen receptor is developed for modulating T cell signaling dynamics. Limited signal persistence is found at key nodes in the intracellular network, constraining the window over which T cells can integrate discrete activation signals.

The molecular genetic basis of pulmonary arterial hypertension (PAH) is heterogeneous, with at least 26 genes displaying putative evidence for disease causality. Heterozygous variants in theWe report three families with a novel, autosomal recessive form of childhood-onset PAH due to biallelicOur findings support biallelic predicted deleterious

Purpose The aims of this study were (a) to longitudinally assess environmental sound recognition (ESR) before and after cochlear implantation in a sample of postlingually deafened adults and (b) to assess the extent to which spectro-temporal processing abilities influence ESR with cochlear implants (CIs). Method In a longitudinal cohort study, 20 postlingually deafened adults were tested with hearing aids on the Familiar Environmental Sound Test–Identification and AzBio sentences in quiet pre-CI and 6 months post-CI. A subset of 11 participants were also tested 12 months post-CI. Pre-CI spectro-temporal processing was assessed using the Spectral-temporally Modulated Ripple Test. Results Average ESR accuracy pre-CI ( M = 63.60%) was not significantly different from ESR accuracy at 6 months ( M = 65.40%) or 12 months ( M = 69.09%) post-CI. In 11 participants (55%), however, ESR improved following implantation by 10.91 percentage points, on average. Pre-CI ESR correlated moderately and significantly with pre-CI and 12-month post-CI AzBio scores, with a trend toward significance for AzBio performance at 6 months. Pre-CI spectro-temporal processing was moderately associated with ESR at 6 and 12 months post-CI but not with speech recognition post-CI. Conclusions The present findings failed to demonstrate an overall significant improvement in ESR following implantation. Nevertheless, more than half of our sample showed some degree of improvement in ESR. Several environmental sounds were poorly identified both before and after implantation. Spectro-temporal processing ability prior to implantation appears to predict postimplantation performance for ESR. These findings indicate the need for greater attention to ESR following cochlear implantation and for developing individualized targets for ESR rehabilitation. Supplemental Material https://doi.org/10.23641/asha.13876745

Path analyses indicated that the relationship between conformity to masculine norms (CMN) and attitudes toward mask-wearing to protect from COVID-19 was mediated by perceived benefits, perceived barriers, confidence in the scientific community, and empathy toward vulnerable persons, and that political ideology moderated the indirect effects from CMN to men’s attitudes. Efforts to improve men’s participation in combatting COVID-19 should address the perceptions and attitudes related to conforming to traditional masculine norms and moderated by political ideology, and might reconstruct masculinity to focus on being a guardian and protector of public health.

Background Influenza-like illness (ILI) and Acute Respiratory Infections (ARI) are a considerable health problem in Europe. Most diagnoses are made by family physicians (FPs) and based on symptoms and clinical signs rather than on diagnostic testing. The International Classification of Primary Care (ICPC) advocates that FPs record patients’ ‘Reasons for Encounters’ (RfEs) as they are presented to them. This study analyses the association of patients’ RfEs with FPs’ diagnoses of ILI and ARI diagnoses and FPs’ management of those patients. Methods Cohort study of practice populations. Over a 4-month period during the winter season 2013–14, eight FPs recorded ILI and ARI patients’ RfEs and how they were managed. FPs recorded details of their patients using the ICPC format, collecting data in an Episode of Care (EoC) structure. Results There were 688 patients diagnosed as having ILI; between them they presented with a total of 2,153 RfEs, most commonly fever (79.7%), cough (59.7%) and pain (33.0%). The 848 patients with ARI presented with a total of 1,647 RfEs, most commonly cough (50.4%), throat symptoms (25.9%) and fever (19.9%). For patients with ILI, 37.0% of actions were related to medication for respiratory symptoms; this figure was 38.4% for patients with ARI. FPs referred six patients to specialists or hospitals (0.39% of all patients diagnosed with ILI and ARI). Conclusions In this study of patients with ILI and ARI, less than half received a prescription from their FPs, and the illnesses were mainly managed in primary care, with few patients’ needing referral. The ICPC classification allowed a standardised data collection system, providing documentary evidence of the management of those diseases.

ObjectivesWith the increasing emphasis on developing effective telemedicine approaches in Otolaryngology, this study explored whether a single composite image stitched from a digital otoscopy video provides acceptable diagnostic information to make an accurate diagnosis, as compared with that provided by the full video.MethodsFive Ear, Nose, and Throat (ENT) physicians reviewed the same set of 78 digital otoscope eardrum videos from four eardrum conditions: normal, effusion, retraction, and tympanosclerosis, along with the composite images generated by a SelectStitch method that selectively uses video frames with computer-assisted selection, as well as a Stitch method that incorporates all the video frames. Participants provided a diagnosis for each item along with a rating of diagnostic confidence. Diagnostic accuracy for each pathology of SelectStitch was compared with accuracy when reviewing the entire video clip and when reviewing the Stitch image.ResultsThere were no significant differences in diagnostic accuracy for physicians reviewing SelectStitch images and full video clips, but both provided better diagnostic accuracy than Stitch images. The inter-reader agreement was moderate.ConclusionEqual to using full video clips, composite images of eardrums generated by SelectStitch provided sufficient information for ENTs to make the correct diagnoses for most pathologies. These findings suggest that use of a composite eardrum image may be sufficient for telemedicine approaches to ear diagnosis, eliminating the need for storage and transmission of large video files, along with future applications for improved documentation in electronic medical record systems, patient/family counseling, and clinical training.Level of EvidenceLevel 3

Objectives Cancer survival rates vary widely between European countries, with differences in timeliness of diagnosis thought to be one key reason. There is little evidence on the way in which different healthcare systems influence primary care practitioners' (PCPs) referral decisions in patients who could have cancer. This study aimed to explore PCPs' diagnostic actions (whether or not they perform a key diagnostic test and/or refer to a specialist) in patients with symptoms that could be due to cancer and how they vary across European countries. Design A primary care survey. PCPs were given vignettes describing patients with symptoms that could indicate cancer and asked how they would manage these patients. The likelihood of taking immediate diagnostic action (a diagnostic test and/or referral) in the different participating countries was analysed. Comparisons between the likelihood of taking immediate diagnostic action and physician characteristics were calculated. Setting Centres in 20 European countries with widely varying cancer survival rates. ParticipantsA total of 2086 PCPs answered the survey question, with a median of 72 PCPs per country. Results PCPs' likelihood of immediate diagnostic action at the first consultation varied from 50% to 82% between countries. PCPs who were more experienced were more likely to take immediate diagnostic action than their peers. Conclusion When given vignettes of patients with a low but significant possibility of cancer, more than half of PCPs across Europe would take diagnostic action, most often by ordering diagnostic tests. However, there are substantial between-country variations., ALN's time is supported by the National Institute for Health Research (NIHR) Imperial Patient Safety Translation Research Centre, with her infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC).

Objective Certain social risk factors (e.g., housing instability, food insecurity) have been shown to directly and indirectly influence pediatric health outcomes; however, there is limited understanding of which social factors are most salient for children admitted to the hospital. This study examines how caregiver-reported social and medical characteristics of children experiencing an inpatient admission are associated with the presence of future health complications. Methods Caregivers of children experiencing an inpatient admission (N = 249) completed a predischarge questionnaire designed to capture medical and social risk factors across systems (e.g., patient, caregiver, family, community, healthcare environment). Electronic health record (EHR) data were reviewed for child demographic data, chronic disease status, and subsequent emergency department visits or readmissions (i.e., acute events) 90 days postindex hospitalization. Associations between risk factors and event presence were estimated using odds ratios (ORs) and confidence intervals (CI), both unadjusted and adjusted OR (aOR) for chronic disease and age. Results Thirty-three percent (N = 82) of children experienced at least one event. After accounting for child age and chronic disease status, caregiver perceptions of child’s health being generally “poor” or “not good” prior to discharge (aOR = 4.7, 95% CI = 2.3, 9.7), having high care coordination needs (aOR = 3.2, 95% CI = 1.6, 6.1), and experiencing difficulty accessing care coordination (aOR = 2.5, 95% CI = 1.4, 4.7) were significantly associated with return events. Conclusions Caregiver report of risks may provide valuable information above and beyond EHR records to both determine risk of future health problems and inform intervention development.

Background: Stress urinary incontinence (SUI) is a debilitating and highly prevalent condition in the UK. The condition is associated with a significant economic burden for affected patients and society. Current treatment options for SUI include minimally invasive therapies, medication and surgical intervention for the most serious cases. Electrical Muscle Stimulator with Multipath technology is a recently developed device for the treatment of SUI that relies on neuromuscular external electrical stimulation (NEES) technology. The clinical efficacy of the device has been proven in previous studies, but existing evidence surrounding its economic viability is limited.Objectives: To assess the cost-utility of the Electrical Muscle Stimulator with Multipath technology Therapy device for the treatment of SUI amongst women in a UK setting.Methods: An economic model was developed to consider the cost-utility (cost per quality-adjusted life-year [QALY] gained) of Electrical Muscle Stimulator with Multipath technology compared with current practice. A Markov model was developed, with costs and health effects estimated over the lifetime of the patient in the base-case analysis. The model was developed to reflect the treatment pathways typically followed by patients with SUI in the UK. Parameter uncertainty was explored in deterministic and probabilistic sensitivity analyses.Results: Base-case results indicate that Electrical Muscle Stimulator with Multipath technology results in cost savings and QALY gains over the patient's lifetime. In the "cure" analysis, the intervention is £250 less costly and leads to a 0.03 QALY gain per patient, while in the "improvement analysis", the intervention is £327 less costly and leads to a 0.13 QALY gain per patient. Results from the probabilistic sensitivity analyses show that the likelihood of Electrical Muscle Stimulator with Multipath technology being cost-effective is greater than 74% across all willingness-to-pay thresholds in the two analyses presented.Conclusions: Electrical Muscle Stimulator with Multipath technology is a potentially cost-effective treatment option for patients with SUI who have failed first-line treatment. It could reduce costs to the health care service and improve quality-of-life for selected patients over their lifetime.

Rehabilitation for patients with developmental dysplasia of the hip (DDH) addresses modifiable factors in an effort to reduce symptoms and prevent or delay the development of osteoarthritis, yet its effect on joint mechanics remains unknown. Our objective was to establish how rehabilitation (muscle strengthening and movement training), simulated with a musculoskeletal model and probabilistic analyses, alters hip joint reaction forces (JRF) in patients with DDH during a single limb squat. In four patients with DDH, hip abductor strengthening was simulated by increasing the maximum isometric force value between 0 and 32.6% and movement training was simulated by decreasing the hip adduction angle between 0 and 10° relative to baseline. 2,000 Monte Carlo simulations were performed separately to simulate strengthening and movement training, from which 99% confidence bounds and sensitivity factors were calculated. Our results indicated that simulated movement training aimed at decreasing hip adduction had a substantially larger influence on hip JRF than strengthening, as indicated by 99% confidence bounds of the resultant JRF (0.88 ± 0.55 xBW vs. 0.31 ± 0.12 xBW, respectively). Relative to baseline, movement training that resulted in a 10° decrease in hip adduction decreased the resultant JRF by 0.78 ± 0.65 xBW, while strengthening the abductors by 17.6% increased resultant JRF by 0.18 ± 0.06 xBW. To our knowledge, these results are the first to provide evidence pertaining to the effect of rehabilitation on joint mechanics in patients with DDH and can be used to inform more targeted interventions.

Ribonucleotide reductase (RR) catalyses the rate-limiting step of dNTP synthesis, establishing it as an important cancer target. While RR is traditionally inhibited by nucleoside-based antimetabolites, we recently discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH) that binds reversibly to the catalytic site (C-site). Here we report the synthesis and in vitro evaluation of 13 distinct compounds (TP1-13) with improved binding to hRR over NSAH (TP8), with lower KD’s and more predicted residue interactions. Moreover, TP6 displayed the greatest growth inhibiting effect in the Panc1 pancreatic cancer cell line with an IC50 of 0.393 µM. This represents more than a 2-fold improvement over NSAH, making TP6 the most potent compound against pancreatic cancer emerging from the hydrazone inhibitors. NSAH was optimised by the addition of cyclic and polar groups replacing the naphthyl moiety, which occupies the phosphate-binding pocket in the C-site, establishing a new direction in inhibitor design.

Developmental dysplasia of the hip (DDH) is characterized by abnormal bony anatomy, which causes detrimental hip joint loading and leads to secondary osteoarthritis. Hip joint loading depends, in part, on muscle-induced joint reaction forces (JRFs), and therefore, is influenced by hip muscle moment arm lengths (MALs) and lines of action (LoAs). The current study used subject-specific musculoskeletal models and in-vivo motion analysis to quantify the effects of DDH bony anatomy on dynamic muscle MALs, LoAs, and their contributions to JRF peaks during early (~17%) and late-stance (~52%) of gait. Compared to healthy hips (N = 15, 16–39 y/o), the abductor muscles in patients with untreated DDH (N = 15, 16–39 y/o) had smaller abduction MALs (e.g. anterior gluteus medius, 35.3 vs. 41.6 mm in early stance, 45.4 vs. 52.6 mm late stance, p ≤ 0.01) and more medially-directed LoAs. Abduction-adduction and rotation MALs also differed for major hip flexors such as rectus femoris and iliacus. The altered MALs in DDH corresponded to higher hip abductor forces, medial JRFs (1.26 vs. 0.87 × BW early stance, p = 0.03), and resultant JRFs (5.71 vs. 4.97 × BW late stance, p = 0.05). DDH anatomy not only affected hip muscle force generation in the primary plane of function, but also their out-of-plane mechanics, which collectively elevated JRFs. Overall, hip muscle MALs and their contributions to JRFs were significantly altered by DDH bony anatomy. Therefore, to better understand the mechanisms of joint degeneration and improve the efficacy of treatments for DDH, the dynamic anatomy-force relationships and multi-planar functions of the whole hip musculature must be collectively considered.

Context: The authors hypothesized that in people with hip-related groin pain, less static ankle dorsiflexion could lead to compensatory hip adduction and contralateral pelvic drop during step-down. Ankle dorsiflexion may be a modifiable factor to improve ability in those with hip-related groin pain to decrease hip/pelvic motion during functional tasks and improve function. Objective: To determine whether smaller static ankle dorsiflexion angles were associated with altered ankle, hip, and pelvis kinematics during step-down in people with hip-related groin pain. Design: Cross-sectional Setting: Academic medical center. Patients: A total of 30 people with hip-related groin pain (12 males and 18 females; 28.7 [5.3] y) participated. Intervention: None. Main Outcome Measures: Weight-bearing static ankle dorsiflexion with knee flexed and knee extended were measured via digital inclinometer. Pelvis, hip, and ankle kinematics during forward step-down were measured via 3D motion capture. Static ankle dorsiflexion and kinematics were compared with bivariate correlations. Results: Smaller static ankle dorsiflexion angles were associated with smaller ankle dorsiflexion angles during the step-down for both the knee flexed and knee extended static measures. Among the total sample, smaller static ankle dorsiflexion angle with knee flexed was associated with greater anterior pelvic tilt and greater contralateral pelvic drop during the step-down. Among only those who did not require a lowered step for safety, smaller static ankle dorsiflexion angles with knee flexed and knee extended were associated with greater anterior pelvic tilt, greater contralateral pelvic drop, and greater hip flexion. Conclusions: Among those with hip-related groin pain, smaller static ankle dorsiflexion angles are associated with less ankle dorsiflexion motion and altered pelvis and hip kinematics during a step-down. Future research is needed to assess the effect of treating restricted ankle dorsiflexion on quality of motion and symptoms in patients with hip-related groin pain.

To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.

OBJECTIVES—: Assessing aging muscle through estimates of muscle heterogeneity may overcome some of the limitations of grayscale analyses. The objectives of this study included determining statistical model parameters that characterize muscle echogenicity and are associated with strength in younger and older participants. METHODS—: Thirty-three community-dwelling participants were assigned to younger and older groups. Quantitative B-mode ultrasound scanning of the rectus femoris and isometric grip strength testing were completed. Shape or dispersion parameters from negative binomial distribution, Nakagami, gamma, and gamma mixture models were fitted to the grayscale histograms. RESULTS—: The mean ages ± SDs of the younger and older groups were 24.0 ± 2.3 and 65.1 ± 6.5 years, respectively. Statistical model shape and dispersion parameters for the grayscale histograms significantly differed between the younger and older participants (P = .002–.006). Among all of the statistical models considered, the gamma mixture model showed the best fit with the grayscale histograms (χ(2) goodness of fit = 62), whereas the Nakagami distribution displayed the poorest fit (χ(2) goodness of fit = 2595). Grayscale values were significantly associated with peak grip strength force in younger adult participants (R(2) = 0.36; P < .008). However, the negative binomial dispersion parameter k (adjusted R(2) = 0.70; P < .001) and gamma shape parameter α (adjusted R(2) = 0.68; P < .01) showed the highest associations with peak grip strength force in older adult participants. CONCLUSIONS—: The negative binomial dispersion parameter k and the gamma shape parameter α have clinical relevance for the assessment of age-related muscle changes. Statistical models of muscle heterogeneity may characterize the association between muscle tissue composition estimates and strength better than grayscale measures in samples of community-dwelling older adults.

Background Surgical resection of vestibular schwannomas (VS) located within the internal auditory canal (IAC) is challenging, especially those located very laterally in the IAC. Various transcranial approaches have been described for resection of intracanalicular VS including retrosigmoid, translabyrinthine, and middle fossa approaches. Each approach has its indications, advantages, and limitations. The middle fossa approach (MFA) is considered by many authors as the gold standard approach for resection of small intracanalicular VS in young patients with serviceable hearing; however, there is often a limitation in complete visualization of the tumor. Methods The authors present an illustrative case to highlight the technical nuances of complementary use of endoscopy in MFA for complete resection of intracanalicular VS located at the IAC fundus, preserving preoperative hearing status and mainting intact facial nerve function. Results In our experience, the combined use of the endoscope and the microspe as described here and illustrated in our case, improves visualization of the IAC and its contents, improving ressection and outcomes. Conclusions MFA allows for a direct yet safe surgical corridor to small intracanalicular VS. The implementation of endoscopy with MFA, especially for VS located laterally in the IAC, allows for better opportunity for complete resection of the tumor with improved preservation of hearing and facial nerve function.

Hypothesis Electrocochleography (ECochG) patterns observed during cochlear implant (CI) electrode insertion may provide information about scalar location of the electrode array. Background Conventional CI surgery is performed without actively monitoring auditory function and potential damage to intracochlear structures. The central hypothesis of this study was that ECochG obtained directly through the CI may be used to estimate intracochlear electrode position and, ultimately, residual hearing preservation. Methods Intracochlear ECochG was performed on 32 patients across 3 different implant centers. During electrode insertion, a 50-ms tone burst stimulus (500 Hz) was delivered at 110 dB SPL. The ECochG response was monitored from the apical-most electrode. The amplitude and phase changes of the first harmonic were imported into an algorithm in an attempt to predict the intracochlear electrode location (scala tympani [ST], translocation from ST to scala vestibuli [SV], or interaction with basilar membrane). Anatomic electrode position was verified using postoperative computed tomography (CT) with image processing. Results CT analysis confirmed 25 electrodes with ST position and 7 electrode arrays translocating from ST into SV. The ECochG algorithm correctly estimated electrode position in 26 (82%) of 32 subjects while 6 (18%) electrodes were wrongly identified as translocated (sensitivity = 100%, specificity = 77%, positive predictive value = 54%, and a negative predictive value = 100%). Greater hearing loss was observed postoperatively in participants with translocated electrode arrays (36 ± 15 dB) when compared with isolated ST insertions (28 ± 20 dB HL). This result, however, was not significant (p = 0.789). Conclusion Intracochlear ECochG may provide information about CI electrode location and hearing preservation.

Objectives: To describe a case of inadvertent hearing preservation following a classical translabyrinthine resection of a vestibular schwannoma of the internal auditory canal in an otherwise healthy patient. Methods: Herein, we describe the case of an otherwise healthy patient who underwent resection of an intracanalicular vestibular schwannoma via a translabyrinthine approach. Furthermore, as part of an ongoing study aimed at characterizing hearing changes due to intraoperative events, cochlear hair cell and nerve activity were monitored using electrocochleography throughout surgery. Unexpectedly, the patient maintained serviceable hearing following surgery. As a result, we are able to provide electrophysiologic evidence of cochlear hair cell activity at various stages of this surgery. Results: Hair cell responses across tested frequencies were detectable prior to and following completion of the translabyrinthine procedure. Neural integrity of the auditory division of cranial nerve VIII was maintained throughout. Lastly, postoperative audiometric testing supported the patient’s subjective assertion of serviceable hearing in the surgical ear. Conclusion: Our results suggest that some degree of hair cell and neural integrity can be maintained throughout the course of the translabyrinthine approach, and if preservation of the auditory division of cranial nerve VIII is feasible, a functional amount of hearing preservation is attainable.

Background: The Approaches and Study Skills Inventory for Students (ASSIST) questionnaire assesses whether learners prefer a deep, strategic or surface approach to learning. This study aimed to establish the effect of time since qualification, gender and work role on ASSIST scores of General Practitioners (GPs) and GP Specialist Trainees (GPSTs). Methods: An anonymous online questionnaire with demographic questions and the ASSIST survey was completed by 1005 GPs and GPSTs from across the United Kingdom. Results: Of the 544 GPs and 461 GPSTs completing the survey, 96.5% preferred a deep and/or strategic approach to learning. There was a significant increase in the preference for a deep approach with time from graduation and significantly less preference for a surface approach. There was no significant change in any of the scores over the GPST years. Men had significantly higher scores for a deep approach than women. Conclusions: GPs and GPSTs prefer deep and strategic approaches to a surface approach. While higher levels of GP experience are associated with a higher deep approach score and a lower surface approach score, this change is not seen during progression through GP training. Men have higher scores for a deep approach than women.

Ribonucleotide reductase (RR), an established cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR reversibly. We herein report the synthesis and biochemical characterization of 25 distinct analogs. We designed each analog through docking to the C-site of hRR based on our 2.7 A X-ray crystal structure (PDB ID: 5TUS). Broad tolerance to minor structural variations preserving inhibitory potency is observed. E-3f (82% yield) displayed an in vitro IC50 of 5.3 ± 1.8 μM against hRR, making it the most potent in this series. Kinetic assays reveal that E-3a, E-3c, E-3t, and E-3w bind and inhibit hRR through a reversible and competitive mode. Target selectivity toward the R1 subunit of hRR is established, providing a novel way of inhibition of this crucial enzyme.

In this work we hypothesized that the chemokine fractalkine can serve as a cancer molecular target. We engineered aptamer micelles functionalized with an outer poly(ethylene glycol) (PEG) corona, and investigated the extent and efficacy of using them as a targeting tool against fractalkine-expressing colon adenocarcinoma cells. In vitro cell binding results showed that aptamer micelles bound and internalized to fractalkine-expressing cancer cells with the majority of the micelles found free in the cytoplasm. Minimal surface binding was observed by healthy cells. Even though partial PEGylation did not prevent serum adsorption, micelles were highly resistant to endonuclease and exonuclease degradation. In vivo biodistribution studies and confocal studies demonstrated that even though both aptamer and control micelles showed tumor accumulation, only the aptamer micelles internalized into fractalkine-expressing cancer cells, thus demonstrating the potential of the approach and showing that fractalkine may serve as a specific target for nanoparticle delivery to cancer cells.

Hypothesis Intraoperative, intracochlear electrocochleography (ECochG) will provide a means to monitor cochlear hair cell and neural response during cochlear implant (CI) electrode insertion. Distinct patterns in the insertion track can be characterized. Background Conventional CI surgery is performed without a means of actively monitoring cochlear hair cell and neural responses. Intracochlear ECochG obtained directly through the CI may be a source of such feedback. Understanding the patterns observed in the "insertion track" is an essential step toward refining intracochlear ECochG as a tool that can be used to assist in intraoperative decision making and prognostication of hearing preservation. Methods Intracochlear ECochG was performed in 17 patients. During electrode insertion, a 50-ms tone burst acoustic stimulus was delivered with a frequency of 500 Hz at 110 dB SPL. The ECochG response was monitored from the apical-most electrode. The amplitude of the first harmonic was plotted and monitored in near real time by the audiologist-surgeon team during CI electrode insertion. Results Three distinct patterns in first harmonic amplitude change were observed across subjects during insertion: Type A (52%), overall increase in amplitude from the beginning of insertion until completion; Type B (11%), a maximum amplitude at the beginning of insertion, with a decrease in amplitude as insertion progressed to completion; and Type C (35%), comparable amplitudes at the beginning and completion of the insertion with the maximum amplitude mid-insertion. Conclusion Three ECochG patterns were observed during electrode advancement into the cochlea. Ongoing and future work will broaden our scope of knowledge regarding the relationship among these patterns, the presence of cochlear trauma, and functional outcomes related to hearing preservation.

1) Environmental sound awareness (ESA) and speech recognition skills in experienced, adult cochlear implant (CI) users will be highly correlated, and, 2) ESA skills of CI users will be significantly lower than those of age-matched adults with normal hearing.Enhancement of ESA is often discussed with patients with sensorineural hearing loss as a potential benefit of implantation and, in some cases, ESA may be a major motivating factor. Despite its ecological validity and patients' expectations, ESA remains largely a presumed skill. The relationship between ESA and speech recognition is not well-understood.ESA was assessed in 35 postlingually deaf, experienced CI users and a control group of 41 age-matched, normal hearing listeners using the validated, computerized familiar environmental sounds test-identification (FEST-I) and a diverse speech recognition battery. Demographic and audiological factors as well as nonverbal intelligence quotient (IQ)/nonverbal reasoning and spectral resolution were assessed.Six of the 35 experienced CI users (17%) demonstrated FEST-I accuracy within the range of the NH controls. Among CI users all correlations between FEST-I accuracy and speech recognition scores were strong. Chronological age at the time of testing, duration of deafness, spectral resolution, and nonverbal IQ/nonverbal reasoning were strongly correlated with FEST-I accuracy. Partial correlation analysis showed that correlations between FEST-I and speech recognition measures remained significant when controlling for the demographic and audiological factors.Our findings reinforce the hypothesis that ESA and speech perception share common underlying processes rather than reflecting truly separate auditory domains.

Rabies virus induces drastic behaviour modifications in infected hosts. The mechanisms used to achieve these changes in the host are not known. The main finding of this study is that a region in the rabies virus glycoprotein, with homologies to snake toxins, has the ability to alter behaviour in animals through inhibition of nicotinic acetylcholine receptors present in the central nervous system. This finding provides a novel aspect to virus receptor interaction and host manipulation by pathogens in general. The neurotoxin-like region of the rabies virus glycoprotein inhibited acetylcholine responses of α4β2 nicotinic receptors in vitro, as did full length ectodomain of the rabies virus glycoprotein. The same peptides significantly altered a nicotinic receptor induced behaviour in C. elegans and increased locomotor activity levels when injected into the central nervous system of mice. These results provide a mechanistic explanation for the behavioural changes in hosts infected by rabies virus.