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Objective: In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase-sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type. Methods: A total of 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disk level. Two independent, clinically masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. Results: Relapsing MS (RMS) patients showed smaller SC GM areas than age- and sex-matched controls (p = 0.008) without significant differences in SC WM areas. Progressive MS patients showed smaller SC GM and SC WM areas compared to RMS patients (all p ≤ 0.004). SC GM, SC WM, and whole cord areas inversely correlated with EDSS (rho: -0.60, -0.32, -0.42, respectively; all p ≤ 0.001). The SC GM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, fluid-attenuated inversion recovery lesion load, T1 lesion load, SC WM area, number of SC T2 lesions, age, sex, and disease duration. Brain and spinal GM independently contributed to EDSS. Interpretation: SC GM atrophy is detectable in vivo in the absence of WM atrophy in RMS. It is more pronounced in progressive MS than RMS and contributes more to patient disability than SC WM or brain GM atrophy.

Background: This study evaluated the prevalence of chronic fatigue syndrome (CFS) among children and adolescents (ages 5 to 17) in an ethnically and socioeconomically diverse community population. Objectives: This investigation attempted to address limitations of previous studies by using a community-based sample and thoroughly evaluating each participant (i.e., using medical and psychological evaluations) to determine a proper diagnosis of CFS. Methods: A community-based sample of children and adolescents aged 5 to 17 were screened for symptoms of chronic fatigue syndrome by telephone. Those reported to suffer from CFS-like symptoms were given medical and psychological evaluations to allow a determination of the CFS diagnosis.Results: The overall prevalence rate for the sample was 60 per 100,000 or .06%. The prevalence for the adolescents (aged 13 to 17) was 181 per 100,000 or .181%. Conclusions: The current prevalence estimate for CFS in adolescents is higher than previous estimates. CFS was more common in adolescents than pre-pubescent children. [ABSTRACT FROM AUTHOR]

Most studies of Chronic Fatigue Syndrome (CFS) have been based on patients recruited from primary or tertiary care settings. Patients from such settings might not be typical of patients in the general population. The present investigation involved examining individuals with CFS from a community-based study. A random sample of 18,675 respondents in Chicago were first interviewed by telephone. A group of individuals with chronic fatigue accompanied by at least four Fukuda et al. (1994) symptoms associated with CFS were given medical and psychiatric examinations. From this sample, a physician review group diagnosed individuals with CFS. Those diagnosed with CFS were subclassified based on frequency of symptoms. Important differences emerged on measures of sociodemographics and disability. The implications of these findings and others are discussed. [ABSTRACT FROM AUTHOR]

The systemic vasculitides are a heterogeneous group of disorders characterized by inflammation of blood vessel walls. They can be classified according to the size of vessel affected and also into primary de novo vasculitides and secondary to other disease processes. Treatments differ and overlap depending on the type of vasculitis. It is therefore important to make the correct diagnosis and treat appropriately to achieve remission as there is a substantial mortality implication. [ABSTRACT FROM AUTHOR]

A community-based screening of over 12,000 households was conducted in order to determine the prevalence of fatigue and CFS-like illness in a sample of 5- to 17-year olds. Results indicate that over 4% of the sample was fatigued and that 2.05% were diagnosed with CFS-like illness. Adolescents had a slightly higher rate of CFS-like illness (2.91%) than did pre-pubescent children (1.96%). Those with CFS-like illness were almost evenly divided between male (47.5%) and female (52.5%). Youngsters of Latino origin had the highest representation in the CFS-like group. Symptom data, family patterns, and other data are presented for both the CFS-like group and the entire sample. [ABSTRACT FROM AUTHOR]

Chronic Fatigue Syndrome (CFS) in children and adolescents presents unique challenges and opportunities to researchers. Issues specific to research conducted on children and adolescents with CFS are discussed. Such issues include the importance of utilizing a consistent definition of CFS and ascertaining that all participants meet with the criteria, the need for attention to wording of questions regarding fatigue, the significance of medical evaluations as part of a research study. Considerations pertaining to research with minors, such as confidentiality and assent, are explored. Finally, suggestions for future research on children is made. [ABSTRACT FROM AUTHOR]

The relationship between chronic heavy drinking and post-traumatic stress disorder (PTSD) is well-documented; however, the impact of more common drinking patterns, such as a single episode leading to a blood alcohol concentration (BAC) of 0.09 g/dL (moderate intoxication), remains underexplored. Given the frequent co-occurrence of PTSD and alcohol misuse, it is essential to understand the biological and behavioral factors driving this comorbidity. We hypothesize that alcohol's immediate sedative effects are coupled with the development of persistent molecular alcohol tolerance, which may disrupt fear extinction learning. To investigate this, we employed a S ingle E pisode E thanol (SEE) in-vivo exposure to mimic binge-like alcohol consumption over a 6-hour period, following contextual conditioning trials. Extinction trials were conducted 24 hours later to assess the effects on extinction learning. Our findings reveal a significant deficit in fear extinction learning in alcohol-treated adolescent male mice compared to saline-treated controls, with no such effects observed in female adolescent mice. These results suggest that even non-chronic alcohol exposure may contribute to the development of trauma- and stress-related disorders, such as PTSD, in males. Additionally, histological analysis revealed significant alterations in FKBP5, β-catenin, and GSK-3β levels in the hippocampus, striatum, and basolateral amygdala of alcohol-treated mice following extinction. The insights gained from this study could reshape our understanding of the risk factors for PTSD and open new avenues for prevention and treatment, targeting the molecular mechanisms that mediate alcohol tolerance., Statement of Significance: This study investigates the impact of binge-like alcohol exposure on context extinction learning, aiming to identify previously unrecognized risks associated with this common drinking pattern and the development of trauma- and stress-related disorders, such as PTSD. Our findings reveal that binge-like alcohol exposure impairs extinction learning in male adolescent mice by disrupting molecular mechanisms within fear memory circuits, suggesting novel therapeutic and preventive targets. Dysregulated candidates include the canonical Wnt/β-catenin signaling proteins, β-catenin and GSK-3β, along with FKBP5, a key player in glucocorticoid signaling and part of a gene network linked to PTSD. These alterations, found in the dorsal hippocampus (dHPC), basolateral amygdala (BLA), striatum, and nucleus accumbens (NAc) core and shell, may serve as promising targets for future pharmacological intervention.

Acne vulgaris is a common dermatological diagnosis observed in pediatric patients with skin of color, often resulting in scarring, keloid formation, and post-inflammatory hyperpigmentation, significantly impacting their quality of life. This exploratory retrospective chart review included 77 black pediatric patients seen at a tertiary care center for acne vulgaris between 2018 and 2023. We analyzed demographics, acne descriptors, and treatment modalities. The most common acne morphology was comedonal acne (83.6%), with 71% of the patients being female. Significant age differences were observed particularly for acne at the chin and overall face. Treatment regimens commonly prescribed included combinations of adapalene and benzoyl peroxide (22%), topical antibiotics, tretinoin, and benzoyl peroxide (34%). Given the higher risk of sequelae for patients with darker skin, it is crucial to address their unique treatment needs. This study highlights the distinctive characteristics of acne in black pediatric patients and calls for further research to enhance our understanding and treatment of this population. Limitations include the lack of direct patient interactions and reliance on chart data. Further studies are needed to compare acne presentation in skin of color of other populations, refining our knowledge of acne clinical presentation, complications, and treatment modalities for diverse patient populations.

Background & Aims: The risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated at around 5%, prompting intensive monitoring strategies. However, the evidence is derived from retrospective studies that under-reported risk factors for liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers., Method: Between 2014-2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. The MTX group included patients who received MTX for ≥6 months, whereas the unexposed group included those who never received MTX. All patients underwent full liver profiling, with transient elastography (TE) and enhanced liver fibrosis (ELF) marker measurements., Results: A total of 999 patients (mean age 60.8 ± 12 years, 62.3% females) were included. Of 976 with valid TE values, 149 (15.3%) had liver stiffness ≥7.9 kPa. Of 892 with a valid ELF, 262 (29.4%) had ELF ≥9.8. Age and BMI were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥7.9 kPa (adjusted odds ratio = 3.19; 95% CI 1.95-5.20; p <0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥9.8 (odds ratio = 1.76; 95% CI 1.20-2.56; p = 0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosis., Conclusion: The risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX., Impact and Implications: Current guidelines recommend intensive (2-3 monthly) monitoring strategies for patients on long-term methotrexate therapy due to the potential risk of liver fibrosis. Evaluation of the association using two validated non-invasive markers of liver fibrosis, liver stiffness and enhanced liver fibrosis score, in a large cohort of patients with rheumatoid arthritis or psoriasis shows that the reported risk has previously been overestimated. The clinical focus should be to improve patients' metabolic risk factors, diabetes and BMI, that are independently associated with liver stiffness. There is a need to consider modifying current treatment monitoring guidelines for methotrexate., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Electrocortical stimulation mapping (ECS) is widely used to identify essential language areas, but sentence-level processing has rarely been investigated., Methods: While undergoing awake surgery in the dominant left hemisphere, 6 subjects were asked to comprehend sentences varying in their demands on syntactic processing., Results: In all 6 subjects, stimulation of the inferior frontal gyrus disrupted comprehension of passive sentences, which critically depend on syntactic processing to correctly assign grammatical roles, without disrupting comprehension of simpler tasks. In 4 of the 6 subjects, these sites were localized to the pars opercularis. Sentence comprehension was also disrupted by stimulation of other perisylvian sites, but in a more variable manner., Conclusions: These findings suggest that there may be language regions that differentially contribute to sentence processing and which therefore are best identified using sentence-level tasks. The functional consequences of resecting these sites remain to be investigated.

Background/objective: To examine rates of counseling on driving for individuals with osteoarthritis (OA) and/or rheumatoid arthritis (RA) and evaluate the Health Assessment Questionnaire Disability Index (HAQ-DI) as a screening tool for further driving evaluation., Methods: A cross-sectional survey was completed by individuals recruited via ResearchMatch (a national web-based recruitment tool) between March 5 and April 20, 2020. Individuals with a current US driver's license, ≥18 years old, with self-reported OA and/or RA diagnosis were surveyed about driving difficulty and vehicle modification and completed a HAQ-DI assessment. Respondents were dichotomized based on reporting vehicle modification(s) due to arthritis versus no modification(s) for univariate and multivariate analyses., Results: Of 4,435 recruited patients, 304 (6.9%) met inclusion/exclusion criteria and completed the surveys. Of all respondents, 259 (85.2%) reported at least some difficulty with one or more driving activities, but only 47 (15.5%) reported discussion with a physician and/or healthcare professional. A total of 184 (60.5%) respondents had HAQ-DI ≥ 1 and were more likely to report vehicle modification(s) compared to respondents with HAQ-DI score < 1 (OR = 5.00, 95% CI = 2.69-9.32, p < 0.011) after controlling for age, gender, type of arthritis, and driving behaviors., Conclusion: Few respondents report discussion of driving difficulties with healthcare providers, although many report driving-related impairments, particularly those with HAQ-DI scores ≥ 1. Our data suggest a strong association between HAQ-DI scores and vehicle modification. The HAQ-DI may serve as a screening tool to predict a patient's need for driving evaluation and vehicle modification(s)., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Romaniello et al.)

Background: Chronic rhinosinusitis (CRS) is characterized by significant accumulation and thickening of mucus in the sinonasal cavities. One contributor of aberrant mucus production and impaired mucociliary clearance (MCC) is altered function of the sinonasal submucosal glands (SMGs), yet contributions of SMGs to upper airway disease initiation and progression remain unknown. The objective of this study was to characterize the morphology and secretory cell identities of the nasal septum SMGs in both healthy and CRS adults., Methods: Biopsies from adult participants with CRS without nasal polyps (CRSsNP, n = 4), CRS with nasal polyps (CRSwNP, n = 8), and non-CRS controls (n = 14) were collected from the posterior septum. Glandular morphology and mucus markers were investigated using histological techniques and high-resolution confocal microscopy., Results: Analysis revealed a significant decrease in gland density in the posterior septum of CRSsNP (28% ± 6.15%) and CRSwNP (23% ± 3.09%) compared to control participants (53% ± 1.59%, p < 0.0001). Further analysis of the CRS SMG secretory function revealed an overall decrease in Mucin 5B+ gland mucus being produced. Dilated and cystic ductal structures filled with inspissated mucus were also common to CRS glands., Conclusion: Here, we describe a significant alteration in SMG structure and function in the adult CRS posterior septum suggesting reduced gland contribution to MCC. The SMGs of both the nose and sinuses may represent targets for future therapeutic approaches., (© 2021 ARS-AAOA, LLC.)

Background and Purpose: Manual segmentation of white matter (WM) bundles requires extensive training and is prohibitively labor-intensive for large-scale studies. Automated segmentation methods are necessary in order to eliminate operator dependency and to enable reproducible studies. Significant changes in the WM landscape throughout childhood require flexible methods to capture the variance across the span of brain development., Methods: Here, we describe a novel automated segmentation tool called Cortically Constrained Shape Recognition (CCSR), which combines two complementary approaches: (1) anatomical connectivity priors based on FreeSurfer-derived regions of interest and (2) shape priors based on 3-dimensional streamline bundle atlases applied using RecoBundles. We tested the performance and repeatability of this approach by comparing volume and diffusion metrics of the main language WM tracts that were both manually and automatically segmented in a pediatric cohort acquired at the UCSF Dyslexia Center (n = 59; 25 females; average age: 11 ± 2; range: 7-14)., Results: The CCSR approach showed high agreement with the expert manual segmentations: across all tracts, the spatial overlap between tract volumes showed an average Dice Similarity Coefficient (DSC) of 0.76, and the fractional anisotropy (FA) on average had a Lin's Concordance Correlation Coefficient (CCC) of 0.81. The CCSR's repeatability in a subset of this cohort achieved a DSC of 0.92 on average across all tracts., Conclusion: This novel automated segmentation approach is a promising tool for reproducible large-scale tractography analyses in pediatric populations and particularly for the quantitative assessment of structural connections underlying various clinical presentations in neurodevelopmental disorders., (© 2021 American Society of Neuroimaging.)

Objectives: Outcomes in laryngology focus primarily on patient reported outcome measures (PROMs). The increasing number of questionnaires may lead to survey fatigue. We sought to determine the relationship between the newest questionnaire, Laryngopharyngeal Universal Measure of Perceived Sensation (LUMP), and other laryngology PROMs., Study Design: Cross-sectional study., Methods: Patients undergoing laryngology multidisciplinary evaluation prospectively completed laryngology questionnaires. Average summed scores between standard laryngology PROMs (ie, VHI-10, RSI, DI, CSI, EAT-10) and LUMP were compared. Expert consensus panel identified the most clinically relevant statements which were then compared to LUMP summed scores, in increasingly additive fashion., Results: Four hundred eighty patients (259 female) were assessed. Average age was 57.1 ± 17.7 years. Intraclass correlation coefficient (ICC) for each PROM in comparison to LUMP ranged from moderate to poor correlation: 0.64 (RSI), 0.55 (EAT-10), 0.50 (DI), 0.48 (CSI), and 0.34 (VHI-10). ICC for combinations of the five most clinically relevant individual items ranged from 0.29-0.53., Conclusions: Patients with self-reported globus had statistically significantly higher scores across all PROMs. RSI had moderate correlation with LUMP, and the five selected expert consensus items demonstrated weaker correlation. While RSI may serve as a moderately selective clinical proxy for the LUMP questionnaire, LUMP remains a validated tool with increased specificity for quantification of globus which may be especially important in the research setting. There is continued question about the need for multiple laryngologic PROMs to evaluate patient complaints, and survey reduction remains an area of interest to decrease respondent fatigue, optimize patient care, and quantify interventional success., Level of Evidence: 4 Laryngoscope, 131:1561-1565, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

In response to bone fracture, periosteal progenitor cells proliferate, expand, and differentiate to form cartilage and bone in the fracture callus. These cellular functions require the coordinated activation of multiple transcriptional programs, and the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) regulate osteochondroprogenitor activation during endochondral bone development. However, recent observations raise important distinctions between the signaling mechanisms used to control bone morphogenesis and repair. Here, we tested the hypothesis that YAP and TAZ regulate osteochondroprogenitor activation during endochondral bone fracture healing in mice. Constitutive YAP and/or TAZ deletion from Osterix-expressing cells impaired both cartilage callus formation and subsequent mineralization. However, this could be explained either by direct defects in osteochondroprogenitor differentiation after fracture or by developmental deficiencies in the progenitor cell pool before fracture. Consistent with the second possibility, we found that developmental YAP/TAZ deletion produced long bones with impaired periosteal thickness and cellularity. Therefore, to remove the contributions of developmental history, we next generated adult onset-inducible knockout mice (using Osx-Cre tetOff ) in which YAP and TAZ were deleted before fracture but after normal development. Adult onset-induced YAP/TAZ deletion had no effect on cartilaginous callus formation but impaired bone formation at 14 days post-fracture (dpf). Earlier, at 4 dpf, adult onset-induced YAP/TAZ deletion impaired the proliferation and expansion of osteoblast precursor cells located in the shoulder of the callus. Further, activated periosteal cells isolated from this region at 4 dpf exhibited impaired osteogenic differentiation in vitro upon YAP/TAZ deletion. Finally, confirming the effects on osteoblast function in vivo, adult onset-induced YAP/TAZ deletion impaired bone formation in the callus shoulder at 7 dpf before the initiation of endochondral ossification. Together, these data show that YAP and TAZ promote the expansion and differentiation of periosteal osteoblast precursors to accelerate bone fracture healing. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Background and Purpose: Neurosurgical resection is one of the few opportunities researchers have to image the human brain pre- and postfocal damage. A major challenge associated with brains undergoing surgical resection is that they often do not fit brain templates most image-processing methodologies are based on. Manual intervention is required to reconcile the pathology, requiring time investment and introducing reproducibility concerns, and extreme cases must be excluded., Methods: We propose an automatic longitudinal pipeline based on High Angular Resolution Diffusion Imaging acquisitions to facilitate a Pathway Lesion Symptom Mapping analysis relating focal white matter injury to functional deficits. This two-part approach includes (i) automatic segmentation of focal white matter injury from anisotropic power differences, and (ii) modeling disconnection using tractography on the single-subject level, which specifically identifies the disconnections associated with focal white matter damage., Results: The advantages of this approach stem from (1) objective and automatic lesion segmentation and tractogram generation, (2) objective and precise segmentation of affected tissue likely to be associated with damage to long-range white matter pathways (defined by anisotropic power), (3) good performance even in the cases of anatomical distortions by use of nonlinear tensor-based registration, which aligns images using an approach sensitive to white matter microstructure., Conclusions: Mapping a system as variable and complex as the human brain requires sample sizes much larger than the current technology can support. This pipeline can be used to execute large-scale, sufficiently powered analyses by meeting the need for an automatic approach to objectively quantify white matter disconnection., (© 2020 American Society of Neuroimaging.)

Investigative studies of white matter (WM) brain structures using diffusion MRI (dMRI) tractography frequently require manual WM bundle segmentation, often called "virtual dissection." Human errors and personal decisions make these manual segmentations hard to reproduce, which have not yet been quantified by the dMRI community. It is our opinion that if the field of dMRI tractography wants to be taken seriously as a widespread clinical tool, it is imperative to harmonize WM bundle segmentations and develop protocols aimed to be used in clinical settings. The EADC-ADNI Harmonized Hippocampal Protocol achieved such standardization through a series of steps that must be reproduced for every WM bundle. This article is an observation of the problematic. A specific bundle segmentation protocol was used in order to provide a real-life example, but the contribution of this article is to discuss the need for reproducibility and standardized protocol, as for any measurement tool. This study required the participation of 11 experts and 13 nonexperts in neuroanatomy and "virtual dissection" across various laboratories and hospitals. Intra-rater agreement (Dice score) was approximately 0.77, while inter-rater was approximately 0.65. The protocol provided to participants was not necessarily optimal, but its design mimics, in essence, what will be required in future protocols. Reporting tractometry results such as average fractional anisotropy, volume or streamline count of a particular bundle without a sufficient reproducibility score could make the analysis and interpretations more difficult. Coordinated efforts by the diffusion MRI tractography community are needed to quantify and account for reproducibility of WM bundle extraction protocols in this era of open and collaborative science., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Background: MR Tractography enables non-invasive preoperative depiction of language subcortical tracts, which is crucial for the presurgical work-up of brain tumors; however, it cannot evaluate the exact function of the fibers., Purpose: A systematic pipeline was developed to combine tractography reconstruction of language fiber bundles, based on anatomical landmarks (Anatomical-T), with language fMRI cortical activations. A fMRI-targeted Tractography (fMRI-T) was thus obtained, depicting the subsets of the anatomical tracts whose endpoints are located inside a fMRI activation. We hypothesized that fMRI-T could provide additional functional information regarding the subcortical structures, better reflecting the eloquent white matter structures identified intraoperatively., Methods: Both Anatomical-T and fMRI-T of language fiber tracts were performed on 16 controls and preoperatively on 16 patients with left-hemisphere brain tumors, using a q -ball residual bootstrap algorithm based on High Angular Resolution Diffusion Imaging (HARDI) datasets ( b = 3000 s/mm 2 ; 60 directions); fMRI ROIs were obtained using picture naming, verbal fluency, and auditory verb generation tasks. In healthy controls, normalized MNI atlases of fMRI-T and Anatomical-T were obtained. In patients, the surgical resection of the tumor was pursued by identifying eloquent structures with intraoperative direct electrical stimulation mapping and extending surgery to the functional boundaries. Post-surgical MRI allowed to identify Anatomical-T and fMRI-T non-eloquent portions removed during the procedure., Results: MNI Atlases showed that fMRI-T is a subset of Anatomical-T, and that different task-specific fMRI-T involve both shared subsets and task-specific subsets - e.g., verbal fluency fMRI-T strongly involves dorsal frontal tracts, consistently with the phonogical-articulatory features of this task. A quantitative analysis in patients revealed that Anatomical-T removed portions of AF-SLF and IFOF were significantly greater than verbal fluency fMRI-T ones, suggesting that fMRI-T is a more specific approach. In addition, qualitative analyses showed that fMRI-T AF-SLF and IFOF predict the exact functional limits of resection with increased specificity when compared to Anatomical-T counterparts, especially the superior frontal portion of IFOF, in a subcohort of patients., Conclusion: These results suggest that performing fMRI-T in addition to the 'classic' Anatomical-T may be useful in a preoperative setting to identify the 'high-risk subsets' that should be spared during the surgical procedure., (Copyright © 2020 Sanvito, Caverzasi, Riva, Jordan, Blasi, Scifo, Iadanza, Crespi, Cirillo, Casarotti, Leonetti, Puglisi, Grimaldi, Bello, Gorno-Tempini, Henry, Falini and Castellano.)

Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8 kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-β as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

According to the U.S. Census Bureau, 18.2 million veterans were living in the United States in 2017, of whom 1.6 million were female. Less than one-half of all veterans receive care at a Veterans Health Administration or military treatment facility, leaving most to receive services from primary care physicians. Injuries and illnesses common among this patient population include musculoskeletal injuries and chronic pain, mental health issues such as posttraumatic stress disorder (PTSD) and moral injury, traumatic brain injury, chemical and noise exposures, and infectious disease concerns. Family physicians should ask about military service and be well informed about the range of veterans' health concerns, particularly PTSD, depression, and suicidality. Physicians should screen veterans for depression using the Patient Health Questionnaire-9 and for PTSD using the PTSD Checklist for DSM-5. Veterans with traumatic brain injury should be screened specifically for comorbid PTSD and chronic pain because the diagnosis informs treatment. Exposures to loud noise, chemicals, and infectious diseases are prevalent and can cause disability. Family physicians can use available resources and clinical practice guidelines such as those from the U.S. Department of Veterans Affairs and Department of Defense to inform care and to assist veterans.

Objective: Herein, the authors report their experience with intraoperative stimulation mapping to locate the descending subcortical motor pathways in patients undergoing surgery for hemispheric gliomas within or adjacent to the rolandic cortex, with particular description of the morbidity and functional outcomes associated with this technique., Methods: This is a retrospective analysis of patients who, in the period between 1997 and 2016, had undergone resection of hemispheric perirolandic gliomas within or adjacent to descending motor pathways. Data regarding intraoperative stimulation mapping and patient postoperative neurological status were collected., Results: Of 702 patients, stimulation mapping identified the descending motor pathways in 300 cases (43%). A new or worsened motor deficit was seen postoperatively in 210 cases (30%). Among these 210 cases, there was improvement in motor function to baseline levels by 3 months postoperatively in 161 cases (77%), whereas the deficit remained in 49 cases (23%). The majority (65%) of long-term deficits (persisting beyond 3 months) were mild or moderate (antigravity strength or better). On multivariate analysis, patients in whom the subcortical motor pathways had been identified with stimulation mapping during surgery were more likely to develop an additional and/or worsened motor deficit postoperatively than were those in whom the subcortical pathways had not been found (45% vs 19%, respectively, p < 0.001). This difference remained when considering the likelihood of a long-term deficit (i.e., persisting > 3 months; 12% vs 3.2%, p < 0.001). A higher tumor grade and the presence of a preoperative motor deficit were also associated with higher rates of motor deficits persisting long-term. A region of restricted diffusion adjacent to the resection cavity was seen in 20 patients with long-term deficits (41%) and was more common in cases in which the motor pathways were not identified (69%). Long-term deficits that occur in settings in which the subcortical motor pathways are not identified seem in large part due to ischemic injury to descending tracts., Conclusions: Stimulation mapping allows surgeons to identify the descending motor pathways during resection of tumors in perirolandic regions and to attain an acceptable rate of morbidity in these high-risk cases.

Background: Diffusion-weighted magnetic resonance imaging tractography can be used to create models of white matter fascicles. Anatomical and pathological variability between subjects can drastically alter the tractography output, so standardizing results across a cohort is nontrivial. Furthermore, tractography methods have inherently low reproducibility due to stochasticity (for probabilistic methods) and subjective decisions, since the final fascicle model often requires a manual intervention step performed by an expert human operator to control both outliers and systematic false-positive pathways, as defined by prior knowledge of anatomy., Methods: We present an approach that computationally assigns a cluster confidence index (CCI) reflecting the reproducibility of that pathway in the context of a streamline dataset. This metric is a tractography algorithm-agnostic tool that can be applied to any dataset of streamlines., Results: Applications of this metric include systematic elimination of outlier streamlines using a CCI threshold and interactive filtering by CCI to facilitate manual segmentation of fascicle models., Conclusions: This method is intended to replace the application of a streamline density threshold so that outliers are eliminated based on low pathway density instead of voxel-wise density., (Copyright © 2017 by the American Society of Neuroimaging.)

Gout is the most common cause of inflammatory arthritis worldwide. Despite clinical cure being achievable and multiple evidence-based guidelines having been published, the incidence and prevalence continues to increase and the condition remains undertreated. Concerns regarding allopurinol have limited its use in those with renal impairment. Febuxostat, a novel xanthine oxidase inhibitor requiring no dose adjustment in mild-moderate renal impairment was launched in the United Kingdom (UK) in 2010. We review published data on the efficacy, safety and tolerability of febuxostat and provide an opinion on its place in the management of gout in the UK in the context of other published guidelines. One phase II trial, multiple phase III trials [febuxostat versus allopurinol controlled trial (FACT), APEX, CONFIRMS] and two open-label extension trials have demonstrated febuxostat given at the doses commonly used in UK practice (80 mg, 120 mg) to reduce serum urate more effectively than those receiving fixed-dose allopurinol. Overall adverse event rates were comparable across treatment groups aside from gout flare (more common in febuxostat-treated patients) and concerns regarding cardiovascular toxicity are being further evaluated in two large trials. If the outcomes of these are favourable, we would anticipate a marked increase in the use of febuxostat in the UK market. We would advocate the use of febuxostat to target a serum urate < 0.3 mmol/l (5 mg/dl) as a second-line urate-lowering therapy in patients with hyperuricaemia, and clinical gout in those intolerant of allopurinol, or in those in whose renal function precludes optimal dose escalation to achieve target serum urate. We would advise prophylaxis against gouty flare with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), or Cyclo-oxygenase-2 selective NSAID (COXIB) after febuxostat initiation., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

In this study, we examined the lived experiences of an understudied subgroup, Portuguese American gay men, within the context of sexual script theory. We employed a phenomenological study design with eight men to provide a more in-depth analysis of their sociocultural sexual behaviours. Recruitment was conducted through word of mouth and a snowball approach beginning with two well-known HIV education and prevention outreach centres in southeastern Massachusetts. In this study, the sexual scripts of the participants were conceptualised within the three domains of cultural, interpersonal and intrapsychic scripts. Our findings suggest the three scripts are constantly interacting and informing one another. This ongoing negotiation influences the way our participants position their sexuality within the broader context of their everyday life within the US Portuguese community. Participants script their sexuality while they navigate multiple but separate entities within their culture, their religion and their families. Learning from these experiences could have important implications for the development of HIV prevention programmes for specific subgroups of men who have sex with men.

Common variable immunodeficiency (CVID) is readily considered in patients presenting with recurrent sino-pulmonary infections, however this disease has a broad range of clinical manifestations and diagnosis can be delayed by several years. We present the case of a 44-year-old postpartum female who presented with nausea, vomiting and abdominal distension. Four years prior, she was hospitalized for treatment of immune thrombocytopenia (ITP) with splenectomy and rituximab followed by two episodes of bacterial meningitis despite immunizations. The recurrent meningitis had been attributed to splenectomy and immunotherapy. During this hospitalization, extensive workup for gastrointestinal pathology was negative and she was diagnosed with intestinal pseudo-obstruction. Her hospital course was complicated by development of severe pseudomonas pneumonia, and subsequent immunoglobulin testing and impaired antibody response to vaccines were consistent with CVID. We review the clinical presentation of CVID, its association with autoimmune disease, and treatment implications, specifically the impact of rituximab therapy and splenectomy on immunoglobulin function and risk of serious infection. Intestinal pseudo-obstruction has been reported in children with CVID, but literature search failed to reveal similar presentation in adults. Physicians must consider the heterogeneous clinical manifestations of CVID to avoid delay in diagnosis and treatment. Institution of appropriate therapy with immunoglobulin replacement is important to decrease risk of serious infection.

OBJECT Diffusion MRI has uniquely enabled in vivo delineation of white matter tracts, which has been applied to the segmentation of eloquent pathways for intraoperative mapping. The last decade has also seen the development from earlier diffusion tensor models to higher-order models, which take advantage of high angular resolution diffusion-weighted imaging (HARDI) techniques. However, these advanced methods have not been widely implemented for routine preoperative and intraoperative mapping. The authors report on the application of residual bootstrap q-ball fiber tracking for routine mapping of potentially functional language pathways, the development of a system for rating tract injury to evaluate the impact on clinically assessed language function, and initial results predicting long-term language deficits following glioma resection. METHODS The authors have developed methods for the segmentation of 8 putative language pathways including dorsal phonological pathways and ventral semantic streams using residual bootstrap q-ball fiber tracking. Furthermore, they have implemented clinically feasible preoperative acquisition and processing of HARDI data to delineate these pathways for neurosurgical application. They have also developed a rating scale based on the altered fiber tract density to estimate the degree of pathway injury, applying these ratings to a subset of 35 patients with pre- and postoperative fiber tracking. The relationships between specific pathways and clinical language deficits were assessed to determine which pathways are predictive of long-term language deficits following surgery. RESULTS This tracking methodology has been routinely implemented for preoperative mapping in patients with brain gliomas who have undergone awake brain tumor resection at the University of California, San Francisco (more than 300 patients to date). In this particular study the authors investigated the white matter structure status and language correlation in a subcohort of 35 subjects both pre- and postsurgery. The rating scales developed for fiber pathway damage were found to be highly reproducible and provided significant correlations with language performance. Preservation of the left arcuate fasciculus (AF) and the temporoparietal component of the superior longitudinal fasciculus (SLF-tp) was consistent in all patients without language deficits (p < 0.001) at the long-term follow-up. Furthermore, in patients with short-term language deficits, the AF and/or SLF-tp were affected, and damage to these 2 pathways was predictive of a long-term language deficit (p = 0.005). CONCLUSIONS The authors demonstrated the successful application of q-ball tracking in presurgical planning for language pathways in brain tumor patients and in assessing white matter tract integrity postoperatively to predict long-term language dysfunction. These initial results predicting long-term language deficits following tumor resection indicate that postoperative injury to dorsal language pathways may be prognostic for long-term clinical language deficits. Study results suggest the importance of dorsal stream tract preservation to reduce language deficits in patients undergoing glioma resection, as well as the potential prognostic value of assessing postoperative injury to dorsal language pathways to predict long-term clinical language deficits.

Importance: In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques., Objectives: To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels., Design, Setting, and Participants: Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital., Main Outcomes and Measures: Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates., Results: Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P < .001 at T8/T9 and 1.37 mm2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P < .001 at T8/T9 and 3.04 mm2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume., Conclusions and Relevance: Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

Purpose of Review: Gout is a true crystal deposition disease, extremely painful and bone and tissue damaging if untreated. It is the only curable form of arthritis. Although we have many treatments to cure gout, it is a disease that is consistently undertreated/mismanaged and perceived by clinicians and the lay public as a 'laughable condition' with the patients' lifestyle often held erroneously to account. This article would give you a good understanding of modern and established pharmacological and nonpharmacological treatments used in the management of acute and chronic gout and how to 'treat to target' to cure the disease., Recent Findings: Many of the drugs we use to manage patients with gouty arthritis have been in existence since the 1970s and 1980s. In the past few years, because of the improved physiological understanding of gout, new innovative treatments such as anti-IL inhibitors, a nonxanthine oxidase inhibitor and the uricase enzymes have been developed adding to our armamentarium of drugs., Summary: With the introduction of new research, we have been able to explore how to also use established treatments more effectively, raising the profile of gout and its best management and introducing the principle of treating the patient to urate target.

Gout is an inflammatory arthritis characterized by self-limiting but excruciatingly painful acute attacks. These are a consequence of monosodium urate (MSU) crystals being deposited within articular or periarticular tissue. Chronic tophaceous gout can develop after years of acute intermittent gout. Recent discoveries, including the role of the inflammasome and intracellular events demonstrating that pro-inflammatory cytokines, IL-1 beta, -8 and TNF-alpha, promote neutrophil influx. Also, genetic advances with the identification of the URAT-1 transporter and genetic variation in SLC 2A9 as a key regulator of urate homoeostasis, have given us deeper understanding of the pathophysiology of gout, and also allow for more targeted treatments. Hopefully, new and emerging therapeutic options will reduce treatment-resistant gout in patients who are unresponsive or unable to take traditional urate lowering therapy. The development of new therapies may also increase patient numbers being treated in the specialist setting, which may have several secondary benefits.

Three experiments were conducted on anestrous ewes of Suffolk, Dorset, and Katahdin breeding to examine the potential value of GnRH to improve ovulation and pregnancy in response to introduction of rams. In Experiment 1, treatment with GnRH 2d after treatment with progesterone (P(4); 25mg i.m.) at introduction of rams was compared to treatment with P(4) alone at the time of introduction of rams. Treatment with GnRH did not increase percentages of ewes with a corpus luteum (CL) 14d after introduction of rams, pregnant 32d after treatment with PGF(2)alpha 14d after introduction of rams, or percent of treated ewes lambing to all services. In Experiment 2, treatments with GnRH on day 2, 7, or both after introduction of rams were compared. Treatments did not differ in mean estrous response, percentages of ewes with a detectable CL or number of CL present on day 11, or mean pregnancy and lambing rates. Therefore, neither one nor two injections of GnRH at these times appeared to be effective to induce anestrous ewes to breed. In Experiment 3, treatments compared included GnRH 4d before introduction of rams, GnRH 4d before and 1d after introduction of rams, ram introduction alone, and treatment with P(4) (25mg i.m.) at the time of introduction of rams. Percentages of ewes with concentrations of P(4) greater than 1ng/mL (indicating formation of CL had occurred) 7d after ram introduction tended to be greater (P<0.07) in ewes treated with GnRH or P(4) than in control ewes treated with ram introduction alone. However, there was no difference in P(4) concentrations between groups by day 11 or 12 after introduction of rams. Estrous response rates and percentages of ewes pregnant 95d after PGF(2)alpha was administered (on day 12 after introduction of rams) tended to be greater (P=0.08 and 0.06, respectively) in ewes treated with GnRH or P(4) than in ewes exposed to rams only. There was no difference in response variables between ewes treated with GnRH 4d before introduction of rams and ewes treated with GnRH 4d before and 1d after introduction of rams. In conclusion, treatment with GnRH 4d before ram introduction showed promise as an alternative to treatment with P(4) to improve the ovulatory response and reproductive performance of ewes introduced to rams during seasonal anestrus.

Objectives: Patients with knee osteoarthritis (OA) often suffer pain that is not fully controlled by analgesics and often require intra-articular therapies. The aim of this study was to compare the benefits of intra-articular corticosteroid injections (CSIs) and tidal irrigation (TI) in patients with OA of the knee., Methods: We performed a dual-centre, single blind, randomised, parallel group trial comparing TI and CSI. Patients with knee OA were randomised to either irrigation using a 3.2mm arthroscope under local anaesthesia or an intra-articular injection of 40 mg triamcinolone acetonide and 1% lidocaine. Patients were followed for 6 months. The primary outcome measure was the Western Ontario and McMaster Universities OA Index total pain score (visual analogue scale, VAS)., Results: One hundred and fifty patients were recruited of whom 71 received TI and 79 CSI. In both treatment groups, over 80% of patients reported improvement at 2 and 4 weeks. After this time, the benefit of CSI decreased whereas that of TI was maintained: at 26 weeks the pain relief afforded by TI was significantly greater than that of CSI. At 26 weeks 29% of the CSI group reported improvement vs 64% of the TI group (P<0.001). Patients with a knee effusion responded better to both treatments, however, this was most apparent for CSI. Patients with less severe radiographic OA also obtained the greatest improvement from both treatments., Conclusion: Both procedures lead to significant short-term pain relief of at least 4 weeks, however, TI displayed a significantly greater duration of benefit. Patients with effusions and milder radiographic change obtained the best response to treatment.

Objective: To investigate the association between biochemical markers of bone, cartilage, and synovial turnover with the presence and severity of knee osteoarthritis (OA) in men., Methods: 176 men aged 59-70 years from the MRC Hertfordshire Cohort were studied. Weightbearing anteroposterior and lateral semiflexed radiographs were taken of both knees. A lifestyle questionnaire including basic demographic details and a questionnaire detailing knee pain was completed. This random sample was stratified based on the Kellgren and Lawrence (K&L) score, and the following biochemical markers were analysed: serum osteocalcin, serum C-terminal crosslinked telopeptide of type I collagen (CTX-I), urinary C-terminal crosslinked telopeptide of type II collagen (CTX-II), and urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-Pyd)., Results: Age, body mass index (BMI), social class, smoking, and alcohol consumption were similar across K&L grades. Only one subject had a grade 4 K&L score, and was amalgamated with grade 3 subjects. A strong significant association was found between the presence of knee OA and urinary CTX-II and urinary Glc-Gal-Pyd (p=0.0001 and p=0.009), which persisted after adjustment for age and BMI. A significant positive association was also found between urinary CTX-II and urinary Glc-Gal-Pyd and the severity of K&L grade, joint space narrowing, and osteophytes scores, which persisted after adjustment for age and BMI. No associations between the presence and severity of knee OA were found for serum CTX-I or serum osteocalcin., Conclusions: Urinary CTX-II and Glc-Gal-Pyd, but not systemic markers of bone turnover, are strongly associated with disease severity and the presence of OA at the tibiofemoral and patellofemoral joints in men.

Rationale, Aims and Objectives: Clinical practice guidelines often grade the 'strength' of their recommendations according to the robustness of the supporting research evidence. The existing methodology does not allow the strength of recommendation (SOR) to be upgraded for recommendations for which randomized controlled trials are impractical or unethical. The purpose of this study was to develop a new method of determining SOR, incorporating both research evidence and expert opinion., Methods: A Delphi technique was employed to produce 10 recommendations for the role of exercise therapy in the management of osteoarthritis of the hip or knee. The SOR for each recommendation was determined by the traditional method, closely linked to the category of research evidence found on a systematic literature search, and on a visual analogue scale (VAS). Recommendations were grouped A-D according to the traditional SOR allocated and the mean VAS calculated. Difference across the groups was assessed by one-way ANOVA variance analysis., Results: Mean VAS scores for the traditional SOR groups A-D and one proposition which was 'not recommended' showed significant linearity on one-way ANOVA. However, certain recommendations which, for practical reasons, could not assessed in randomized controlled trials and therefore could not be recommended strongly by the traditional methodology, were allocated a strong recommendation by VAS., Conclusions: This new system of grading strength of SOR is less constrained than the traditional methodology and offers the advantage of allowing SOR for procedures which cannot be assessed in RCTs for practical or ethical reasons to be upgraded according to expert opinion.

Objective: To investigate risk factors for adult lumbar spine osteoarthritis (OA) including polymorphisms of the vitamin D receptor gene (VDR) and birthweight., Methods: Plain radiographs of the lumbar spine were taken in 392 healthy subjects and graded for osteophytes and disc space narrowing (DSN); demographic data were collected. Details of birthweight and weight at 1 year were retrieved from historical records. VDR gene allelic variation was analyzed in 291 subjects., Results: The mean age of the cohort was 65.8 years; mean weight was 68.9 kg in women and 80.1 kg and men. Osteophytes of grade >/= 2 were found in 63.5% of this cohort; DSN >/= 2 was present in 14.3% of subjects. Increasing osteophyte severity was significantly associated with age, adult weight, and manual social class; DSN was not. Presence and severity of osteophytes were associated with low birthweight and lower weight at 1 year in men, but not in women. No associations were found for DSN. The B allele of the VDR gene was associated with increasing severity of osteophyte. There was a significant interaction between birthweight and VDR gene in determining risk of osteophytosis in men (p for interaction = 0.04). The VDR-birthweight interaction pattern was similar but not statistically significant in women., Conclusion: Lumbar spine OA was a prevalent finding in this cohort. Both birthweight and polymorphisms in the VDR gene were associated with the presence of lumbar spine osteophytes and a significant interaction was observed between these 2 factors in men.