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Purpose: After anterior cruciate ligament reconstruction (ACL-R), a localised scar tissue called cyclops lesion may develop anterior to the graft causing knee extension deficits, pain, oedema, clicking and reduced knee function. This study determined the incidence of arthroscopic resection of a cyclops lesion within 2 years after ACL-R and investigated the associations of patient characteristics and surgical techniques with the need for arthroscopic resection of a cyclops lesion., Methods: This study included patients who underwent primary ACL-R with adult surgical technique from 2005 to 2019 at Aarhus University Hospital, Denmark. The cohort was identified in a national registry. To identify patients who had resected a cyclops lesion within the first 2 years after ACL-R, patients' surgical records were reviewed., Results: In 2005-2019, 2556 patients underwent primary ACL-R; 176 developed cyclops lesions that were resected within 2 years, equivalent to an incidence of 6.9% (95% confidence interval [CI]: 5.9-7.9). When stratified by the femoral drilling technique used, this incidence was 8.9% (95% CI: 7.7-10.3) with the anteromedial technique and 1.9% (95% CI: 1.0-3.1) with the transtibial technique. The incidence was 8.5% (95% CI: 6.8-10.3) in women and 5.7% (95% CI: 4.6-7.1) in men. Age, graft choice and the presence of cartilage or meniscal lesions did not affect the incidence., Conclusion: The overall incidence of a cyclops lesion removal within 2 years post-ACL-R was 6.9%. This was five times higher with the anteromedial femoral drilling technique than with the transtibial technique. Women had a 47% higher incidence of cyclops lesion removal than men. This is relevant for the surgeon when planning an ACL-R., Level of Evidence: Level II., (© 2024 European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: While outcomes of posterior cruciate ligament (PCL) injuries treated surgically are well described, prospective studies reporting outcomes of exercise interventions are lacking., Purpose: The purpose of this study was to investigate changes in patient-reported outcomes of a physiotherapy-led exercise and support brace intervention in patients with acute injury of the PCL over a two-year follow-up period. Furthermore, this study sought to investigate changes in isometric knee muscle strength over an eight-month follow-up period, and finally to report conversion to surgical reconstruction over a two-year follow-up period., Study Design: Case series study, prospective., Methods: Fifty patients with an acute injury of the PCL were treated with a brace and a physiotherapy-led exercise intervention and followed prospectively. Changes in patient-reported outcomes were measured with the International Knee Documentation Committee Subjective Knee Form (IKDC-SKF) and the Knee injury and Osteoarthritis Outcome Score (KOOS) from baseline (diagnosis) to two-year follow-up. Furthermore, changes in isometric knee flexion and extension strength were measured with a static strength dynamometer from 16 weeks after diagnosis to one-year follow-up. Conversion to surgery was prospectively extracted from medical records. Mean changes were analyzed with a mixed effects model with time as a fixed factor., Results: The IKDC-SKF score improved 28 (95%CI 24-33) IKDC points from baseline to two-year follow-up. Isometric knee flexion strength of the injured knee increased 0.18 (95%CI 0.11-0.25) Nm/kg from 16 weeks after diagnosis to one-year follow-up, corresponding to an increase of 16%. In contrast, isometric knee extension strength of the injured knee did not change (0.12 (95%CI 0.00-0.24) Nm/kg, p=0.042). Over two years, seven patients converted to PCL surgical reconstruction. One and two-year follow-up were completed by 46 and 31 patients, respectively., Conclusions: The physiotherapy-led exercise and support brace intervention demonstrated clinically relevant improvements in patient-reported outcomes and knee flexion strength, and the risk of PCL surgical reconstruction was considered low within the first two years., Level of Evidence: 3b©The Author(s)., Competing Interests: The authors declare that they have no financial or non-financial interests to disclose.

In family caregiving interventions for adults with health problems, tailoring has become the norm. Studies that evaluate tailored interventions, however, have rarely included intentional variation in dosage or explored the dosage-outcome association. In this Part 1 secondary analysis, we examine dosage and outcomes in intervention families ( N = 116) who participated in the Oregon Health & Science University/Kaiser Permanente Northwest Region Family Care Study. The Family Care Study was a randomized controlled trial to evaluate the preparedness, skill, enrichment, and predictability (PREP) intervention with caregiving families of frail older adults referred for skilled home health. Tailoring of PREP began with assessment by the PREP nurse. Families then identified and selected care-related issues to work on with their PREP nurse; family needs and preferences guided the number and timing of nurse visits and calls. Families selected a median of 3 (range = 0 to 10) care-related issues in five categories: direct care (chosen by 57% of families), transitions (40%), caregiver strain and health (40%), arranging care (33%), and enrichment (22%). The number of issues strongly predicted number of PREP nurse visits and calls, whereas nurse visits in turn predicted caregivers' reports of improved family care and usefulness of home health assistance, highlighting the importance of visits for achieving outcomes. [ Research in Gerontological Nursing, 16 (2), 57-70.].

Purpose: Social, emotional and behavioural difficulties (SEBD) in childhood are associated with negative consequences across the life course. Children with developmental language disorder have been identified as being at risk of developing SEBD but it is unclear whether a similar risk exists for children with speech sound disorder, a condition which impacts on children's ability to make themselves understood and has been shown to be associated with poor educational outcomes., Methods: Participants were children who attended the 8-year-old clinic in the Avon Longitudinal Study of Parents and Children ( N  = 7390). Children with speech sound disorder that had persisted beyond the period of typical speech acquisition (persistent speech disorder [PSD]) at age 8 were identified from recordings and transcriptions of speech samples ( N  = 263). Parent-, teacher- and child-reported questionnaires and interviews including the Strengths and Difficulties Questionnaire, Short Moods and Feelings Questionnaire and measures for antisocial and risk-taking behaviour were used to provide outcome scores for SEBD at 10-14 years in a series of regression analyses., Results: Following adjustment for biological sex, socio-economic status and Intelligence Quotient, children with PSD at age 8 were more likely to show peer problems at age 10-11 years compared with their peers, as reported by teachers and parents. Teachers were more likely to report problems with emotionality. Children with PSD were no more likely to report symptoms of depression than their peers. No associations were observed between PSD, risk of antisocial behaviour, trying alcohol at age 10 or smoking cigarettes at age 14., Conclusions: Children with PSD may be at risk in terms of their peer relationships. This could impact on their wellbeing and, while not observed at this age, may lead to depressive symptoms in older childhood and adolescence. There is also the potential that these symptoms may impact on educational outcomes., Competing Interests: The authors have declared that they have no competing or potential conflicts of interest., (© 2023 The Authors. JCPP Advances published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Nitric oxide (NO) is a free radical with a signaling capacity. Its cellular functions are achieved mainly through S-nitrosation where thioredoxin (hTrx) is pivotal in the S-transnitrosation to specific cellular targets. In this study, we use NMR spectroscopy and mass spectrometry to follow the mechanism of S-(trans)nitrosation of hTrx. We describe a site-specific path for S-nitrosation by measuring the reactivity of each of the 5 cysteines of hTrx using cysteine mutants. We showed the interdependence of the three cysteines in the nitrosative site. C73 is the most reactive and is responsible for all S-transnitrosation to other cellular targets. We observed NO internal transfers leading to C62 S-nitrosation , which serves as a storage site for NO. C69-SNO only forms under nitrosative stress, leading to hTrx nuclear translocation.

Aim: To assess revision rates and postoperative mortality in patients undergoing hip arthroplasty (HA) for inflammatory arthritis compared to hip osteoarthritis (OA)., Methods: The analysis was conducted among cases of HA that were recorded in the National Joint Registry for England and Wales (NJR) between April 2003 and December 2012 and linked to Office for National Statistics mortality records. Procedures were identified where the indication for surgery was listed as seropositive rheumatoid arthritis (RA), ankylosing spondylitis (AS), other inflammatory arthritis (otherIA), or OA. 5-year revision risk and 90-day postoperative mortality according to indication were compared using Cox regression models adjusted for age, sex, American Society of Anaesthesiologists (ASA) grade, year of operation, implant type, and surgical approach., Results: The cohort included 1457 HA procedures conducted for RA, 615 for AS, 1000 for otherIA, and 183,108 for OA. When compared with OA, there was no increased revision risk for any form of inflammatory arthritis (adjusted HRs: RA: 0.93 (0.64-1.35); AS: 1.14 (0.73-1.79); otherIA: 1.08 (0.73-1.59)). Postoperative 90-day mortality was increased for RA when compared with OA (adjusted HR: 2.86 (1.68-4.88)), but not for AS (adjusted HR: 1.56 (0.59-4.18)) or otherIA (adjusted HR: 0.64 (0.16-2.55))., Conclusions: The revision risk in HA performed for all types of inflammatory arthritis is similar to that for HA performed for OA. The 3-fold increased risk of 90-day mortality in patients with RA compared with OA highlights the need for active management of associated comorbidities in RA patients during the perioperative period.

BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein present on many cancers. Zilovertamab vedotin (ZV) is an antibody–drug conjugate comprising a monoclonal antibody recognizing extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin monomethyl auristatin E. METHODS: In this phase 1, first-in-human, dose-escalation study, we accrued patients with previously treated lymphoid cancers to receive ZV every 3 weeks until the occurrence of cancer progression or unacceptable toxicity had occurred. RESULTS: We enrolled 32 patients with tumor histologies of mantle cell lymphoma (MCL) (n=15), chronic lymphocytic leukemia (n=7), diffuse large B-cell lymphoma (DLBCL) (n=5), follicular lymphoma (n=3), Richter transformation lymphoma (n=1), or marginal zone lymphoma (n=1). Patients had received a median of four previous drug and/or cellular therapies. Starting dose levels were 0.5 (n=1), 1.0 (n=3), 1.5 (n=3), 2.25 (n=11), and 2.5 (n=14) mg per kg of body weight (mg/kg). Pharmacokinetic and pharmacodynamic data documented systemic ZV exposure and exposure-dependent ZV targeting of ROR1 on circulating tumor cells. As expected with an monomethyl auristatin E-containing antibody–drug conjugate, adverse events (AEs) included acute neutropenia and cumulative neuropathy resulting in a recommended ZV dosing regimen of 2.5 mg/kg every 3 weeks. No clinically concerning AEs occurred to suggest ROR1-mediated toxicities or nonspecific ZV binding to normal tissues. ZV induced objective tumor responses in 7 of 15 patients with MCL (47%; 4 partial and 3 complete) and in 3 of 5 patients with DLBCL (60%; 1 partial and 2 complete); objective tumor responses were not observed among patients with other tumor types. CONCLUSIONS: In heavily pretreated patients, ZV demonstrated no unexpected toxicities and showed evidence of antitumor activity, providing clinical proof of concept for selective targeting of ROR1 as a potential new approach to cancer therapy. (ClinicalTrials.gov number, NCT03833180.)

Anthrax is caused by Bacillus anthracis and can result in nearly 100% mortality due in part to anthrax toxin. Antimalarial amodiaquine (AQ) acts as a host-oriented inhibitor of anthrax toxin endocytosis. Here, we determined the pharmacokinetics and safety of AQ in mice, rabbits, and humans as well as the efficacy in the fly, mouse, and rabbit models of anthrax infection. In the therapeutic-intervention studies, AQ nearly doubled the survival of mice infected subcutaneously with a B. anthracis dose lethal to 60% of the animals (LD 60 ). In rabbits challenged with 200 LD 50 of aerosolized B. anthracis , AQ as a monotherapy delayed death, doubled the survival rate of infected animals that received a suboptimal amount of antibacterial levofloxacin, and reduced bacteremia and toxemia in tissues. Surprisingly, the anthrax efficacy of AQ relies on an additional host macrophage-directed antibacterial mechanism, which was validated in the toxin-independent Drosophila model of Bacillus infection. Lastly, a systematic literature review of the safety and pharmacokinetics of AQ in humans from over 2 000 published articles revealed that AQ is likely safe when taken as prescribed, and its pharmacokinetics predicts anthrax efficacy in humans. Our results support the future examination of AQ as adjunctive therapy for the prophylactic anthrax treatment.

Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL), typically to an aggressive lymphoma. Treatment options for RS are limited and the disease is often fatal. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed on CLL cells and other cancers but not on healthy adult tissues, making it an attractive, tumor-specific therapeutic target. VLS-101 is being developed as an antibody-drug conjugate (ADC) for therapy of ROR1-expressing (ROR1+) cancers. VLS-101 comprises UC-961 (a humanized immunoglobulin G1 monoclonal antibody that binds an extracellular epitope of human ROR1), a maleimidocaproyl-valine-citrulline-para-aminobenzoate linker, and the antimicrotubule cytotoxin monomethyl auristatin E (MMAE). VLS-101 binding to ROR1 results in rapid cellular internalization and delivery of MMAE to induce tumor cell death. We studied 4 RS patient-derived xenografts (RS-PDXs) with varying levels of ROR1 expression (11%, 32%, 85%, and 99% of cells). VLS-101 showed no efficacy in the lowest-expressing RS-PDX but induced complete remissions in those with higher levels of ROR1 expression. Responses were maintained during the posttherapy period, particularly after higher VLS-101 doses. In systemic ROR1+ RS-PDXs, VLS-101 dramatically decreased tumor burden in all RS-colonized tissues and significantly prolonged survival. Animals showed no adverse effects or weight loss. Our results confirm ROR1 as a target in RS and demonstrate the therapeutic potential of using an ADC directed toward ROR1 for the treatment of hematological cancers. A phase 1 clinical trial of VLS-101 (NCT03833180) is ongoing in patients with RS and other hematological malignancies., (© 2021 by The American Society of Hematology.)

A primary goal in pain treatment is restoration of behaviors that are disrupted by pain. Measures of pain interference indicate the degree to which pain interferes with activities in pain patients, and these measures are used to evaluate the effects of analgesic drugs. As a result of the emphasis on the expression and treatment of functional impairment in clinical settings, preclinical pain researchers have attempted to develop procedures for evaluation of pain-related functional impairment in laboratory animals. The goal of the present study was to develop and validate a low cost procedure for the objective evaluation of pain-related depression of home cage behavior in mice. On test days, a 5 × 5 cm Nestlet was weighed prior to being suspended from the wire lid of the home cage of individually housed male and female ICR mice. Over the course of experimental sessions, mice removed pieces of the suspended Nestlet, and began to build a nest with the material they removed. Thus, the weight of the pieces of Nestlet that remained suspended at various time points in the session provided an indicator of the rate of this behavior. The results indicate that Nestlet shredding was stable with repeated testing, and shredding was depressed by intra-peritoneal injection of 0.32% lactic acid. The non-steroidal anti-inflammatory drug ketoprofen blocked 0.32% lactic acid-induced depression of shredding, but did not block depression of shredding by a pharmacological stimulus, the kappa opioid receptor agonist U69,593. The μ-opioid receptor agonist morphine did not block 0.32% lactic acid-induced depression of shredding when tested up to doses that depressed shredding in the absence of lactic acid. When noxious stimulus intensity was reduced by decreasing the lactic acid concentration to 0.18%, morphine was effective at blocking pain-related depression of behavior. In summary, the data from the present study support consideration of the Nestlet shredding procedure for use in studies examining mechanisms, expression, and treatment of pain-related functional impairment., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Children with persistent speech disorder (PSD) are at higher risk of difficulties with literacy, with some evidence suggesting an association with poorer educational attainment. However, studies to date have either used small clinical samples, which exclude children who have not been referred to clinical services, or relied on parent-teacher report of children's speech development. There is a need for an inclusive study to investigate the impact of PSD on educational outcomes using a population-based sample and robust measures of speech development., Aim: Using a large prospective UK population-based study-the Avon Longitudinal Study of Parents and Children (ALSPAC)-this study investigated: (1) how children identified with PSD at age 8 years perform on educational attainment tests at ages 10-11 and 13-14 years in comparison with children without PSD; and (2) whether children identified with PSD at age 8 years are more likely to receive a label of special educational needs (SEN) in secondary school., Methods & Procedures: We examined the data for 263 children with PSD and 6399 controls who had speech assessed at age 8 years in a research clinic. Educational attainment was measured using data from English school standard attainment tests. Data on SEN categorization were obtained between 11 and 13 years of age. Children with PSD and controls were compared using regression analyses adjusted for biological sex, maternal age, verbal, performance and full-scale IQ., Outcomes & Results: Children with PSD at age 8 years were more likely to achieve lower attainment scores at ages 10-11 years in English and mathematics and across all three subjects of English, mathematics and science at ages 13-14 years after controlling for biological sex and maternal education; score below target levels for English at both time points after controlling for verbal IQ, and at ages 13-14 years after controlling for performance IQ; and receive a label of SEN (typically for the category of cognition and learning needs or communication and interaction needs) in secondary school., Conclusions & Implications: PSD identified at age 8 years is associated with poor educational attainment at ages 10-11 and 13-14 years in the core subjects of English, mathematics and science. Children with PSD at age 8 years are more likely to be identified with SEN at ages 11-13 years, particularly cognition and learning needs, and communication and interaction needs. We need to be aware of the potential for the long-term impact of PSD on educational attainment in providing appropriate and effective support throughout school. What this paper adds What is already known on the subject Speech-sound disorder is associated with reading and spelling difficulties, with some evidence to suggest that PSD is associated with a higher risk of literacy difficulties. Limited evidence also suggests that speech-sound disorder may be associated with poorer educational attainment. However, studies to date have used small clinical samples or parent-teacher report of speech development and there is a need to determine whether the association is observed in larger and more inclusive population-based samples. What this paper adds to existing knowledge This prospective, longitudinal study of a large community-based sample of English children has shown that PSD is associated with poorer educational attainment at the end of primary school and at ages 13-14 years. Children with PSD are also more likely to be identified as having SEN in secondary school, especially communication and interaction needs but also including cognition and learning needs. What are the potential or actual clinical implications of this work? Understanding the long-term implications of PSD on educational attainment highlights the importance of ongoing monitoring and support to enable children to reach their potential throughout primary and secondary school. The identification of children with a history of PSD during transition to secondary school will enable effective support to be put in place. The intervention for children with PSD should involve close collaboration between speech and language therapists and education professionals., (© 2021 The Authors. International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Purpose: To evaluate if High-volume Image-guided Injection (HVIGI)-treatment for chronic Patellar tendinopathy (PT) improve function and reduce pain at 16-months follow-up., Methods: Patients with resistant PT who failed to improve after a three-month eccentric loading program were included in the study. Maximal tendon thickness was assessed with ultrasound. All patients were injected with 10 mL of 0.5% Marcaine, 0.5 mL Triamcinolonacetonid (40 mg/mL) and 40 mL of 0.9% NaCl saline solution under real-time ultrasound-guidance and high pressure. All outcome measures were recorded at baseline and at 16 months. A standardised Heavy Slow Resistance rehabilitation protocol was prescribed after HVIGI-treatment. Clinical outcome was assessed with the Victorian Institute of Sports Assessment-Patella tendon questionnaire (VISA-P) and statistically analyses were performed., Results: The study included 28 single treatment HVIGI procedures in PT in 23 patients (19 men, 4 women) with a mean age of 30.3 (range 19-52). The mean duration of symptoms before HVIGI was 33 months. The baseline VISA-P score of 43 ± 17 (range 15-76) improved to 76 ± 16 (range 42-95) after 16 months (p < 0.01). Of the 28 HVIGI procedures 12 patients (15 PT) were not satisfied after the initial HVIGI procedure. Of these, 5 patients (5 PT) had additional HVIGI, 2 patients (2 PT) had corticoid injection and 6 patients (8 PT) needed surgery. Of the remaining 11 patients (13 PT), 9 patients had more than a 13-point improvement in the VISA-P score after 16 months., Conclusions: In this retrospective case-study, only 9 patients (32%) did benefit of a single HVIGI treatment at 16-months and a 33-point significant improvement was seen on the VISA-P score.

It has been repeatedly demonstrated that when performing a visual search task, items can pop out of a display such that they are identified rapidly, independent of the number of distractors present. It has been less clear whether this type of pop-out is limited to static displays (e.g., images) or whether it can also occur in scenes containing movement, more akin to how we experience the real world. Recently, Jardine and Moore (Journal of Experimental Psychology: Human Perception and Performance, 42, 617-630, 2016) examined whether pop-out also occurs in displays consisting of dynamic motion - wherein items in the display rotated continuously until a critical frame that would elicit pop-out under static presentation conditions - and found that search was greatly impaired. It remains unclear, however, whether such impairment is exerted equivalently across all types of dynamic motions or if it is specific to orientation. In the present study, we replicate the original Jardine and Moore (Journal of Experimental Psychology: Human Perception and Performance, 42, 617-630, 2016) finding and extend this examination to another dimension - color change. We also explore whether search efficiency can be improved with dynamic context if aspects of the display become predictable. The results suggest that not all types of dynamic change impair search performance. Specifically, oddball color targets continue to pop out even when the items in the display are dynamic. Interestingly, adding predictable context did not aid search accuracy as expected, rather resulting in poorer performance. Taken together, the findings suggest that the influence of dynamic context on search performance is not absolute.

Purpose: To evaluate if High-volume Image-guided Injection (HVIGI)-treatment for chronic mid-portion Achilles tendinopathy (AT) improve function and reduce pain at 12-months follow-up., Methods: Patients with resistant mid-portion AT who failed to improve after a three-month eccentric loading program were included in the study. Maximal tendon thickness was assessed with ultrasound. All patients were injected with 10 mL of 0.5% Marcaine, 0.5 mL Triamcinolonacetonid (40 mg/mL) and 40 mL of 0.9% NaCl saline solution under real-time ultrasound-guidance and high pressure. All outcome measures were recorded at baseline and 12 months. A standardized eccentric rehabilitation protocol was prescribed after HVIGI-treatment. Clinical outcome was assessed with the Victorian Institute of Sports Assessment-Achilles tendon questionnaire (VISA-A) and statistically analyses were performed., Results: The study included 30 single treatment HVIGI procedures in AT in 28 patients (23 men, 5 women) with a mean age of 45.1 (range 16-63). The mean duration of symptoms before HVIGI was 37 months. The baseline VISA-A score of 50 ± 15 (range 14-74) improved to 61 ± 21 (range 31-94) after 1 year (p = 0.04). Of the 30 AT procedures 10 patients (11 AT) were not satisfied after the initial HVIGI procedure. Of these, 8 patients (9 AT) needed additional HVIGI and two patients needed surgery. Of the remaining 18 patients (19 AT), 10 patients had more than a 10-point improvement in the VISA-A score after 1 year., Conclusions: In this retrospective case-study, only 10 patients (33%) did benefit of a single HVIGI treatment at 12-months and an 11-point significant improvement was seen at on the VISA-A score.

Purpose: The purpose of the present study was to investigate the effects of a 3-month multimodal intervention including patient education, a simple hip exercise program, footwear adjustment, and foot orthoses to reduce symptoms in patients with patellafemoral pain (PFP)., Methods: Patients were diagnosed based on a physical examination, patient symptoms and ruled out intra-articular knee pathologies by MRI. Patients were educated on PFP and participated in a 3-month exercise program; shoes with solid heel-caps were recommended, and custom made orthoses with arch support were recommended to patients with foot pronation. The Anterior Knee Pain Scale (AKPS) and the pain numeric rating scale (NRS) were used to evaluate the outcomes of the intervention and collected at baseline, 3 and 12-months follow-ups., Results: Sixty-five patients (age 18 years (9-32)) were included in a consecutive prospective cohort. The AKPS score improved from 71 ± 24 to 89 ± 9 (p < 0.01) at 12 months follow up. The NRS-rest and NRS-activity improved from 3 to 0 (p < 0.01) and 7 to 3 (p < 0.01) respectively. 78% of the patients clinically improved (i.e., demonstrated a > 10-point improvement (minimal clinically important difference (MCID))) considering the AKPS; and 76% and 73% clinically improved (i.e., demonstrated (MCID) a ≥ 2-point improvement) in their NRS-rest and NRS-activity, respectively. No patients experienced a decrease in their AKPS score or an increase in their NRS-rest and NRS-activity scores at 12-months., Conclusion: A 3-month PFP multimodal treatment strategy focusing on patient education, footwear adjustment, orthoses, and simple hip muscle exercises significantly improved functional outcomes and reduced pain at a 12 month follow-up.

This study investigated the in vitro activity of finafloxacin against panels of the biodefence pathogens. Broth microdilution assays were performed at neutral and acidic pH, to determine the effectiveness of the antibiotics in conditions typical of an intracellular environment. In all instances, finafloxacin demonstrated superior activity at low pH. These results highlight the importance of evaluating antimicrobial efficacy in conditions relevant to those encountered in vivo ., (© Crown copyright 2019.)

Pain is a significant public health problem, and assessment of pain-related impairment of behavior is a key clinical indicator and treatment target. Similar to opioids and NSAIDs, dopamine (DA) transporter inhibitors block pain-related depression of intracranial self-stimulation (ICSS) in rats. The primary goal of the present study was to determine if the effects of monoamine uptake inhibitors on pain-related depression of ICSS in rats extend to an assay of pain-related depression of nesting in mice. We hypothesized that the DA transporter-selective uptake inhibitor bupropion would block depression of nesting behavior produced by intraperitoneal injection of lactic acid, whereas selective serotonin transporter-selective citalopram, norepinephrine transporter-selective nisoxetine, and the mixed action selective serotonin transporter/norepinephrine transporter inhibitor milnacipran would be ineffective. Effects of the NSAID ketoprofen were also obtained to facilitate interpretation of the effects of the monoamine uptake inhibitors. Consistent with previous findings, ketoprofen blocked pain-related depression of nesting. In contrast, none of the monoamine uptake inhibitors blocked pain-related depression of nesting, although they all blocked pain-related stimulation of stretching. Unlike findings from studies of pain-related depression of ICSS, these results do not support consideration of DA uptake inhibitors for treatment of pain-related depression of behavior.

As monotherapy, modified proline-rich antimicrobial peptides (PrAMPs) protect animals from experimental bacteremia in a dose-dependent manner. We evaluated the in vitro synergy of a modified PrAMP, A3-APO, a dimer, previously shown to inhibit the 70 kDa bacterial heat shock protein DnaK, with imipenem or colistin against two antibiotic-resistant pathogens; a carbapenemase-expressing Klebsiella pneumoniae strain K97/09 and Acinetobacter baumannii (ATCC BAA-1605). Combining antimicrobials resulted in synergy for PrAMP/colistin combination against both K. pneumoniae and A. baumannii (ΣFIC = 0.08 both) and additive activity for the A3-APO/imipenem combination against K. pneumoniae (ΣFIC = 0.53). Chex1-Arg20, (designated as ARV-1502 in preclinical development), the single chain PrAMP monomer of A3-APO, showed synergy with meropenem against a carbapenem-resistant uropathogenic Escherichia coli strain (ΣFIC = 0.38). In a murine bacteremia model using K97/09, A3-APO at 1 mg/kg demonstrated improved survival when co-administered with standard (10 mg/kg) or subtherapeutic (1 mg/kg) doses of colistin at 36 h ( p < 0.05). Surprisingly, the survival benefit of A3-APO was augmented when the A3-APO dose was decreased by 50% to 0.5 mg/kg ( p < 0.02) in conjunction with a subtherapeutic colistin dose (1 mg/kg). ARV-1502, as monotherapy demonstrated prolonged (>24 h) activity in a mouse Escherichia coli infection assay. Co-treatment with ARV-1502 and subtherapeutic doses of ceftazidime (150 mg/kg) was studied in a mouse model of melioidosis. ARV-1502 provided a 50% improvement in long-term (62 days) survival, but only at the lowest of 3 administered doses; survival advantage was demonstrated at 2.5 mg/kg but not at 5 or 10 mg/kg. The mortality benefit of combination therapies was not routinely accompanied by a parallel decline in blood or tissue bacterial counts in surviving animals, suggesting that the anti-infective activity of the host defense peptides (HDP) is broader than simply bacterial eradication. In fact, the hormetic effect observed in either animal models suggest that low dose HDP treatment may change the dominant mode of action in experimental bacteremia.

It has been unclear whether an associations of child ADHD with socio-economic disadvantage (SES) could be accounted for by (a) parental ADHD explaining both low SES and child ADHD, and/or (b) the joint overlap of ODD or CD with low SES and ADHD. Study 1 used a community-recruited case-control sample with detailed evaluation of SES indicators, child ADHD, child externalizing, and parent ADHD symptoms (n = 931 children, 521 ADHD, 577 boys, 354 girls) in a path modeling analysis with latent variables. Study 2 evaluated ADHD and externalizing behavior in a regression model using a poverty index for SES, in 70,927 children (48.2% female) aged 5-17 years from the US 2011-2012 National Survey of Children's Health (NSCH). In Study 1, lower SES was related to the ADHD latent variable, β = -.18, p < .001; 95%CI [-.25,-.12]. This effect held when parent ADHD and child ODD and CD were in the model, β = -.11, p < .01, 95% CI [-.09,-.03], equivalent to OR = 1.50, 95% CI[1.12-2.04]). In Study 2, these results replicated. Adjusting only for age and sex, children from families who were below 200% of the federal poverty line were more likely to have moderate or severe ADHD than no ADHD, versus children above that line, OR = 2.13, 95% CI[1.79,2.54], p < .001. The effect held after adjusting for disruptive/externalizing problems, OR = 1.61, p < .01, 95%CI [1.32,1.96]. The effect size for comparable models was similar across both studies, lending higher confidence to the results. It is concluded that the SES association with child ADHD is not explained by artifact and requires a mechanistic explanation.

Sit-stand workstations are a popular workplace intervention. Organizations often require a medical professional's guidance for implementation. Therefore, it is important to understand potential negative outcomes associated with standing work, such as lower limb discomfort and peripheral vascular issues. The objective of this study was to compare changes in lower limb discomfort, blood pressure and blood flow accumulation during a light-load repetitive upper limb work task accomplished from seated and standing postures. At the Jewish Rehabilitation Hospital (Laval, Quebec, Canada), 16 participants were outfitted with Laser Doppler Flow (LDF) electrodes to measure blood flow in the lower limb, and a sphygmomanometer to measure lower limb mean arterial blood pressure (MAP). Participants completed simulated work over 34 min in standing and seated conditions. Repeated measures ANOVAs (Posture x Time) were used to assess the differences. There were significant effects for both Posture (p = 0.003) and Time (p = 0.007) for LDF-measured of blood flow accumulation in the soleus and the foot, with a mean increase of 77% blood flow over time in the standing posture, when compared to seated work. There was a significant 'Posture × Time' (p = 0.0034) interaction effect and a significant Posture (p = 0.0001) effect for MAP, with higher values in the standing posture by a mean of 37.2 mmHg. Posture had a significant effect (p < 0.001) on lower limb discomfort, with standing posture reporting higher levels. These results suggest that recommendations for using static standing work postures should be tempered, and physicians' guidance on workstation changes should consider the impacts on the lower limb.

Di-n-octylphthalate (DNOP) is a phthalate used in the manufacturing of a wide variety of polyvinyl chloride-containing medical and consumer products. A study on chronic exposure to DNOP in rodents showed the development of pre-neoplastic hepatic lesions following exposure to a tumor initiator. The objective of this study was to identify the mechanisms by which DNOP leads to pre-neoplastic hepatic lesions. Mouse hepatocyte AML-12 and FL83B cells were treated with DNOP. The rate of cell proliferation was increased in treated cells in a concentration-dependent manner. DNOP increased the expression of transforming growth factor-β (tgf-β) in both cell lines, and primary culture mouse hepatocytes. The TGF-β receptor inhibitor LY2109761 impaired the effect of DNOP. The presence of pro-apoptotic proteins decreased in the presence of DNOP. Our observation indicates that DNOP, through an increase in the expression of tgf-β and a decrease in the levels of pro-apoptotic proteins, acts as a proliferative agent in normal mouse hepatocytes. We also studied the morphological and functional changes of the mouse liver upon a short-term treatment of DNOP. Mice exposed to DNOP displayed an epithelial-to-mesenchymal transition and cholestasis, which was reflected in an increase in hepatic bile acids and glutathione levels., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aim of this study was to determine outcomes and survivorship of the Triathlon knee replacement up to 5 years post-operation. A cohort of 266 patients receiving a Triathlon knee replacement were assessed before surgery and at 3 months, 1 year, 2 years, 3 years and 5 years post-operation. Assessments included patient-reported outcome measures, American Knee Society Score, complications and survivorship. The largest improvements in pain, function, stiffness and knee-related quality of life occurred in the first 3 months post-operation. Further smaller improvements were reported between 3 and 12 months post-operation, and then a plateauing of outcomes was observed up to 5 years. A high percentage of patients (86%) were satisfied with their outcome at 5 years. Survivorship with revision as the endpoint was 96.6% (95% CI 93.2-98.1%) at 5 years post-operation. In conclusion, this study observed good mid-term patient outcomes and survivorship of the Triathlon knee replacement.

The in vitro activity and in vivo efficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague, Bacillus anthracis and Yersinia pestis , respectively. MICs of OMC were determined by broth microdilution according to CLSI guidelines for 30 isolates each of Y. pestis and B. anthracis The in vivo efficacy of omadacycline was studied at a range of dosages in both a postexposure prophylaxis (PEP) murine model of anthrax and plague as well as in a delayed treatment model of inhalational anthrax. Omadacycline was active in vitro against Y. pestis (MIC 90 of 1 μg/ml) and B. anthracis (MIC 90 of 0.06 μg/ml). Omadacycline was less active in vitro than ciprofloxacin (CIP) against Y. pestis (CIP MIC 90 of 0.03 μg/ml) but was more potent in vitro against B. anthracis (CIP MIC 90 of 0.12 μg/ml). In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control ( P = 0.004). The median survival for the vehicle-treated controls was 6 days postchallenge, while all antibiotic-treated mice survived the entire study. Omadacycline treatment with 5, 10, or 20 mg/kg of body weight twice daily for 14 days had significant efficacy over the vehicle control in the treatment of aerosolized B. anthracis Additionally, for postexposure prophylaxis treatment of mice infected with Y. pestis , the survival curves for omadacycline (40 mg/kg twice daily), ciprofloxacin, and doxycycline cohorts differed significantly from the vehicle control ( P < 0.0001). Omadacycline is potent and demonstrates efficacy against both B. anthracis and Y. pestis The well-characterized oral and intravenous pharmacokinetics, safety, and tolerability warrant further assessment of the potential utility of omadacycline in combating these serious biothreat organisms., (Copyright © 2017 Steenbergen et al.)

Telehealth approaches to delivering ergonomics assessment hold great potential to improve service delivery in rural and remote settings. This case study describes a telehealth-based ergonomics service delivery process, and compares in-person and telehealth-based ergonomics approaches at an Alberta-based non-profit advocacy group. This project demonstrates that telehealth approaches to ergonomics do not lead to significantly different scoring outcomes for assessment of ergonomics issues, when compared to in-person assessments. This project also outlines the importance of live real-time video conferencing to improving communication, attaining key assessment information, and demonstrating ergonomic adjustments. However, some key considerations of bandwidth and hardware capabilities need to be taken into account. Key communication strategies are outlined to improve rapport, maintain employee confidentiality, and reduce client anxiety around telehealth ergonomics assessments. This project provides further support for telehealth approaches to office ergonomics, and outlines some key implementation strategies and barriers that should be considered.

Purpose: The purpose of this study was to determine prevalence and predictors of persistent speech sound disorder (SSD) in children aged 8 years after disregarding children presenting solely with common clinical distortions (i.e., residual errors)., Method: Data from the Avon Longitudinal Study of Parents and Children (Boyd et al., 2012) were used. Children were classified as having persistent SSD on the basis of percentage of consonants correct measures from connected speech samples. Multivariable logistic regression analyses were performed to identify predictors., Results: The estimated prevalence of persistent SSD was 3.6%. Children with persistent SSD were more likely to be boys and from families who were not homeowners. Early childhood predictors identified as important were weak sucking at 4 weeks, not often combining words at 24 months, limited use of word morphology at 38 months, and being unintelligible to strangers at age 38 months. School-age predictors identified as important were maternal report of difficulty pronouncing certain sounds and hearing impairment at age 7 years, tympanostomy tube insertion at any age up to 8 years, and a history of suspected coordination problems. The contribution of these findings to our understanding of risk factors for persistent SSD and the nature of the condition is considered., Conclusion: Variables identified as predictive of persistent SSD suggest that factors across motor, cognitive, and linguistic processes may place a child at risk.

Rationale: From allergies to plant reproduction, pollens have important impacts on the health of human and plant populations, yet identification of pollen grains remains difficult and time-consuming. Low-volatility flavonoids generated from pollens cannot be easily characterized and quantified with current analytical techniques., Methods: Here we present the novel use of atmospheric solids analysis probe mass spectrometry (ASAP-MS) for the characterization of flavonoids in pollens. Flavonoid patterns were generated for pollens collected from different plant types (trees and bushes) in addition to bee pollens from distinct geographic regions. Standard flavonoids (kaempferol and rhamnazin) and those produced from pollens were compared and assessed with ASAP-MS using low-energy collision MS/MS. Results for a semi-quantitative method for assessing the amount of a flavonoid in pollens are also presented., Results: Flavonoid patterns for pollen samples were distinct with variability in the number and relative abundance of flavonoids in each sample. Pollens contained 2-5 flavonoids, and all but Kochia scoparia contained kaempferol or kaempferol isomers. We establish this method as a reliable and applicable technique for analyzing low-volatility compounds with minimal sample preparation. Standard curves were generated using 0.2-5 μg of kaempferol; from these experiments, it was estimated that there is approximately 2 mg of kaempferol present in 1 g of P. nigra italica pollen., Conclusions: Pollens can be characterized with a simple flavonoid pattern rather than analyzing the whole product pattern or the products-temperature profiles. ASAP-MS is a rapid analytical technique that can be used to distinguish between plant pollens and between bee pollens originating from different regions. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Radon gas has recently become more prominent in discussions of lung cancer prevention nationally and in Iowa. A review in 2013 of cancer plans in the National Comprehensive Cancer Control Program found that 42% of cancer plans, including Iowa's, had terminology on radon. Plans included awareness activities, home testing, remediation, policy, and policy evaluation., Community Context: Iowa has the highest average radon concentrations in the United States; 70% of homes have radon concentrations above the Environmental Protection Agency's action levels. Radon control activities in Iowa are led by the Iowa Cancer Consortium, the Iowa Department of Public Health, and the Iowa Radon Coalition., Methods: A collaborative approach was used to increase levels of awareness, testing, and (if necessary) mitigation, and to introduce a comprehensive radon control policy in Iowa by engaging partners and stakeholders across the state., Outcome: The multipronged approach and collaborative work in Iowa appears to have been successful in increasing awareness: the number of radon tests completed in Iowa increased by 20% from 19,600 in 2009 to 23,500 in 2014, and the number of mitigations completed by certified mitigators increased by 108% from 2,600 to more than 5,400., Interpretation: Through collaboration, Iowa communities are engaged in activities that led to increases in awareness, testing, mitigation, and policy. States interested in establishing a similar program should consider a multipronged approach involving multiple entities and stakeholders with different interests and abilities. Improvements in data collection and analysis are necessary to assess impact.

Atmospheric solid analysis probe mass spectrometry has the capability of capturing full product patterns simultaneously including both volatile and semi-volatile compounds produced at elevated temperatures. Real-time low-energy collision-induced fragmentation combined with ion mobility separations enables rapid identification of the chemical structures of products. We present here for the first time the recognition of full product patterns resulting from the thermal degradation of β-carotene at temperatures up to 600 °C. Solvent vapor-induced ionization enhancement is observed, which reveals parallel thermal dissociation processes that lead to even- and odd-numbered mass products. The drift-time distributions of high mass products, along with β-carotene, were monitored with temperature, showing multiple conformations that are associated with the presence of two β-rings. Products of masses 346/347, however, show a single conformation distribution, which indicates the separation of two β-rings resulting from the direct bond scission at the polyene hydrocarbon chain. The thermal degradation pathways are evaluated and discussed., (Published 2016. This article is a U.S. Government work and is in the public domain in the USA.)

Little is known about risk factors for Tourette syndrome (TS) and chronic tic disorders (CT) but maternal psychological morbidity in pregnancy may be associated with TS/CT. We examined whether pre- and post-natal parental anxiety and/or depression are associated with risk of TS/CT in the Avon Longitudinal Study of Parents and Children. We compared self-reported anxiety and depression measures collected prospectively at four time points (18 and 32 weeks prenatally, and 8 weeks and 8 months post-natally) among parents of children who subsequently met criteria for TS/CT at 13 years of age as compared to other children from the cohort. We adjusted for various socioeconomic measures and tested both for time period-specific exposure and chronic exposure using multivariable logistic regression models. 122 children had TS/CT (50 TS, 72 CT) and 5968 children had no tics. In crude analyses, both pre- and post-natal maternal anxiety and depression, but only post-natal paternal depression at 8 months, showed associations with TS/CT. In the final, adjusted multivariable models, chronic maternal anxiety (odds ratio 2.17, 95% CI 1.23, 3.84, p = 0.007) and pre-natal maternal depression (odds ratio 1.86, 95% CI 1.02, 3.39, p = 0.04) showed associations with TS/CT though the latter was consistent with chance (p = 0.07) after adjustment for past maternal depression. We find associations between maternal psychological morbidity pre- and post-natally and risk of future TS/CT in offspring. These associations may reflect either shared genetic susceptibility or a pre-natal exposure. Further work is required to see if these findings can be replicated in larger datasets.

Background: Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6., Objective: To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319., Methods: We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap., Results and Conclusions: READ1 and KIAHap show interdependence--READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

This final overarching study in a series documents research and recommendations RAND offered to the Air Force to help strengthen the development of a new office responsible for monitoring and promoting resilience among Air Force Airmen, civilian employees, and Air Force families. Efforts to boost resilience have become an important military response to suicide and other markers of distress and poor health. The study reviews the concepts and measures of resilience, resilience factors, hardiness and flourishing. It describes how resilience and the military's Total Force Fitness concepts are related. The study brings together highlights from the eight companion studies on each Total Force Fitness domain and characterizes types of Air Force data that could be used to track resilience.

Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930., (© 2015 by The American Society of Hematology.)

Modification of the dipeptide of phenylalanine, FF, with a boronic acid (BA) functionality imparts unique aqueous self-assembly behavior that responds to multiple stimuli. Changes in pH and ionic strength are used to trigger hydrogelation via the formation of nanoribbon networks. Furthermore, we show for the first time that the binding of polyols to the BA functionality can modulate a peptide between its assembled and disassembled states.

Canadian fish-based environmental effects monitoring programs use individual and population-level endpoints to assess aquatic health. Impacts of coal mining and selenium (Se) exposure were assessed in slimy sculpin (Cottus cognatus) from reference streams located both inside and outside of a coal zone, and from 1 stream with a history of coal mining, using traditional environmental effects monitoring endpoints. In addition, physical characteristics of the streams and benthic macro-invertebrate communities were assessed. To determine whether the assessment of effects could be improved by including molecular markers, real-time polymerase chain reaction assays were optimized for genes associated with reproduction (vtg, esr1, star, cyp19a1, and gys2), and oxidative and cellular stress (sod1, gpx, gsr, cat, and hsp 90). Water Se levels exceeded guidelines in the stream with historical mining (4 μg/L), but benthic macroinvertebrates did not exceed dietary thresholds (2-3 μg/g dry wt). Whole-body Se levels were above British Columbia's tissue guideline in fish from all streams, but only above the draft US Environmental Protection Agency (USEPA) criterion (7.91 μg/g dry wt) at the reference stream inside the coal zone. Some markers of cellular and oxidative stress were elevated in fish liver at the exposed site (sod1, gpx), but some were lower (cat, sod1, gpx, gsr, hsp90) in the gonads of fish inside the coal zone. Some of the differences in gene expression levels between the reference and impacted sites were sex dependent. Based on benthic macroinvertebrate assessments, the authors hypothesize that traditional and molecular differences in slimy sculpin at impacted sites may be driven by food availability rather than Se exposure. The present study is the first to adapt molecular endpoints in the slimy sculpin for aquatic health assessments., (© 2015 SETAC.)

Research on opioid analgesics such as morphine suggests that expression of abuse-related effects increases with repeated exposure. Repeated exposure to opioids often occurs clinically in the context of pain management, and a major concern for clinicians is the risk of iatrogenic addiction and dependence in patients receiving opioids for treatment of pain. This study compared abuse-related morphine effects in male rats in an intracranial self-stimulation (ICSS) procedure after repeated treatment either with morphine alone or with morphine in combination with a repeated noxious stimulus (intraperitoneal administration of dilute acid). The study also permitted comparison of morphine potency and effectiveness to block acid-induced depression of ICSS (antinociception) and to produce enhanced facilitation of ICSS (abuse-related effect). There were 3 main findings. First, initial morphine exposure to drug naïve rats did not produce abuse-related ICSS facilitation. Second, repeated daily treatment with 3.2 mg/kg/day morphine for 6 days increased expression of ICSS facilitation. This occurred whether morphine was administered in the absence or presence of the noxious stimulus. Finally, a lower dose of 1.0 mg/kg/day morphine was sufficient to produce antinociception during repeated acid treatment, but this lower dose did not reliably increase abuse-related morphine effects. Taken together, these results suggest that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. However, it may be possible to relieve pain with relatively low morphine doses that do not produce increases in abuse-related morphine effects., ((c) 2015 APA, all rights reserved).)

This article reviews the scientific literature on the epidemiology, prevention, and treatment of problematic Internet use (PIU) with the goal of informing Air Force policies aimed at mitigating PIU's negative impact on operations and the mental health of Airmen. The study is motivated by a recent RAND study estimating that 6 percent of Airmen have PIU. Individuals with PIU, similar to people with substance addictions, suffer from excessive and compulsive online activities, symptoms of tolerance and withdrawal, and functional impairment. PIU is also strongly associated with other mental health problems including major depression. However, at present there is no single accepted definition of PIU, and no up-to-date estimates of the prevalence of PIU in the general U.S. population are available. A range of prevention and treatment approaches have been developed, but none has been rigorously tested in clinical trials. Prevention programs rely on workplace Internet policies and strategies to help individuals self-regulate their Internet use. Treatment approaches that have proven feasible and acceptable to patients with PIU include adaptations of cognitive-behavioral therapy, an evidence-based treatment for depression and anxiety, to the specific symptoms of PIU. Based on our findings, we recommend: (1) increasing awareness of PIU among organizational leadership and mental health professionals, (2) incorporating content related to PIU into existing trainings related to mental health, (3) providing support for self-regulation of Internet use on the job by incorporating PIU management principles into Internet use policies, and (4) continuing monitoring of the emerging scientific literature on PIU.

Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the μ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.

The aim of this study was to refine the population prevalence estimate of Tourette Syndrome (TS) in children and to investigate potential sources of heterogeneity in previously published studies. A systematic review was conducted and all qualifying published studies of TS prevalence were examined. Extracted data were subjected to a random-effects meta-analysis weighted by sample size; meta-regressions were performed to examine covariates that have previously been proposed as potential sources of heterogeneity. Twenty-six articles met study inclusion criteria. Studies derived from clinically referred cases had prevalence estimates that were significantly lower than those derived from population-based samples (P = 0.004). Among the 21 population-based prevalence studies, the pooled TS population prevalence estimate was 0.52% (95% confidence interval CI: 0.32-0.85). In univariable meta-regression analysis, study sample size (P = 0.002) and study date (P = 0.03) were significant predictors of TS prevalence. In the final multivariable model including sample size, study date, age, and diagnostic criteria, only sample size (P < 0.001) and diagnostic criteria (omnibus P = 0.003; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR]: P = 0.005) were independently associated with variation in TS population prevalence across studies. This study refines the population prevalence estimate of TS in children to be 0.3% to 0.9%. Study sample size, which is likely a proxy for case assessment method, and the use of DSM-IV-TR diagnostic criteria are the major sources of heterogeneity across studies. The true TS population prevalence rate is likely at the higher end of these estimates, given the methodological limitations of most studies. Further studies in large, well-characterized samples will be helpful to determine the burden of disease in the general population., (© 2014 International Parkinson and Movement Disorder Society.)

Pain-related depression of behavior and mood is a key therapeutic target in the treatment of pain. Clinical evidence suggests a role for decreased dopamine (DA) signaling in pain-related depression of behavior and mood. Similarly, in rats, intraperitoneal injection of dilute lactic acid (IP acid) serves as a chemical noxious stimulus to produce analgesic-reversible decreases in both (1) extracellular DA levels in nucleus accumbens (NAc) and (2) intracranial self-stimulation (ICSS), an operant behavior reliant on NAc DA. Intraperitonial acid-induced depression of ICSS is blocked by DA transporter (DAT) inhibitors, but clinical viability of selective DAT inhibitors as analgesics is limited by abuse potential. Drugs that produce combined inhibition of both DA and serotonin transporters may retain efficacy to block pain-related behavioral depression with reduced abuse liability. Amitifadine is a "triple uptake inhibitor" that inhibits DAT with approximately 5- to 10-fold weaker potency than it inhibits serotonin and norepinephrine transporters. This study compared amitifadine effects on IP acid-induced depression of NAc DA and ICSS and IP acid-stimulated stretching in male Sprague-Dawley rats. Amitifadine blocked IP acid-induced depression of both NAc DA and ICSS and IP acid-stimulated stretching. In the absence of the noxious stimulus, amitifadine increased NAc levels of both DA and serotonin, and behaviorally, amitifadine produced significant but weak abuse-related ICSS facilitation. Moreover, amitifadine was more potent to block IP acid-induced depression of ICSS than to facilitate control ICSS. These results support consideration of amitifadine and related monoamine uptake inhibitors as candidate analgesics for treatment of pain-related behavioral depression.

Despite interest in the idea that transgenerational effects of adverse exposures might contribute to population health trends, there are few human data. This non-genetic inheritance is all the more remarkable when transmission is down the male-line as reported in a historical Swedish study, where the paternal grandfather's food supply in mid childhood was associated with the mortality rate in his grandsons. Using the Avon Longitudinal Study of Parents and Children's questionnaire data on smoking and smoking onset from 9886 fathers, we examined the growth of their children from 7-17 years. Adjusting for potential confounders, we assessed associations between body mass index (BMI), waist circumference, total fat mass and lean mass with the age at which the father had started smoking regularly. Of 5376 fathers who reported having ever smoked, 166 reported regular smoking <11 years of age. Before adjustment, those offspring whose fathers started smoking <11 years had the highest mean BMIs at each age tested. The adjusted mean differences in BMI, waist circumference and total fat mass in those sons whose fathers started smoking <11 years, compared with all other sons, increased with age, being significantly greater from 13 years onwards. There were no significant BMI associations in daughters, but they showed a reduction in total lean mass. Our results highlight the importance of the developmental timing of the paternal exposure as well as gender differences in offspring outcomes. Smoking by boys in mid childhood may contribute to obesity in adolescent boys of the next generation.

Background: Recently, arthroscopic-based treatment for hip-related pain with radiological findings of femoroacetabular impingement and labral lesions has been developed.We aim to present clinical outcome in a single centre patient cohort of patients treated arthroscopically for hip-related pain due to femoroacetabular impingement., Methods: A total of 117 consecutive patients operated in 2009-2011 were included in this prospective case series (41% male; mean age 37 years; (range 15-70). The indication for arthroscopic treatment of hip-related pain was mechanical hip symptoms and radiological findings of femoroacetabular impingement.To evaluate hip function and pain level at 1-year and 2-5 years follow up (FU) mHHS (Modified Harris Hip Score), HOS (Hip Outcome Score) and a Numeric Rating Scale (NRS) pain score were used., Results: Labral tears were seen in 91% of the hip arthroscopies. Cartilage lesions (ICRS grade 2 and above) were seen at the acetabular and femoral articular surfaces in 79% and 15% of cases, respectively. The therapeutic procedures were in 99% of the arthroscopies osteochondroplasty and/or acetabular rim-trimming. In 77% of procedures labral reattachment was performed. The patient evaluated outcome demonstrated significant increases in mHHS and HOS at 1-year follow up and at final FU compared to preoperatively (1 yr: mHHS: 72.1 to 85.3, HOS: 71.4 to 85.1; final FU: mHHS: 72.1 to 83.8, HOS: 71.4 to 83.7). Pain levels decreased significantly from preoperatively to follow ups. Five patients underwent total hip replacement within the follow up period after hip arthroscopy., Conclusions: Arthroscopic treatment of femoroacetabular impingement improves patient evaluated outcomes. Further studies are needed to determine failure rates and risk factors.

Pain in older adults is a prevalent problem that affects quality of life and challenges nurses, particularly those caring for older adults living in long term care settings. Despite the national priority of pain management, insufficient knowledge of nurses about geriatric pain is a documented barrier to effective geriatric pain management in all long term care settings. To address this knowledge gap, a website (GeriatricPain.org) was developed by the National Geriatric Pain Collaborative with a grant from the MayDay Fund to provide a single site for evidenced-based, easy-to-use, downloadable resources on pain management. This paper describes the development of the most recent addition to the website, a set of evidence-based core geriatric pain management competencies and a geriatric pain knowledge assessment, and discusses their potential uses in improving pain care for older adults., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Previously, in the Avon Longitudinal Study of Parents and Children (ALSPAC), we have shown different sex-specific birth anthropometric measurements contingent upon whether or not prenatal smoking was undertaken by paternal grandmother (PGM±), maternal grandmother (MGM±), and the study mother (M±). The findings raised the question as to whether there were long-term associations on the growth of the study children over time., Methods: Measures of weight, height, body mass index, waist circumference, lean mass, and fat mass of children in the ALSPAC study from 7 to 17 years of age were used. We compared growth in four categories at each age: PGM+M- with PGM-M-; MGM+M- with MGM-M-; PGM+M+ with PGM-M+; MGM+M+ with MGM-M+; and adjusted for housing tenure, maternal education, parity, and paternal smoking at the start of the study pregnancy., Results: We found that if the PGM had, but the study mother had not, smoked in pregnancy, the girls were taller and both genders had greater bone and lean mass. However, if the MGM had smoked prenatally but the mother had not (MGM+M-), the boys became heavier than expected with increasing age-an association that was particularly due to lean rather than fat mass, reflected in increased strength and fitness. When both the maternal grandmother and the mother had smoked (MGM+M+) girls had reduced height, weight, and fat/lean/bone mass when compared with girls born to smoking mothers whose own mothers had not smoked (MGM-M+)., Conclusions: This study indicates that smoking in humans can have sex-specific transgenerational effects., (© 2014 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc.)

Objectives: Transgenerational effects of different environmental exposures are of major interest, with rodent experiments focusing on epigenetic mechanisms. Previously, we have shown that if the study mother is a non-smoker, there is increased mean birth weight, length and body mass index (BMI) in her sons if she herself had been exposed prenatally to her mother's smoking. The aim of this study was to determine whether the prenatal smoke exposure of either parent influenced the growth of the fetus of a smoking woman, and whether any effects were dependent on the fetal sex., Design: Population-based prebirth cohort study., Setting: Avon Longitudinal Study of Parents and Children., Participants: Participants were residents of a geographic area with expected date of delivery between April 1991 and December 1992. Among pregnancies of mothers who smoked during pregnancy, data were available concerning maternal and paternal prenatal exposures to their own mother smoking for 3502 and 2354, respectively., Primary and Secondary Outcome Measures: Birth weight, length, BMI and head circumference., Results: After controlling for confounders, there were no associations with birth weight, length or BMI. There was a strong adjusted association of birth head circumference among boys whose fathers had been exposed prenatally (mean difference -0.35 cm; 95% CI -0.57 to -0.14; p=0.001). There was no such association with girls (interaction p=0.006). Similar associations were found when primiparae and multiparae were analysed separately. In order to determine whether this was reflected in child development, we examined the relationships with IQ; we found that the boys born to exposed fathers had lower IQ scores on average, and that this was particularly due to the verbal component (mean difference in verbal IQ -3.65 points; 95% CI -6.60 to -0.70)., Conclusions: Head size differences concerning paternal fetal exposure to smoking were unexpected and, as such, should be regarded as hypothesis generating., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Reading disability (RD) and language impairment (LI) are common neurodevelopmental disorders with moderately strong genetic components and lifelong implications. RD and LI are marked by unexpected difficulty acquiring and processing written and verbal language, respectively, despite adequate opportunity and instruction. RD and LI-and their associated deficits-are complex, multifactorial, and often comorbid. Genetic studies have repeatedly implicated the DYX2 locus, specifically the genes DCDC2 and KIAA0319, in RD, with recent studies suggesting they also influence LI, verbal language, and cognition. Here, we characterize the relationship of the DYX2 locus with RD, LI, and IQ. To accomplish this, we developed a marker panel densely covering the 1.4 Mb DYX2 locus and assessed association with reading, language, and IQ measures in subjects from the Avon Longitudinal Study of Parents and Children. We then replicated associations in three independent, disorder-selected cohorts. As expected, there were associations with known RD risk genes KIAA0319 and DCDC2. In addition, we implicated markers in or near other DYX2 genes, including TDP2, ACOT13, C6orf62, FAM65B, and CMAHP. However, the LD structure of the locus suggests that associations within TDP2, ACOT13, and C6orf62 are capturing a previously reported risk variant in KIAA0319. Our results further substantiate the candidacy of KIAA0319 and DCDC2 as major effector genes in DYX2, while proposing FAM65B and CMAHP as new DYX2 candidate genes. Association of DYX2 with multiple neurobehavioral traits suggests risk variants have functional consequences affecting multiple neurological processes. Future studies should dissect these functional, possibly interactive relationships of DYX2 candidate genes.

Intracranial self-stimulation (ICSS) is a behavioral procedure in which operant responding is maintained by pulses of electrical brain stimulation. In research to study abuse-related drug effects, ICSS relies on electrode placements that target the medial forebrain bundle at the level of the lateral hypothalamus, and experimental sessions manipulate frequency or amplitude of stimulation to engender a wide range of baseline response rates or response probabilities. Under these conditions, drug-induced increases in low rates/probabilities of responding maintained by low frequencies/amplitudes of stimulation are interpreted as an abuse-related effect. Conversely, drug-induced decreases in high rates/probabilities of responding maintained by high frequencies/amplitudes of stimulation can be interpreted as an abuse-limiting effect. Overall abuse potential can be inferred from the relative expression of abuse-related and abuse-limiting effects. The sensitivity and selectivity of ICSS to detect abuse potential of many classes of abused drugs is similar to the sensitivity and selectivity of drug self-administration procedures. Moreover, similar to progressive-ratio drug self-administration procedures, ICSS data can be used to rank the relative abuse potential of different drugs. Strengths of ICSS in comparison with drug self-administration include 1) potential for simultaneous evaluation of both abuse-related and abuse-limiting effects, 2) flexibility for use with various routes of drug administration or drug vehicles, 3) utility for studies in drug-naive subjects as well as in subjects with controlled levels of prior drug exposure, and 4) utility for studies of drug time course. Taken together, these considerations suggest that ICSS can make significant contributions to the practice of abuse potential testing., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Animal data suggest that tobacco smoke exposure of a mother when she is in utero influences DNA methylation patterns in her offspring and that there is an effect on the respiratory system, particularly airway responsiveness. The only study, to our knowledge, in humans suggests that there is a similar effect on asthma. The present study tests whether an association with respiratory problems can be confirmed in a large population study and aims to determine whether in utero exposure of the father has similar effects on his offspring., Methods: Information from the Avon Longitudinal Study of Parents and Children was used to compare the offspring of women and of men who had themselves been exposed to cigarette smoke in utero; separate analyses were performed for children of women smokers and nonsmokers. The outcome measures were trajectories of history of early wheezing, doctor-diagnosed asthma by age 7 years, and results of lung function and methacholine challenge tests at 8 years. A variety of social and environmental factors were taken into account; offspring sexes were examined separately., Results: There was no association with any outcome in relation to maternal prenatal exposure. There was some evidence of an increase in asthma risk with paternal prenatal exposure when the study mother was a nonsmoker (adjusted OR, 1.17; 95% CI, 0.97-1.41). This was particularly strong for girls (adjusted OR, 1.39; 95% CI, 1.04-1.86)., Conclusions: We did not find that maternal prenatal exposure to her mother's smoking had any effect on her children's respiratory outcomes. There was suggestive evidence of paternal prenatal exposure being associated with asthma and persistent wheezing in the granddaughters.

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414., (© 2014 by The American Society of Hematology.)

Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension study. Adverse events (AEs) occurring in 20% or more patients (total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), and chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These trials were registered at clinicaltrials.gov as NCT00710528 and NCT01090414., (© 2014 by The American Society of Hematology.)

Background: Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population., Methods: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy., Results: The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab., Conclusions: The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).