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Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.

Herein, we review the magnetic, superconducting and structural phase diagrams of the title systems, with an emphasis on our recent results form magnetic and structural neutron diffraction, magnetic susceptibility and system, and indicate the occurrence of frustrated phase separation on a nanoscopic length scale in the La2-xSrxCuO4 system with O < x ≲ 0.05. 139La nuclear quadrupole resonance measurements. The results clarify the miscibility gap in the La2CuO4+δ. © 1994.

Heat capacity measurements from 150 to 300 K were carried out on a single crystal of La2CuO4+x synthesized by subjecting an La2CuO4 crystal to 3 kbar oxygen pressure at 575 °C. The data reveal three small (about 1%) anomalies at temperatures (T) of 206, 222 and 259 K. The first two are tentatively attributed to CuO inclusions in the crystal. The third is observed on warming, but not on cooling, and is attributed to the previously documented first-order transition from the orthorhombically distorted K2NiF4 structure to a low T mixture of nearly stoichiometric La2CuO4 and oxygen-rich superconducting La2CuO4+y (y>x). The size of the anomaly at 259 K is about one-seventh of that observed previously for a single crystal of La2CuO4 at the second-order tetragonal-to-orthorhombic phase transition temperature of about 530 K. Magnetization measurements from 5 to 300 K and from 50 G to 50 kG are also reported for the La2CuO4+x crystal. The normal state magnetic susceptibility χ(T) is quite anisotropic, with χ(T) for H perpendicular to the CuO2 layers (χc) in good agreement with previous data on a different, but similarly prepared, crystal. The anisotropy in χ is nearly independent of T from 40 to 300 K and the magnitude of χc-χab per CuO2 layer is very similar to that at high T in YBa2Cu3O6.1, La2CuO4, Sr2CuO2Cl2 and La2-xMxCuO4 (MSr, Ba). © 1992.

Purpose: The aim of the present study is to present epidemiology and clinical outcome after revision anterior cruciate ligament (ACL) reconstruction with an intermediate follow-up time of up to 9 years.Methods: A retrospective study of patients treated with ACL revision from 2001 to 2007 at a university referral clinic was conducted. Study follow-up was performed in 2010; this follow-up included objective IKDC scores, KOOS, Tegner and SANE subjective scores, KT-1000 knee laxity measurements and registration of reoperations and complications.Results: One hundred and twenty-eight patients were available for follow-up. Median follow-up time was 6 (2-9) years. Mean age was 32 years, 50% were men. Eleven percent required staged procedures, 30% were reconstructed with allograft tendons and 23% had collateral ligament reconstruction in combination with the ACL revision. SANE knee global score (0-100) was 74 at follow-up, KOOS sub-scores were preoperatively 66, 69, 77, 42 and 39 for pain, symptoms, activity of daily living, sports and quality of life, respectively. At follow-up, scores were 70, 76, 81, 50 and 50, respectively. Sport and quality of life scores increased significantly. KT-1000 was 6.2 mm preoperatively and 2.5 at follow-up (P < 0.05). Six percent were re-revised and 2 patients had total knee replacements.Conclusion: Despite objective findings of acceptable sagittal knee stability at follow-up, subjective outcome scores indicate significant knee impairment with low scores in sport and quality of life. A re-revision rate of 6% after 6 years is acceptable. It is imperative that patients eligible for ACL revision receive proper counseling in terms of outcome expectancies.Level Of Evidence: Retrospective case series, Level IV. [ABSTRACT FROM AUTHOR]

Rationale: Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein. Objectives: To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF. Methods: Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles. Measurements and Main Results: The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults. Conclusions: In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00458341). [ABSTRACT FROM AUTHOR]

Many tools are available for the assessment of pain in nonverbal older adults; however, guidelines are needed to help clinicians select the proper instrument for use in the nursing home setting. This article describes a project to identify clinically useful pain-behavioral assessment tools that have undergone sufficient psychometric testing. Phase 1 of the project included a comprehensive review and critique of currently available tools. In Phase 2, the National Nursing Home Pain Collaborative developed criteria to evaluate an updated list of tools and then rated 14 tools using these criteria. As a result, two tools were recommended as most representative of current state of the science, most clinically relevant, and practically applicable to integrate into everyday practice and support adherence to regulatory guidelines. Such recommendations for selection of best-available pain assessment tools are a cornerstone for clinicians in regard to managing pain of nursing home residents who, due to dementia, are unable to self-report pain. Copyright 2010, SLACK Incorporated. [ABSTRACT FROM AUTHOR]

The quality of care provided to nursing home residents has been the subject of broad criticism for years. Mounting evidence suggests that the quality of nursing home care can be improved by strengthening the roles of nurses in these facilities. This article reviews the literature on programs designed to enhance nursing leadership in long-term care, examines outcomes associated with leadership in long-term care, and outlines recommendations for programs to enhance nursing leadership in nursing home settings. The findings suggest that nursing leadership training programs for nurses working in nursing homes are urgently needed to improve quality in the nation's nursing homes and stabilize the workforce. To maximize their effectiveness, these leadership training programs should be part of a continuum of leadership development that begins in nursing education programs and persists throughout a nurse's career trajectory. [ABSTRACT FROM AUTHOR]

Background: The rising incidence of malignant melanoma and the lack of curative therapies for metastatic disease represent a therapeutic challenge. New agents effective in treating this disease are needed.Purpose: Because of the additive antitumor effects of interleukin 1 alpha (IL-1 alpha) and indomethacin in vivo, we conducted a phase II trial of this combination in patients with melanoma. We used the recommended dose determined from our phase I trial to ascertain the antitumor activity of the combination.Methods: From August 1, 1990, through July 28, 1992, 49 patients entered the study. They were stratified into two groups based on the presence of visceral (n = 14) and nonvisceral (n = 35) metastases. The patients received 7 days of both IL-1 alpha (O.1 micrograms/kg per day by intravenous bolus) infusion) and indomethacin (50 mg orally every 8 hours). At least two cycles of therapy, repeated at 21-day intervals, were planned. Additional treatment was given to those patients who had stable or responding lesions. A chi-squared test for homogeneity of proportions was used to compare groups on several measures. All P values resulted from two-sided tests.Results: Fever, chills, and hypotension were among the most common side effects. None of the 14 patients with visceral metastases responded to the treatment. Of the 35 patients with non-visceral metastases, three showed a partial response for 6 months each and one showed a complete response for more than 34 months; the response rate was 11% (95% confidence interval [CI] = 5%-26%). All responding patients required phenylephrine for treatment of IL-1 alpha-induced hypotension, whereas six (19%) of 31 of the nonresponding patients with nonvisceral metastases required phenylephrine (P = .0008). The response rate in women was higher; three of 10 women (30%; 95% CI = 11%-60%) responded, whereas one of 25 men (4%; 95% CI = 0%-20%) responded (P = .029). All three women were positive for human leukocyte antigen (HLA) B7 expression (P = .011).Conclusions: The combination of IL-1 alpha and indomethacin has minimal antitumor activity in melanoma patients. All responses were confined to patients with nonvisceral metastases. IL-1 alpha-induced hypotension, gender, and HLA B7 expression were positively associated with response.Implications: Administration of higher doses of IL-1 alpha alone has been shown to produce hypotension in a large proportion of patients but can be given safely with phenylephrine support. Because of the association of hypotension with antitumor activity, treatment with higher IL-1 alpha doses alone may be a strategy for attaining better response rates. [ABSTRACT FROM AUTHOR]

BACKGROUND: Insulin-like growth factor I (IGF-I) is a hormone that mediates the effects of growth hormone and plays a critical role in somatic growth regulation and organ development. It is hypothesized that it also plays a key role in human brain development. Previous studies have investigated the association of low IGF-I levels attributable to growth hormone receptor deficiency with intelligence but produced mixed results. We are aware of no studies that investigated the association of IGF-I levels with IQ in population samples of normal children. OBJECTIVES: To investigate the association of circulating levels of IGF-I and its principle binding protein, IGF-binding protein-3 (IGFBP-3), in childhood with subsequent measures of IQ. METHODS: The cohort study was based on data for 547 white singleton boys and girls, members of the Avon Longitudinal Study of Parents and Children, with IGF-I and IGFBP-3 measurements (obtained at a mean age of 8.0 years) and IQ measured with the Wechsler Intelligence Scale for Children (at a mean age of 8.7 years). We also investigated associations with measures of speech and language based on the Wechsler Objective Reading Dimensions test (measured at an age of 7.5 years) and the Wechsler Objective Language Dimensions test (listening comprehension subtest only, measured at an age of 8.7 years). For some children (n = 407), IGF-I (but not IGFBP-3) levels had been measured at approximately 5 years of age in a previous study. Linear regression models were used to investigate associations of the IGF-I system with the measures of cognitive function. RESULTS: Three hundred one boys and 246 girls were included in the sample. IGF-I levels (mean +/- SD) were 142.6 +/- 53.9 ng/mL for boys and 154.4 +/- 51.6 ng/mL for girls. IQ scores (mean +/- SD) were 106.05 +/- 16.6 and 105.27 +/- 15.6 for boys and girls, respectively. IGF-I levels were associated positively with intelligence. For every 100 ng/mL increase in IGF-I, IQ increased by 3.18 points (95% confidence interval [CI]: 0.52 to 5.84 points). These positive associations were seen in relation to the verbal component (coefficient: 4.27; 95% CI: 1.62 to 6.92), rather than the performance component (coefficient: 1.06; 95% CI: -1.67 to 3.78), of IQ. There was no evidence that associations with overall IQ differed between boys and girls. In a data set with complete information on confounders (n = 484), controlling for birth weight (adjusted for gestation), breastfeeding, and BMI slightly strengthened the associations of IGF-I levels with IQ. Additionally controlling for maternal education and IGFBP-3 levels attenuated the associations (change in IQ for every 100 ng/mL increase in IGF-I levels: 2.51 points; 95% CI: -0.42 to 5.44 points). The weakening of associations in models controlling for markers of parental socioeconomic position and education could reflect shared influences of parental IGF levels on parents' own educational attainment and their offspring's IGF-I levels. In unadjusted models examining associations of Wechsler Objective Reading Dimensions and Wechsler Objective Language Dimensions test scores with IGF-I levels, there was no strong evidence that performance on either of these tests was associated with circulating IGF-I levels, although positive associations were seen with both measures. Associations between IGF-I levels measured at age 5 and Wechsler Intelligence Scale for Children scores (n = 407) were similar to those for IGF-I levels measured at age 7 to 8. For every 100 ng/mL increase in IGF-I levels at 5 years of age, IQ increased by 2.3 points (95% CI: -0.21 to 4.89 points). CONCLUSIONS: This study provides some preliminary evidence that IGF-I is associated with brain development in childhood. Additional longitudinal research is required to clarify the role of IGF-I in neurodevelopment. Because IGF-I levels are modifiable through diet and other environmental exposures, this may be one pathway through which the childhood environment may influence neurodevelopment. [ABSTRACT FROM AUTHOR]

BACKGROUND: In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. METHODS: This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. FINDINGS: Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p<0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0.0001) and in eight of the 21 patients in the second cycle (p<0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. INTERPRETATION: In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction. [ABSTRACT FROM AUTHOR]

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.