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Summary: Acinetobacter baumannii is an important nosocomial pathogen capable of causing wound infections, pneumonia, and bacteremia. During infection, A. baumannii must acquire Zn to survive and colonize the host. Vertebrates have evolved mechanisms to sequester Zn from invading pathogens by a process termed nutritional immunity. One of the most upregulated genes during Zn starvation encodes a putative cell wall-modifying enzyme which we named ZrlA. We found that inactivation of zrlA diminished growth of A. baumannii during Zn starvation. Additionally, this mutant strain displays increased cell envelope permeability, decreased membrane barrier function, and aberrant peptidoglycan muropeptide abundances. This altered envelope increases antibiotic efficacy both in vitro and in an animal model of A. baumannii pneumonia. These results establish ZrlA as a crucial link between nutrient metal uptake and cell envelope homeostasis during A. baumannii pathogenesis, which could be targeted for therapeutic development. : Acinetobacter baumannii must acquire zinc during infection. During zinc starvation, A. baumannii expresses a peptidase named ZrlA. Lonergan et al. discovered ZrlA is required for bacterial cell envelope integrity and overcoming zinc limitation. Inactivation of zrlA increases bacterial membrane permeability, which improves antibiotic efficacy in vitro and during infection. Keywords: zinc, peptidase, calprotectin, Acinetobacter, peptidoglycan, metals, antibiotics, infection, nutritional immunity

Background The aim of this study was to identify modifiable clinical factors associated with radiographic osteoarthritis progression over 1 to 2 years in people with painful medial knee osteoarthritis. Methods A longitudinal study was conducted within a randomised controlled trial, the “Long-term Evaluation of Glucosamine Sulfate” (LEGS study). Recruitment occurred in 2007–2009, with 1- and 2-year follow-up assessments by blinded assessors. Community-dwelling people with chronic knee pain (≥4/10) and medial tibiofemoral narrowing (but retaining >2mm medial joint space width) on radiographs were recruited. From 605 participants, follow-up data were available for 498 (82%, mean [sd] age 60 [8] years). Risk factors evaluated at baseline were pain, physical function, use of non-steroidal anti-inflammatory drugs (NSAIDs), statin use, not meeting physical activity guidelines, presence of Heberden’s nodes, history of knee surgery/trauma, and manual occupation. Multivariable logistic regression analysis was conducted adjusting for age, sex, obesity, high blood pressure, allocation to glucosamine and chondroitin treatment, and baseline structural disease severity (Kellgren and Lawrence grade, joint space width, and varus alignment). Radiographic osteoarthritis progression was defined as joint space narrowing ≥0.5mm over 1 to 2 years (latest follow-up used where available). Results Radiographic osteoarthritis progression occurred in 58 participants (12%). Clinical factors independently associated with radiographic progression were the use of NSAIDs, adjusted odds ratios (OR) and 95% confidence intervals (CI) 2.05 (95% CI 1.1 to 3.8), and not meeting physical activity guidelines, OR 2.07 (95% CI 0.9 to 4.7). Conclusions Among people with mild radiographic knee osteoarthritis, people who use NSAIDs and/or do not meet physical activity guidelines have a greater risk of radiographic osteoarthritis progression. Trial registration ClinicalTrials.gov, NCT00513422. This original study trial was registered a priori, on August 8, 2007. The current study hypothesis arose before inspection of the data.

Iron is an indispensable metabolic cofactor in both pro- and eukaryotes, which engenders a natural competition for the metal between bacterial pathogens and their human or animal hosts. Bacteria secrete siderophores that extract Fe(3+) from tissues, fluids, cells, and proteins; the ligand gated porins of the Gram-negative bacterial outer membrane actively acquire the resulting ferric siderophores, as well as other iron-containing molecules like heme. Conversely, eukaryotic hosts combat bacterial iron scavenging by sequestering Fe(3+) in binding proteins and ferritin. The variety of iron uptake systems in Gram-negative bacterial pathogens illustrates a range of chemical and biochemical mechanisms that facilitate microbial pathogenesis. This document attempts to summarize and understand these processes, to guide discovery of immunological or chemical interventions that may thwart infectious disease.

Atypical femur fractures (AFF) are a rare but serious complication of long-term bisphosphonate use. Although clearly defined by ASBMR criteria, a proportion of patients with AFFs may go unrecognized and the use of qualitative fracture criteria may lead to uncertainty in AFF diagnosis, with significant therapeutic implications. A score that rapidly and accurately identifies AFFs among subtrochanteric femur fractures using quantitative, measurable parameters is needed. In a retrospective cohort of 110 female patients presenting with AFFs or typical femur fractures (TFFs), multiple logistic regression and decision tree analysis were used to develop the Sydney AFF score. This score, based on demographic and femoral geometry variables, uses three dichotomized independent predictors and adds one point for each: (age ≤80 years) + (femoral neck width

The non-homogenous and often insufficiently characterised nature of rock slopes requires mining geotechnical engineers to ensure that pit design is supported by appropriate operational controls. The consequences and near misses from recent large open pit slope failures (>500 m3 failed volume) have driven industry bodies to further refine the delineation of wall failure runout distances. In managing failure hazards, a standoff distance is typically determined by the prediction of potential failure mechanism, volume, and runout distance. Accurate prediction of the runout distance is critical to mine operations for safety and economic reasons. Whilst a comprehensive dataset and research history exists for slope runout predictions in environments such as rock avalanches, landslides, and natural debris flows, similar work directly applicable to the open cut coal mining industry is in its infancy. In particular, the travel angle, or Fahrboschung angle, is a well-recognised relationship that has been used for excavated slopes but is not commonly applied to open cut coal slopes less than 100 m. This investigation has taken the opportunity to gather and interpret new data points from historic failures to improve the accuracy of runout distance predictions. The new dataset included over 50 additional historic open cut highwall failures from eight open cut coal mines situated across the Bowen Basin and the Hunter Valley. Systematic characterisation of runout distances was based on geotechnical parameters such as in situ wall failure height, floor dip, slope angle, failure mechanism, volume of failed material, and geotechnical domain. Through detailed analysis, this new dataset has been statistically evaluated and showed comparable results to previously published data, including the coal industry specific slope stability assessment methodology (SSAM) tool, as well as new empirical trends. Additionally, the investigation has considered initial works for a Fahrboschung angle relationship. This database can be used as a proactive tool to inform failure run out predictions, and also to ensure learnings and data from past failure history is captured and used by the next generation of geotechnical engineers without having to experience past failures.

Streptococcus gordonii is a commensal oral organism. Harmless in the oral cavity, S. gordonii is an opportunistic pathogen. S. gordonii adheres to body surfaces using surface adhesive proteins (adhesins), which are critical to subsequent formation of biofilm communities. As in most Gram-positive bacteria, S. gordonii surface proteins containing the C-terminal LPXTG motif cleavage sequence are processed by sortase A (SrtA) to become covalently attached to the cell wall. To characterize the functional diversity and redundancy in the family of SrtA-processed proteins, an S. gordonii DL1 markerless deletion mutant library was constructed of each of the 26 putative SrtA-processed proteins. Each library member was evaluated for growth in rich medium, biofilm formation on plastic, saliva and salivary fractions, cell surface hydrophobicity (CSH), hemagglutination, and integration into an ex vivo plaque biofilm community. Library members were compared to the non-SrtA-processed adhesins AbpA and AbpB. While no major growth differences in rich medium were observed, many S. gordonii LPXTG/A proteins impacted biofilm formation on one or more of the substrates. Several mutants showed significant differences in hemagglutination, hydrophobicity, or fitness in the ex vivo plaque model. From the identification of redundant and unique functions in these in vitro and ex vivo systems, functional stratification among the LPXTG/A proteins is apparent. IMPORTANCES. gordonii interactions with its environment depend on the complement of cell wall proteins. A subset of these cell wall proteins requires processing by the enzyme sortase A (SrtA). The identification of SrtA-processed proteins and their functional characterization will help the community to better understand how S. gordonii engages with its surroundings, including other microbes, integrates into the plaque community, adheres to the tooth surface, and hematogenously disseminates to cause blood-borne infections. This study identified 26 putative SrtA-processed proteins through creation of a markerless deletion mutant library. The library was subject to functional screens that were chosen to better understand key aspects of S. gordonii physiology and pathogenesis.

Aims To assess whether the Royal College of Paediatrics and Child Health ‘Facing the Future: Standards for acute general paediatric services’ (2015) are being achieved and if changes to service have improved performance. Method Between May and August 2018 there was a phased reconfiguration of services, with merging of two inpatient units and redesign of middle grade and consultant rotas at our tertiary paediatric hospital (68,000 unscheduled care attendances per annum). This redesign has ensured compliance with Standards 1,4 and 6–10. We performed a retrospective case note review of admissions in May and September 2018 to assess performance against Standards 2, 3 and 5. A list of all acute general paediatric admissions was obtained and electronic patient records for every patient admitted on 12 pre-selected days each month were reviewed to document when children were first reviewed by senior clinicians (tier 2 doctors and consultants). Results 219/265(82.6%) patients were reviewed by a tier 2 doctor or above in May 2018 and 244/284(85.9%) in September 2018 (table 1). Review within 4 hours occurred in 124/265(46.8%) in May and 159/284(56%) in September. Most patients admitted over 14 hours had a consultant review during admission (87.9% in May and 79.3% in September); however, this review was often out with 14 hours. Conclusion Facing the Future Standards were considered during the design of acute paediatric services. We achieve seven of ten standards, with senior clinician review of most children during admission. However, with a large volume of unscheduled care attendances, early review remains the biggest challenge. Subsequent changes to our service have included expansion of consultant workforce and relocation of senior clinicians to the Emergency Department. 2019 data are collected and being analysed for comparison.

Discovered over a half-century ago, lipoteichoic acid (LTA) is an abundant polymer found on the surface of Gram-positive bacteria. Although LTA is essential for the survival of many Gram-positive species, knowledge of how LTA contributes to bacterial physiology has remained elusive. Recently, LTA-deficient strains have been generated in some Gram-positive species, including the human oral commensal Streptococcus gordonii. The significance of our research is that we utilized an LTA-deficient strain of S. gordonii to address why LTA is physiologically important to Gram-positive bacteria. We demonstrate that in S. gordonii, LTA plays an important role in the presentation of many cell surface-associated proteins, contributing to cell envelope homeostasis, cell-to-cell interactions in biofilms, and adhesion to eukaryotic cells. These data may broadly reflect a physiological role of LTA in Gram-positive bacteria., Lipoteichoic acid (LTA) is an abundant polymer of the Gram-positive bacterial cell envelope and is essential for many species. Whereas the exact function of LTA has not been elucidated, loss of LTA in some species affects hydrophobicity, biofilm formation, and cell division. Using a viable LTA-deficient strain of the human oral commensal Streptococcus gordonii, we demonstrated that LTA plays an important role in surface protein presentation. Cell wall fractions derived from the wild-type and LTA-deficient strains of S. gordonii were analyzed using label-free mass spectroscopy. Comparisons showed that the abundances of many proteins differed, including (i) SspA, SspB, and S. gordonii 0707 (SGO_0707) (biofilm formation); (ii) FtsE (cell division); (iii) Pbp1a and Pbp2a (cell wall biosynthesis and remodeling); and (iv) DegP (envelope stress response). These changes in cell surface protein presentation appear to explain our observations of altered cell envelope homeostasis, biofilm formation, and adhesion to eukaryotic cells, without affecting binding and coaggregation with other bacterial species, and provide insight into the phenotypes revealed by the loss of LTA in other species of Gram-positive bacteria. We also characterized the chemical structure of the LTA expressed by S. gordonii. Similarly to Streptococcus suis, S. gordonii produced a complex type I LTA, decorated with multiple d-alanylations and glycosylations. Hence, the S. gordonii LTA appears to orchestrate expression and presentation of cell surface-associated proteins and functions. IMPORTANCE Discovered over a half-century ago, lipoteichoic acid (LTA) is an abundant polymer found on the surface of Gram-positive bacteria. Although LTA is essential for the survival of many Gram-positive species, knowledge of how LTA contributes to bacterial physiology has remained elusive. Recently, LTA-deficient strains have been generated in some Gram-positive species, including the human oral commensal Streptococcus gordonii. The significance of our research is that we utilized an LTA-deficient strain of S. gordonii to address why LTA is physiologically important to Gram-positive bacteria. We demonstrate that in S. gordonii, LTA plays an important role in the presentation of many cell surface-associated proteins, contributing to cell envelope homeostasis, cell-to-cell interactions in biofilms, and adhesion to eukaryotic cells. These data may broadly reflect a physiological role of LTA in Gram-positive bacteria.

Objective To evaluate the long-term benefit of providing a post-acute, outpatient group exercise program for patients following primary total knee replacement (TKR) surgery for osteoarthritis. Methods A multicenter randomized clinical trial was conducted in 12 Australian public and private hospital centers. A total of 422 participants, ages 45–75 years, were randomly allocated prior to hospital discharge to the post-acute group exercise program or to usual care and were assessed at 6 weeks, 6 months, and 12 months after surgery. The main outcomes were operated knee pain and activity limitations at 12 months using the Western Ontario and McMaster Universities Osteoarthritis Index questionnaire. Secondary outcomes included health-related quality of life (Short Form 12 health survey), knee extension and flexion strength, stair-climb power, 50-foot walk speed, and active knee range of motion. Results While both allocation groups achieved significant improvements in knee pain and activity limitations over the 12-month followup period, there were no significant differences in these main outcomes, or in the secondary physical performance measures, between the 2 treatment allocations. Twelve months after TKR, 69% and 72% of participants allocated to post-acute exercise and usual acute care, respectively, were considered to be treatment-responders. While population normative values for self-report measures of pain, activity limitation, and health-related quality of life were attained 12 months after TKR, marked deficits in physical performance measures remained. Conclusion Providing access to a post-acute group exercise program did not result in greater reductions in long-term knee pain or activity limitations than usual care. Patients undergoing primary TKR retain marked physical performance deficits 12 months after surgery.

Objective To evaluate the prevalence and determinants of clinically important fatigue before and up to 12 months after total knee replacement (TKR) surgery. Methods This study was a secondary analysis of a prospective cohort study conducted among 422 patients (ages 45–74 years) undergoing primary TKR for osteoarthritis (OA) who participated in the Maximum Recovery After Knee Replacement randomized clinical trial. Assessments were carried out before, and at 6 weeks, 6 months, and 12 months after surgery. Self-reported fatigue was assessed on a 10-cm visual analog scale. Patients also completed a number of questionnaires evaluating knee pain, activity limitations, psychological well-being, comorbidity, and physical activity. Linear regression analyses were conducted to explore 6- and 12-month cross-sectional and longitudinal associations with self-reported fatigue. Results Clinically important fatigue (≥6.7 of 10) was reported by 145 patients (34%) before surgery, decreasing to 14%, 12%, and 8% at 6 weeks, 6 months, and 12 months after surgery, respectively. In multivariate analyses, muscle strength was strongly associated with fatigue at 6 months, and knee pain, activity limitations, number of comorbidities, and lack of energy were strongly associated with fatigue at both 6 and 12 months after TKR surgery. Female sex, number of comorbidities, depression, and fatigue were all early predictors of fatigue 12 months after TKR. Conclusion Among patients undergoing TKR for OA, clinically important fatigue is considerably prevalent both before and for at least 6 months after surgery. Identifying and addressing early predictors of ongoing fatigue has the potential to improve the quality of life following TKR surgery.

Objective To determine the prevalence and burden of pain and activity limitations associated with retaining presurgery self-reported knee instability 6 months after total knee replacement (TKR) surgery and to identify early potentially modifiable risk factors for retaining knee instability in the operated knee after TKR surgery. Methods A secondary analysis was performed using measures obtained from 390 participants undergoing primary unilateral TKR and participating in a randomized clinical trial. Self-reported knee instability was measured using 2 items from the Activities of Daily Living Scale of the Knee Outcome Survey. Outcome measures were knee pain (range 0–20) and physical function (range 0–68) on the Western Ontario and McMaster Universities Arthritis Index (WOMAC), stair-climb power, 50-foot walk time, knee range of motion, and isometric knee flexion and extension strength. Results In this study, 72% of participants reported knee instability just prior to surgery, with 32% retaining instability in the operated knee 6 months after surgery. Participants retaining operated knee instability had significantly more knee pain and activity limitations 6 months after surgery, with mean ± SD WOMAC scores of 4.8 ± 3.7 and 17.5 ± 11.1, respectively, compared to participants without knee instability, with 2.9 ± 3.1 and 9.8 ± 9.2. The multivariable predictor model for retained knee instability included a high comorbidity score (>6), low stair-climb power ( 7 of 20), and younger age (

Sensitive assays of biochemical specificity, affinity, and capacity are valuable both for basic research and drug discovery. We created fluorescent sensors that monitor high-affinity binding reactions and used them to study iron acquisition by ESKAPE bacteria, which are frequently responsible for antibiotic-resistant infections. By introducing site-directed Cys residues in bacterial iron transporters and modifying them with maleimide fluorophores, we generated living cells or purified proteins that bind but do not transport target compounds. These constructs sensitively detected ligand concentrations in solution, enabling accurate, real-time spectroscopic analysis of membrane transport by other cells. We assessed the efficacy of these "fluorescent decoy" (FD) sensors by characterizing active iron transport in the ESKAPE bacteria. The FD sensors monitored uptake of both ferric siderophores and hemin by the pathogens. An FD sensor for a particular ligand was universally effective in observing the uptake of that compound by all organisms we tested. We adapted the FD sensors to microtiter format, where they allow high-throughput screens for chemicals that block iron uptake, without genetic manipulations of the virulent target organisms. Hence, screening assays with FD sensors facilitate studies of mechanistic biochemistry, as well as discovery of chemicals that inhibit prokaryotic membrane transport. With appropriate design, FD sensors are potentially applicable to any pro- or eukaryotic high-affinity ligand transport process.

Summary Calprotectin (CP) inhibits bacterial viability through extracellular chelation of transition metals. However, how CP influences general metabolism remains largely unexplored. We show here that CP restricts bioavailable Zn and Fe to the pathogen Acinetobacter baumannii, inducing an extensive multi-metal perturbation of cellular physiology. Proteomics reveals severe metal starvation, and a strain lacking the candidate ZnII metallochaperone ZigA possesses altered cellular abundance of multiple essential Zn-dependent enzymes and enzymes in de novo flavin biosynthesis. The ΔzigA strain exhibits decreased cellular flavin levels during metal starvation. Flavin mononucleotide provides regulation of this biosynthesis pathway, via a 3,4-dihydroxy-2-butanone 4-phosphate synthase (RibB) fusion protein, RibBX, and authentic RibB. We propose that RibBX ensures flavin sufficiency under CP-induced Fe limitation, allowing flavodoxins to substitute for Fe-ferredoxins as cell reductants. These studies elucidate adaptation to nutritional immunity and define an intersection between metallostasis and cellular metabolism in A. baumannii.

Objective: This study aims to evaluate the prevalence and determinants of inadequate physical activity and excessive sedentary behaviour before and after total knee replacement. Design, setting and subjects: Secondary analysis was performed on data from a cohort of 422 adults (45–74 years), drawn from 12 public or private hospitals, undergoing primary unilateral or bilateral total knee replacement surgery. Main measures: Questionnaires were used to determine the presence of inadequate physical activity and excessive sedentary behaviour before and 6 and 12 months after total knee replacement surgery. Knee pain, activity limitations, comorbidities, muscle strength, psychological well-being, fatigue, sleep and body mass index were measured/assessed as possible determinants of physical activity or sedentary behaviour. Results: Before surgery, 77% ( n = 326) of the cohort participated in inadequate physical activity according to World Health Organization guidelines, and 60% ( n = 253) engaged in excessive sedentary behaviour. Twelve months after surgery, 53% ( n = 185) of the cohort engaged in inadequate physical activity and 45% ( n = 157) in excessive sedentary behaviour. Inadequate physical activity before surgery ( P = 0.02), obesity ( P = 0.07) and comorbidity score >6 ( P = 0.04) predicted inadequate physical activity 12 months after surgery. Excessive sedentary behaviour and activity limitations before surgery predicted excessive sedentary behaviour 12 months after surgery. Conclusion: Although there were improvements after total knee replacement, 12 months after surgery about half the cohort did not meet World Health Organization recommendations for activity. Pre-surgery assessment of physical activity, activity limitations, sedentary behaviour and body mass index is essential to identify patients at risk for long-term inactivity.

Objective To determine, at 6 weeks postsurgery, if a monitored home exercise program (HEP) is not inferior to usual care rehabilitation for patients undergoing primary unilateral total knee replacement (TKR) surgery for osteoarthritis. Methods We conducted a multicenter, randomized clinical trial. Patients ages 45–75 years were allocated at the time of hospital discharge to usual care rehabilitation (n = 196) or the HEP (n = 194). Outcomes assessed 6 weeks after surgery included the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function subscales, knee range of motion, and the 50-foot walk time. The upper bound of the 95% confidence interval (95% CI) mean difference favoring usual care was used to determine noninferiority. Results At 6 weeks after surgery there were no significant differences between usual care and HEP, respectively, for pain (7.4 and 7.2; 95% CI mean difference [MD] −0.7, 0.9), physical function (22.5 and 22.4; 95% CI MD −2.5, 2.6), knee flexion (96° and 97°; 95% CI MD −4°, 2°), knee extension (−7° and −6°; 95% CI MD −2°, 1°), or the 50-foot walk time (12.9 and 12.9 seconds; 95% CI MD −0.8, 0.7 seconds). At 6 weeks, 18 patients (9%) allocated to usual care and 11 (6%) to the HEP did not achieve 80° knee flexion. There was no difference between the treatment allocations in the number of hospital readmissions. Conclusion The HEP was not inferior to usual care as an early rehabilitation protocol after primary TKR.

Summary Objective The increasingly shorter hospitalization following total knee arthroplasty (TKA) requires patients to assume earlier responsibility to self-manage their pain. Poorly managed acute pain increases the risk of persistent pain, reduces quality of life and increases unnecessary healthcare utilization. This study aims to examine post-discharge pain intensity, pain management behaviors and potential barriers to optimal self-management of pain. Design We administered a questionnaire at 2 weeks after discharge to 174 patients undergoing TKA in 10 Australian hospitals. Participants rated pain expectation and severity, use of analgesics and non-pharmacological methods, side-effects, walking and exercise times, perceptions of analgesics, adequacy of pain management information provided and satisfaction with pain relief. Results Of 171 (98%) participants who completed the questionnaire, 88 (52%) reported that the worst pain period occurred during the first 2 weeks at home. During the first 2 weeks at home, the average pain was ‘severe/extreme' for 40 (23%) participants and 92 (54%) experienced severe pain at least some of the time. Many participants sought further medical help for their pain. Adequate information on analgesics and non-pharmacological methods for pain relief were reported by only 73% and 47%, respectively. Approximately 20% had negative perceptions about analgesic use. Higher pain severity was associated with lower satisfaction and less time spent walking daily. Conclusions Effective pain relief after hospital discharge following TKA is a challenge. Many participants reported significant pain, sought further medical help for pain relief and had inadequate information at discharge to effectively self-manage their postoperative knee pain.

SummaryObjectiveTo determine the burden and risk factors associated with reduced work productivity among people with chronic knee pain.MethodA longitudinal study, nested within a randomised controlled trial (RCT) evaluating the long-term effects of dietary supplements, was conducted among people with chronic knee pain in paid employment (n = 360). Participants recorded days off work (absenteeism) and reduced productivity while at work (presenteeism) for seven days every two months over a 12-month period in a study specific diary. Examined risk factors included knee pain severity, occupational group, radiographic disease severity, physical activity, body mass index (BMI), health-related quality of life (SF-12) and co-morbidity.ResultsOver the 12-month follow up period, 50 (14%) participants reported one or more days off work due to knee problems, while 283 (79%) reported reduced productivity while at work (presenteeism

Gram-negative bacteria acquire ferric siderophores through TonB-dependent outer membrane transporters (TBDT). By fluorescence spectroscopic hgh-throughput screening (FLHTS), we identified inhibitors of TonB-dependent ferric enterobactin (FeEnt) uptake through Escherichia coli FepA (EcoFepA). Among 165 inhibitors found in a primary screen of 17,441 compounds, we evaluated 20 in secondary tests: TonB-dependent ferric siderophore uptake and colicin killing and proton motive force-dependent lactose transport. Six of 20 primary hits inhibited TonB-dependent activity in all tests. Comparison of their effects on [ 59 Fe]Ent and [ 14 C]lactose accumulation suggested several as proton ionophores, but two chemicals, ebselen and ST0082990, are likely not proton ionophores and may inhibit TonB-ExbBD. The facility of FLHTS against E. coli led us to adapt it to Acinetobacter baumannii . We identified its FepA ortholog (AbaFepA), deleted and cloned its structural gene, genetically engineered 8 Cys substitutions in its surface loops, labeled them with fluorescein, and made fluorescence spectroscopic observations of FeEnt uptake in A. baumannii . Several Cys substitutions in AbaFepA (S279C, T562C, and S665C) were readily fluoresceinated and then suitable as sensors of FeEnt transport. As in E. coli , the test monitored TonB-dependent FeEnt uptake by AbaFepA. In microtiter format with A. baumannii , FLHTS produced Z′ factors 0.6 to 0.8. These data validated the FLHTS strategy against even distantly related Gram-negative bacterial pathogens. Overall, it discovered agents that block TonB-dependent transport and showed the potential to find compounds that act against Gram-negative CRE (carbapenem-resistant Enterobacteriaceae) /ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species) pathogens. Our results suggest that hundreds of such chemicals may exist in larger compound libraries. IMPORTANCE Antibiotic resistance in Gram-negative bacteria has spurred efforts to find novel compounds against new targets. The CRE/ESKAPE pathogens are resistant bacteria that include Acinetobacter baumannii , a common cause of ventilator-associated pneumonia and sepsis. We performed fluorescence high-throughput screening (FLHTS) against Escherichia coli to find inhibitors of TonB-dependent iron transport, tested them against A. baumannii , and then adapted the FLHTS technology to allow direct screening against A. baumannii . This methodology is expandable to other drug-resistant Gram-negative pathogens. Compounds that block TonB action may interfere with iron acquisition from eukaryotic hosts and thereby constitute bacteriostatic antibiotics that prevent microbial colonization of human and animals. The FLHTS method may identify both species-specific and broad-spectrum agents against Gram-negative bacteria.

The overall aim of this study was to identify risk factors for knee osteoarthritis (OA) structural disease progression. More specifically, we aimed to identify what personal factors (age, sex, obesity, co-morbidity, Herberden’s nodes, history of injury, manual occupation and medication use), radiographic findings (Kellgren and Lawrence (K&L) grade, joint space width, alignment) and activity limitations (self-reported physical activity and physical function) independently predict medial knee joint space narrowing (JSN) over 2 years in people with painful medial knee OA.

Zinc (Zn) is an essential metal that vertebrates sequester from pathogens to protect against infection. Investigating the opportunistic pathogen Acinetobacter baumannii's response to Zn starvation, we identified a putative Zn metallochaperone, ZigA, which binds Zn and is required for bacterial growth under Zn-limiting conditions and for disseminated infection in mice. ZigA is encoded adjacent to the histidine (His) utilization (Hut) system. The His ammonia-lyase HutH binds Zn very tightly only in the presence of high His and makes Zn bioavailable through His catabolism. The released Zn enables A. baumannii to combat host-imposed Zn starvation. These results demonstrate that A. baumannii employs several mechanisms to ensure bioavailability of Zn during infection, with ZigA functioning predominately during Zn starvation, but HutH operating in both Zn-deplete and -replete conditions to mobilize a labile His-Zn pool.

Foundational concepts in psychology are introduced to "27% of all full-time students" in postsecondary institutions each year (Scheirer & Rogers, 1985), constituting an annual North American class size of more than one million adults. In part, these numbers reflect the growth in popularity and perceived value of academic psychology since it was made part of university and college curricula. Understandably, teachers of psychology and their professional organizations have expended considerable effort to set the pedagogical goals for this introduction to the topic (e.g., Gilliland, 1932; Goodwin, 1992; Irion, 1976; Sanford, 1910; Wolfle, 1942). Primary among these goals is that of imparting to students academic psychology's orientation, guiding principles, and facts, on the assumption that there is agreement about the conceptual heart of the discipline. The present study is intended to contribute to the identification of the conceptual core of the introductory psychology curriculum.Scrutiny of the introductory textbook is a common strategy for determining core psychology concepts. However, empirical investigations of textbook content are divided on the issue of content consistency. A number of studies employing gross measures of topic coverage (e.g., page counts devoted to a topic) in different texts at a single time point (Griggs, Jackson, & Napolitano, 1994), in the same text over time (Griggs & Jackson, 1996), and in different texts over time (Webb, 1991) give an impression of coherence and stable consensus about the introductory conceptual corpus. Other studies using similar approaches suggest a picture of variation and inconsistency (Harari & Jacobsen, 1984; Weiten, 1988). Efforts at identifying core concepts using more fine-grained analyses of index terms (Boneau, 1990; Quereshi, 1993; Quereshi & Sackett, 1977; Quereshi & Zulli, 1975), glossaries (Boneau, 1990; Zechmeister & Zechmeister, 2000) or page-by-page content (Landrum, 1993) have led some to see convergence and coherence (Quereshi, 1993) and others to suggest that there is little compelling evidence of a sizeable set of common concepts (Zechmeister & Zechmeister, 2000).A variety of methodological issues have undoubtedly contributed to the equivocal character of work in this area, including differences in chosen sets of textbooks to study; extraneous sources of content variance in the indices, glossaries, and textbook design; and variation in the criteria used for determining that a concept is common to a number of textbooks. This state of affairs leaves ample room for interpretive disagreement about the extent and nature of consensus about core concepts. Whereas Quereshi (1993) reported that recent texts were "more comprehensive and more similar to each other" (p. 220) than previously examined texts, Zechmeister and Zechmeister (2000) found "evidence for incoherence rather than coherence, instability as opposed to stability..." (p. 6) when they examined Quereshi's (1993) data.The point of departure for the present study is the observation that however lamentably small the number, recent studies (Landrum 1993; Quereshi, 1993; Zechmeister & Zechmeister, 2000) have nonetheless been able to identify a number of core concepts in the introductory curriculum ranging from as few as 64 (Zechmeister & Zechmeister, 2000) using a 100% inclusion criteria in 10 books, to 141 in 75% of 52 books (Quereshi, 1993). Landrum's (1993) finding of 126 concepts common to all six texts he reviewed falls in this range. The thrust of our approach is to explore further where in the introductory curriculum consensus about core concepts exists. Using a content analysis approach, we specifically sought to identify which, if any, areas in the introductory curriculum exhibit consensus about core concepts.Two previous studies have examined concepts by topic or area. Quereshi (1993) classified 137 terms found common to 75% of 52 books into four broad areas: biopsychology, clinical psychology, learning and development, and popular psychology. …

We describe a female neonate with spondylocostal dysostosis and a translocation resulting in monosomy for the region 6q25-->qter and trisomy for the region 15q11.1-->pter. The finding of a Mendelian disorder with a chromosomal abnormality may help in the localization of the gene(s) involved in this disease.

Well interpretation and successful field modelling depend on the availability of high quality data and the identification of time-equivalent units and events. Biostratigraphy has been proven to provide the data neccessary for confidently constraining the age of depositional sequences and identifying and constraining stratigraphic hiatuses. Interpretation of biostratigraphic data can be achieved both by reference to established, regional zonations and by the construction of local schemes based on high definition quantitative analyses to identify very localised, correlative field scale changes in individual taxon occurrences and the representation of groups indicative of particular environmental factors. High resolution biostratigraphic monitoring at wellsite enables accurate placement of casing and coring picks, identifies small scale faultsand hiatuses, and can play a major role in geosteering horizontal wells with a high degree of accuracy over long distances.

Objective To determine whether Tai Chi or hydrotherapy classes for individuals with chronic symptomatic hip or knee osteoarthritis (OA) result in measurable clinical benefits. Methods A randomized controlled trial was conducted among 152 older persons with chronic symptomatic hip or knee OA. Participants were randomly allocated for 12 weeks to hydrotherapy classes (n = 55), Tai Chi classes (n = 56), or a waiting list control group (n = 41). Outcomes were assessed 12 and 24 weeks after randomization and included pain and physical function (Western Ontario and McMaster Universities Osteoarthritis Index), general health status (Medical Outcomes Study Short Form 12 Health Survey [SF-12], version 2), psychological well-being, and physical performance (Up and Go test, 50-foot walk time, timed stair climb). Results At 12 weeks, compared with controls, participants allocated to hydrotherapy classes demonstrated mean improvements (95% confidence interval) of 6.5 (0.4, 12.7) and 10.5 (3.6, 14.5) for pain and physical function scores (range 0–100), respectively, whereas participants allocated to Tai Chi classes demonstrated improvements of 5.2 (−0.8, 11.1) and 9.7 (2.8, 16.7), respectively. Both class allocations achieved significant improvements in the SF-12 physical component summary score, but only allocation to hydrotherapy achieved significant improvements in the physical performance measures. All significant improvements were sustained at 24 weeks. In this almost exclusively white sample, class attendance was higher for hydrotherapy, with 81% attending at least half of the available 24 classes, compared with 61% for Tai Chi. Conclusion Access to either hydrotherapy or Tai Chi classes can provide large and sustained improvements in physical function for many older, sedentary individuals with chronic hip or knee OA.

Clinical trials evaluating potential ’disease-modifying’ agents for osteoarthritis are required to demonstrate both symptomatic and structural benefit. Ideally, to reduce ceiling or floor effects, study participants are required to have at least moderate pain, yet retain sufficient tibiofemoral joint space to allow the measurement of narrowing over time. To describe study recruitment procedures and baseline demographics of people with symptomatic knee osteoarthritis participating in the Long-term Evaluation of Glucosamine Sulphate (LEGS) study (NCT00513422).

Background With an ageing population and increased trend to delay retirement worldwide, the number of people in the workforce affected by knee osteoarthritis will increase(1). There is a paucity of research examining the burden of work disability among people with knee osteoarthritis(2). Previous population and patient-based surveys have mostly been limited to evaluating absenteeism and have all required lengthy recall periods(2). Objectives To determine the burden and risk factors associated with work disability (absenteeism and presenteeism) among people with chronic knee pain. Methods A longitudinal study nested within a randomised controlled trial evaluating the long-term effect of dietary supplements. The study cohort consisted of the 336 (55%) trial participants in paid employment. A Participant Diary required reporting on days off work (absenteeism) and reduced productivity while at work (presenteeism) for seven days, every two months over a 12 month follow up period. Baseline risk factors included knee pain, patient global assessment, occupational group, radiographic disease severity, physical activity, body mass index, health-related quality of life (SF-12) and self-reported co-morbidity. Results Among the 336 participants in paid employment, 36 (12%) withdrew from the LEGS study during the 12 month follow up period. A total of 219 (65%) completed all six Participant Diaries while 269 (80%) completed at least five of the six Participant Diaries. Most participants were in professional and managerial roles (46%) and less than 60 years of age (69%). While all participants had medial tibiofemoral joint space narrowing in at least one knee, most knees were Kellgren and Lawrence grade 1 or 2 (∼90%) indicating mild to moderate radiographic disease(3). Over the 12 month follow up period, 44 (13%) participants reported 1 or more days off work due to knee problems. Almost half (43%) of the cohort reported Conclusions This longitudinal study demonstrated marked work disability among people with chronic knee pain, but mostly only mild radiographic disease severity. Physical disability, older age, manual labour and knee pain were clearly associated with reduced productivity while at work. References Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. [Review] [69 refs]. Bull World Health Organ 2003;81:646-56. Bieleman HJ, Oosterveld FG, Oostveen JC, Reneman MF, Groothoff JW. Work participation and health status in early osteoarthritis of the hip and/or knee: a comparison between the Cohort Hip and Cohort Knee and the Osteoarthritis Initiative. Arthritis Care Res 2010;62:683-9. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957;16:494-502. Disclosure of Interest None Declared

Attempted suicide is a behavioural pattern with complex psychological and sociological determinants, many of which have been extensively studied in recent years. The basic facts of its changing incidence, its demography, and its place within a broader spectrum of self-destructive behaviour are well established but authorities are still divided on many issues related to its aetiology, its function in the individual, and the kinds of services required for its clinical management. (Kessel 1965, Anderson 1974, Weissman 1974, Henderson and Williams 1974). The study reported here was designed partly to define the characteristics of a group of patients for whom clinical services were being planned and partly as a pilot study to develop a methodology for a more extensive controlled study which we hope to carry out next year. The preliminary findings are sufficiently interesting to report now.

Disopyramide (2 mg/kg intravenously in 10 minutes) was administered to 14 patients with myocardial infarction within 36 hours of their infarct. Heart rate (HR) increased significantly five minutes after completion of the injection, but profound tachycardia was not seen. Mean wedge pressure (WP) rose and stroke volume (SV) fell. Disopyramide therefore showed a negative inotropic effect on the heart. Systemic vascular resistance (SVR) increased but blood pressure was not significantly altered. Diastolic and mean pulmonary arterial (PA) pressure was also increased by disopyramide. Peak plasma disopyramide level was reached five minutes after injection. The implications of the haemodynamic effects of disopyramide are discussed.

Intravenous nitroglycerin (IVNG) was used in 12 instances (11 patients) to relieve pain, following myocardial infarction or unstable angina. The strength of IVNG infusion could be easily controlled and relief of pain was prompt and satisfactory. Excessive tachycardia or severe headache was not encountered and marked hypotension was seen in one patient only. This patient had three vessel coronary artery disease, extensive myocardial damage and vein graft closure. Cardiovascular stability was provided by IVNG, prior to and during cardiac catheterisation and cineangiography, transportation to another hospital and vein graft surgery. IVNG appears to be a safe and effective drug in the management of patients with acute coronary artery disease (unstable angina and myocardial infarction). In those with both right and left ventricular wall infarction, however, the usefulness of IVNG needs to be established.

Doxazosin, a quinazoline derivative, has alpha 1- adrenoreceptor antagonist properties similar to those of prazosin. This antihypertensive agent has a longer elimination half-life than prazosin. The pharmacokinetic properties of doxazosin are not significantly different in patients with renal insufficiency compared with healthy controls. In this study eight hypertensive patients with renal insufficiency were studied during a two week washout period, followed by a two week single blind placebo phase and an eight week open doxazosin treatment period. Doxazosin was commenced in a dose of 1 mg daily and titrated if necessary, with the dose being doubled every two weeks. In all but one patient doxazosin was successful in controlling the blood pressure. Treatment with doxazosin for eight weeks had no adverse effects on the effective renal plasma flow or glomerular filtration rate of these patients. Six of the eight patients suffered side effects attributable to doxazosin.