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The environmental conditions that marine populations experience are being altered because of climate change. In particular, changes in temperature and increased variability can cause shifts in spatial distribution, leading to changes in local physiological rates and recruitment success. Yet, management of fish stocks rarely accounts for variable spatial dynamics or changes in movement rates when estimating management quantities such as stock abundance or maximum sustainable yield. To address this concern, a management strategy evaluation (MSE) was developed to evaluate the robustness of the international management system for Pacific hake, an economically important migratory stock, by incorporating spatio-temporal population dynamics. Alternative hypotheses about climate-induced changes in age-specific movement rates, in combination with three different harvest control rules (HCR), were evaluated using a set of simulations that coupled single-area estimation models with alternative operating models representing spatial stock complexity. Movement rates intensified by climate change caused a median decline in catches, increased annual catch variability, and lower average spawning biomass. Impacts varied by area and HCR, underscoring the importance of spatial management. Incorporating spatial dynamics and climate change effects into management procedures for fish stocks with spatial complexity is warranted to mitigate risk and uncertainty for exploited marine populations.

Background QRS complex prolongation is an established prognostic marker in patients with heart failure, (HF) and identifies patients for whom standard treatment includes cardiac resynchronization therapy (CRT). In contrast, the role of QRS width progression over time on clinical status and whether it can be predicted has been incompletely explored. Purpose To provide pilot data that could help to identify features associated with QRS progression and deteriorating clinical status. Methods The present retrospective analysis relates to 100 consecutive attendees to our HF clinic between April and August 2021. Each patient with a least one past visit including an ECG was included and a maximum of 4 past visits were assessed per patient. Results In total 240 datasets were generated from at least two consecutive visits and included clinical status, electrocardiographic (ECG), laboratory and echocardiographic data. Mean age and left ventricular ejection fraction were 58±13 years and 36±10%. The mean time between visits was 227 days. Datasets were stratified into tertiles based on change in QRS duration (mm/month). These were labelled as “QRS width regression” (>−0.34 ms/month), “QRS stability” (−0.33 to 0.49 ms/month and “QRS width progression” (>0.50 ms/month). The incidence of the combined endpoint of worsening symptomatic HF (deterioration in NYHA class by at least one grade) and HF hospitalisation was significantly higher in the QRS progression group compared with the stable group (Log Rank test: progression v stability p=0.013). In addition, patients with QRS progression had a higher baseline plasma NT-pro-BNP levels (p=0.008) and higher baseline heart rate (p=0.007). To explore whether patients at higher risk of QRS progression could be identified at baseline, we built a prediction model based upon baseline NTproBNP levels and baseline heart rate. We determined that an NT-pro-BNP >837 pg/ml and a heart rate >83/bpm were reliable thresholds for greater risk of QRS progression (Figure 1A & B). Both of these variables were independent of guideline-directed medical HF therapy (including beta-antagonist use and dose). An interaction analysis revealed that combining these two risk factors was associated with a 14-fold increased risk of QRS progression compared with neither or either alone, suggesting synergism between these variables (HR: 14.2 [95% 6.9–53.6]; p Conclusion In the current pilot study, we demonstrate that QRS progression is associated with future risk of clinical deterioration of HF. In addition, we show that higher baseline NTproBNP plasma levels combined with higher baseline heart rate indicate a group at markedly increased risk of progression of QRS width, independently of HF therapy. These parameters might therefore identify people potentially benefitting from intensified follow up, optimisation of GDMT and could also help coordinate the application of a more personalised approach to device therapy Funding Acknowledgement Type of funding sources: None.

Fisheries policy inherently relies on an explicit definition of management boundaries that delineate the spatial extent over which stocks are assessed and regulations are implemented. However, management boundaries tend to be static and determined by politically negotiated or historically identified population (or multi-species) units, which create a potential disconnect with underlying, dynamic population structure. The consequences of incoherent management and population or stock boundaries were explored through the application of a two-area spatial simulation–estimation framework. Results highlight the importance of aligning management assessment areas with underlying population structure and processes, especially when fishing mortality is disproportionate to vulnerable biomass among management areas, demographic parameters (growth and maturity) are not homogenous within management areas, and connectivity (via recruitment or movement) unknowingly exists among management areas. Bias and risk were greater for assessments that incorrectly span multiple population segments (PSs) compared to assessments that cover a subset of a PS, and these results were exacerbated when there was connectivity between PSs. Directed studies and due consideration of critical PSs, spatially explicit models, and dynamic management options that help align management and population boundaries would likely reduce estimation biases and management risk, as would closely coordinated management that functions across population boundaries.

Negative supercoiling by DNA gyrase is essential for maintaining chromosomal compaction, transcriptional programming, and genetic integrity in bacteria. Questions remain as to how gyrases from different species have evolved profound differences in their kinetics, efficiency, and extent of negative supercoiling. To explore this issue, we analyzed homology-directed mutations in the C-terminal, DNA-wrapping domain of the GyrA subunit of Escherichia coli gyrase (the ‘CTD’). The addition or removal of select, conserved basic residues markedly impacts both nucleotide-dependent DNA wrapping and supercoiling by the enzyme. Weakening CTD–DNA interactions slows supercoiling, impairs DNA-dependent ATP hydrolysis, and limits the extent of DNA supercoiling, while simultaneously enhancing decatenation and supercoil relaxation. Conversely, strengthening DNA wrapping does not result in a more extensively supercoiled DNA product, but partially uncouples ATP turnover from strand passage, manifesting in futile cycling. Our findings indicate that the catalytic cycle of E. coli gyrase operates at high thermodynamic efficiency, and that the stability of DNA wrapping by the CTD provides one limit to DNA supercoil introduction, beyond which strand passage competes with ATP-dependent supercoil relaxation. These results highlight a means by which gyrase can evolve distinct homeostatic supercoiling setpoints in a species-specific manner.

Background The long-term frequencies of cardiac arrhythmias in hospitalized coronavirus disease 2019 (COVID-19) patients have not been thoroughly investigated. Purpose To describe the prevalence of cardiac arrhythmias, 3–4 months after hospitalization for COVID-19. Methods and results Participants with COVID-19 discharged from five large Norwegian hospitals were invited to participate in a prospective cohort study. We examined 201 participants (44% females, mean age 58.5 years) with 24-hour electrocardiogram 3–4 months after discharge. Body mass index (BMI) was 28.3±4.5 kg/m2 (mean ± SD), and obesity (BMI >30) was found in 70 participants (34%). Clinically significant arrhythmias were defined as; ventricular tachycardia (non-sustained or sustained), premature ventricular contractions (PVC) exceeding 200/24 h, or coupled PVC, atrial fibrillation/flutter, second-degree atrioventricular block (AV-block) type 2, complete AV-block, sinoatrial (SA) block exceeding 3 s, premature AV-nodal beats in bigeminy, supraventricular tachycardia (SVT) exceeding 30 s, and sinus bradycardia with less than 30 beats/min. High-sensitive cardiac troponin T (hs-cTnT) was measured at the 3-month follow-up. Results Cardiac arrhythmias were found in 27% (n=54) of the participants. Ventricular premature contractions and non-sustained ventricular tachycardia were the most common arrhythmias, found in 22% (n=44) of the participants. Premature ventricular contractions were the most frequent cardiac arrhythmia. More than 200 PVCs per day were observed in 37 participants (18%) with a mean of 1300 PVC/day, and in 35 (95%) of these participants, the PVCs were polymorphic. Among 10 patients experiencing NSVT, 5 participants had previous CVD, including coronary heart disease (n=1), 1 atrial fibrillation, 2 venous thromboembolism, 4 heart failure. Atrial fibrillation was found in seven patients (3%), none of them of new-onset. SA block >3 seconds was only observed in one patient, and no incidence of high degree AV block was discovered. Pre-existing cardiovascular disease or hypertension (CVDH) were reported in 40% (n=81) of the participants. The CVDH group had an increased amount of arrhythmia compared to the group free of CVDH (p=0.04). High PVCs showed a fair correlation with hs-cTnT levels at 3 months (ρ=0.21 p=0.048). Conclusions Three months following hospital discharge with COVID-19, cardiac arrhythmia was found in every fourth participant and was associated with a higher concentration of hs-cTnT at 3 months. The clinical implications of persistent ventricular arrhythmia following COVID-19 is not clear, but ventricular ectopy has been linked to increased risk of cardiac disease, including cardiomyopathy and sudden cardiac death. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The National Association for Heart, Lung diseases and the Norwegian Health Association and Akershus University Hospital.

This study aimed to consider childhood poverty in relation to a count measure of adverse childhood experiences (ACEs) as a predictor of adult health outcomes and to determine whether associations are sensitive to how childhood poverty is operationalized. A sample of 10,784 adult residents was derived using data 2014–2015 Wisconsin annual Behavioral Risk Factor Survey data, derived from the Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System (BRFSS). Adult health outcomes (health risk behaviors, general health problems, chronic health problems, and depression) were predicted using a more conservative and severe indicator of childhood poverty, and authors tested whether observed associations were attenuated by the inclusion of an ACE count variable. Findings showed that severe indicators of childhood poverty are associated with general and chronic health problems as well as adult depression. These associations are attenuated, but remain intact, when ACEs are included in regression models. Using the CDC BRFSS data for Wisconsin, the study showed that associations between childhood poverty and adult health are sensitive to the way in which childhood poverty is operationalized. The relationship between childhood poverty and other ACEs is complex and thus warrants treating the former as a distinct childhood adversity rather than an item in an ACE summary score.

Introduction: Introduction Sleep disturbances are common in adolescents with neurodevelopmental disorders (NDDs). Inclusion of vulnerable populations such as adolescents with NDDs into sleep intervention efforts is essential as they are at high-risk for poor physical/mental health outcomes. The objective of this study is to pilot a sequential, multiple assignment, randomized trial (SMART) design to compare the impact of a sequence of sleep interventions, based on treatment response, to optimize sleep health in adolescents with NDDs. Methods: Methods Recruitment began June 2019 using convenience sampling. The SMART pilot feasibility study includes 1-week of baseline sleep data, and two 4-week periods of a sleep intervention (9-week total study enrollment). Interventions include exogenous melatonin, The Bedtime Bank, and their combination. Exogenous melatonin (liquid, immediate release, 3mg) is administered 30 minutes before bedtime. The Bedtime Bank, a behavioral sleep intervention, is based upon contingency contracting that relies on a credit- or debt-based system to hold adolescents accountable for maintaining a consistent bedtime. At baseline participants completed demographics, PROMIS pediatric sleep questionnaires, the Cleveland Adolescent Sleepiness Questionnaire (CASQ), salivary & urinary endogenous melatonin measurement, and one week of actigraphy. Upon enrollment, participants were randomly assigned to either melatonin or The Bedtime Bank. Participants who respond (nightly increase in total sleep time (TST) ≥18 minutes) remain on the assigned intervention; if non-responsive participants are re-randomized to a different sleep intervention or combination. Results: Results At baseline, participants (n=29, aged 10–18 years) had an average TST of 7 hours 11 minutes. PROMIS Sleep Disturbance (M=64.3, SE=2.5), PROMIS Sleep-Related Impairment scores (M=58.9, SE=2.2), and CASQ scores (M=40.0, SD= 10.5) were higher than reported normative values. Salivary DLMO & urinary 6-sulfatoyxmelatonin analysis is ongoing. For participants who completed the full 9-week trial, nearly 30% (n=7/24) were responsive (increased baseline TST ≥18 minutes) to one of the 4-week interventions. Conclusion: Conclusion Baseline data of the enrolled participants demonstrates poor indicators of TST, sleep disturbance, and sleep related impairment. Preliminary results of this SMART indicate some adolescents are responsive to sleep interventions aimed to improve their TST. Support (if any) Support: This clinical trial is funded by the National Institute of Nursing Research, National Institutes of Health (1K01NR017465-01A1).

BackgroundFatigue is a consistently reported, severe symptom among patients with gliomas throughout the disease trajectory. Genomic pathways associated with fatigue in glioma patients have yet to be identified.MethodsClinical factors (performance status, tumor details, age, gender) were collected by chart review on glioma patients with fatigue (“I have lack of energy” on Functional Assessment of Cancer Therapy-Brain), as well as available genotyping data. Candidate genes in clock and inflammatory pathways were identified from a literature review, of which 50 single nucleotide polymorphisms (SNPs) in 7 genes were available. Clinical factors and SNPs identified by univariate analyses were included in a multivariate model for moderate-severe fatigue.ResultsThe study included 176 patients (median age = 47 years, 67% males). Moderate-severe fatigue was reported by 43%. Results from multivariate analysis revealed poor performance status and 2 SNPs were associated with fatigue severity. Moderate-severe fatigue was more common in patients with poor performance status (OR = 3.52, P < .01). For each additional copy of the minor allele in rs934945 (PER2) the odds of fatigue decreased (OR = 0.51, P < .05). For each additional copy of the minor allele in rs922270 (ARTNL2) the odds of fatigue increased (OR = 2.38, P < .01). Both of these genes are important in the circadian clock pathway, which has been implicated in diurnal preference, and duration and quality of sleep. No genes in the inflammatory pathway were associated with fatigue in the current study.ConclusionsIdentifying patients at highest risk for fatigue during treatment allows for improved clinical monitoring and enrichment of patient selection for clinical trials.

A large data set of L1 psycholinguistic norms (Balotaet al.2007) was used to assess spoken L2 English lexical proficiency in cross-sectional and longitudinal learner corpora. Behavioral norms included lexical decision and word naming latencies (i.e. reaction times) and accuracies for 40,481 English words. A frequency measure was included to compare the relative strength of the norms to a traditional lexical measure when explaining proficiency and growth. The cross-sectional study revealed that learners identified as more lexically proficient by human raters produced words that were recognized more slowly and named more slowly and less accurately in L1 experimental settings. Moreover, lexical decision latencies explained more variance in ratings than frequency, while frequency and word naming latencies were comparable. The longitudinal study indicated that words produced by L2 speakers over time were recognized less accurately and named more slowly and less accurately by L1 subjects, while the frequency of those words decreased over time. Together, results demonstrate that L1 psycholinguistic information can index L2 lexical proficiency and growth across corpora while adding unique information to our understanding of L2 lexical knowledge.

One way to address the growing problem of antimicrobial resistance is to revive old compounds that may have intrinsic lethal activity that is obscured by protective factors. Bicyclomycin is an old inhibitor of the Rho transcription terminator that by itself shows little rapid lethal activity. However, bicyclomycin participates in bacteriostatic synergy, which raises the possibility that conditions for lethal synergy may exist, perhaps through a suppression of protective factors.Bicyclomycin was combined with bacteriostatic inhibitors of gene expression, and bactericidal activity was measured with several cultured Gram-negative pathogens.When used alone, bicyclomycin failed to rapidly kill growing cultures of Escherichia coli; however, the additional presence of bacteriostatic concentrations of tetracycline, chloramphenicol or rifampicin led to rapid killing. Four other pathogen species, Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella enterica serotype Typhimurium and Shigella dysenteriae, also exhibited enhanced killing when bicyclomycin was combined with tetracycline or rifampicin. This lethal synergy was achieved at low concentrations (slightly above the MIC) for all agents tested in combinations. Follow-up work with E. coli indicated that lethal synergy arose from a blockage of transcription elongation. Moreover, lethal synergy was reduced when bicyclomycin was added 60 min before tetracycline, suggesting that bicyclomycin induces a protective factor.The action of bicyclomycin illustrates the potential present in a largely abandoned antibacterial agent; it exhibits lethal synergy when coadministered with known, bacteriostatic inhibitors of gene expression. The identification of protective factors, which are currently uncharacterized, may reveal new ways to promote the lethal action of some old antibiotics.

Type IIA topoisomerases control DNA supercoiling and separate newly replicated chromosomes using a complex DNA strand cleavage and passage mechanism. Structural and biochemical studies have shown that these enzymes sharply bend DNA by as much as 150°; an invariant isoleucine, which has been seen structurally to intercalate between two base pairs outside of the DNA cleavage site, has been suggested to promote deformation. To test this assumption, we examined the role of isoleucine on DNA binding, bending and catalytic activity for a bacterial type IIA topoisomerase, Escherichia coli topoisomerase IV (topo IV), using a combination of site-directed mutagenesis and biochemical assays. Our data show that alteration of the isoleucine (Ile172) did not affect the basal ATPase activity of topo IV or its affinity for DNA. However, the amino acid was important for DNA bending, DNA cleavage and supercoil relaxation. Moreover, an ability to bend DNA correlated with efficacy with which nucleic acid substrates stimulate ATP hydrolysis. These data show that DNA binding and bending by topo IV can be uncoupled, and indicate that the stabilization of a highly curved DNA geometry is critical to the type IIA topoisomerase catalytic cycle.

Summary The importance of serum immunoglobulin (Ig)G concentration in IgG replacement therapy for primary immunodeficiency diseases is established in certain settings. Generally, IgG is infused via the intravenous (IVIG) or subcutaneous (SCIG) route. For IVIG infusion, published data demonstrate that higher IgG doses and trough levels provide patients with improved protection from infection. The same conclusions are not yet accepted for SCIG; data from two recent Phase III studies and a recent post-hoc analysis, however, suggest the same correlation between higher SCIG dose and serum IgG concentration and decreased incidence of infection seen with IVIG. Other measures of clinical efficacy have not been considered similarly. Thus, combined analyses of these and other published SCIG studies were performed; a full comparison of the 13 studies was, however, limited by non-standardized definitions and reporting. Despite these limitations, our analyses indicate that certain clinical outcomes improve at higher SCIG doses and associated higher serum IgG concentrations, and suggest that there might be opportunity to improve patient outcomes via SCIG dose adjustment.

We search for the most basic kaonic nuclear state, K−pp, by studying an exclusive p + p → p + Λ + K process at Tp = 3.1 GeV using FOPI apparatus at GSI, Darmstadt, Germany. A possible signature of the K−pp is searched as a p+p → K−pp+K+ → p+Λ+K reaction in the event sample of pΛK three body process. A missing-mass ΔM(pK) spectrum, a Λp invariant-mass M(Λp) spectrum and a mono energetic kaon will characterize such a two body process. The reaction channel is basically the same as the one which T. Yamazaki et al. very recently reported a possible hint of such state with M = 2267 MeV/c and Γ = 118 MeV from a re-analysis of the DISTO experiment data. The DISTO data was taken at Tp = 2.85 GeV. The beam energy of the FOPI experiment is chosen to optimize the signal to background ratio and also to see the background shape separately. FOPI data taking took place in August-September 2009 and analysis is currently undergoing.

The replisome is a multi-component molecular machine responsible for rapidly and accurately copying the genome of an organism. A central member of the bacterial replisome is DnaB, the replicative helicase, which separates the parental duplex to provide templates for newly synthesized daughter strands. A unique RNA polymerase, the DnaG primase, associates with DnaB to repeatedly initiate thousands of Okazaki fragments per replication cycle on the lagging strand. A number of studies have shown that the stability and frequency of the interaction between DnaG and DnaB determines Okazaki fragment length. More recent work indicates that each DnaB hexamer associates with multiple DnaG molecules and that these primases can coordinate with one another to regulate their activities at a replication fork. Together, disparate lines of evidence are beginning to suggest that Okazaki fragment initiation may be controlled in part by crosstalk between multiple primases bound to the helicase.

This paper uses data from the National Longitudinal Survey of Youth to explore links between mothers' returns to work within 12 weeks of giving birth and health and developmental outcomes for their children. OLS models and propensity score matching methods are utilised to account for selection bias. Considerable associations between early returns to work and children's outcomes are found suggesting causal relationships between early returns to work and reductions in breastfeeding and immunisations, as well as increases in externalising behaviour problems. These results are generally stronger for mothers who return to work full-time within 12 weeks of giving birth. New mothers in the US return to work very quickly by international standards. A third of new mothers in the US return to work within 3 months of giving birth (Klerman and Leibowitz, 1990, 1994, 1999; Smith and Bachu, 1999). These figures stand in sharp contrast to figures for other advanced industrialised nations. In Germany, Sweden and the UK, for instance, only about 5% of new mothers return to work so quickly (Gustafsson et al., 1996). The fact that US mothers return to work so quickly is a potential concern if early returns to work result in negative outcomes for their children. Staying home for at least 6 weeks after delivery (8 weeks if the delivery was by Caesarean section) allows new mothers time to recover from birth, facilitates breastfeeding and may help prevent some adverse health consequences for the mother and child. Indeed, in many countries, maternity leave laws specifically prohibit mothers from working until at least 6 weeks have elapsed. And, in most industrialised countries, maternity leave laws provide for an extended period ofjob-protected leave, at least a portion of which is paid. The situation in the US is very different. In the US, the primary source of maternity leave coverage has been employer policies, whether established voluntarily or as part of collective bargaining agreements. Under these employer policies, a new mother can typically stay home for up to 6 weeks, as long as she has the available leave time (e.g., through vacation, sick days, and/or temporary disability coverage) and obtains a doctor's note. In some instances, a longer period of leave is permitted but rarely with pay. Beginning in the early 1970s, some US states passed maternity leave laws requiring firms to provide job-protected leaves to at least some employees. The most generous of these laws provide 18 weeks of leave; the least generous, only 4 weeks of leave. US policy was somewhat formalised in 1993, with the passage of the federal Family and Medical Leave Act (FMLA). Although the FMLA is limited * Funding for this research was provided by the National Institute of Child Health and Human

A multistate cooperative study was conducted to study the current issue of tail length in docked lambs and its relationship to incidence of rectal prolapse. A total of 1,227 lambs at six locations were randomly allocated to two or three tail dock treatments: 1) short--tail was removed as close to the body as possible, 2) medium--tail was removed at a location midway between the attachment of the tail to the body and the attachment of the caudal folds to the tail, and 3) long--tail was removed at the attachment of the caudal folds to the tail. Short-docked lambs had a greater (P < 0.05) incidence of rectal prolapse (7.8%) than lambs with a medium (4.0%) or a long (1.8%) dock. Female lambs had a higher (P < 0.05) incidence of rectal prolapse than male lambs. At two stations, lambs were finished either in a feedlot on a high-concentrate diet or on pasture with no grain supplementation. At one station, with a very low incidence of rectal prolapse, there was no difference in incidence between lambs finished in the feedlot or on pasture; however, at the station with a relatively high incidence of rectal prolapse, lambs in the feedlot had a higher (P < 0.05) incidence than lambs on pasture. The half-sib estimate of heritability for the incidence of rectal prolapse was low (0.14). The results of this study strongly implicate short dock length as a cause of rectal prolapse in lambs finished on high-concentrate diets. Furthermore, the results of this study and the only other study known conducted on this issue strongly suggest that docking lambs at the site of the attachment of the caudal folds to the tail will result in a negligible incidence of rectal prolapse.

Two analytical methods developed for degradation studies in soil were compared for the simultaneous determination of sulfonylurea herbicides. The compounds were extracted with phosphate buffer from soil samples after purification and enrichment steps by solid-phase extraction. Samples were analyzed by liquid chromatography (LC) or capillary electrophoresis (CE) with UV detection. Amidosulfuron, bensulfuron-methyl, chlorimuron-ethyl, chlorsulfuron, ethametsulfuron-methyl, metsulfuron-methyl, nicosulfuron, primisulfuron-methyl, sulfometuron-methyl, thifensulfuron-methyl, triasulfuron, and tribenuron-methyl were separated within 90 and 35 min by LC and CE, respectively. Average recoveries, determined with LC for 5 sulfonylureas in 1–100 μg/kg soil ranged from 74 to 103%, and those determined with CE for 10 sulfonylureas in 2-20 μg/kg soil ranged from 87 to 105%. Bensulfuron-methyl was recovered at lower levels of 52%. The limits of quantitation were 1.0 and 2.0 μg/kg soil for LC and CE, respectively. Coefficients of variation were higher for CE than for LC. Although both methods are suitable, the LC method, which is more sensitive and accurate than the CE method, is preferred for field studies. However, CE, which was shown to be faster with lower operating costs and unlimited repeatability of the analysis due to little injection volumes, is preferred for laboratory studies.

Background: Amplified DNA probes provide powerful tools for the detection of infectious diseases, cancer, and genetic diseases. Commercially available amplification systems suffer from low throughput and require decontamination schemes, significant hands-on time, and specially trained laboratory staff. Our objective was to develop a DNA probe system to overcome these limitations. Methods: We developed a DNA probe system, the BDProbeTecTMET, based on simultaneous strand displacement amplification and real-time fluorescence detection. The system uses sealed microwells to minimize the release of amplicons to the environment. To avoid the need for specially trained labor, the system uses a simple workflow with predispensed reagent devices; a programmable, expandable-spacing pipettor; and the 96-microwell format. Amplification and detection time was 1 h, with potential throughput up to 564 patient results per shift. We tested 122 total patient specimens obtained from a family practice clinic with the BD ProbeTecET and the Abbott LCx® amplified system for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae. Results: Based on reportable results, the BDProbeTecET results for both organisms were 100% sensitive and 100% specific relative to the LCx. Conclusions: The BDProbeTecET is an easy-to-use, high-throughput, closed amplification system for the detection of nucleic acid from C.trachomatis and N.gonorrhoeae and other organisms.

Prolonged intravenous immunoglobulin (IVIg) therapy is frequently used for the treatment of chronic autoimmune neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Recent studies of the electrophysiology and immunology of various neurological diseases, including CIDP, suggest that antibody-induced reversible dysfunction of nodes of Ranvier plays an important role in conduction block and morbidity 1. This may be more important, at least in the short term, than demyelination or axon destruction. The IVIg doses and dosing intervals are usually chosen empirically due to a paucity of data from dose-response and pharmacodynamic studies. The use of 2 g/kg as loading dose and maintenance doses of 1 g/kg every 3–4 weeks are common. European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines suggest that the dose and frequency of IVIg should be tailored to an individual patient's needs 2. However, there are no recommendations as to how this can be achieved or the outcomes upon which adjustments in therapy should be based. Clinical observations suggest that with currently used immunoglobulin (Ig) regimens the beneficial effects of each dose of IVIg may be transient, wearing off before the next cycle of treatment is required. These observations have been confirmed by case reports. A patient with CIDP repeatedly showed improvement in ankle dorsiflexion over the first 5–9 days following the administration of IVIg. The improvement was sustained for approximately 10 days but then declined, reaching pretreatment levels by the end of the month 3. These periodic fluctuations in strength were also reported in a patient with MMN on monthly IVIg therapy 4. However, this patient was switched to subcutaneous immunoglobulin (SCIg) therapy and, with a 25% increase in total monthly dose, his disease stabilized. Weekly SCIg has been investigated as a means of continuously maintaining high serum IgG levels, resulting in stabilization of neuromuscular function in CIDP and MMN patients 5–8. Significant variations in IgG metabolism have been reported among patients with CIDP 9. These differences were unrelated to the administered dose, weight, body mass index or degree of functional improvement. However, the patient-specific post-infusion rise in IgG levels, which may be dependent upon the individual rate of IgG metabolism, may explain the interpatient differences in infusion frequency requirements. The optimum dosage and frequency of IVIg infusions appears to be patient-specific 9. It has been shown that actual doses and dosing intervals vary from conventional empirical dosing, suggesting that physicians may already be adjusting doses based on the individual patient's clinical condition and treatment response 10. A prospective study has shown that CIDP patients maintain strength optimally when their IgG levels reach a plateau supported by infusions as frequent as once every 10 days. The intra- and interpatient variability in IgG may indicate that individualized constant levels of IgG facilitate achieving clinical stability 11. Overall, these studies show that many patients with CIDP have increased benefit when IVIg is administered at more frequent intervals, with 30–60% of patients showing improvement when IVIg is administered at intervals of 10–14 days or less 9–11. An ongoing study supported by CSL Behring in collaboration with AxelaCare has demonstrated that grip strength and disability measurements performed frequently by the patient at home can be reported wirelessly, collected by a database service, and reported to the physician 12. This information can prove useful for assessing the extent and duration of responses to individual IgG doses. In addition, this type of frequent data collection can be used to identify patients who would benefit from weekly SCIg rather than IVIg every 3−4 weeks and those in whom IgG therapy is ineffective. Currently, Ig replacement therapy is widely used in the treatment of chronic autoimmune neuropathies. Individualization of IgG treatment regimens may optimize efficacy and minimize disability. Further studies are needed to determine whether patient-specific regimens result in improved long-term outcomes.

Sleep-wake disturbances are defined as perceived or actual alterations in sleep that result in impaired daytime functioning. Unlike other cancers, there is limited information about sleep-wake disturbances in adults with primary brain tumors throughout the illness trajectory. Sleep-wake disturbance is among the most severe and common symptoms reported by primary brain-tumor patients, particularly those undergoing radiation therapy. As with other cancers and neurologic illness, sleep-wake disturbance may also be clustered or related to other symptoms such as fatigue, depression, and cognitive impairment. There is increasing evidence for a genetic basis of normal sleep and sleep regulation in healthy adults. Specific mutations and single nucleotide variants have been reported to be associated with both fatigue and sleep-wake disorders, and both inflammation and alterations in circadian rhythms have been postulated to have a potential role. Guidelines for assessment and interventions have been developed, with cognitive behavioral therapy, exercise, and sleep hygiene demonstrating benefit in patients with other solid tumors. Further research is needed to identify risk and appropriate treatment in the brain-tumor patient population.

A strong association between arterial hypertension and Type 2 diabetes mellitus has been known for more than 70 years. However, there are many unanswered questions with regard to the hypothesis of a causal relationship between insulin resistance/hyperinsulinaemia and arterial hypertension. At present, there is no hard evidence for a close (causal) linkage between insulin resistance (or hyperinculinaemia) and arterial hypertension. Currently available antihypertensive drugs in prudent and effective dosages do not result in a deterioration of insulin sensitivity, or in the development of insulin resistance, or an increased incidence of Type 2 diabetes mellitus.

The radical oxidation capability of several classes of iron minerals, including biotite, hematite, magnetite, minette, nemalite, pyrite, vivianite and two chrysotiles (asbestos), was investigated by using a double experimental approach. One involved the electron spin resonance spin-trapping measurement of organic radicals obtained by the reaction of activated oxygen species, released upon incubation of the minerals in phosphate buffered solutions with formate used as the target molecule. In addition, the formation of mineral-mediated oxidation purine decomposition products, including 7,8-dihydro-8-oxo-2'-deoxyguanosine and 7,8-dihydro-8-oxo-2'-deoxyadenosine, was searched within nucleosides and DNA by using specific and sensitive HPLC electrochemical assays. Emphasis was placed on the mechanistic aspects of the radical oxidation reactions involved in the formation of the two C(8) hydroxylated purine decomposition products.

A 2-yr experiment was conducted to determine whether isolation of ewes from rams is necessary to achieve a high response to the ram effect and whether ewes respond as well in May as in June. The experiment was conducted at two locations, with the same four treatments at each location. The four treatments differed with respect to ewe proximity to rams before mating (isolated vs adjacent) and date of joining with novel breeding rams (May 15 vs June 15). The proximity treatment at one location was changed in the 2nd yr; teaser rams were joined with the ewes instead of being adjacent to them. Overall, 86% of the eligible ewes were judged to have responded to the ram effect. A period of isolation before mating did not increase response compared with ewes that remained adjacent to, or in contact with, rams (86 vs 85%). Response was greater (P less than .05) in June and in the 2nd yr (P = .05). A physiological response, different from that generally described, was identified. Ewes ovulated approximately 8 d (8.0 +/- .19 d) after joining with breeding rams. The subsequent ovulation, accompanied by estrus, occurred approximately 15 d later (15.3 +/- .29 d). Eighty-five percent (87/102) of the ewes sampled responded in this manner. However, 82% (31/38) of a sample of these ewes had at least one morphologically normal corpus luteum when examined by laparoscopy 4 d after joining. It seems that these corpora lutea were not completely functional with respect to progesterone production. The ram effect can be achieved without prior isolation of ewes from rams.(ABSTRACT TRUNCATED AT 250 WORDS)

Phthalocyanine mediated photosensitization of 2'-deoxyguanosine (dG) in oxygen saturated aqueous solution has previously been shown to result in the addition of molecular oxygen to the guanine base generating the 4R* and 4S* diastereoisomers of 4,8-dihydro-4-hydroxy-8-oxo-2'-deoxyguanosine (dO) (the asterisk denotes unambiguous assignment of the 4R and 4S diastereoisomers). The data presented here show that the same guanine modified bases are generated in a 1:1 ratio when thymidylyl-(3',5')-2'-deoxyguanosine (d(TpG)) is similarly photo-oxidized. These modified dinucleoside monophosphates, labelled d(TpO)-A and -B, have been isolated by high performance liquid chromatography and characterized by proton NMR spectrometry, fast atom bombardment mass spectrometry, and enzymatic digestions. Photosensitization in D2O instead of H2O leads to an increase in the rate of d(TpO) formation that is consistent with a type II (singlet oxygen) reaction mechanism. Three interesting properties of these modified dinucleoside monophosphates are: i) the rate of their digestion with spleen phosphodiesterase is greatly reduced relative to d(TpG), ii) they are not digested by snake venom phosphodiesterase, and iii) they are stable to 1.0 M piperidine at 90 degrees C for 30 min. The latter observation indicates that 4,8-dihydro-4-hydroxy-8-oxoguanine is not a base lesion responsible for the strand breaks observed following hot piperidine treatment of DNA exposed to type II photosensitizers or chemically generated singlet oxygen.

Recombinant DNA technology will soon allow physicians an opportunity to carry out both somatic cell- and germ-line gene therapy. While somatic cell gene therapy raises no new ethical problems, gene therapy of gametes, fertilized eggs or early embryos does raise several novel concerns. The first issue discussed here relates to making a distinction between negative and positive eugenics; the second issue deals with the evolutionary consequences of lost genetic diversity. In distinguishing between positive and negative eugenics, the concept of malady is applied as a definitional criterion for identifying genetic disorders that could qualify for germ-line therapy. Because gene replacement techniques are currently unavailable for humans, and because even if they were possible the number of people involved would be quite small, the loss of diversity concern seems moot. Finally, we discuss the issue of iatrogenic disorders associated with gene therapy and discuss several 'real world considerations.'

[Figure][1] Roger Dawson Milkman Photo courtesy of Marianne Milkman Roger Dawson Milkman, professor, population geneticist, and polyglot, died from a stroke and complications of Alzheimer's disease on January 5, 2011, in Washington, DC. He was 80 years old. Milkman's research interests

With the advent of modern technology, human activity has altered the biosphere in ways that are harmful to living systems. As a result, human populations face a series of difficult challenges, such as economic and geographic displacement and adverse changes in health. Social work can play an important role in facilitating human adaptation to such ecological change. To do so, the profession will need to articulate values and purposes that encompass ecological concerns.

The combination of RNA interference (RNAi) with the tetracycline-controlled transcription activation (tet) system promises to become a powerful method for conditional gene inactivation in cultured cells and in whole organisms. Here, we tested critical sequence elements that originated from miRNA mR-30 for optimal efficiency of RNAi-based gene knockdown in mammalian cells. Rationally designed miRNAs, expressed conditionally via the tet system, led to an efficient knockdown of the expression of both reporter genes and the endogenous mitotic spindle protein TPX2 in HeLa cells. Quantitative studies of the tet-controlled gene inactivation revealed that the residual expression of the target gene is an intrinsic attribute of all cells that cannot be eliminated either by increasing the miRNA to target mRNA ratio or by simultaneous expression of miRNAs targeting different sequences within the transcript. The kinetic analysis of the reversibility of the miRNA mediated knockdown suggests that the recovery of target gene expression is primarily driven by cell division. Our miRNA design provides a useful tool for conditional gene inactivation in combination with the RNA-polymerase II based tet system. The identified characteristics of the conditional RNAi-mediated knockdown need to be considered for its application in cell culture or in vivo.

Passing is the social process by which gay men and lesbians present themselves to the world as heterosexuals. A questionnaire survey of same-sex couples, recruited through a national support organization, examined the impact of passing on relationship quality. Passing was not related to self-reported love for partner. However, respondents who were known to significant others as homosexual were more likely to report satisfaction with their relationships. Social workers providing services to gay and lesbian couples are alerted to the primary role played by significant others in the same-sex couple relationship.