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Objective: To map the current testing being undertaken following pregnancy loss across the UK and to examine the clinical utility in terms of identifying a cause for the loss and in identifying couples at risk of an unbalanced liveborn child.Design: Retrospective audit.Setting: UK, for the year 2014.Population: An audit of 6465 referrals for genetic testing of tissue samples following pregnancy loss.Methods: Data were obtained by questionnaire from 15 UK regional genetics laboratories.Main Outcome Measures: Data were analysed with respect to gestational age, the presence of identified fetal anomalies, methodologies used, abnormality rates and the presence of a parental balanced rearrangement.Results: Of 6465 referrals a genetic cause was identified in 22% of cases (before 12 weeks' gestation, in 47%; at 12-24 weeks, in 14%; after 24 weeks, in 6%). In 0.4% of cases a balanced parental rearrangement was identified where there was a risk of an affected liveborn child in a future pregnancy. Eighty percent of genetic imbalances identified were aneuploidy or triploidy and could be identified by quantitative fluorescence polymerase chain reaction alone. There was significant variation across the UK in acceptance criteria, testing strategies and thus level of resolution of testing.Conclusions: Genetic testing of tissues following pregnancy loss identifies a probable cause of fetal demise in 22% of cases, but it is of low clinical utility in identifying couples at risk of a future unbalanced liveborn child. A comprehensive multidisciplinary review is needed to develop proposals for an affordable and equitable service.Tweetable Abstract: UK audit of genetic testing of fetal loss shows variation in access to and resolution of analysis. [ABSTRACT FROM AUTHOR]

Production of subtropical eucalypt cuttings is limited by low temperatures but nothing is known about the effects of temperature variation on biomass partitioning within eucalypt stock plants. This study determined whether changing the temperature from 28/23 °C (day/night) to 18/13, 23/18 or 33/ 28 °C affected the distribution of biomass among the roots, pruned hedge and cuttings of Corymbia citriodora, Eucalyptus cloeziana and E. dunnii stock plants. Root/shoot ratio was signiicantly higher at 18/13 °C than at 33/28 °C, with the roots of the three respective species comprising 36, 50 and 37% of total plant biomass at 18/13 °C but only 24, 27 and 18% of total plant biomass at 33/28 °C. The responses to low temperature in the Eucalyptus species were highly unusual since root/shoot ratio was elevated at 18/13 °C because of an increase in root mass. Subtropical eucalypt stock plants divert biomass production from their shoots to their roots under conditions of low temperature. Thus, sustained cutting production may require that nurseries upgrade the climatic protection for stock plants during winter conditions. [ABSTRACT FROM AUTHOR]

Propagation of tropical and subtropical eucalypts is often limited by reduced production of rooted cuttings in winter. We assessed whether changing the temperature of stock plants of Eucalyptus cloeziana from 28/23 (day/night) to 18/13, 23/18 or 33/28 °C affected the production, nutrient concentrations and percentages of cuttings that subsequently formed roots. Lowering the temperature to 18/13 or 23/18 °C greatly reduced the number of cuttings harvested from stock plants but did not affect the percentage of cuttings that formed roots. However, raising the temperature to 33/28 °C greatly increased the number of cuttings produced by stock plants and the ensuing percentage of cuttings that formed adventitious roots, thereby increasing the final number of rooted cuttings produced from each stock plant. The effects of stock plant temperatures on rooting were not the result of altered nutrient concentrations. However, consistent relationships were found between adventitious root formation and boron concentration. Rooting percentages were very low (1-14%) but rooted cutting production per stock plant (e.g. 12 rooted cuttings over a 14-week period at 33/28 °C) was sufficient to establish field tests for clonal plantation forestry. [ABSTRACT FROM AUTHOR]

The serological relatedness of forty-seven strains of type 1 and type 2 herpes simplex virus was investigated by reciprocal and non-reciprocal neutralization kinetics. Early rabbit antisera divided the virus strains into two distinct groups where confident identification of virus type was possible. Hyperimmune mouse and rabbit antisera did not divide the two virus types into distinct non-overlapping groups. The extent of overlap varied with the particular attribute of the virus being studied. The virus types were best discriminated by their neutralizability by type I antisera and least well by their neutralizability by type 2 antisera. The results of reciprocal kinetic neutralization tests with hyperimmune mouse antisera were analysed by multidimensional duster analysis. Hyperimmune mouse or rabbit antisera could not be discriminated with respect to their immunogenic type by their absolute neutralization rate constants against either type 1 or type 2 virus, but could be distinguished on a group basis by their relative neutralizability against both virus types (antiserum specificity attribute); however, using this latter criterion, the type of immunogen could only be predicted in seven of the forty antisera under test. 'Early' mouse antisera could also be distinguished as groups by their absolute k-values against type 1 herpes virus. Thus, immunogenic identification, on other than a group basis, was unreliable. The specificity of a given serum was inversely related to its titre. There was a positive correlation between the specificity of a given virus strain and of its corresponding antiserum. [ABSTRACT FROM AUTHOR]

Aim: To discuss nurses' use of networks to address nursing recruitment and retention in London, UK., Design: Qualitative evaluation of the Capital Nurse programme reporting on 30 narrative interviews with executive, clinical and student nurses in 2019., Results: Executive nurses within the Capital Nurse programme recognized the importance of sociomaterial contexts in the health and social care system in London and worked strategically across these contexts to achieve change. Supported through the Capital Nurse programme, executive nurses from health organizations across London initiated collaborative working to improve recruitment and retention. Primarily by designing and delivering sociomaterial products (organizational and educational) to support nurses to build a career in London. Drawing on ideas from actor network theory, in particular sociomaterial contexts, nurses' actions at all levels to develop and sustain networks to address nursing recruitment and retention across the NHS in London are described., Conclusions: Capital Nurse supported collaborative working both within single organizations and across organizations in London. There is evidence of change in how nurses across the capital work together to improve patient care, improve recruitment and retention. Findings may resonate with nurses in other settings who seek to address the problem of recruitment and retention. They show how nurses coming together in networks to effect changes in practice can work successfully., Impact: Nurses' use of networks led to novel models of communication and action to address the problems of recruitment and retention in London. We argue that sociomateriality should be considered outside the clinical practice setting, as part of nurses' professional development and organizational practice, that is how they plan their career, how they address recruitment and retention, how they communicate across organizations about nursing issues., No Patient or Public Contribution: This was an evaluation of a staff development project in London, which sought to elicit nurses' experiences of participation in Capital Nurse., (© 2023 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

This phase 1 study characterized the effect of multiple doses of upadacitinib, an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22) received a single oral dose of bupropion 150 mg alone (study period 1) and on day 12 of a 16-day regimen of upadacitinib 30 mg once daily (study period 2). Serial blood samples for measurement of bupropion and hydroxybupropion plasma concentrations were collected in each study period. The central values (90% confidence intervals) for the ratios of change were 0.87 (0.79-0.96) for bupropion maximum plasma concentration (C max ), 0.92 (0.87-0.98) for bupropion area under the plasma-concentration time curve from time 0 to infinity (AUC inf ), 0.78 (0.72-0.85) for hydroxybupropion C max , and 0.72 (0.67-0.78) for hydroxybupropion AUC inf when administered with, relative to when administered without, upadacitinib. After multiple-dose administration of upadacitinib 30 mg once daily, upadacitinib mean ± SD AUC 0-24 was 641 ± 177 ng·h/mL, and C max was 83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant effect on pharmacokinetics of substrates metabolized by CYP2B6., (© 2020 AbbVie Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Upadacitinib is a selective Janus Kinase 1 inhibitor which is being developed for the treatment of several inflammatory diseases including rheumatoid arthritis. Upadacitinib was evaluated in Phase 3 studies as an oral extended-release (ER) formulation administered once daily. The purpose of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for upadacitinib ER formulation. The pharmacokinetics of four upadacitinib extended-release formulations with different in vitro release characteristics and an immediate-release capsule formulation of upadacitinib were evaluated in 20 healthy subjects in a single-dose, randomized, crossover study. In vivo pharmacokinetic data and in vitro dissolution data (USP Dissolution Apparatus 1; pH 6.8; 100 rpm) were used to establish a level A IVIVC. Three formulations were used to establish the IVIVC, and the fourth formulation was used for external validation. A non-linear IVIVC best described the relationship between upadacitinib in vitro dissolution and in vivo absorption profiles. The absolute percent prediction errors (%PE) for upadacitinib C max and AUC were less than 10% for all three formulations used to establish the IVIVC, as well as for the %PE for the external validation formulation and the overall mean internal validation. Model was cross-validated using the leave-one-out approach; all evaluated cross-validation runs met the regulatory acceptance criteria. A level A IVIVC was successfully developed and validated for upadacitinib ER formulation, which meets the FDA and EMA regulatory validation criteria and can be used as surrogate for in vivo bioequivalence.

Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open-label, single-dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15-mg dose of the upadacitinib extended-release formulation in subjects with mild (n = 6) and moderate (n = 6) hepatic impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child-Pugh classification. Relative to subjects with normal hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration-versus-time profile from time 0 to infinity (AUC inf ) for subjects with mild and moderate hepatic impairment were 1.28 (0.91-1.79) and 1.24 (0.87-1.76), respectively. The central ratios of upadacitinib maximum observed concentration (C max ) were 1.04 (0.77-1.39) and 1.43 (1.05-1.95) in subjects with mild and moderate hepatic impairment, respectively, compared with subjects with normal hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics., (© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group). A single 15-mg dose of upadacitinib extended-release formulation was administered under fasting conditions. Serial plasma and urine samples were assayed to evaluate the effect of renal impairment on upadacitinib exposure through regression analysis and analysis of covariance. The primary analysis was the regression analysis of upadacitinib exposures versus estimated glomerular filtration rate. The point estimates for upadacitinib plasma exposure ratios (90% confidence interval [CI]) in subjects with mild, moderate, and severe renal impairment were 1.18 (90%CI, 1.06-1.32), 1.33 (90%CI, 1.11-1.59), and 1.44 (90%CI, 1.14-1.82) for area under the plasma concentration-time curve and 1.06 (90%CI, 0.92-1.23), 1.11 (90%CI, 0.88-1.40), and 1.14 (90%CI, 0.84-1.56) for maximum observed plasma concentration, respectively, relative to subjects with normal renal function based on the regression analysis. The analysis of covariance categorical analysis provided consistent results. Upadacitinib was well tolerated by all subjects, and no safety issues were identified in subjects with renal impairment. Renal impairment has a limited effect on upadacitinib pharmacokinetics. This is in agreement with the known limited role of urinary excretion in upadacitinib elimination. Based on the limited impact on exposure, no dose adjustment is necessary for upadacitinib in subjects with impaired renal function., (© 2019, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Upadacitinib is a novel selective oral Janus kinase 1 (JAK) inhibitor being developed for treatment of several inflammatory diseases. Oral contraceptives are anticipated to be a common concomitant medication in the target patient populations. This study was designed to evaluate the effect of multiple doses of upadacitinib on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female subjects. This phase I, single-center, open-label, 2-period crossover study evaluated the effect of multiple doses of 30 mg once daily extended-release upadacitinib on the pharmacokinetics of a single oral dose of ethinylestradiol/levonorgestrel (0.03/0.15 mg; administered alone in period 1 and on day 12 of a 14-day regimen of upadacitinib in period 2) in 22 healthy female subjects. The ratios (90% confidence intervals) for maximum plasma concentration and area under the plasma drug concentration-time curve from time zero to infinity following administration of ethinylestradiol/levonorgestrel with upadacitinib compared with administration of ethinylestradiol/ levonorgestrel alone were 0.96 (0.89-1.02) and 1.1 (1.04-1.19), respectively, for ethinylestradiol, and 0.96 (0.87-1.06) and 0.96 (0.85-1.07), respectively, for levonorgestrel. The harmonic mean terminal half-life for ethinylestradiol (7.7 vs 7.0 hours) and levonorgestrel (37.1 vs 33.1 hours) was similar in the presence and absence of upadacitinib. Ethinylestradiol and levonorgestrel were bioequivalent in the presence and absence of upadacitinib. Therefore, upadacitinib can be administered concomitantly with oral contraceptives containing ethinylestradiol or levonorgestrel., (© 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

The anticancer effects of combined gemcitabine and birinapant were demonstrated as synergistic in PANC-1 cells in vitro. In this study, pharmacokinetic information derived from experiments and the literature was utilized to develop full physiologically-based pharmacokinetic (PBPK) models that characterize individual drugs. The predicted intra-tumor drug concentrations were used as the driving force within a linked PBPK/PD model for treatment-mediated changes in tumor volume in a xenograft mouse model. The efficacy of the drug combination in vivo was evaluated mathematically as exhibiting additivity. The network model developed for drug effects in the in vitro cell cultures was applied successfully to link the in vivo tumor drug concentrations with tumor growth inhibition, incorporating more mechanistic features and accounting for disparate drug interaction outcomes in vitro and in vivo.

Objective: To map the current testing being undertaken following pregnancy loss across the UK and to examine the clinical utility in terms of identifying a cause for the loss and in identifying couples at risk of an unbalanced liveborn child., Design: Retrospective audit., Setting: UK, for the year 2014., Population: An audit of 6465 referrals for genetic testing of tissue samples following pregnancy loss., Methods: Data were obtained by questionnaire from 15 UK regional genetics laboratories., Main Outcome Measures: Data were analysed with respect to gestational age, the presence of identified fetal anomalies, methodologies used, abnormality rates and the presence of a parental balanced rearrangement., Results: Of 6465 referrals a genetic cause was identified in 22% of cases (before 12 weeks' gestation, in 47%; at 12-24 weeks, in 14%; after 24 weeks, in 6%). In 0.4% of cases a balanced parental rearrangement was identified where there was a risk of an affected liveborn child in a future pregnancy. Eighty percent of genetic imbalances identified were aneuploidy or triploidy and could be identified by quantitative fluorescence polymerase chain reaction alone. There was significant variation across the UK in acceptance criteria, testing strategies and thus level of resolution of testing., Conclusions: Genetic testing of tissues following pregnancy loss identifies a probable cause of fetal demise in 22% of cases, but it is of low clinical utility in identifying couples at risk of a future unbalanced liveborn child. A comprehensive multidisciplinary review is needed to develop proposals for an affordable and equitable service., Tweetable Abstract: UK audit of genetic testing of fetal loss shows variation in access to and resolution of analysis., (© 2016 Royal College of Obstetricians and Gynaecologists.)

Background: Postgraduate nursing students' negative perceptions about a core research subject at an Australian university led to a revision and restructure of the subject using a Communities of Inquiry framework. Negative views are often expressed by nursing and midwifery students about the research process. The success of evidence-based practice is dependent on changing these views. A Community of Inquiry is an online teaching, learning, thinking, and sharing space created through the combination of three domains-teacher presence (related largely to pedagogy), social presence, and cognitive presence (critical thinking)., Objectives: Evaluate student satisfaction with a postgraduate core nursing and midwifery subject in research design, theory, and methodology, which was delivered using a Communities of Inquiry framework., Setting, Participants, and Methods: This evaluative study incorporated a validated Communities of Inquiry survey (n=29) and interviews (n=10) and was conducted at an Australian university. Study participants were a convenience sample drawn from 56 postgraduate students enrolled in a core research subject. Survey data were analysed descriptively and interviews were coded thematically., Results: Five main themes were identified: subject design and delivery; cultivating community through social interaction; application-knowledge, practice, research; student recommendations; and technology and technicalities. Student satisfaction was generally high, particularly in the areas of cognitive presence (critical thinking) and teacher presence (largely pedagogy related). Students' views about the creation of a "social presence" were varied but overall, the framework was effective in stimulating both inquiry and a sense of community., Conclusions: The process of research is, in itself, the creation of a "community of inquiry." This framework showed strong potential for use in the teaching of nurse research subjects; satisfaction was high as students reported learning, not simply the theory and the methods of research, but also how to engage in "doing" research by forging professional and intellectual communities., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Action observation activates brain areas involved in performing the same action and has been shown to increase motor learning, with potential implications for neurorehabilitation. Recent work indicates that the effects of action observation on movement can be increased by motor imagery or by directing attention to observed actions. In voluntary imitation, activation of the motor system during action observation is already increased. We therefore explored whether imitation could be further enhanced by imagery or attention. Healthy participants observed and then immediately imitated videos of human hand movement sequences, while movement kinematics were recorded. Two blocks of trials were completed, and after the first block participants were instructed to imagine performing the observed movement (Imagery group, N = 18) or attend closely to the characteristics of the movement (Attention group, N = 15), or received no further instructions (Control group, N = 17). Kinematics of the imitated movements were modulated by instructions, with both Imagery and Attention groups being closer in duration, peak velocity and amplitude to the observed model compared with controls. These findings show that both attention and motor imagery can increase the accuracy of imitation and have implications for motor learning and rehabilitation. Future work is required to understand the mechanisms by which these two strategies influence imitation accuracy.

Delivery of mental health care relies upon professionals with the latest evidence upon which to base their care. This research reports on a pre-test/post-test evaluation of a four-week education program delivered to Pacific Island participants (n = 18) to enhance knowledge, skills, and attitudes (KSAs). The education program used a combination of formal lectures, tutorials, clinical visits, simulations, and laboratory sessions. The measure used was the Nurse Self Report (NSR) questionnaire. Results indicate an education intervention can be an effective tool for improving the knowledge, skills, and attitudes of Pacific Island people who care for persons experiencing mental health problems.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder resulting from mutations in the NBS1 gene, which encodes for the DNA double strand break repair protein nibrin. NBS is clinically characterized by microcephaly, dysmorphic features, immunodeficiency, and increased susceptibility to malignancy, mainly of lymphoid origin. Here, we describe a 7-year-old girl with NBS who is homozygous for the NBS1 698del4 mutation. She had been diagnosed with perianal rhabdomyosarcoma (RMS) and experienced severe toxicity from chemotherapy. RMS arising perianally is extremely uncommon but has been previously described in two cases with NBS. The strong association of perianal RMS with NBS should, therefore, be considered when confronted with a perianal RMS, as this carries important clinical implications in terms of potential need for therapy modification and follow up investigations. In addition, it suggests a role for the NBS1 gene and the nibrin dependent pathway in the pathogenesis of RMS, especially those arising perianally.

CTO/IOC legislation is a bewildering array of presumptions and inconsistencies. It is a reaction to the inherent difficulties of de-institutionalizing treatment into the community and has been based on heated arguments of misconceptions and misunderstandings of various proponents and opponents of CTOs/IOC. Legislators in the United Stated have implemented widely varying legislation over the past twenty-five years yet there is little common basis for states to proceed on or even to analyse when conceptualizing IOC legislation. It isn't surprising that Canada, after looking towards the United States as a leader in mental health legislation, is also encountering inconsistent and illogical legislation from province to province. To compound Canada's own inconsistencies, Canadian courts have not generally followed the lead of the United States of protecting fundamental rights within Canadian mental health legislation. As a result, Canadian provinces still rely on a broad parens patriae justification when infringing the rights of mental health patients and have not truly effected the narrower danger standard that is stated within its legislation. Provincial legislators should be very careful when proposing CTO legislation that will further erode patients' rights. Many provinces and states use the least restrictive alternative to justify the use of CTOs/IOC, either as a catch phrase or as a legitimate factor in considering options. Generally, though, the principle is used in terms of coerced treatment rather than a person's fundamental right to liberty or not to be arbitrarily detained. Legislators have translated the institutional model of medical treatment to the community by intrinsically linking treatment to committal. The most obvious contradictions of community treatment is the backwards slide of preventive commitment based on deterioration rather than purely danger. This includes the arbitrariness of releasing hospitalized patients on a continuing deterioration or even danger basis rather than fully discharging them. Another major problem is taking away a patient's inherent right, either by denying the patient's own decision-making if competent, or by ignoring prior wishes or substitute decision-making, to accept or refuse treatment. Legislators have succumbed to an artificial concept that mentally ill persons are dangerous or incompetent and do not have the ability to choose treatment when they are decompensating. Thus they have provided for patients' treatment in a confusing array of CTOs/IOC, all dependent on interference or restriction of a person's basic right to decide for himself. Very few studies have been able to isolate the key factors of what makes CTO/IOC work, although recent studies seem to suggest that CTOs/IOC won't work if there isn't the corresponding support/service system. At the same time, there have been studies of voluntary treatment plans that are succeeding, such as assertive community treatment, that do not rely on coerced treatment. Among these are PACT, case management, mobile crisis units and early intervention methods such as the delivery of emergency services (at a facility) when so requested. When considering CTOs as part of recommended amendments to the Hospitals Act, the Law Reform Commission certainly started on the right track by consulting a broad range of stakeholders and advisory groups within the Nova Scotia's mental health system. Unfortunately, the Commission derailed and did not fully develop its inquiry. Ideally, the Departments of Justice (or the Law Reform Commission), Community Services, and Health should have modelled a full-scale investigation after the RAND study developed for the California Senate. Consultation is definitely necessary, but it needs to be followed up with empirical evidence or at the very least other studies. Realistically, this may be beyond the financial means and resources of the Nova Scotia government. However, it is not beyond the reach of the Commission to explore such controversial issues further to see why certain legislation has been implemented in different provinces and whether it has proved effective or not. As New Brunswick is currently the only province that has considered and rejected CTOs, concentrating instead on community services and supports development, they deserve more than a cursory glance by the Commission and any inquiry performed by New Brunswick may contribute valuable insight as to why not legislate CTOs. This would be a more practical approach for the Commission to take rather than doing a survey of what other provinces are legislating and then accepting it blindly with or without the support of their stakeholders and advisory groups. The focus of the de-institutionalization movement was to revolutionalize how persons with mental illness are treated. A return to an institution mentality is not needed. Patience and the support of a new and better system that puts voluntariness and the mental health consumer in the centre of decision-making is the most promising way to effective mental health care.