Haploinsufficiency of the Parkinson's disease gene synaptojanin1 is associated with abnormal responses to psychomotor stimulants and mesolimbic dopamine signaling.

The synaptojanin-1 (SYNJ1) gene is known to be important for dopamine-related disorders. Recent evidence has demonstrated that Synj1 deficient mice (Synj1 +/-) have impairments in dopaminergic synaptic vesicular recycling. However, less is known about how Synj1 deficits affect the mesolimbic system, reward processing, and motivated behavior. To examine the role of the Synj1 gene in motivated behavior, we subjected male and female Synj1 +/- and Synj1 +/+ mice to a battery of behavioral tests evaluating hedonic responses, effortful responding, and responses to psychomotor stimulants. We observed that Synj1 +/- mice exhibit few differences in reward processing and motivated behavior, with normal hedonic responses and motivated responding for sucrose. However, male but not female Synj1 +/- demonstrated an attenuated conditioned place preference for cocaine that could not be attributed to deficits in spatial memory. To further understand the dopamine signaling underlying the attenuated response to cocaine in these mutant mice, we recorded nucleus accumbens dopamine in response to cocaine and observed that Synj1 +/- male and female mice took longer to reach peak dopamine release following experimenter-administered cocaine. However, female mice also showed slower decay in accumbens dopamine that appear to be linked to differences in cocaine-induced DAT responses. These findings demonstrate that SYNJ1 deficiencies result in abnormal mesolimbic DA signaling which has not previously been demonstrated. Our work also highlights the need to develop targeted therapeutics capable of restoring deficits in DAT function, which may be effective for reversing the pathologies associated with Synj1 mutations.

Diaphragm electrical activity during weaning of nasal high-flow therapy in preterm infants.

OBJECTIVE: To determine whether electrical activity of the diaphragm (Edi) changes with weaning nasal high-flow (HF) therapy in preterm infants according to a standardised protocol. DESIGN: Prospective observational cohort study. SETTING: Neonatal intensive care unit. PATIENTS: Preterm infants born at <32 weeks gestation, receiving nasal HF as part of routine clinical care. INTERVENTIONS: Infants recruited to the study had their HF weaned according to set clinical criteria. Edi was measured using a modified gastric feeding tube serially from baseline (pre-wean) to 24-hours post-wean. MAIN OUTCOME MEASURES: Change in Edi from baseline was measured at four time points up to 24 hours after weaning. Minimum Edi during expiration, maximum Edi during inspiration and amplitude of the Edi signal (Edidelta) were measured. Clinical parameters (heart rate, respiratory rate and fraction of inspired oxygen) were also recorded. RESULTS: Forty preterm infants were recruited at a mean corrected gestational age of 31.6 (±2.7) weeks. Data from 156 weaning steps were analysed, 91% of which were successful. Edi did not change significantly from baseline during flow reduction steps, but a significant increase in diaphragm activity was observed when discontinuing HF (median increase in Edidelta immediately post-discontinuation 1.7 µV (95% CI: 0.6 to 3.0)) and at 24 hours 1.9 µV (95% CI: 0.7 to 3.8)). No significant difference in diaphragm activity was observed between successful and unsuccessful weaning steps. CONCLUSIONS: A protocolised approach to weaning has a high probability of success. Edi does not change with reducing HF rate, but significantly increases with discontinuation of HF from 2 L/min.

The use of mentoring for knowledge translation by allied health: a scoping review.

OBJECTIVE: To describe how allied health professionals have used mentoring as a knowledge translation strategy to inform practice. INTRODUCTION: Mentoring has been reported to be used by nursing and medicine as a knowledge translation strategy. It is not known if allied health professionals have also used mentoring to improve their use of research in practice, or what the key mentoring characteristics are that guide its application in allied health settings. Improved understanding of the barriers and facilitators to mentoring in allied health settings may be used to guide the design of future mentoring programs to assist knowledge translation. INCLUSION CRITERIA: Eligible studies must have included allied health professionals, and used the concept of mentoring to support knowledge translation in the context of healthcare. Primary empirical and synthesized studies were eligible. METHODS: An a-priori protocol was followed to complete a search of six databases (MEDLINE [OVID], EMBASE [OVID], CINAHL [EBSCO], PsycInfo [OVID], PDQ-Evidence ( www.pdq-evidence.org ), and Cochrane on the 9 March 2021. Screening for eligibility was conducted by two authors at the title and abstract stage and the full text stage. Selection criteria and the data extraction tool were established prior to the search. Findings are presented in narrative and tabular formats. RESULTS: A total of 2053 studies met the inclusion criteria for screening and nine were determined to be eligible for inclusion. Mentoring has been used by allied health professionals to improve the translation of interventional research evidence by clinicians, and to establish clinician skills and knowledge relating to knowledge translation processes. Mentoring was predominantly used as part of a multifaceted knowledge translation strategy alongside educational strategies. Mentoring characteristics such as structure, context, goals, resourcing and dosage varied depending on the context of translation. The specific barriers reported to using mentoring were varied, whereas the facilitators to mentoring were primarily related to the mentor's approach and expertise. The impact of mentoring was primarily measured through the mentee's experience of mentoring. CONCLUSIONS: Allied health professionals have used mentoring as a knowledge translation strategy to enhance the use of research evidence in their practice and to learn the process of knowledge translation. Mentoring is mostly used in conjunction with other strategies in practice, such as education. The limited number of identified barriers and facilitators to using mentoring as a knowledge translation strategy supports the need for future research to deepen our understanding about the mentoring process.

Tissue culture tools for selenium hyperaccumulator Neptunia amplexicaulis for development in phytoextraction.

Neptunia amplexicaulis is an herbaceous legume endemic to the Richmond area in central Queensland, Australia and is one of the strongest known Selenium hyperaccumulators on earth, showing significant potential to be utilised in Se phytoextraction applications. Here a protocol was established for in vitro micropropagation of Se hyperaccumulator N. amplexicaulis using nodal segments from in vitro-germinated seedlings. Shoot multiplication was achieved on Murashige and Skoog (MS) basal media supplemented with various concentrations of 6-Benzylaminopurine (BA) (1.0, 2.0, 3.0 mg L-1) alone or in combination with low levels of Naphthaleneacetic acid (NAA) (0.1, 0.2, 0.3 mg L-1), with 2.0 mg L-1 BA + 0.2 mg L-1 NAA found to be most effective. Elongated shoots were rooted in vitro using NAA, with highest root induction rate of 30% observed at 0.2 mg L-1 NAA. About 95% of the in vitro rooted shoots survived acclimatization. Clonally propagated plantlets were dosed with selenate/selenite solution and assessed for Se tissue concentrations using Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES) and found to retain their ability to hyperaccumulate. The protocol developed for this study has potential to be optimised for generating clonal plants of N. amplexicaulis for use in research and phytoextraction industry applications.

A diencephalic circuit in rats for opioid analgesia but not positive reinforcement.

Mu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain, and here we found that it is a potent site for MOR-agonist analgesia-like responses in rats. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain.

Stress reveals a specific behavioral phenotype for opioid abuse susceptibility.

Susceptibility to stress has long been considered important for the development of substance use disorders. Nonetheless, behavioral and physiological responses to stress are highly variable, making it difficult to identify the individuals who are most likely to abuse drugs. In the present study, we employed a comprehensive battery of tests for negative valence behaviors and nociception to identify individuals predisposed to opioid seeking following oral opioid self-administration. Furthermore, we examined how this profile was affected by a history of stress. We observed that mice receiving foot shock stress failed to exhibit a preference for sucrose, showed increased immobility in the forced swim task, and exhibited mechanical hypersensitivity when compared to controls. When considering these behaviors in light of future fentanyl-seeking responses, we observed that heightened mechanical sensitivity corresponded to higher opioid preference in mice with a history of stress, but not controls. Moreover, we were surprised to discover that paradoxically high sucrose preferences predicted fentanyl preference in shock mice, while signs of anhedonia predicted fentanyl preference in controls. Taken together, these results indicate that stress can act as a physiological modulator, shifting profiles of opioid abuse susceptibility depending on an individual's history.

Cryopreservation of Woody Crops: The Avocado Case.

Recent development and implementation of crop cryopreservation protocols has increased the capacity to maintain recalcitrant seeded germplasm collections via cryopreserved in vitro material. To preserve the greatest possible plant genetic resources globally for future food security and breeding programs, it is essential to integrate in situ and ex situ conservation methods into a cohesive conservation plan. In vitro storage using tissue culture and cryopreservation techniques offers promising complementary tools that can be used to promote this approach. These techniques can be employed for crops difficult or impossible to maintain in seed banks for long-term conservation. This includes woody perennial plants, recalcitrant seed crops or crops with no seeds at all and vegetatively or clonally propagated crops where seeds are not true-to-type. Many of the world's most important crops for food, nutrition and livelihoods, are vegetatively propagated or have recalcitrant seeds. This review will look at ex situ conservation, namely field repositories and in vitro storage for some of these economically important crops, focusing on conservation strategies for avocado. To date, cultivar-specific multiplication protocols have been established for maintaining multiple avocado cultivars in tissue culture. Cryopreservation of avocado somatic embryos and somatic embryogenesis have been successful. In addition, a shoot-tip cryopreservation protocol has been developed for cryo-storage and regeneration of true-to-type clonal avocado plants.

pMAT: An open-source software suite for the analysis of fiber photometry data.

The combined development of new technologies for neuronal recordings and the development of novel sensors for recording both cellular activity and neurotransmitter binding has ushered in a new era for the field of neuroscience. Among these new technologies is fiber photometry, a technique wherein an implanted fiber optic is used to record signals from genetically encoded fluorescent sensors in bulk tissue. Fiber photometry has been widely adapted due to its cost-effectiveness, ability to examine the activity of neurons with specific anatomical or genetic identities, and the ability to use these highly modular systems to record from one or more sensors or brain sites in both superficial and deep-brain structures. Despite these many benefits, one major hurdle for laboratories adopting this technique is the steep learning curve associated with the analysis of fiber photometry data. This has been further complicated by a lack of standardization in analysis pipelines. In the present communication, we present pMAT, a 'photometry modular analysis tool' that allows users to accomplish common analysis routines through the use of a graphical user interface. This tool can be deployed in MATLAB and edited by more advanced users, but is also available as an independently deployable, open-source application.

Mentoring for knowledge translation in allied health: a scoping review protocol.

OBJECTIVE: The primary objective of this review is to identify how allied health staff have used mentoring as a knowledge translation strategy to support practice change. Secondary objectives include identifying barriers and enablers to using mentoring as a knowledge translation strategy, and the methods used to evaluate the strategy. INTRODUCTION: Mentoring provides professional support and guidance while attending to the learning needs of the individual. Mentoring has been described in previous knowledge synthesis reviews as a strategy for nursing and medicine practitioners to improve capability and capacity to participate in knowledge translation to create practice change. To the authors' knowledge, a synthesis of the use of mentoring as a knowledge translation strategy by allied health staff has not been reported. INCLUSION CRITERIA: This scoping review will consider all studies that describe the use of mentoring with allied health staff to support practice change as directed by research evidence. The scoping review will not investigate the use of mentoring to increase the conduct of research in a clinical setting, nor will studies be included if the majority of participants are students. METHODS: A three-step search strategy will be undertaken. Two independent authors will screen articles and perform data extraction. The results will be presented in a narrative Summary of Findings, alongside a presentation of the data in diagrammatic or tabular form. The findings will inform future use of mentoring as a knowledge translation strategy in a regional health service.

Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. METHODS: We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. RESULTS: In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 µg/mL. A steady-state trough serum concentration of 1.3 µg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. CONCLUSIONS: In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis.

A systematic review of the amount and timing of light in association with objective and subjective sleep outcomes in community-dwelling adults.

Light is considered the dominant environmental cue, or zeitgeber, influencing the sleep-wake cycle. Despite recognizing the importance of light for our well-being, less is known about the specific conditions under which light is optimally associated with better sleep. Therefore, a systematic review was conducted to examine the association between the amount and timing of light exposure in relation to sleep outcomes in healthy, community-dwelling adults. A systematic search was conducted of four databases from database inception to June 2016. In total, 45 studies met the review eligibility criteria with generally high study quality excepting for the specification of eligibility criteria and the justification of sample size. The majority of studies involved experimental manipulation of light (n = 32) vs observational designs (n = 13). Broad trends emerged suggesting that (1) bright light (>1000 lux) has positive implications for objectively assessed sleep outcomes compared to dim (<100 lux) and moderate light (100-1000 lux) and (2) bright light (>1000 lux) has positive implications for subjectively assessed sleep outcomes compared to moderate light (100-1000 lux). Effects due to the amount of light are moderated by the timing of light exposure such that, for objectively assessed sleep outcomes, brighter morning and evening light exposure are consistent with a shift in the timing of the sleep period to earlier and later in the day, respectively. For subjectively assessed sleep outcomes, brighter light delivered in the morning was associated with self-reported sleep improvements and brighter evening light exposure was associated with worse self-reported sleep.

Directional coherent light via intensity-induced sideband emission.

We introduce a unique technique for generating directional coherent emissions that could be utilized to create coherent sources in a wide range of frequencies from the extreme ultraviolet (XUV) to the deep infrared. This is accomplished without population inversion by pumping a two-level system with a far-detuned strong optical field that induces the splitting of the two-level system. A nonlinear process of four-wave mixing then occurs across the split system, driving coherent emission at sidebands both red- and blue-detuned from the pump frequency, and propagates both forward and backward along the pump beam path. We observed this phenomenon in dense rubidium vapor along both the D1 and D2 transitions. The sideband emission exhibits a short pulse duration (<1 ns) with threshold-like behavior dependent on both the pump intensity and Rb vapor density. This technique offers a new capability for manipulating the emission frequency simply through intensity-induced atomic modulation that can be scaled to most frequency regimes using various atomic/molecular ensembles and pump energies.

Process mapping evaluation of medication reconciliation in academic teaching hospitals: a critical step in quality improvement.

BACKGROUND: Medication reconciliation (MedRec) has been a mandated or recommended activity in Canada, the USA and the UK for nearly 10 years. Accreditation bodies in North America will soon require MedRec for every admission, transfer and discharge of every patient. Studies of MedRec have revealed unintentional discrepancies in prescriptions but no clear evidence that clinically important outcomes are improved, leading to widely variable practices. Our objective was to apply process mapping methodology to MedRec to clarify current processes and resource usage, identify potential efficiencies and gaps in care, and make recommendations for improvement in the light of current literature evidence of effectiveness. METHODS: Process engineers observed and recorded all MedRec activities at 3 academic teaching hospitals, from initial emergency department triage to patient discharge, for general internal medicine patients. Process maps were validated with frontline staff, then with the study team, managers and patient safety leads to summarise current problems and discuss solutions. RESULTS: Across all of the 3 hospitals, 5 general problem themes were identified: lack of use of all available medication sources, duplication of effort creating inefficiency, lack of timeliness of completion of the Best Possible Medication History, lack of standardisation of the MedRec process, and suboptimal communication of MedRec issues between physicians, pharmacists and nurses. DISCUSSION: MedRec as practised in this environment requires improvements in quality, timeliness, consistency and dissemination. Further research exploring efficient use of resources, in terms of personnel and costs, is required.

Incidence and predictors of annual chlamydia testing among 15-29 year olds attending Aboriginal primary health care services in New South Wales, Australia.

BACKGROUND: For the past two decades, chlamydia has been the most commonly notified infectious disease among young people (15-29 year olds) in Australia, the United States of America and the United Kingdom and rates have increased annually in these three countries. In Australia, rates of chlamydia are three times higher in Aboriginal compared with non-Aboriginal people. Australian sexually transmissible infection guidelines recommend annual chlamydia testing for 15-29 year old females and males. This analysis will examine the incidence and predictors of annual chlamydia testing in 15-29 year olds attending four Aboriginal Community Controlled Health Services (ACCHS) in Australia. METHODS: From 2009-2011, attendance and chlamydia testing data were extracted from the patient system to calculate the number and proportion of 15-29 year olds that were tested for chlamydia and that tested positive for chlamydia by gender (male, female), age-group (15-19, 20-24, 25-29 years), Aboriginal status (Aboriginal, non-Aboriginal people) and by the four ACCHSs sites (1, 2, 3 and 4). A cohort was created to calculate the incidence rate per 100 person-years (PY) and predictors of an annual chlamydia test (a test within 12-months of a previous test/visit) by the above factors using Cox regression. Unadjusted and adjusted hazard ratios (AHR) and their 95 % confidence intervals (CIs) and p-values were calculated with significance at p < 0.05. RESULTS: From 2009-2011, there were 2896 individuals who attended the four ACCHSs. Overall , 17 % (22 % of females and 10 % of males) were tested for chlamydia and 9 % tested positive (8 % of females and 14 % of males). The median time to an annual chlamydia test was 10.7 months. The cohort included 2318 individuals. Overall the incidence rate of an annual chlamydia test was 9.1 per 100 PY (11.6 in females and 5.8 in males). Predictors of an annual chlamydia test were being female (AHR: 1.7, 95 % CI: 1.2-2.2, p < 0.01), being 15-19 years old (AHR: 1.6, 95 % CI: 1.1-2.3, p < 0.01) and attending ACCHS site 2 (AHR: 3.8, 95 % CI: 1.8-8.0, p < 0.01). CONCLUSIONS: This analysis highlights that opportunistic STI testing strategies are needed to increase annual chlamydia testing in young people; especially males.

A sexual health quality improvement program (SHIMMER) triples chlamydia and gonorrhoea testing rates among young people attending Aboriginal primary health care services in Australia.

BACKGROUND: In Australia, chlamydia is the most commonly notifiable infection and over the past ten years chlamydia and gonorrhoea notification rates have increased. Aboriginal compared with non-Aboriginal Australians have the highest notifications rates of chlamydia and gonorrhoea. Regular testing of young people for chlamydia and gonorrhoea is a key prevention strategy to identify asymptomatic infections early, provide treatment and safe sex education. This study evaluated if a sexual health quality improvement program (QIP) known as SHIMMER could increase chlamydia and gonorrhoea testing among young people attending four Aboriginal primary health care services in regional areas of New South Wales, Australia. METHODS: We calculated the proportion of 15-29 year olds tested and tested positivity for chlamydia and gonorrhoea in a 12-month before period (March 2010-February 2011) compared with a 12-month QIP period (March 2012-February 2013). Logistic regression was used to assess the difference in the proportion tested for chlamydia and gonorrhoea between study periods by gender, age group, Aboriginal status and Aboriginal primary health service. Odds ratios (OR) and their 95 % confidence intervals (CIs) were calculated with significance at p < 0.05. RESULTS: In the before period, 9 % of the 1881 individuals were tested for chlamydia, compared to 22 % of the 2259 individuals in the QIP period (OR): 1.43, 95 % CI: 1.22-1.67). From the before period to the QIP period, increases were observed in females (13 % to 25 %, OR: 1.32, 95 % CI: 1.10-1.59) and males (3 % to 17 %, OR: 1.85, 95 % CI: 1.36-2.52). The highest testing rate in the QIP period was in 15-19 year old females (16 % to 29 %, OR: 1.02, 95 % CI: 0.75-1.37), yet the greatest increase was in 20-24 year olds males (3 % to 19 %, OR: 1.65, 95 % CI: 1.01-2.69). Similar increases were seen in gonorrhoea testing. Overall, there were 70 (11 %) chlamydia diagnoses, increasing from 24 in the before to 46 in the QIP period. Overall, 4 (0.7 %) gonorrhoea tests were positive. CONCLUSIONS: The QIP used in SHIMMER almost tripled chlamydia and gonorrhoea testing in young people and found more than twice as many chlamydia infections. The QIP could be used by other primary health care centres to increase testing among young people.

Attendance patterns and chlamydia and gonorrhoea testing among young people in Aboriginal primary health centres in New South Wales, Australia.

UNLABELLED: Background To inform a sexual health quality improvement program we examined chlamydia and gonorrhoea testing rates among 15-29 year olds attending Aboriginal Community Controlled Health Services (ACCHS) in New South Wales, Australia, and factors associated with chlamydia and gonorrhoea testing. METHODS: From 2009 to 2011, consultation and testing data were extracted from four ACCHS. Over the study period, we calculated the median number of consultations per person and interquartile range (IQR), the proportion attending (overall and annually), the proportion tested for chlamydia and gonorrhoea, and those who tested positive. We examined factors associated with chlamydia and gonorrhoea testing using logistic regression. RESULTS: Overall, 2896 15-29-year-olds attended the ACCHSs, 1223 were male and 1673 were female. The median number of consultations was five (IQR 2-12), four (IQR 1-8) for males and seven (IQR 3-14) for females (P<0.001). Nineteen percent of males and 32% of females attended in each year of the study (P<0.001). Overall, 17% were tested for chlamydia (10% of males and 22% of females, P<0.001), and 7% were tested annually (3% of males and 11% of females, P<0.001). Findings were similar for gonorrhoea testing. In the study period, 10% tested positive for chlamydia (14% of males and 9% of females, P<0.001) and 0.6% for gonorrhoea. Factors independently associated with chlamydia testing were being female (adjusted odds ratio (AOR) 2.64, 95% confidence interval (CI) 2.07-3.36), being 20-24 years old (AOR: 1.58, 95% CI: 1.20-2.08), and having >3 consultations (AOR: 16.97, 95% CI: 10.32-27.92). CONCLUSIONS: More frequent attendance was strongly associated with being tested for chlamydia and gonorrhoea. To increase testing, ACCHS could develop testing strategies and encourage young people to attend more frequently.

A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 2 dosing regimens of fostamatinib in patients with rheumatoid arthritis with an inadequate response to a tumor necrosis factor-α antagonist.

OBJECTIVE: Our 24-week study (NCT01197755; OSKIRA-3) compared the efficacy and safety of fostamatinib versus placebo in patients taking background methotrexate treatment with active rheumatoid arthritis (RA) and an inadequate response to a single tumor necrosis factor-α antagonist. METHODS: Adult patients were randomized (1:1:1) to fostamatinib [100 mg bid for 24 weeks (n=105; Group A)], or 100 mg bid for 4 weeks, then 150 mg qd (n=108; Group B), or to placebo (n=110; Group C) for 24 weeks. Nonresponders at Week 12 could enter a longterm extension study. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at Week 24. RESULTS: Baseline characteristics were well balanced. Significantly more patients in fostamatinib Group A (36.2%; p=0.004), but not B (27.8%; p=0.168), achieved ACR20 at Week 24 versus placebo (21.1%). Frequently reported adverse events were diarrhea, hypertension, and headache. Elevated blood pressure (≥140/90 mm Hg) at ≥1 visit was observed in 46.7%, 51.9%, and 26.6% of patients, respectively. There were 2 deaths in the study, 1 in Group B and 1 in the placebo group. CONCLUSION: Fostamatinib 100 mg bid, but not fostamatinib 100 mg bid for 4 weeks then 150 mg qd, achieved statistical improvements in ACR20 at 24 weeks versus placebo. Because of efficacy and safety results from the phase III clinical program, the companies developing fostamatinib have decided not to study it further in RA at this time.

Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density.

This randomized double-blind study, with 24-week treatment and 24-week posttreatment periods, evaluated the effects of elagolix (150 mg every day, 75 mg twice a day) versus subcutaneous depot medroxyprogesterone acetate (DMPA-SC) on bone mineral density (BMD), in women with endometriosis-associated pain (n = 252). All treatments induced minimal mean changes from baseline in BMD at week 24 (elagolix 150 mg: -0.11%/-0.47%, elagolix 75 mg: -1.29%/-1.2%, and DMPA-SC: 0.99%/-1.29% in the spine and total hip, respectively), with similar or less changes at week 48 (posttreatment). Elagolix was associated with improvements in endometriosis-associated pain, assessed with composite pelvic signs and symptoms score (CPSSS) and visual analogue scale, including statistical noninferiority to DMPA-SC in dysmenorrhea and nonmenstrual pelvic pain components of the CPSSS. The most common adverse events (AEs) in elagolix groups were headache, nausea, and nasopharyngitis, whereas the most common AEs in the DMPA-SC group were headache, nausea, upper respiratory tract infection, and mood swings. This study showed that similar to DMPA-SC, elagolix treatment had minimal impact on BMD over a 24-week period and demonstrated similar efficacy on endometriosis-associated pain.

Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study.

This Phase 2 study evaluated the safety and efficacy of elagolix for treating endometriosis-associated pain. A total of 155 women with laparoscopically confirmed endometriosis were randomized to placebo, elagolix 150 mg, or elagolix 250 mg once daily for 12 weeks. Placebo patients were rerandomized to elagolix and elagolix patients continued their dosing assignment for 12 additional weeks; the primary efficacy measure was changed from baseline in the monthly mean numerical rating scale for pain at week 12. Monthly mean (standard error of the mean) reductions were greater with elagolix versus placebo (-1.19 ± 0.18, -1.25 ± 0.18, and -0.88 ± 0.18 for elagolix 150 mg, 250 mg, and placebo, respectively); differences were not statistically significant. Monthly mean dysmenorrhea and nonmenstrual pelvic pain scores were reduced with elagolix, with significant differences for dysmenorrhea at weeks 8 and 12 versus placebo (P < .05). Minimal bone mineral density changes were observed with elagolix treatment. In women with endometriosis-associated pain, elagolix demonstrated an acceptable efficacy and safety profile in this Phase 2 study.