Telephone follow-up after early medical abortion using Australia's first low sensitivity urine pregnancy test.

BACKGROUND: Follow-up after early medical abortion (EMA) in Australia often entails tracking serum human chorionic gonadotropin levels or performing ultrasonography in-clinic. In other countries, methods of follow-up such as using a low-sensitivity urine pregnancy test (LSUPT), telephone evaluation and a questionnaire have been demonstrated to be safe and acceptable. AIMS: To evaluate the safety and efficacy of telephone follow-up after EMA using an LSUPT and questionnaire. MATERIALS AND METHODS: A prospective observational cohort study of patients undergoing telephone follow-up after EMA using an LSUPT and questionnaire was conducted from March 26 to July 31, 2020. Outcomes of patients who returned to clinic because of a positive LSUPT were evaluated and adverse event rates were calculated. Routinely collected adverse event information was used to compare complication rates during the evaluation period with that prior to introduction of the LSUPT. RESULTS: During the study period, 2223 patients underwent the new protocol. One hundred and ninety-seven patients had a positive LSUPT at their telephone follow-up. One hundred and thirty-two had an incomplete abortion, 11 had a continuing pregnancy, 53 had a complete abortion and one left the clinic before full assessment. CONCLUSIONS: Introduction of telephone follow-up with an at-home LSUPT reduced the number of patients requiring unnecessary clinic appointments, with over 90% of patients completing their follow-up at home. Complication rates during the study period were found to be at least comparable with previously identified organisational adverse events.

A Wide Dynamic Range CMOS Image Sensor with a Charge Splitting Gate and Two Storage Diodes.

In this paper, a wide dynamic range (WDR) CMOS image sensor (CIS) with a charge splitting gate (SG) and two storage diodes (SDs) is presented. By using single-gate on/off control with the SG, photocurrent path to the first (SD1) or second storage diodes (SD2) is switched alternatively and periodically during exposure and signal electrons generated in a photodiode (PD) are transferred to and accumulated in the SD1 or SD2. By setting a large ratio of the off-time to on-time of the SG, two different sensitivity signals, which are originated by the same photodiode, are generated and a WDR image signal is obtained. This technique has a distinct advantage on mitigating the problem of motion artifact in WDR imaging with high and low sensitivity signals and flexible dynamic control of the dynamic range. An experimental WDR CMOS image sensor with 280 (H) × 406 (V)-pixel array consisting of 14 sub-arrays, each of which have 20 (H) × 406 (V) pixels, was implemented and tested. For the SG on/off-time ratio of 30 and 279, the DR of 93 dB and 104 dB, respectively, was demonstrated. The effect of the proposed WDR imaging operation on the reduced motion artifact was experimentally confirmed.

Self-assessment of success of early medical abortion using a self-performed urine pregnancy test.

Purpose: The European Society of Contraception Expert Group on Abortion identified as one of its priorities the need to disseminate up-to-date evidence-based information on the use of urine pregnancy tests by women for the self assessment of the success of early medical abortion (EMA). Methods and materials: A concise communication was produced which summarises the latest research in an easy-to-read format suitable for busy clinicians. Information about individual urinary pregnancy tests is presented in boxes for ease of reference. Results: Urinary pregnancy tests (low sensitivity, high sensitivity and multilevel) can be used in combination with signs and symptoms of pregnancy to exclude an ongoing pregnancy after EMA. Conclusion: Women are able to determine the success of early medical abortion (EMA) themselves using a combination of signs, symptoms and a urine pregnancy test. This simplifies EMA, expands the range of professionals able to provide EMA and most importantly gives women greater control over their bodies and treatment.

Importance of the 3'-Terminal Nucleotide of the Forward Primer for Nucleoprotein Gene Detection of Viral Hemorrhagic Septicemia Virus by Conventional Reverse-Transcription PCR.

Viral hemorrhagic septicemia virus (VHSV), causing severe diseases in farmed fish, is detected and genotyped using conventional reverse-transcription PCR (cRT-PCR) targeting the nucleoprotein gene with corresponding VN F (forward) and VN R (reverse) primers. However, these primers have low sensitivity to VHSV subtype IVa; I investigated the cause for the poor cRT-PCR performance using various primer combinations. The results demonstrated that a 3'-end mismatch in the VN F primer reduced sensitivity and plays a critical role in VHSV detection by cRT-PCR.

Hormonal Therapy Resistant Estrogen-receptor Positive Metastatic Breast Cancer Cohort (HORSE-BC) Study : Current Status of Treatment Selection in Japan.

The Hormonal therapy resistant estrogen-receptor positive metastatic breast cancer cohort (HORSE-BC) study is a multicenter observational study evaluating the efficacy and safety of secondary endocrine therapy (ET) for postmenopausal cases of metastatic breast cancer (MBC) with poor response to primary ET. In this initial report we analyze the HORSE-BC baseline data to clarify the current status of treatment selection for MBC in Japan. Baseline data for the 50 patients enrolled in HORSE-BC were analyzed, including patient characteristics, types of secondary ET, and reasons for selecting secondary ET. Postoperative recurrence was detected in 84% of patients (42/50) and de novo stage IV breast cancer in 16% (8/50). Forty-one patients (41/50; 82%) received fulvestrant, 5 patients (10%) received selective estrogen receptor modulators (SERMs), 3 patients (6%) received ET plus a mammalian target of rapamycin (mTOR) inhibitor, and 1 patient received an aromatase inhibitor (AI) as the secondary ET. Forty-five patients selected their secondary ET based on its therapeutic effect, while 14 patients selected it based on side effects. Most patients with progression after primary ET selected fulvestrant as the secondary ET based on its therapeutic and side effects. We await the final results from the HORSE-BC study.

Construction and Modification of Nitrogen-Rich Polycyclic Frameworks: A Promising Fused Tricyclic Host-Guest Energetic Material with Heat Resistance, High Energy, and Low Sensitivity.

The construction and modification of novel energetic frameworks to achieve an ideal balance between high energy density and good stability are a continuous pursuit for researchers. In this work, a fused [5,6,5]-tricyclic framework was utilized as the energetic host to encapsulate the oxidant molecules for the first time. A series of new pyridazine-based [5,6] and [5,6,5] fused polycyclic nitrogen-rich skeletons and their derivatives were designed and synthesized. Two strategies, amino oxidation and host-guest inclusion, were used to modify the skeleton in only one step. All compounds exhibit good comprehensive properties (Td (onset) > 200 °C, ρ > 1.85 g cm-3, Dv > 8400 m s-1, IS > 20 J, FS > 360 N). Benefiting from the pyridazine-based fused tricyclic structure with more hydrogen bonding units and larger conjugated systems, the first example of [5,6,5]-tricyclic host-guest energetic material triamino-9H-pyrazolo[3,4-d][1,2,4]triazolo[4,3-b]pyridazine-diperchloric acid (10), shows high decomposition temperature (Td (onset) = 336 °C), high density and heats of formation (ρ = 1.94 g cm-3, ΔHf = 733.4 kJ mol-1), high detonation performance (Dv = 8820 m s-1, P = 36.2 GPa), high specific impulse (Isp = 269 s), and low sensitivity (IS = 30 J, FS > 360 N). The comprehensive performance of 10 is superior to that of high-energy explosive RDX and heat-resistant explosives such as HNS and LLM-105. 10 has the potential to become a comprehensive advanced energetic material that simultaneously satisfies the requirements of high-energy and low-sensitivity explosives, heat-resistant explosives, and solid propellants. This work may give new insights into the construction and modification of a nitrogen-rich polycyclic framework and broaden the applications of fused polycyclic framework for the development of host-guest energetic materials.

Series of Azido and Fused-Tetrazole Explosives: Combining Good Thermal Stability and Low Sensitivity.

The introduction of azido groups into the energetic skeleton has the advantages of increasing the energy level. In this work, a series of azido compounds with good stability and low sensitivity as well as tetrazole-fused compounds based on energetic salts are synthesized. The detonation pressures and velocities of these new compounds fall in the ranges of 18.9-27.3 GPa and 7153-8450 m s-1, respectively. The detonation velocity of the tetrazole-fused compounds based on the potassium salts 3, 6, and 7 are 7810, 7153, and 7989 m s-1, respectively. Also, their decomposition temperatures (244, 237, and 240 °C, respectively) are higher than that of traditional explosive RDX (204 °C). Notably, two representative compounds 2 and 5 possess higher decomposition temperature (2: 196 °C and 5: 178 °C) and overall detonation properties (2: D = 8129 m s-1 and P = 26.6 GPa and 5: D = 8336 m s-1 and P = 27.3 GPa) as well as relativity lower sensitivities (2: IS = 12 J and FS = 240 N and 5: IS = 10 J and FS = 144 N) than that of primary explosive 2-diazo-4,6-dinitrophenol (Td = 157 °C, D = 6900 m s-1, P = 24.7 GPa, IS = 1 J, and FS = 24.7 N). Moreover, the initiation capacity of compounds 2 and 5 was also assessed through the initiation tests. The results indicate that the two compounds could be a promising environmentally friendly primary explosive.

Efficacy of a low-sensitivity urine pregnancy test for identifying ongoing pregnancy after medication abortion at 64 to 70 days of gestation.

OBJECTIVES: We assessed whether a low-sensitivity pregnancy test is effective at identifying ongoing pregnancy after medication abortion at 64 to 70 days of gestation. STUDY DESIGN: From October 2018 to March 2020, we performed a prospective observational study of participants in England and Wales undergoing medication abortion. Participants were scheduled to return to the clinic 14 ± 3 days after mifepristone administration to perform a low-sensitivity pregnancy test (human chorionic gonadotropin threshold of 1000 mIU/mL) and symptom checklist, and state whether they thought the abortion was complete. Clinicians also assessed the low-sensitivity pregnancy test and performed an ultrasound to determine abortion status. We calculated the sensitivity, specificity, negative and positive predictive value of the low-sensitivity pregnancy test (with and without a symptom checklist) for detecting ongoing pregnancy. RESULTS: We enrolled 757 participants. Thirty-one did not progress to abortion and 558 (76.9%) completed follow-up. Most (79.6%) attended per-protocol; 22 (3.9%) attended earlier than 11 days and 92 (16.5%) later than 17 days. Thirteen participants (2.3%) had an ongoing pregnancy. The low-sensitivity pregnancy test correctly identified all the ongoing pregnancies (sensitivity = 100%; specificity = 84.8%; negative predictive value = 100%; positive predictive value = 13.5%). The symptom checklist alone had a sensitivity of 76.9% and a negative predictive value of 99.4% for identifying ongoing pregnancies. Participants and clinicians agreed on the interpretation of the low-sensitivity pregnancy test 94.6% of the time. CONCLUSIONS: Patient self-assessment of a low-sensitivity pregnancy test after medication abortion between 64- and 70 days' gestation has high sensitivity and negative predictive value for identification of ongoing pregnancy. IMPLICATIONS: Patients can be offered a low-sensitivity pregnancy test to assess for ongoing pregnancy after medication abortion up to 70 days of gestation thereby reducing the need for in-person visits. Services should be prepared to provide in-person assessments after positive or inconclusive results to ensure early identification of abortion complications.

Research progress of EMOFs-based burning rate catalysts for solid propellants.

Energetic Metal Organic Frameworks (EMOFs) have been a hotspot of research on solid propellants in recent years. In this paper, research on the application of EMOFs-based burning rate catalysts in solid propellants was reviewed and the development trend of these catalysts was explored. The catalysts analyzed included monometallic organic frameworks-based energetic burning rate catalysts, bimetallic multifunctional energetic burning rate catalysts, carbon-supported EMOFs burning rate catalysts, and catalysts that can be used in conjunction with EMOFs. The review suggest that monometallic organic frameworks-based burning rate catalysts have relatively simple catalytic effects, and adding metal salts can improve their catalytic effect. Bimetallic multifunctional energetic burning rate catalysts have excellent catalytic performance and the potential for broad application. The investigation of carbon-supported EMOFs burning rate catalysts is still at a preliminary stage, but their preparation and application have become a research focus in the burning rate catalyst field. The application of catalysts that can be compounded with EMOFs should be promoted. Finally, environmental protection, high energy and low sensitivity, nanometerization, multifunctional compounding and solvent-free are proposed as key directions of future research. This study aims to provide a reference for the application of energetic organic burning rate catalysts in solid propellants.

The insensitive mechanism of poultry to zearalenone: A review.

Zearalenone (ZEN) is one of the most common contaminating mycotoxins and is mainly produced by Fusarium graminearum. ZEN and its metabolites can interfere with estrogen function and affect animals' reproductive ability. Pigs are most susceptible to ZEN, and ZEN is less harmful to poultry than to pigs. The exact mechanism for the difference in susceptibility remains unclear. In this review, we summarized some possible reasons for the relative insensitivity of poultry to ZEN, such as the lower total amount of α-zearalenol (α-ZOL) and the α-ZOL-to-ß-ZOL ratio which reduce the toxicity of ZEN to poultry. The faster hepatic and enteric circulation, and excretion capacity in poultry can excrete more ZEN and its metabolites. There are other possible factors such as the transformation of intestinal microorganisms, differences in hydroxysteroid dehydrogenases' activity, high estrogen levels, and low estrogen receptors affinity which can also cause poultry to be relatively insensitive to ZEN. In this review, we summarized the hazards, pollution status, metabolic pathways, and some measures to mitigate ZEN's harmfulness. Specifically, we discussed the possible mechanisms of low reproductive toxicity by ZEN in poultry.

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells.

Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-κB p65, and an NF-κB inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-κB p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-κB pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-κB inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-κB pathway.

Comparison of two home pregnancy tests for self-confirmation of medication abortion status: A randomized trial.

OBJECTIVES: To evaluate individuals' ability to perform and comprehend low-sensitivity and multilevel urine pregnancy tests during medication abortion follow-up. STUDY DESIGN: We conducted a pilot study of individuals using mifepristone and misoprostol for medication abortion through 63-days gestation. We randomly assigned participants to use a 1000 mIU/mL low-sensitivity pregnancy test or a five-level multilevel pregnancy test. Seven days after mifepristone, participants performed their test and completed a questionnaire. One week later, participants performed another test if day 7 low-sensitivity test had been positive or day 7 multilevel test had not shown a one-level drop. We assessed comprehension of abortion status based on participants' final test interpretation, and defined correct comprehension when patient report of pregnancy status was consistent with pregnancy test result. We also assessed usability with a 100-mm Visual Analogue Scale (0 'very easy'; 100 'very difficult') and satisfaction. RESULTS: We enrolled and randomized 88 participants to low-sensitivity (n = 43) and multilevel (n = 45) test groups. Comprehension was correct in 38/39 (97%) and 41/45 (91%) of low-sensitivity and multilevel test users, respectively (p = 0.37). When the test indicated a possible ongoing pregnancy, all three low-sensitivity test users and two of three multilevel test users accurately comprehended their results. Participants rated ease of use as 7.5 (range 0-68) for low-sensitivity and 9.0 (range 0-52) for multilevel (p = 0.24) tests. Most participants were likely or very likely to recommend use of their test (32/36 [89%] low-sensitivity and 42/44 [95%] multilevel test users, p = 0.66). CONCLUSIONS: Patients could comprehend and use low-sensitivity and multilevel tests during medication abortion follow-up with similar satisfaction. IMPLICATIONS: Individuals are able to independently use both the low-sensitivity and multilevel tests for medication abortion follow-up. Both are acceptable for medication abortion follow-up without in-person contact, but future, larger studies to compare comprehension of both tests may be necessary.

Feasibility of self-performed urine pregnancy testing for follow-up after medical abortion.

OBJECTIVES: Medical termination of pregnancy (MToP) follow-up can be simplified by combining a clinical assessment with blood and urine human chorionic gonadotropin (hCG) measurements, the later using a low sensitivity urinary pregnancy (LSUP) testing. This study aimed to describe follow-up modalities of MToP in real-life conditions, and assess the benefit of a self-performed urine semiquantitative test in the follow-up of MToP and its feasibility, acceptability and user-friendliness as well as the women capacity to interpret it correctly. Concordance between qualitative results from LSUP test and quantitative values from the blood hCG measurement was also assessed. STUDY DESIGN: From May to November 2013, we conducted a national, prospective, observational study with 17 centres offering MToP. Pregnant women with at least 63 days of amenorrhea (DA) requesting MToP were recruited during a consultation visit for medical abortion. RESULTS: A total of 322 women were included (mean age: 28.1 ± 6.4 years). The mean term of pregnancy at the time of MToP was 44.1 ± 6.2 DA. Two regimens were mostly used: 200 and 600 mg mifepristone followed by 800 µg of misoprostol (51.5 and 33.3% of patients, respectively). 82.0% of women attended the follow-up visit (N=264), 5.0% were reached by phone and 13.0% were lost to follow-up. 86.2% of women performed blood and urine measurements, as requested, on the same day (± one day). The MToP success rate was 93.6% of women. There were two ongoing pregnancies (0.7%) and 16 retained products of conception (5.7%). The overall concordance between urine and blood hCG levels was estimated at 94.5% CI95% [90.2%; 97.4%]. According to the physician's opinion, a majority of women (89.6%) read the urine test correctly. Self-performing the LSUP test at home was found reassuring for 39.9% of women, and satisfactory for 25.8% of them, but 2.8% considered it to be alarming and 11.8% unsettling. CONCLUSION: In our study, a self-performed LSUP test showed good concordance with blood test and appeared to be relevant, efficient and safe for women to monitor MToP success.

The shifting sands of medico-legal intra-partum Ctg (I-P Ctg) monitoring.

Intra-partum (IP) surveillance of the unborn child by cardiotacography (CTG) monitoring is the commonest obstetric procedure in the developed world.(1) It is also the most medico-legally contested obstetric procedure in labour. In 2011, 'birth asphyxia' comprised 50% of the UK National Health Service (NHS) litigation costs,(2) and in the 2000-2010 decade, the same NHS paid out £3.1 billion for maternity medico-legal claims (the highest of any speciality), mostly involving cerebral palsy and CTG misinterpretation.(3) This article looks at a number of characteristics of IP CTG monitoring which argue for its questionable solidity of base in court proceedings.

Can women determine the success of early medical termination of pregnancy themselves?

OBJECTIVE: To determine the outcome of early medical termination of pregnancy (TOP) among women who choose a "self assessment" follow up comprising a self-performed low sensitivity urine pregnancy test with instructions on signs/symptoms that mandate contacting the TOP service. STUDY DESIGN: A retrospective review of computer databases of 1726 women choosing self-assessment after early medical TOP (<9 weeks) in the UK. The main outcome measures were (a) number of women choosing self-assessment, (b) contact rates with TOP service and (c) time to presentation with an ongoing pregnancy (failed TOP). RESULTS: Ninety-six percent of women having an early medical TOP and going home to expel the pregnancy chose self-assessment. Two percent of women made unscheduled visits to the TOP service. One hundred and eighty-eight women (11%) telephoned the service about concerns related to complications or the success of treatment. There were eight ongoing pregnancies (0.5%; 95% confidence interval 0.2-0.9%). Four were detected within 4 weeks of treatment; the remainder were not detected until one or more missed menses after the procedure. CONCLUSIONS: Most women having an early medical TOP, who go home to expel the pregnancy, choose self-assessment. Relatively few women make unscheduled visits or telephone the TOP service. Most ongoing pregnancies are recognized at an early stage, although late presentation (as with all methods of follow up) does still occur. IMPLICATIONS STATEMENT: If women are given clear instructions on how and when to conduct a urine pregnancy test and on signs/symptoms that mandate contacting the TOP service, then they can confirm the success of early medical TOP themselves. Late presentation due to failure to recognize an ongoing pregnancy is rare.

RU OK? The acceptability and feasibility of remote technologies for follow-up after early medical abortion.

OBJECTIVES: We tested the effectiveness and feasibility of remote communication technologies to increase follow-up after early medical abortion. STUDY DESIGN: Women (n=999) were randomized to 'remote' follow-up incorporating a low-sensitivity pregnancy test and standardized symptom questionnaire administered online, by text message or telephone by a non-clinical call center operator 2 weeks after treatment, or to 'clinic-based' follow-up with ultrasound at 1 week. Women in the clinic-based group who could not return performed a high-sensitivity pregnancy test at 3 weeks and had a telephone call with clinic staff. The primary outcome was completion of follow-up. Rates of complications, acceptability and preferences were compared. RESULTS: The overall follow-up rate did not differ by group {clinic-based, 73% vs. remote, 69%; risk ratio (RR) 1.0 [95% confidence interval (CI) 0.9-1.2]}. In the clinic-based group, 83% did not return for an ultrasound scan and were followed up by phone. In the remote group, follow-up by phone or text was more successful than online (text: 75.4%; phone: 73.7%; online: 46.5%, p<.001). The proportion of women receiving additional care was 9% in the clinic-based group and was 4% in the remote group [RR 1.8 (95% CI 1.1-3.1)]. Most women found their follow-up method acceptable but would prefer follow-up by phone or text message if needed in future. CONCLUSIONS: Follow-up after medical abortion using remote communication is feasible and, for most women, preferable to a clinic visit. IMPLICATIONS: Medical abortion protocols typically use follow-up visits to ensure early identification of complications. This study demonstrates that follow-up can be achieved using remote communication technologies. This model may reduce the burden of multiple clinic visits on patients and providers.

Probing the non-canonical interface for agonist interaction with an α5 containing nicotinic acetylcholine receptor.

Nicotinic acetylcholine receptors (nAChRs) containing the α5 subunit are of interest because genome-wide association studies and candidate gene studies have identified polymorphisms in the α5 gene that are linked to an increased risk for nicotine dependence, lung cancer, and/or alcohol addiction. To probe the functional impact of an α5 subunit on nAChRs, a method to prepare a homogeneous population of α5-containing receptors must be developed. Here we use a gain of function (9') mutation to isolate populations of α5-containing nAChRs for characterization by electrophysiology. We find that the α5 subunit modulates nAChR rectification when co-assembled with α4 and ß2 subunits. We also probe the α5-α4 interface for possible ligand-binding interactions. We find that mutations expected to ablate an agonist-binding site involving the α5 subunit have no impact on receptor function. The most straightforward interpretation of this observation is that agonists do not bind at the α5-α4 interface, in contrast to what has recently been demonstrated for the α4-α4 interface in related receptors. In addition, our mutational results suggest that the α5 subunit does not replace the α4 or ß2 subunits and is relegated to occupying only the auxiliary position of the pentameric receptor.

Selective potentiation of (α4)3(ß2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats.

Prefrontal glutamate release evoked through activation of α4ß2* nicotinic acetylcholine receptors (nAChRs) situated on thalamic glutamatergic afferents mediates cue detection processes and thus contributes to attentional performance. However, little is known about the respective contributions of the high sensitivity and low sensitivity (LS) stoichiometries of the α4ß2 nAChR, (α4)2(ß2)3 and (α4)3(ß2)2, to these processes. In the present study we employed glutamate-sensitive microelectrodes and the (α4)3(ß2)2-selective positive allosteric modulator (PAM) NS9283 to investigate the importance of the LS α4ß2 nAChR for glutamate release in the rat medial prefrontal cortex (mPFC). Firstly, the signaling evoked by physiologically relevant ACh concentrations through the (α4)3(ß2)2 nAChR in HEK293 cells was potentiated by NS9283, consistent with the classification of NS9283 as a PAM. In urethane-anesthetized rats, intra-prefrontal pressure ejections of NS9283 evoked glutamatergic transients. Importantly, this glutamate release was attenuated by removal of cholinergic projections to the recording area. This finding indicates that the effects of NS9283 depend on endogenous ACh, again consistent with effects of a PAM. We then conducted microdialysis to demonstrate the presence of extracellular ACh in urethane-anesthetized control rats. While detectable, those levels were significantly lower than in awake rats. Finally, the amplitudes of glutamatergic transients evoked by local pressure ejections of a low concentration of nicotine were significantly augmented following systemic administration of NS9283 (3.0mg/kg). In conclusion, our results indicate that a LS α4ß2 nAChR PAM such as NS9283 may enhance the cholinergic modulation of glutamatergic neurotransmission in the cortex, thereby perhaps alleviating the attentional impairments common to a range of brain disorders.