Chelation enables selectivity control in enantioconvergent Suzuki-Miyaura cross-couplings on acyclic allylic systems.

Asymmetric Suzuki-Miyaura cross-couplings with aryl boronic acids and allylic electrophiles are a powerful method to convert racemic mixtures into enantioenriched products. Currently, enantioconvergent allylic arylations are limited to substrates that are symmetrical about the allylic unit, and the absence of strategies to control regio-, E/Z- and enantioselectivity in acyclic allylic systems is a major restriction. Here, using a system capable of either conjugate addition or allylic arylation, we have discovered the structural features and experimental conditions that allow an acyclic system to undergo chemo- and regioselective, enantioconvergent allylic Suzuki-Miyaura-type arylation. A wide variety of boronic acid coupling partners can be used, and both alkyl and aromatic substituents are tolerated on the allylic unit so that a wide variety of structures can be obtained. Preliminary mechanistic studies reveal that the chelating ability of the ester group is crucial to obtaining high regio- and enantioselectivity. Using this method, we were able to synthesize the natural products (S)-curcumene and (S)-4,7-dimethyl-1-tetralone and the clinically used antidepressant sertraline (Zoloft).

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin (HTT) gene. We report the design of a series of HTT pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of HTT mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable HTT-splicing modulator 27. This compound reduced canonical splicing of the HTT RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound 27 is a structurally diverse HTT-splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.

Pediatric Pharmacy Services: Current Models and Justification for Expansion.

Despite recommendations from numerous health care bodies, some hospitals that care for children have struggled to establish or expand pediatric pharmacy services. The current state of dedicated pediatric operational and clinical pharmacy services was characterized by results from a survey of hospitals that provide care to pediatric patients. The discussion of quality of care, safety, and financial impact is meant to provide concepts for justification of pediatric pharmacy service expansion.

Transnational Child Sexual Abuse: Outcomes from a Roundtable Discussion.

The phenomenon of men who travel across international borders to engage in child sexual abuse presents significant public health, legal, diplomatic, cultural, and research challenges. Briefed in the current scope of this issue by relevant stakeholders across legislation, research, and social policy, a roundtable discussion held in London aimed to synthesise plenary discussions from multidisciplinary attendees across law enforcement, academia, non-profit, and industry sectors with direct relevance to the UK. Specifically, the roundtable discussions aimed to gather the central themes relating to attendee discussions on the key challenges, affected countries, response strategies, and knowledge gaps. Four key themes were identified from the data, relating to the definition of Transnational Child Sexual Abuse (TCSA), criminal justice, geographical considerations, and issues surrounding tourism/hospitality. The data highlighted four priorities for future development and research, namely developing offender typologies, victim-centric investigative practice, prevalence and definitions, and collaborations. These themes provide insight into the issue of transnational child sexual abuse from the perspective of different disciplines and offer a strategy to prioritise, and collaborate, in the efforts against transnational child sexual abuse.

"It's Not Something I Chose You Know": Making Sense of Pedophiles' Sexual Interest in Children and the Impact on Their Psychosexual Identity.

Sexual interest in children is one of the most strongly predictive of the known risk factors for sexual reconviction. It is an important aspect of risk assessment to identify the presence of such interest, and an important task for treatment providers to address such a sexual interest where it is present. It has been argued that understanding pedophiles' deviant sexual interest in children can enhance risk assessment, management, and treatment planning. This research study aims to explore the phenomenology of deviant sexual interest in children, the impact it has on pedophilic offenders' identities, and their views on the treatability of that interest. The study used semistructured interviews and repertory grids to make sense of participants' experiences. The results revealed three superordinate themes: "'living' with a deviant sexual interest," "relational sexual self," and "possible and feared sexual self." The analysis unpacks these themes and repertory grid analysis is used to explore a subset of participants' identities in more detail. The results reveal that there needs to be an acceptance from both client and therapist that their sexual interest in children may never go away. Through this acceptance, clients could work on enhancing sexual self-regulation, recognizing their triggers, and so managing their sexual thoughts, feelings, and behavior. Implications for treatment are also discussed.

Single-longitudinal-mode ring diamond Raman laser.

We demonstrate a single-longitudinal-mode ring diamond Raman laser, pumped by a tunable single-mode Ti:sapphire laser. Two methods to achieving unidirectional operation have been demonstrated: increasing gain for one direction using a reinjecting mirror and increasing loss for one direction using sum frequency mixing in BBO. Both methods result in a stable single-longitudinal-mode operation.

How Effective Is Supplemental Intraseptal Anesthesia in Patients with Symptomatic Irreversible Pulpitis?

INTRODUCTION: Previous studies have reported high levels of success with intraseptal injection for various dental procedures but provide limited information on the use of the injection during endodontic treatment. Therefore, the purpose of this prospective study was to determine the anesthetic efficacy of the supplemental intraseptal technique in mandibular posterior teeth diagnosed with symptomatic irreversible pulpitis when the conventional inferior alveolar nerve (IAN) block failed. METHODS: One hundred patients with a diagnosis of symptomatic irreversible pulpitis in a mandibular posterior tooth were recruited. Following profound lip numbness after the administration of the conventional IAN block, endodontic treatment was initiated. Patients still experiencing moderate to severe pain during treatment were administered mesial and distal supplemental intraseptal injections using 0.7 mL 4% articaine with 1:000,000 epinephrine administered with a computer-controlled local anesthetic delivery unit. Success was defined as the ability to perform endodontic access and instrumentation with mild to no pain. RESULTS: Success with the IAN block was achieved in 25% of patients. Supplemental intraseptal injections provided success in 29% of patients. CONCLUSIONS: Supplemental intraseptal injections achieved profound pulpal anesthesia in 29% of patients when the IAN block failed. This low level of success would not provide predictable levels of anesthesia for patients requiring emergency endodontic treatment for symptomatic irreversible pulpitis in mandibular posterior teeth.

Stop It Now! A Pilot Study Into the Limits and Benefits of a Free Helpline Preventing Child Sexual Abuse.

Stop It Now! aims to prevent child sexual abuse using a free anonymous helpline. It provides information, advice, and guidance to anyone concerned about child sexual abuse. It targets people who have sexually abused children or who are worried that they might do so. This article presents findings from a pilot study on the operation and outcomes of the helplines in the United Kingdom and the Netherlands. The findings underline the strength of the public health approach to prevention efforts. More specifically, benefits reported by helpline users are shown to correspond with the aims of the helplines. A number of factors were reported by users that helped them modify their own or others' actions to minimize risk of abuse. However, a challenge that remains is ensuring that helplines are accessible to those most in need. Recommendations are included to further expand the effect of Stop It Now! in reducing CSA.

Fetal shielding combined with state of the art CT dose reduction strategies during maternal chest CT.

PURPOSE: Custom bismuth-antimony shields were previously shown to reduce fetal dose by 53% on an 8DR (detector row) CT scanner without dynamic adaptive section collimation (DASC), automatic tube current modulation (ATCM) or adaptive statistical iterative reconstruction (ASiR). The purpose of this study is to compare the effective maternal and average fetal organ dose reduction both with and without bismuth-antimony shields on a 64DR CT scanner using DASC, ATCM and ASiR during maternal CTPA. MATERIALS AND METHODS: A phantom with gravid prosthesis and a bismuth-antimony shield were used. Thermoluminescent dosimeters (TLDs) measured fetal radiation dose. The average fetal organ dose and effective maternal dose were determined using 100 kVp, scanning from the lung apices to the diaphragm utilizing DASC, ATCM and ASiR on a 64DR CT scanner with and without shielding in the first and third trimester. Isolated assessment of DASC was done via comparing a new 8DR scan without DASC to a similar scan on the 64DR with DASC. RESULTS: Average third trimester unshielded fetal dose was reduced from 0.22 mGy ± 0.02 on the 8DR to 0.13 mGy ± 0.03 with the conservative 64DR protocol that included 30% ASiR, DASC and ATCM (42% reduction, P<0.01). Use of a shield further reduced average third trimester fetal dose to 0.04 mGy ± 0.01 (69% reduction, P<0.01). The average fetal organ dose reduction attributable to DASC alone was modest (6% reduction from 0.17 mGy ± 0.02 to 0.16 mGy ± 0.02, P=0.014). First trimester fetal organ dose on the 8DR protocol was 0.07 mGy ± 0.03. This was reduced to 0.05 mGy ± 0.03 on the 64DR protocol without shielding (30% reduction, P=0.009). Shields further reduced this dose to below accurately detectable levels. Effective maternal dose was reduced from 4.0 mSv on the 8DR to 2.5 mSv on the 64DR scanner using the conservative protocol (38% dose reduction). CONCLUSION: ASiR, ATCM and DASC combined significantly reduce effective maternal and fetal organ dose during CTPA. Shields continue to be an effective means of fetal dose reduction.

Simple and rapid determination of norethindrone in human plasma by supported liquid extraction and ultra performance liquid chromatography with tandem mass spectrometry.

We report for the first time an ultra performance liquid chromatographic method with tandem mass spectrometric detection (UPLC/MS/MS) for the determination of norethindrone alone in human plasma over the concentration range of 50.0-25000 pg mL(-1) using a sample volume of 0.250 mL. Norethindrone and its internal standard (ISTD), norethindrone-(13)C(2), were extracted from human plasma by supported liquid extraction (SLE). After evaporation of the organic solvent, samples were reconstituted and analyzed on an UPLC/MS/MS system. The UPLC system used a Waters BEH C18 (100 mm × 2.1mm, 1.7 µm) column with mobile phase A of 0.05% formic acid in water:acetonitrile (65:35, v/v) and mobile phase B of 0.05% formic acid in methanol:acetonitrile (50:50, v/v). The flow rate was 0.500 mL min(-1). The method was fully validated. The inter-run accuracy and precision at the lower limit of quantitation (LLOQ), low, mid and high quality control (QC) concentration levels were 99.2-108.4% with a <8.1% CV (coefficient of variation), respectively. The validated method has been successfully applied to analysis of thousands of pharmacokinetic samples.

Force-insensitive optical cavity.

We describe a rigidly mounted optical cavity that is insensitive to inertial forces acting in any direction and to the compressive force used to constrain it. The design is based on a cubic geometry with four supports placed symmetrically about the optical axis in a tetrahedral configuration. To measure the inertial force sensitivity, a laser is locked to the cavity while it is inverted about three orthogonal axes. The maximum acceleration sensitivity is 2.5×10⁻¹¹/g (where g=9.81 ms⁻²), the lowest passive sensitivity to be reported for an optical cavity.

Lead versus bismuth-antimony shield for fetal dose reduction at different gestational ages at CT pulmonary angiography.

PURPOSE: To compare the effective fetal dose reduction at different stages of gestation during maternal computed tomographic (CT) pulmonary angiography by using traditional lead apron and bismuth-antimony shields combined with limited z-axis and tube current. MATERIALS AND METHODS: Phantom with gravid prosthesis, 0.5-mm lead, and two grades of bismuth-antimony shield was used. Thermoluminescent dosimeters (TLDs) measured radiation in the first- to third-trimester uterus. Fetal dose was determined for each gestation by using 100 kVp to the costophrenic angles (CPAs) with and without shielding for a total of 12 scans. Eight third-trimester scans were used to compare shields using 120 kVp to CPAs versus those using 100 kVp to the diaphragm. RESULTS: Average fetal dose increased with gestation with use of 100 kVp to CPAs, from 0.11 mGy in first trimester to 0.50 mGy in third trimester. Average third-trimester unshielded fetal dose was reduced from 0.82 mGy by using 120 kVp to CPAs to 0.17 mGy (79%, P < .001) by using 100 kVp to the diaphragm. Lead apron reduced dose more than either of the bismuth-antimony shields (72%-79% vs 57%-81%) with use of 100 kVp to CPAs. Shields reduced the dose by 73% (lead), 62% (90% attenuation bismuth-antimony), and 72% (95% attenuation bismuth-antimony) (P < .01) at 120 kVp to CPAs. No significant difference between shields was demonstrated with 100 kVp to the diaphragm (P < .01). Maternal dose was 8.13 mSv at 120 kVp to CPAs, 4.90 mSv at 100 kVp to CPAs, and 4.02 mSv at 100 kVp to the diaphragm. CONCLUSION: Reducing voltage and limiting z-axis is more effective than shields at reducing fetal dose. Shielding improves reduction with no significant difference between lead and bismuth-antimony shields when conservative scanning parameters are observed.

Influences on the provision of drug services in England: the experiences and views of front line treatment workers.

Whilst service users' views of treatment have been explored, little research exists that has examined front line treatment workers' views on what they perceive are the facilitators and barriers to service provision. This study aimed to fill that gap using a qualitative methodology to explore the experiences of treatment workers. A purposive sample of four Drugs Action Teams or Drug and Alcohol Teams was selected and, in total, 32 front line treatment workers were interviewed across a range of services. Participants indicated that the influences on treatment delivery occurred at three levels. The first level was structural impacts. These included the degree to which services were resourced, the role of targets and a competitive tendering environment, and challenges to partnership working between criminal justice services and community-based services. At the second level, participants identified the influence of the local organisation of services, in particular, the importance of co-ordination in care planning and streamlining for complex cases. The final level was the impact of specific working practices. Good communication was seen as facilitating information sharing; however, a lack of support by management could undermine the benefits of both supervision and peer-support. Unmet training needs were identified by staff across a range of services and particular issues in the relationship between drug treatment and mental health services were identified. Overall, the participants indicated that drug treatment in England was delivered within a complex structure by services that had varied treatment philosophies and that sometimes competed for funding. Despite this, the system was seen as functioning due to the high level of commitment of the people who work within it.

Frequency measurement of the 2S(1/2)-2D(3/2) electric quadrupole transition in a single 171Yb+ ion.

We report on precision laser spectroscopy of the 2S(1/2)(F = 0)-2D(3/2) (F = 2, m(F) = 0) clock transition in a single ion of 171Yb+. The absolute value of the transition frequency, determined using an optical frequency comb referenced to a hydrogen maser, is 688358979309310 +/- 9 Hz. This corresponds to a fractional frequency uncertainty of 1.3 x 10(-14).

The construction and preliminary validation of the Internet Behaviours and Attitudes Questionnaire (IBAQ).

This study describes the construction and preliminary validation of a measure of the attitudes and behaviours of convicted men whose offences are related to Internet child 'pornography' (abusive images). An initial measure was constructed through the generation of items with reference to the emerging literature on these offenders. Phase 1 involved piloting this first version of the measure with 40 Internet sexual offenders incarcerated in Her Majesty's Prison Service. Phase 2 involved the validation of an improved version of the IBAQ with 123 Internet sexual offenders both incarcerated in Her Majesty's Prison Service and subject to community dispositions. The measure had excellent internal consistency. Following factor analysis a two factor solution, 'distorted thinking', and 'self-management' emerged from the attitudinal items. The attitude measure was not influenced by social desirability, and was able to discriminate participants who disclosed the greater number of 'offending behaviours'. These results are discussed in terms of their clinical implications.

Science and society: art and science collaborations in the United Kingdom.

In this Perspective article, I consider ways in which the contemporary arts and sciences can interact with each other, and I outline the current opportunities for funding in the United Kingdom. I examine the view that, in an art-science collaboration, it is the artist who benefits most, and I cautiously suggest that this is an oversimplification. Evidence from interviews with scientists who have been involved in these collaborations shows that artistic experience and skills are of value in the scientific research process.

Identifying schemas in child molesters, rapists, and violent offenders.

One focus of research concerning offending behavior has been the concept of the cognitive distortion, although the importance of the need for research into the underlying cognitive structures in offenders has been highlighted. This study examined schemas in child molesters, rapists, and violent offenders, predicting content differences in the offence-related schemas between these groups. In accordance with previous research, the prevalence of a "suspiciousness/hostility to women" schema in rapists was predicted. Twelve rapists, twelve child molesters, and twelve violent offenders incarcerated in a male maximum-security prison completed "Life Maps" (autobiographies) and the My Life questionnaire (R. E. Mann & C. R. Hollin, 2001), both designed to indicate the presence of schemas. A content analysis template containing nine schemas was constructed and applied to the Life Map data. Results showed a significant difference in the prevalence of schema type between the three groups. There was a prevalence of a "hostility/distrust of women" schema in the rapists. Analysis of the My Life questionnaire revealed a difference between violent offenders and rapists only. This study highlights the need for further research into schemas with sexual and violent offenders.