The implicit power of positive thinking: The effect of positive episodic simulation on implicit future expectancies.

Previous research demonstrating that positive episodic simulation enhances future expectancies has relied on explicit expectancy measures. The current study investigated the effects of episodic simulation on implicit expectancies. Using the Future Thinking Implicit Relational Assessment Procedure (FT-IRAP), participants made true/false decisions to indicate whether or not they expected positive/negative outcomes after adopting orientations consistent or inconsistent with an optimistic disposition. The outcome measure, DIRAP, was based on response time differences between consistent and inconsistent blocks. Participants then engaged in either positive simulation training, in which they imagined positive future events, or a neutral visualisation task before repeating the FT-IRAP twice following 10-minute intervals. Positive simulation training increased DIRAP scores for don't-expect-negative trials-boosting participants' readiness to affirm that negative events were unlikely to happen to them. Although findings did not generalise across all trial types, they show potential for positive simulation training to enhance implicit future expectancies.

A survey about the practice of regional anesthesia in Manchester and Lancashire.

INTRODUCTION: In 2021, the UK Royal College of Anaesthetists published an updated curriculum which outlines specific peripheral nerve blocks in which all anesthetists must achieve competency during their training. Little is known about which nerve blocks anesthetists in the UK can perform, nor which techniques they use to perform them. METHODS: We conducted a survey of anesthetists in North West England to discover their experience in anesthesia, which nerve blocks they can perform, and which techniques they use to perform them. RESULTS: Overall, 195 responses were received. Seventy-nine respondents (44%) preferred to perform nerve blocks on anesthetized patients, 70 (40%) preferred to perform nerve blocks with the patient awake with no sedation. One hundred and thirty-seven (85%) respondents used ultrasound only to localize nerves when performing a block. Among consultant respondents, 21 (19%) were unable to perform any upper limb block, and 48 (44%) were unable to perform any block of the thorax, both are a required competency of trainees under the 2021 curriculum. DISCUSSION: Trainees may struggle to achieve the required competencies of the new curriculum given many consultants are also unable to perform them. A structured placement in regional anesthetic training in each stage of training could help improve the acquisition of skills and knowledge among trainees. Further studies are needed to assess the ability of anesthetists nationwide in regional anesthesia.

A Randomized Phase I Study of the Anti-Interleukin-33 Antibody Tozorakimab in Healthy Adults and Patients With Chronic Obstructive Pulmonary Disease.

Tozorakimab is a human monoclonal antibody that neutralizes interleukin (IL)-33. IL-33 is a broad-acting epithelial "alarmin" cytokine upregulated in lung tissue of patients with chronic obstructive pulmonary disease (COPD). This first-in-human, phase I, randomized, double-blind, placebo-controlled study (NCT03096795) evaluated the safety, tolerability, pharmacokinetics (PKs), immunogenicity, target engagement, and pharmacodynamics (PDs) of tozorakimab. This was a 3-part study. In part 1, 56 healthy participants with a history of mild atopy received single escalating doses of either intravenous or subcutaneous tozorakimab or placebo. In part 2, 24 patients with mild COPD received multiple ascending doses of subcutaneous tozorakimab or placebo. In part 3, 8 healthy Japanese participants received a single intravenous dose of tozorakimab or placebo. The safety data collected included treatment-emergent adverse events (TEAEs), vital signs, and clinical laboratory parameters. Biological samples for PKs, immunogenicity, target engagement, and PD biomarker analyses were collected. No meaningful differences in the frequencies of TEAEs were observed between the tozorakimab and placebo arms. Three tozorakimab-treated participants with COPD experienced treatment-emergent serious adverse events. Subcutaneous or intravenous tozorakimab demonstrated linear, time-independent PKs with a mean half-life of 11.7-17.3 days. Treatment-emergent anti-drug antibody frequency was low. Engagement of tozorakimab with endogenous IL-33 in serum and nasal airways was demonstrated. Tozorakimab significantly reduced serum IL-5 and IL-13 levels in patients with COPD compared with placebo. Overall, tozorakimab was well tolerated, with a linear, time-independent serum PK profile. Additionally, biomarker studies demonstrated proof of mechanism. Overall, these data support the further clinical development of tozorakimab in COPD and other inflammatory diseases.

A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

OBJECTIVE: Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands. DESIGN: Assessment of the effect of HTL0030310 on hormone secretion in human ACTH- and GH-secreting pituitary adenomas in vitro. METHODS: Primary cultures from 3 ACTH-secreting and 5 GH-secreting pituitary adenomas were treated with 1, 10 and 100 nM HTL0030310 alone or with 10 nM CRH or GHRH, respectively. Parallel incubations with 10 nM pasireotide were also carried out. ACTH and GH secretion were assessed after 4 and 24 hour incubation; SSTR2, SSTR3, SSTR5, GH and POMC expression were evaluated after 24 hours. RESULTS: HTL0030310 reduced unchallenged ACTH and POMC levels up to 50% in 2 ACTH-secreting adenomas and blunted CRH-stimulated ACTH/POMC by 20-70% in all 3 specimens. A reduction in spontaneous GH secretion was observed in 4 GH-secreting adenomas and in 2 specimens during GHRH co-incubation. SSTRs expression was detected in all specimens. CONCLUSIONS: This first study on a novel somatostatin receptor 5-preferring ligand indicates that HTL0030310 can inhibit hormonal secretion in human ACTH- and GH-secreting pituitary adenomas. These findings suggest a potential new avenue for somatostatin ligands in the treatment of Cushing's disease and acromegaly.

Potency of the novel PolC DNA polymerase inhibitor CRS0540 in a disseminated Listeria monocytogenes intracellular hollow-fibre model.

BACKGROUND: Listeriosis is an orphan disease, which is nevertheless fatal in immunocompromised people. CRS0540 is a novel PolC DNA polymerase inhibitor that has demonstrated good in vitro and in vivo activity against Listeria monocytogenes. METHODS: Rodent-to-human allometry projection-based human population pharmacokinetics of CRS0540 were used for all studies. CRS0540 pharmacokinetics/pharmacodynamics studies in an intracellular hollow-fibre system model of disseminated listeriosis (HFS-Lister) examined the effect of eight treatment doses, administered daily over 7 days, in duplicate units. Total bacterial burden versus AUC/MIC exposures on each day were modelled using the inhibitory sigmoid Emax model, while CRS0540-resistant bacterial burden was modelled using a quadratic function. Ten thousand-subject Monte Carlo simulations were used to predict an optimal clinical dose for treatment. RESULTS: The mean CRS0540 intracellular/extracellular AUC0-24 ratio was 34.07 (standard error: 15.70) as measured in the HFS-Lister. CRS0540 demonstrated exposure-dependent bactericidal activity in the HFS-Lister, with the highest exposure killing approximately 5.0 log10 cfu/mL. The free drug AUC0-24/MIC associated with 80% of maximal kill (EC80) was 36.4. Resistance emergence versus AUC/MIC was described by a quadratic function, with resistance amplification at an AUC/MIC of 54.8 and resistance suppression at an AUC/MIC of 119. Monte Carlo simulations demonstrated that for the EC80 target, IV CRS0540 doses of 100 mg/kg achieved PTAs of >90% at MICs up to 1.0 mg/L. CONCLUSIONS: CRS0540 is a promising orphan drug candidate for listeriosis. Future PK/PD studies comparing it with penicillin, the standard of care, could lead to this drug as a new treatment in immunocompromised patients.

Phase 1 and preclinical profiling of ESM-HDAC391, a myeloid-targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia.

AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS: This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS: ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.

Omadacycline efficacy in the hollow fibre system model of pulmonary Mycobacterium avium complex and potency at clinically attainable doses.

OBJECTIVES: The standard of care (SOC) for the treatment of pulmonary Mycobacterium avium complex (MAC) disease (clarithromycin, rifabutin, and ethambutol) achieves sustained sputum conversion rates of only 54%. Thus, new treatments should be prioritized. METHODS: We identified the omadacycline MIC against one laboratory MAC strain and calculated drug half life in solution, which we compared with measured MAC doubling times. Next, we performed an omadacycline hollow fibre system model of intracellular MAC (HFS-MAC) exposure-effect study, as well as the three-drug SOC, using pharmacokinetics achieved in patient lung lesions. Data was analysed using bacterial kill slopes (γ-slopes) and inhibitory sigmoid Emax bacterial burden versus exposure analyses. Monte Carlo experiments (MCE) were used to identify the optimal omadacycline clinical dose. RESULTS: Omadacycline concentration declined in solution with a half-life of 27.7 h versus a MAC doubling time of 16.3 h, leading to artefactually high MICs. Exposures mediating 80% of maximal effect changed up to 8-fold depending on sampling day with bacterial burden versus exposure analyses, while γ-slope-based analyses gave a single robust estimate. The highest omadacycline monotherapy γ-slope was -0.114 (95% CI: -0.141 to -0.087) (r2 = 0.98) versus -0.114 (95% CI: -0.133 to -0.094) (r2 = 0.99) with the SOC. MCEs demonstrated that 450 mg of omadacycline given orally on the first 2 days followed by 300 mg daily would achieve the AUC0-24 target of 39.67 mg·h/L. CONCLUSIONS: Omadacycline may be a potential treatment option for pulmonary MAC, possibly as a back-bone treatment for a new MAC regimen and warrants future study in treatment of this disease.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 2, risks of adverse outcome in common anomalies.

After diagnosis of a fetal neurological anomaly, prospective parents want to know the best and worst-case scenarios and an estimation of the risk to their infant of having an atypical developmental outcome. The literature on developmental outcomes for fetal neurological anomalies is poor: studies are characterized by retrospective design, small sample size, often no standardized assessment of development, and differing definitions of anomalies. This review provides an aide-memoir on the risks of adverse neurodevelopmental outcome for ventriculomegaly, cortical anomalies, microcephaly, macrocephaly, agenesis of the corpus callosum, posterior fossa anomalies, and myelomeningocele, to assist healthcare professionals in counselling. The data in this review should be used alongside recommendations on counselling and service design described in part 1 to provide antenatal counselling.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 1, experiences and recommendations for service design.

Prospective parents whose fetus is diagnosed with a neurological anomaly go through a complex range of emotions. They describe their discussions of antenatal counselling from health care professionals as focusing too much on the nature of the anomaly involving unintelligible medical terminology, when what they really want is a picture of the best- and worst-case scenarios. Whilst information on the level of risk for their fetus is important, it is not the parents' primary concern. When statistics for risk are given, they may not be as well understood as the health care professionals think. This review discusses the published evidence on antenatal counselling and recommendations for explaining risk to parents of fetuses with neurological anomalies. From this data we make recommendations for the organization of antenatal counselling services.

The use of a bespoke website developed for people with dementia and carers: Users' experiences, perceptions and support needs.

Background: Current policy emphasises the role of digital technologies in facilitating the management of long-term conditions. While digital resources have been developed for carers, there has been little attention to their development for people with dementia. The Caregiverspro-MMD website was developed as a joint resource for people with dementia and carers, delivering access to information, informal content, games and peer support. Research Design and Methods: This study explored the experiences of dyads consisting of people with dementia and carers of using the website. Interviews and focus groups were conducted with 43 participants. Findings: Thematic analysis identified 10 subthemes grouped under three superordinate themes which highlight participants' experiences of and responses to the website functions; important aspects of the website design and delivery; and barriers to use. Discussion: Findings highlight the value of a credible information source which negated the need for arduous online searches, the pleasure associated with playing games and interacting with others online. However, participants were reluctant to share personal information online, preferring to create 'informal content' which celebrated everyday life, and were reluctant to 'friend' people online who they had not met in person. The importance of training and support to use the website was highlighted. Health problems, lack of interest or difficulties using technology, and time were all identified as barriers to use.

Characterizing Frequency Stability Measurements Having Multiple Data Gaps.

Time series measurements with data gaps (dead times) prevent accurate computations of frequency stability variances such as the Allan variance (AVAR) and its square-root the Allan deviation (ADEV). To extract frequency distributions, time-series data must be sequentially ordered and equally spaced. Data gaps, particularly large ones, make ADEV estimates unreliable. Gap imputation by interpolation, zero-padding, or adjoining live segments, all fail in various ways. We have devised an algorithm that fills gaps by imputing an extension of preceding live data and explaining its advantages. To demonstrate the effectiveness of the algorithm, we have implemented it on 513-length original datasets and have removed 30% (150 values). The resulting data is consistent with the original in all three major criteria: the noise characteristic, the distribution, and the ADEV levels and slopes. Of special importance is that all ADEV measurements on the imputed dataset lie within 90% confidence of the statistic for the original dataset.

Transoral robotic resection of a lingual thyroid: a novel treatment for obstructive sleep apnoea.

A 34-year-old woman with a history of congenital hypothyroidism and 15 years of obstructive sleep apnoea was admitted with a left submandibular swelling secondary to a dental infection. A CT scan of the neck identified an incidental 27 mm tongue base mass and the absence of any cervical thyroid tissue. This mass was not observable on examination of the oropharynx but was seen on fine nasendoscopy while thyroid function tests showed good thyroid stimulating hormone suppression. Her acute dental infection was treated and, following multidisciplinary team discussion, she was diagnosed with an ectopic lingual thyroid. She was offered different management options including no intervention and radio-iodide treatment but opted for transoral robotic resection. The lesion was resected en bloc with clear margins and histology confirmed lingual thyroid tissue. Since the procedure, she has remained free of sleep apnoea with a significantly improved quality of life.

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome in pregnancy.

The syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a rare mitochondrial disease with few documented cases in pregnancy. In this case report, we discuss the presentation and management of a 39-year-old grand multiparous lady with MELAS syndrome, which was diagnosed prior to her eighth pregnancy, discuss potential implications of the condition in pregnancy and summarise the current guidelines for the management of this rare condition.

Implementing a program to reduce restraint and seclusion utilization in a public-sector hospital: Clinical innovations, preliminary findings, and lessons learned.

The Alternative to Restraint and Seclusion State Incentive Grant was a national initiative to reduce restraint and seclusion use in psychiatric hospitals and community based mental health settings sponsored by the National Association of State Mental Health Program Directors. This initiative was implemented in a large public sector psychiatric hospital. It involved the use of a restraint and seclusion prevention project team and a Patient-Staff Steering Committee collaborating on violence prevention. It also entailed systematic data collection and case reviews, staff-training on trauma-sensitive care and other relevant topics, employee recognition, as well as the use of specific restraint prevention tools including sensory modulation, positive behavioral support plans, comfort rooms, Wellness Recovery Action Plans, modified restraint orders, and new debriefing protocols. Compared with a 4-year baseline period, a 4-year implementation phase showed a reduction in annual restraints hours by 89%, annual staff injuries by 18%, and annual Workmen's Compensation medical costs by 24%. The findings illustrate the value of implementing systemic evidence-based practices to reduce restraint use, enhance the quality of care in tertiary care settings, and promote a new, patient-centered and recovery-oriented institutional culture. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Training people with dementia/cognitive impairment and their carers in the use of web-based supportive technologies (Innovative practice).

Little is known about the training and support people with dementia and their carers need to use digital solutions. This paper shares learning from a bespoke programme that successfully trained people with dementia or mild cognitive impairment and their informal carers to use a social networking website. This work was undertaken as part of the European Horizon 2020 Caregiverspro-mmd trial (ISRCTN15654731). The training methods described offer an improved understanding of how best to deliver digital skills training that meets the needs of a diverse client group. The effectiveness of the programme is evidenced with qualitative and quantitative data.

The CAREGIVERSPRO-MMD Platform as an Online Informational and Social Support Tool for People Living With Memory Problems and Their Carers: An Evaluation of User Engagement, Usability and Usefulness.

People living with dementia or cognitive impairment (PwD) and their carers often have unmet needs for informational and social support postdiagnosis. Web-based platforms have the potential to address these needs, although few have been developed for use by both PwD and carers. The CAREGIVERSPRO-MMD platform was developed to provide both user groups with informational and peer-to-peer social support. Platform logging data were analyzed to assess the extent to which PwD (n = 37) and carers (n = 37) engaged with the platform and its social/informational features in their daily lives. Participants also provided feedback on the usefulness and usability of the platform. The majority of PwD and carers found the platform and its social/informational features useful and usable, and significant subsets of both groups utilized the platform regularly. However, carers engaged with the informational and social features to a greater extent than PwD, and users highlighted that PwD typically required regular support to use the platform.

Intraperitoneal transfusion for severe, early-onset rhesus disease requiring treatment before 20 weeks of gestation: A consecutive case series.

OBJECTIVE: To describe the management and perinatal outcomes of pregnancies affected by severe, early onset Rhesus isoimmunization treated with fetal intraperitoneal transfusions (IPTs). STUDY DESIGN: A ten-year consecutive case series of fetuses undergoing IPTs before 20 weeks gestation at Wessex Fetal Medicine Unit, Southampton, UK. Women with fetuses at risk of early onset fetal anaemia (before 20 weeks gestation) were identified from their obstetric history and maternal antibody levels at the time of booking. They were referred to our tertiary referral center. The decision to initiate transfusion was aided by middle cerebral artery peak systolic velocity as an indicator of fetal anaemia. No fetus was hydropic at the first transfusion. IPTs were commenced from as early as 15 weeks gestation in fetuses with difficult vascular access and performed regularly using this method until the cord could be successfully entered for intravascular transfusions. The main outcome measures were procedure and non procedure-related perinatal losses. RESULTS: 11 fetuses underwent 45 IPTs. 10/11 (91%) were delivered after 33 weeks gestation. There was one perinatal loss 1/11 (9%: 95% C.I 1.6-38%) from a cord accident during intravascular transfusion at 26 weeks gestation. There were no procedure related fetal losses or complications at the time of early IPTs. CONCLUSIONS: Previous studies report a perinatal loss rate with early intrauterine transfusion of 24% in gestations below 20 weeks using the intravascular route. This series suggests that intraperitoneal transfusion can be a safe and effective treatment for severe fetal anaemia at early gestations where vascular access is difficult.

A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity.

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.