Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia.

The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A1R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A1R co-bound to adenosine, MIPS521 and a Gi2 heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts.

Selective Inhibition of NaV1.8 with VX-548 for Acute Pain.

BACKGROUND: The NaV1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of NaV1.8, on control of acute pain is being studied. METHODS: After establishing the selectivity of VX-548 for NaV1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo. RESULTS: A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548. CONCLUSIONS: As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.).

Understanding decision-making for and against oncoplastic breast-conserving surgery as an alternative to a mastectomy in early breast cancer: UK ANTHEM qualitative study.

BACKGROUND: Oncoplastic breast-conserving surgery may allow women with early breast cancer to avoid a mastectomy, but many women undergo more extensive surgery, even when breast-conserving options are offered. The aim of the ANTHEM qualitative study was to explore factors influencing women's surgical decision-making for and against oncoplastic breast-conserving surgery. METHODS: Semi-structured interviews were conducted with a purposive sample of women who had received either oncoplastic breast-conserving surgery or a mastectomy with or without immediate breast reconstruction to explore their rationale for procedure choice. Interviews were transcribed verbatim and analysed thematically. Trial registration number: ISRCTN18238549. RESULTS: A total of 27 women from 12 centres were interviewed. Out of these, 12 had chosen oncoplastic breast-conserving surgery and 15 had chosen a mastectomy with or without immediate breast reconstruction. Overwhelmingly, women's decisions were guided by their surgical teams. Decision-making for and against oncoplastic breast-conserving surgery was influenced by three key inter-related factors: perceptions of oncological safety; the importance of maintaining/restoring femininity and body image; and practical issues. Oncological safety was paramount. Women who reported feeling reassured that oncoplastic breast-conserving surgery was oncologically safe were happy to choose this option. Those who were not reassured were more likely to opt for a mastectomy, as a perceived 'safer' option. Most women wished to maintain/restore femininity, with the offer of immediate breast reconstruction essential to make a mastectomy an acceptable option. Practical issues such as the perceived magnitude of the surgery were a lesser concern. CONCLUSION: Decision-making is complex and heavily influenced by the surgical team. High-quality, accurate information about surgical options, including appropriate reassurance about the short- and long-term oncological safety of oncoplastic breast-conserving surgery is vital if women are to make fully informed decisions.

The OdonAssist inflatable device for assisted vaginal birth-the ASSIST II study (United Kingdom).

BACKGROUND: Decreasing rates of assisted vaginal birth have been paralleled with increasing rates of cesarean deliveries over the last 40 years. The OdonAssist is a novel device for assisted vaginal birth. Iterative changes to clinical parameters, device design, and technique have been made to improve device efficacy and usability. OBJECTIVE: This study aimed to determine if the feasibility, safety, and efficacy of the OdonAssist device were sufficient to justify conducting a future randomized controlled trial. STUDY DESIGN: An open-label nonrandomized study of 104 participants having a clinically indicated assisted vaginal birth using the OdonAssist was undertaken at Southmead Hospital, Bristol, United Kingdom. Data were also collected from participants who consented to participate in the study but for whom trained OdonAssist operators were not available, providing a nested cohort. The primary clinical outcome was the proportion of births successfully expedited with the OdonAssist. Secondary outcomes included clinical, patient-reported, operator-reported, device and health care utilization. Neonatal outcome data were reviewed at day 28, and maternal outcomes were investigated up to day 90. Given that the number of successful OdonAssist births was ≥61 out of 104, the hypothesis of a poor rate of 50% was rejected in favor of a good rate of ≥65%. RESULTS: Between August 2019 and June 2021, 941 (64%) of the 1471 approached, eligible participants consented to participate. Of these, 104 received the OdonAssist intervention. Birth was assisted in all cephalic vertex fetal positions, at all stations ≥1 cm below the ischial spines (with or without regional analgesia). The OdonAssist was effective in 69 of the 104 (66%) cases, consistent with the hypothesis of a good efficacy rate. There were no serious device-related maternal or neonatal adverse reactions, and there were no serious adverse device effects. Only 4% of neonatal soft tissue bruising in the successful OdonAssist group was considered device-related, as opposed to 20% and 23% in the unsuccessful OdonAssist group and the nested cohort, respectively. Participants reported high birth perception scores. All practitioners found the device use to be straightforward. CONCLUSION: Recruitment to an interventional study of a new device for assisted vaginal birth is feasible; 64% of eligible participants were willing to participate. The success rate of the OdonAssist was comparable to that of the Kiwi OmniCup when introduced in the same unit in 2002, meeting the threshold for a randomized controlled trial to compare the OdonAssist with current standard practice. There were no disadvantages of study participation in terms of maternal and neonatal outcomes. There were potential advantages of using the OdonAssist, particularly reduced neonatal soft tissue injury. The same application technique is used for all fetal positions, with all operators deeming the device straightforward to use. This study provides important data to inform future study design.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury (EBB-TBI): Protocol for a Phase 2a Intervention Design Study.

Traumatic brain injury is a leading cause of death and disability worldwide. Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24 h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.Trial registration ISRCTN, ISRCTN11038397, registered retrospectively 07/01/2021 https://www.isrctn.com/ISRCTN11038397.

Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study.

BACKGROUND: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed. METHODS: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score. RESULTS: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 µg/kg/min, with increments every 30 min of 5 µg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen. CONCLUSIONS: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 ).

Assessing Appearance, Speech, and Hearing (dis)Satisfaction in Individuals with Cleft Lip and/or Palate: A Contribution to General Population Norms.

BACKGROUND: Individuals with cleft lip and/or palate (CL/P) may grow up with a visible facial difference, alongside speech and/or hearing challenges. Self-perceptions are stronger predictors of psychosocial adjustment than objective assessments, highlighting the importance of patient-reported outcome measures. Previously titled the Satisfaction with Appearance (SwA) questionnaire, the Cleft Hearing, Appearance and Speech Questionnaire (CHASQ) has been used in several countries to assess patient satisfaction, guide clinical decision-making, and conduct craniofacial research, but has lacked general population norms from which to draw comparisons. The aim of this study was to contribute to the development of norms by utilising existing data collected in the United Kingdom (UK) in 2004 using the original SwA. METHODS: SwA data collected from school pupils (n = 761) aged 10-16 years were analysed across age and gender. RESULTS: Hair, Eyes and Ears received the highest ratings, while Teeth received the lowest ratings. Those who were younger, and those who were male, generally rated their appearance more favourably. Thresholds are proposed to identify young people in need of clinical monitoring (10%) and intervention (5%). DISCUSSION: This study supports the potential of the CHASQ as a clinically useful outcome measure and research tool with the ability to identify appearance concerns in relation to specific facial features, as well as overall appearance satisfaction in young people with and without CL/P. Further validation of its use in the CL/P population and other patient groups, as well as countries outside the UK would add additional weight to the CHASQ's utility.

Detection and Characterization of Rapidly Equilibrating Glycosylation Reaction Intermediates Using Exchange NMR.

The stereoselective introduction of glycosidic bonds (glycosylation) is one of the main challenges in the chemical synthesis of carbohydrates. Glycosylation reaction mechanisms are difficult to control because, in many cases, the exact reactive species driving product formation cannot be detected and the product outcome cannot be explained by the primary reaction intermediate observed. In these cases, reactions are expected to take place via other low-abundance reaction intermediates that are in rapid equilibrium with the primary reaction intermediate via a Curtin-Hammett scenario. Despite this principle being well-known in organic synthesis, mechanistic studies investigating this model in glycosylation reactions are complicated by the challenge of detecting the extremely short-lived reactive species responsible for product formation. Herein, we report the utilization of the chemical equilibrium between low-abundance reaction intermediates and the stable, readily observed α-glycosyl triflate intermediate in order to infer the structure of the former species by employing exchange NMR. Using this technique, we enabled the detection of reaction intermediates such as ß-glycosyl triflates and glycosyl dioxanium ions. This demonstrates the power of exchange NMR to unravel reaction mechanisms as we aim to build a catalog of kinetic parameters, allowing for the understanding and eventual prediction of glycosylation reactions.

Impact of procedure type on revisional surgery and secondary reconstruction after immediate breast reconstruction in a population-based cohort.

BACKGROUND: Women considering immediate breast reconstruction require high-quality information about the likely need for secondary reconstruction and the long-term risk of revisional surgery to make fully informed decisions about different reconstructive options. Such data are currently lacking. This study aimed to explore the impact of reconstruction type on the number of revisions and secondary reconstructions performed 3, 5, and 8 years after immediate breast reconstruction in a large population-based cohort. METHODS: Women undergoing unilateral mastectomy and immediate breast reconstruction for breast cancer or ductal carcinoma in situ in England between 1 April 2009 and 31 March 2015 were identified from National Health Service Hospital Episode Statistics. Numbers of revisions and secondary reconstructions in women undergoing primary definitive immediate breast reconstruction were compared by procedure type at 3, 5, and 8 years after index surgery. RESULTS: Some 16 897 women underwent immediate breast reconstruction with at least 3 years' follow-up. Of these, 14 069 had a definitive reconstruction with an implant only (5193), latissimus dorsi flap with (3110) or without (2373) an implant, or abdominal free flap (3393). Women undergoing implant-only reconstruction were more likely to require revision, with 69.5 per cent (747 of 1075) undergoing at least one revision by 8 years compared with 49.3 per cent (1568 of 3180) in other reconstruction groups. They were also more likely to undergo secondary reconstruction, with the proportion of women having further reconstructive procedures increasing over time: 12.8 per cent (663 of 5193) at 3 years, 14.3 per cent (535 of 3752) at 5 years, and 17.6 per cent (189 of 1075) at 8 years. CONCLUSION: Long-term rates of revisions and secondary reconstructions were considerably higher after primary implant-based reconstruction than autologous procedures. These results should be shared with patients to support informed decision-making.

BACKGROUND: Breast reconstruction is performed to improve well-being for women who need mastectomy (removal of the breast) as part of breast cancer treatment. There are many different types of breast reconstruction operation, and it can be difficult for women to decide which operation, if any, is right for them. Information about the number of extra operations that a woman is likely to need after breast reconstruction surgery is an important factor in helping them make this decision. This study aimed to investigate the number of extra operations that women who had breast reconstruction needed by 3, 5, and 8 years after surgery, and how this differed by the type of breast reconstruction surgery they had. Routinely collected hospital record data were used to identify women having breast reconstruction at the time of mastectomy for breast cancer, and identify any extra operations performed for problems related to the reconstruction in the 8 years after the first operation. The number of extra operations performed after different types of breast reconstructions was compared at 3, 5, and 8 years after the mastectomy. Women who had implant-based reconstruction required more extra operations than those having reconstruction using their own tissue. They were also more likely to have the implant replaced with another type of breast reconstruction than women undergoing tissue-based reconstruction at 3, 5, and 8 years after the first surgery. This information should be discussed with women thinking about breast reconstruction to help them decide what type of operation would be best for them.

Long-term patient-reported outcomes of immediate breast reconstruction after mastectomy for breast cancer: population-based cohort study.

BACKGROUND: Breast reconstruction is offered to improve quality of life for women after mastectomy for breast cancer, but information regarding the long-term patient-reported outcomes of different reconstruction procedures is currently lacking. The Brighter study aimed to evaluate long-term patient-reported outcomes after immediate breast reconstruction (IBR) in a population-based cohort. METHODS: Women who underwent mastectomy with IBR for breast cancer in England between 1 January 2008 and 31 March 2009 were identified from National Health Service Hospital Episode Statistics. Surviving women were invited to complete the BREAST-Q, EQ-5D-5L™, and ICECAP-A at least 12 years after the index procedure. Questionnaires were scored according to developers' instructions and compared by IBR type. RESULTS: Some 1236 women underwent IBR; 343 (27.8 per cent) had 2-stage expander/implant, 630 (51.0 per cent) latissimus dorsi, and 263 (21.3 per cent) abdominal flap reconstructions, with a mean(s.d.) follow-up of 13.3(0.5) years. Women who underwent abdominal flap reconstruction reported higher scores in all BREAST-Q domains than those who had other procedures. These differences remained statistically significant and clinically meaningful after adjusting for age, ethnicity, geographical region, socioeconomic status, smoking, BMI, and complications. The greatest difference was seen in scores for satisfaction with breasts; women who had abdominal flap reconstructions reported scores that were 13.17 (95 per cent c.i. 9.48 to 16.87) points; P < 0.001) higher than those among women who had two-stage expander/implant procedures. Women who underwent latissimus dorsi reconstruction reported significantly more pain/discomfort on the EQ-5D-5L™, but no other differences between procedures were seen. CONCLUSION: Long-term patient-reported outcomes are significantly better following abdominal flap reconstruction than other traditional procedure types. These findings should be shared with women considering IBR to help them make informed decisions about their surgical options.

Readily Accessible Strained Difunctionalized trans-Cyclooctenes with Fast Click and Release Capabilities.

The click reaction between a functionalized trans-cyclooctene (TCO) and a tetrazine (Tz) is a compelling method for bioorthogonal conjugation in combination with payload releasing capabilities. However, the synthesis of difunctionalized TCOs remains challenging. As a result, these compounds are poorly accessible, which impedes the development of novel applications. In this work, the scalable and accessible synthesis of a new bioorthogonal difunctionalized TCO is reported in only four single selective high yielding steps starting from commercially available compounds. The TCO-Tz click reaction was assessed and revealed excellent kinetic rates and subsequently payload release was shown with various functionalized derivatives. Tetrazine triggered release of carbonate and carbamate payloads was demonstrated up to 100 % release efficiency and local drug release was shown in a cellular toxicity study which revealed a >20-fold increase in cytotoxicity.

Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories.

Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond 'know' towards 'know how to'. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.

BRIVEST: A 'real-world' observational, single-centre study investigating the efficacy, safety and tolerability of Brivaracetam.

OBJECTIVE: Via measures of efficacy, tolerability, and safety, this open-label, single-center study assessed the overall effectiveness of Brivaracetam (BRV) for the treatment of epilepsy in the context of 'real-world' clinical practice. METHODS: Unselected consecutive patients were recruited and stratified into 3 cohorts with either fully prospective, fully retrospective or mixed data collection, dependent on whether their BRV prescriptions were historical, current, or pending. Prospective data were obtained at baseline, 3 and 6 months, and at 6-month intervals thereafter, from patient interviews and seizure diaries, and retrospective data from medical records. Efficacy variables were derived from seizure-related changes, and tolerability and safety variables from reported treatment-emergent adverse events (TEAEs), BRV withdrawal, and changes to questionnaire scores. Additionally, we investigated treatment outcomes for those with previous levetiracetam (LEV) use, a history of psychiatric comorbidity, a learning disability, and of older age. RESULTS: One hundred and nine patients (58.7% female, mean age 42 years, range: 18 to 72) were included, 59 with prospective follow-up for a minimum of 6 (47 patients, excluding those who withdrew) and a maximum of 24 months (2 patients). Of the full cohort, 87.2% had drug-resistant epilepsy. Retention: At the study end, the median treatment duration was 384 days (range: 6 to 1514 days), and BRV retention was 68.8%. Kaplan-Meier survival functions predicted retention rates of 74.0% and 70.0% at 6 and 12 months respectively. EFFICACY: At the last follow-up, there was a ≥ 50% responder rate of 30.8%, with 12.1% seizure-free. Seizure frequency categories improved in 31.4% of patients, remained the same in 44.2%, and worsened in 24.4%. Monthly tonic-clonic seizure frequency had significantly decreased, and of those reporting these seizures, 58.3% showed reductions and 25.0% showed complete tonic-clonic seizure freedom. TOLERABILITY: 91.7% of patients reported at least 1 TEAE, with fatigue (30.3%), irritability (29.4%), and depression/low mood (28.4%) as the most common. Only 58.4% of all TEAEs were persistent. Brivaracetam discontinuation due to side effects occurred in 27.5% of the cohort. Depression and anxiety scores remained stable over time, and quality-of-life scores improved. Subgroups: Measures of BRV efficacy and tolerability did not differ according to previous LEV exposure. Tolerability profiles of those with learning disabilities, histories of psychiatric comorbidities, and older age did not greatly differ from the rest of the cohort. Of note, specific history of depression predicted the reporting of suicidal ideation. CONCLUSION: The BRIVEST study provides real-world evidence of the effectiveness of BRV, suggesting that neither drug-resistant epilepsy nor previous LEV failure should preclude its use. Furthermore, BRV appears to be well-tolerated, even among those from vulnerable patient populations.

Use of silicone wristbands to measure firefighters' exposures to polycyclic aromatic hydrocarbons (PAHs) during live fire training.

Firefighters experience exposures to carcinogenic and mutagenic substances, including polycyclic aromatic hydrocarbons (PAHs). Silicone wristbands (SWBs) have been used as passive samplers to assess firefighters' exposures over the course of a shift but their utility in measuring short term exposures, source of exposure, and correlations with other measurements of exposure have not yet been investigated. In this study, SWBs were used to measure the concentrations of 16 priority PAHs inside and outside of firefighters' personal protective equipment (PPE) while firefighting. SWBs were placed on the wrist and jacket of 20 firefighters conducting live fire training. Correlations were made with matching data from a sister project that measured urinary concentrations of PAH metabolites and PAH concentrations from personal air samples from the same participants. Naphthalene, acenaphthylene and phenanthrene had the highest geometric mean concentrations in both jacket and wrist SWB, with 1040, 320, 180 ng/g SWB for jacket and 55.0, 4.9, and 6.0 ng/g SWB for wrist, respectively. Ratios of concentrations between the jacket and wrist SWBs were calculated as worker protection factors (WPFs) and averaged 40.1 for total PAHs and ranged from 2.8 to 214 for individual PAHs, similar to previous studies. Several significant correlations were observed between PAHs in jacket SWBs and air samples (e.g., total and low molecular weight PAHs, r = 0.55 and 0.59, p < 0.05, respectively). A few correlations were found between PAHs from SWBs worn on the wrist and jacket, and urinary concentrations of PAH metabolites and PAH concentrations in air samples. The ability of the SWBs to accurately capture exposures to various PAHs was likely influenced by short sampling time, high temperatures, and high turbulence. Future work should further examine the limitations of SWBs for PAH exposures in firefighting, and other extreme environments.

A prospective comparison of invasive and non-invasive blood pressure in children undergoing cardiac catheterization.

BACKGROUND: Blood pressure measurement is a standard of monitoring during general anesthesia. Invasive measurement is considered the gold standard but is less commonly used than non-invasive. Automated oscillometric blood pressure devices measure the mean arterial pressure (MAP) and use an algorithm to determine the systolic and diastolic pressures. Few devices have been validated in children, particularly during anesthesia. Few studies have assessed the agreement between invasive and non-invasive blood pressure measurements in children. METHODS: This was a multi-center prospective observational study of children under 16 years undergoing cardiac catheterization with general anesthesia. Paired invasive and non-invasive blood pressure measurements were recorded for each patient during stable periods of the procedure. Correlation within and between sites was assessed with Pearson's correlation coefficient, and agreement was examined using Bland-Altman methodology to determine bias. Agreement during episodes of hypotension and for age and weight was also determined. Bias greater than 5 mmHg and standard deviation greater than 8 mmHg was considered clinically significant. The primary end point was agreement of MAP measurements. RESULTS: A total of 683 paired blood pressure values were collected from 254 children in three pediatric hospitals. Median [IQR] age and weight were 3 [1-7] years and 13.9 [8-23] Kg. The overall bias (SD) for mean arterial pressure values was 7.2 (11.4) mmHg. During hypotension (190 readings), the bias (SD) was 15 (11.0) mmHg. The non-invasive MAP was frequently higher than invasive MAP during infancy, and lower in older children. CONCLUSION: Automated oscillometric blood pressure measurement is unreliable in anesthetized children during cardiac catheterization. Invasive pressure measurement should be considered for high-risk cases.

Evaluating the Efficacy of a Social Media-Based Intervention (Warna-Warni Waktu) to Improve Body Image Among Young Indonesian Women: Parallel Randomized Controlled Trial.

BACKGROUND: Body dissatisfaction is a global issue, particularly among adolescent girls and young women. Effective body image interventions exist but face barriers to scaling up, particularly in lower- and middle-income countries, such as Indonesia, where a need exists. OBJECTIVE: We aimed to evaluate the acceptability and efficacy of Warna-Warni Waktu, a social media-based, fictional 6-episode video series with self-guided web-based activities for improving body image among young Indonesian adolescent girls and young women. We hypothesized that Warna-Warni Waktu would increase trait body satisfaction and mood and decrease internalization of appearance ideals and skin shade dissatisfaction relative to the waitlist control condition. We also anticipated improvements in state body satisfaction and mood immediately following each video. METHODS: We conducted a web-based, 2-arm randomized controlled trial among 2000 adolescent girls and young women, aged 15 to 19 years, recruited via telephone by an Indonesian research agency. Block randomization (1:1 allocation) was performed. Participants and researchers were not concealed from the randomized arm. Participants completed self-report assessments of trait body satisfaction (primary outcome) and the internalization of appearance ideals, mood, and skin shade dissatisfaction at baseline (before randomization), time 2 (1 day after the intervention [T2]), and time 3 (1 month after the intervention [T3]). Participants also completed state body satisfaction and mood measures immediately before and after each video. Data were evaluated using linear mixed models with an intent-to-treat analysis. Intervention adherence was tracked. Acceptability data were collected. RESULTS: There were 1847 participants. Relative to the control condition (n=923), the intervention group (n=924) showed reduced internalization of appearance ideals at T2 (F1,1758=40.56, P<.001, partial η2=0.022) and T3 (F1,1782=54.03, P<.001, partial η2=0.03) and reduced skin shade dissatisfaction at T2 (F1,1744=8.05, P=.005, partial η2=0.005). Trait body satisfaction improvements occurred in the intervention group at T3 (F1, 1781=9.02, P=.005, partial η2=0.005), which was completely mediated by the internalization change scores between baseline and T2 (indirect effect: ß=.03, 95% CI 0.017-0.041; direct effect: ß=.03, P=.13), consistent with the Tripartite Influence Model of body dissatisfaction. Trait mood showed no significant effects. Dependent sample t tests (2-tailed) found each video improved state body satisfaction and mood. Cumulative analyses found significant and progressive improvements in pre- and poststate body satisfaction and mood. Intervention adherence was good; participants watched an average of 5.2 (SD 1.66) videos. Acceptability scores were high for understandability, enjoyment, age appropriateness, usefulness, and likelihood to recommend. CONCLUSIONS: Warna-Warni Waktu is an effective eHealth intervention to reduce body dissatisfaction among Indonesian adolescent girls and young women. Although the effects were small, Warna-Warni Waktu is a scalable, cost-effective alternative to more intense interventions. Initially, dissemination through paid social media advertising will reach thousands of young Indonesian women. TRIAL REGISTRATION: ClinicalTrials.gov NCT05383807, https://clinicaltrials.gov/ct2/show/NCT05383807 ; ISRCTN Registry ISRCTN35483207, https://www.isrctn.com/ISRCTN35483207. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/33596.

Outcomes from a community speech and language therapy service treatment waiting list: The natural history of 525 children with identified speech and language needs.

BACKGROUND: Understanding the natural history of developmental speech and language impairments can support the selection of children whose difficulties are persistent rather than transitory. It can also provide information against which the effectiveness of intervention can be evaluated. However, natural history data are difficult to collect ethically. Furthermore, as soon as an impairment is identified, the behaviour of those around changes, thus creating some level of intervention. Longitudinal cohort studies, where intervention is minimal, or the control arm of randomized trials have provided the best evidence. However, occasional opportunities arise where service waiting lists can provide data about the progress of children who have not received intervention. This natural history study arose within an ethnically diverse, community paediatric speech and language therapy service in the UK where levels of social disadvantage are high. AIMS: To identify (1) the characteristics of the children who attended initial assessment and were selected for treatment; (2) the differences between children who did and did not attend reassessment; and (3) the factors associated with outcomes. METHODS & PROCEDURES: A cohort of 545 children were referred and assessed as in need of therapy. Due to resource constraints, intervention was not available for an average of 12 months. Children were invited to attend for a reassessment of need. Initial and follow-up assessments were conducted by experienced clinicians using service guidelines and the Therapy Outcomes Measures Impairment Scale (TOM-I). Descriptive and multivariate regression analyses examined child outcomes for changes in communication impairment, demographic factors and length of wait. OUTCOMES & RESULTS: At initial assessment, 55% of children presented with severe and profound communication impairments. Children offered appointments at clinics in areas of high social disadvantage were less likely to attend reassessment. By reassessment, 54% of children showed spontaneous improvement (mean TOM-I rating change = 0.58). However, 83% were still judged to require therapy. Approximately 20% of children changed their diagnostic category. Age and impairment severity at initial assessment were the best predictors of continuing requirement for input. CONCLUSIONS & IMPLICATIONS: Although children do make spontaneous progress post-assessment and without intervention, it is likely that the majority will continue to be assigned case status by a Speech and Language Therapist. However, when evaluating the effectiveness of interventions, clinicians need to factor in the progress that a proportion of the caseload will make spontaneously. Services should be mindful that a lengthy wait may disproportionately impact children who already face health and educational inequalities. WHAT THIS PAPER ADDS: What is already known on the subject Data from longitudinal cohorts (where intervention has been minimal) and the no treatment control arms of randomized controlled trials have provided the best evidence of the natural progression of speech and language impairments in children. These studies provide a varied rate of resolution and progress depending on the case definitions and measurements used. What this study adds to existing knowledge Uniquely, this study has evaluated the natural history of a large cohort of children who had been waiting for treatment for up to 18 months. Data showed that, over a period of waiting for intervention, the majority of those identified as a case by a Speech and Language Therapist remained a case. Using the TOM, on average children in the cohort made just over half a rating point progress during their waiting period. What are the potential or actual clinical implications of this work? The maintenance of treatment waiting lists is probably an unhelpful service strategy for two reasons: first, the case status of the majority of the children is unlikely to change whilst they await intervention and thus children and their families are subjected to further limbo waiting time; second, the dropout from the waiting list may disproportionately affect children who are offered appointments in clinics where there are higher levels of social disadvantage, thus exacerbating inequalities in the system. Currently, a suggested reasonable outcome of intervention is a 0.5 rating change in one domain of TOMs. Study findings suggest this is insufficiently stringent for a paediatric community clinic caseload. There is a need to evaluate spontaneous improvement which may occur in other TOM domains (i.e., Activity, Participation and Wellbeing) and to agree an appropriate change metric for a community paediatric caseload.

An unusual case of a grade I meningioma with perineural spread.

A 39-year-old lady with worsening intermittent diplopia and headaches was diagnosed with a WHO Grade I Meningothelial Meningioma with highly unusual perineural spread on imaging, making this the first reported case of this behaviour. Complete surgical resection was deemed too great a risk and the patient remains under observation. The process of perineural spread is not restricted to more aggressive brain tumours.

To Bag or Not to Bag? How AudioMoth-Based Passive Acoustic Monitoring Is Impacted by Protective Coverings.

Bare board AudioMoth recorders offer a low-cost, open-source solution to passive acoustic monitoring (PAM) but need protecting in an enclosure. We were concerned that the choice of enclosure may alter the spectral characteristics of recordings. We focus on polythene bags as the simplest enclosure and assess how their use affects acoustic metrics. Using an anechoic chamber, a series of pure sinusoidal tones from 100 Hz to 20 kHz were recorded on 10 AudioMoth devices and a calibrated Class 1 sound level meter. The recordings were made on bare board AudioMoth devices, as well as after covering them with different bags. Linear phase finite impulse response filters were designed to replicate the frequency response functions between the incident pressure wave and the recorded signals. We applied these filters to ~1000 sound recordings to assess the effects of the AudioMoth and the bags on 19 acoustic metrics. While bare board AudioMoth showed very consistent spectral responses with accentuation in the higher frequencies, bag enclosures led to significant and erratic attenuation inconsistent between frequencies. Few acoustic metrics were insensitive to this uncertainty, rendering index comparisons unreliable. Biases due to enclosures on PAM devices may need to be considered when choosing appropriate acoustic indices for ecological studies. Archived recordings without adequate metadata may potentially produce biased acoustic index values and should be treated cautiously.

Effectiveness of dermal cleaning interventions for reducing firefighters' exposures to PAHs and genotoxins.

Firefighters are exposed to carcinogenic and mutagenic combustion emissions, including polycyclic aromatic hydrocarbons (PAHs). Fire service and firefighter cancer advocacy groups recommend skin cleaning using wipes or washing with detergent and water after exposure to smoke, although these strategies have not been proven to reduce exposures to harmful combustion products such as PAHs. This study assessed dermal decontamination methods to reduce PAH exposures by firefighters participating in live fire training scenarios. Study participants (n = 88) were randomly assigned to an intervention group (i.e., two types of commercial skin wipes, detergent and water, or a control group who did not use any skin decontamination). PAHs were measured in personal air (during the fire) and dermal wipe samples (before and after fire suppression and after dermal decontamination). PAH metabolites and mutagenicity were measured in urine samples before and after fire suppression. Airborne PAH concentrations during the fire ranged between 200 and 3,970 µg/m3 (mean = 759 µg/m3, SD = 685 µg/m3). Firefighters had higher total PAHs and high-molecular-weight PAHs on their skin after the fire compared to before (1.3- and 2.2-fold, respectively, p < 0.01). Urinary PAH metabolites increased significantly following exposure to the training fires by 1.7 to 2.2-fold (depending on the metabolite, p < 0.001). Urinary mutagenicity did not differ significantly between pre- and post-fire for any of the decontamination methods. Detergent and water was the only intervention that removed a significant amount of total PAHs from the skin (0.72 ng/cm2 preintervention vs. 0.38 ng/cm2 postintervention, p < 0.01). However, fold changes in urinary PAH metabolites (i.e., pre- vs. post-exposure levels) did not differ among any of the dermal decontamination methods or the control group. These data suggest that despite on-site attempts to remove PAHs from firefighters' skin, the examined interventions did not reduce the internal dose of PAHs. Future work should investigate preventing initial exposure using other interventions, such as improved personal protective equipment.