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Background: Systemic ketamine can trigger apoptosis in the brain of rodents and primates during susceptible developmental periods. Clinically, spinally administered ketamine may improve the duration or quality of analgesia in children. Ketamine-induced spinal cord toxicity has been reported in adult animals but has not been systematically studied in early development.Methods: In anesthetized rat pups, intrathecal ketamine was administered by lumbar percutaneous injection. Changes in mechanical withdrawal threshold evaluated dose-dependent antinociceptive and carrageenan-induced antihyperalgesic effects in rat pups at postnatal day (P) 3 and 21. After intrathecal injection of ketamine at P3, 7, or 21, spinal cords were examined for apoptosis (Fluoro-Jade C and activated caspase-3), histopathologic change, and glial responses (ionized calcium-binding adapter molecule 1 and glial fibrillary acid protein). After maximal doses of ketamine or saline at P3 or P21, sensory thresholds and gait analysis were evaluated at P35.Results: Intrathecal injection of 3 mg/kg ketamine at P3 and 15 mg/kg at P21 reverses carrageenan-induced hyperalgesia. Baseline neuronal apoptosis in the spinal cord was greater at P3 than P7, predominantly in the dorsal horn. Intrathecal injection of 3-10 mg/kg ketamine in P3 pups (but not 15 mg/kg at P21) acutely increased apoptosis and microglial activation in the spinal cord and altered spinal function (reduced mechanical withdrawal threshold and altered static gait parameters) at P35.Conclusions: Because acute pathology and long-term behavioral change occurred in the same dose range as antihyperalgesic effects, the therapeutic ratio of intrathecal ketamine is less than one in the neonatal rat. This measure facilitates comparison of the relative safety of spinally administered analgesic agents. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long-term function after intrathecal morphine in the neonatal rat.Methods: Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P) 3, 10, and 21. The relationship between injectate volume and segmental spread was assessed postmortem and by in vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 min after intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis, and glial response were evaluated 1 and 7 days after P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35.Results: Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally mediated analgesia at all ages with lower dose requirements in younger pups. High-dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function.Conclusions: The therapeutic ratio for intrathecal morphine (toxic dose/antinociceptive dose) was at least 300 at P3 and at least 20 at P21 (latter doses limited by side effects). These data provide relative efficacy and safety for comparison with other analgesic preparations and contribute supporting evidence for the validity of this preclinical neonatal safety model. [ABSTRACT FROM AUTHOR]

Cancer-induced bone pain (CIBP) is a major clinical problem with up to 85% of patients with bony metastases having pain, often associated with anxiety and depression, reduced performance status, and a poor quality of life. Malignant bone disease creates a chronic pain state through sensitization and synaptic plasticity within the spinal cord that amplifies nociceptive signals and their transmission to the brain. Fifty per cent of patients are expected to gain adequate analgesia from palliative radiotherapy within 4-6 weeks of treatment. Opioid analgesia does make a useful contribution to the management of CIBP, especially in terms of suppressing tonic background pain. However, CIBP remains a clinical challenge because the spontaneous and movement-related components are more difficult to treat with opioids and commonly used analgesic drugs, without unacceptable side-effects. Recently developed laboratory models of CIBP, which show congruency with the clinical syndrome, are contributing to an improved understanding of the neurobiology of CIBP. This chronic pain syndrome appears to be unique and distinct from other chronic pain states, such as inflammatory or neuropathic pain. This has clear implications for treatment and development of future therapies. A translational medicine approach, using a highly iterative process between the clinic and the laboratory, may allow improved understanding of the underlying mechanisms of CIBP to be rapidly translated into real clinical benefits in terms of improved pain management. [ABSTRACT FROM AUTHOR]

Significant advances in the assessment and management of acute pain in children have been made, and are supported by an increase in the availability and accessibility of evidence-based data. However, methodological and practical issues in the design and performance of clinical paediatric trials limit the quantity, and may influence the quality, of current data, which lags behind that available for adult practice. Collaborations within research networks, which incorporate both preclinical and clinical studies, may increase the feasibility and specificity of future trials. In early life, the developing nervous system responds differently to pain, analgesia, and injury, resulting in effects not seen in later life and which may have long-term consequences. Translational laboratory studies further our understanding of developmental changes in nociceptor pathway structure and function, analgesic pharmacodynamics, and the impact of different forms of injury. Chronic pain in children has a negative impact on quality of life, resulting in social and emotional consequences for both the child and the family. Despite age-related differences in many chronic pain conditions, such as neuropathic pain, management in children is often empirically based on data from studies in adults. There is a major need for further clinical research, training of health-care providers, and increased resources, to improve management and outcomes for children with chronic pain. [ABSTRACT FROM AUTHOR]

The aim of this prospective study of the use of transvaginal power Doppler ultrasound was to assess the subjectivity of the grading system and to elucidate, on a much larger series (200) of treatment cycles, the findings of previous authors. Vascular perfusion was studied using a grading system based on the percentage of follicular circumference (grade 1 < 25%, grade 2 < 50%, grade 3 < 75% and grade 4 > 75%) that depicted an echo signal. Interobserver variation was low (k = 0.81 + 0.08). A total of 1285 follicles were studied, of which 64% were of high (grades 3 or 4) and 36% were of low (grades 1 or 2) grade vascularity. Mean follicular diameter, oocyte retrieval rate, number of mature oocytes recovered and fertilization rates were all significantly higher (P < 0.05) and triploidy rate significantly lower (P < 0.05) from the cohort of follicles with high grade vascularity. There was no correlation between embryo morphology and vascularity grade. The pregnancy rate for cycles where the embryos transferred were derived from follicles with uniformly high grade (3 or 4 only) vascularity was significantly higher than for those cycles where the embryos transferred were derived from mixed (1 to 4) or low (1 or 2 only) grade follicles [24/72 (34.7%) versus 22/122 (18%); P < 0.05]. There were no significant differences in uterine artery or intraovarian pulsatility index values between the pregnant and non-pregnant treatment cycles. This study suggests that follicles with high grade vascularity are associated with better outcome variables. Thus, follicular assessment may be used prospectively to improve the outcome in in-vitro fertilization treatment cycles. [ABSTRACT FROM AUTHOR]

1. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium-99m DTPA was followed by gamma scintigraphy, and the corresponding plasma drug concentration-time profiles after oral and i.v. administration were used to relate pharmacokinetic and transit data. 2. Gastric emptying time (0.8 +/- 0.4 h, mean +/- s.d.), and the time to arrival in the colon (3.8 +/- 0.7 h) were reasonably consistent after administration of the Oros system to fasted subjects, as were the calculated small intestine transit times (3.0 +/- 0.7 h). As expected there were wide individual variations in colonic transit, so that recorded values for total transit ranged from 6 to 32 h (median, 24.7 h). 3. Absorption of oxprenolol occurred throughout the GI tract including the colon. Plasma drug concentration-time profiles and input functions (calculated by deconvolution) could be related to transit behaviour and in vitro release. Inflexions in the calculated rate of drug input when the Oros system was located in the colon corresponded with periods of stagnation at the hepatic and splenic flexures in two subjects and the ileocaecal junction in two others. The mechanism of these changes is unclear. [ABSTRACT FROM AUTHOR]

The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRps) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus and human metapneumovirus incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses., Competing Interests: Conflict of interest M. G. received funding from Gilead Sciences in support for studies on the mechanism of action of nucleotide analog polymerase inhibitors. J. P., D. S. S., J. K. P., J. Y. F., and J. P. B. are current or former Gilead employees., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/Objectives : This retrospective case series analyzed visual outcomes in patients with a prior history of implantable collamer lens (ICL) implantation who underwent cataract extraction (CE). A secondary aim was to investigate the relationship between vault height and the rate of cataract development. Methods : Visual acuity and refraction measurements were collected after CE at one week, one month and six months. Vault height measurements were correlated to the time until symptomatic cataracts were removed. Results : A total of 44 eyes were analyzed at six months after CE with efficacy and safety indexes of 1.20 ± 1.11 and 1.50 ± 1.06, respectively. In addition, 70% of eyes had a post-operative uncorrected distance visual acuity (UDVA) within one line of pre-operative corrected distance visual acuity (CDVA). Refractive predictability at six months demonstrated that 43% and 69% of eyes were within ±0.25 D and ±0.50 D of SEQ target, respectively. Astigmatism measured by refractive cylinder was ≤0.25 D in 17% and ≤0.50 D in 34% of eyes pre-operatively compared to 40% and 60% of eyes, respectively, at six months post-operatively. Vault heights one week after ICL ( p < 0.0081) and one week before CE ( p < 0.0154) demonstrated a positive linear regression with the time until CE. Conclusions : This sample population achieved favorable visual outcomes six months after CE, similar to six months after ICL implantation. Patients with a history of ICL implantation will similarly have a good visual prognosis after CE.

STAT5B has been reported as a recurrent mutation in myeloid neoplasms with eosinophilia, but its overall frequency and importance across a spectrum of myeloid neoplasms are largely unknown. We conducted a multicenter study on a series of 82 myeloid neoplasms with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutations in myeloid neoplasms was low, <0.5%, but mutations were detected in all categories of such neoplasms, including myelodysplastic syndrome (MDS, 28%), acute myeloid leukemia (AML, 26%), myelodysplastic/myeloproliferative neoplasm (MDS/MPN, 18%), Philadelphia chromosome-negative classic MPN (12%), systemic mastocytosis (1%), and, with a notably high frequency, chronic eosinophilic leukemia, not otherwise specified (CEL-NOS, 15%). STAT5B mutations occurred preferentially in the SH2 domain (95%), involved 12 different codons, with the N642H hotspot being the most common (78%). Co-mutations were present in all cases and clonal hierarchy analysis showed that STAT5B mutations tended to be subclonal in AML, MPN, and MDS, but frequently dominant/co-dominant in CEL-NOS (83%), followed by MDS/MPN (40%). Across the group, eosinophilia and/or basophilia were common (41%), frequently observed in cases in which STAT5B mutations were detected at initial diagnosis (P<0.0001), with a high variant allele frequency (median 42.5%, P=0.0001), as a dominant/ co-dominant clone (P<0.0001), involving the canonical N642H (P=0.0607), and associated with fewer co-mutations (P=0.0009). Our data show that the characteristics and importance of a STAT5B mutation differ among myeloid neoplasms, but if present as a dominant mutation and detected at initial diagnosis, it appears to be a driver mutation in a subgroup of chronic myeloid neoplasms, preferentially promoting a proliferation of eosinophils and basophils.

Since industrialization began, atmospheric CO2 ([CO2]) has increased from 270 to 415 ppm and is projected to reach 800-1000 ppm this century. Some Arabidopsis thaliana (Arabidopsis) genotypes delayed flowering in elevated [CO2] relative to current [CO2], while others showed no change or accelerations. To predict genotype-specific flowering behaviors, we must understand the mechanisms driving flowering response to rising [CO2]. [CO2] changes alter photosynthesis and carbohydrates in plants. Plants sense carbohydrate levels, and exogenous carbohydrate application influences flowering time and flowering transcript levels. We asked how organismal changes in carbohydrates and transcription correlate with changes in flowering time under elevated [CO2]. We used a genotype (SG) of Arabidopsis that was selected for high fitness at elevated [CO2] (700 ppm). SG delays flowering under elevated [CO2] (700 ppm) relative to current [CO2] (400 ppm). We compared SG to a closely related control genotype (CG) that shows no [CO2]-induced flowering change. We compared metabolomic and transcriptomic profiles in these genotypes at current and elevated [CO2] to assess correlations with flowering in these conditions. While both genotypes altered carbohydrates in response to elevated [CO2], SG had higher levels of sucrose than CG and showed a stronger increase in glucose and fructose in elevated [CO2]. Both genotypes demonstrated transcriptional changes, with CG increasing genes related to fructose 1,6-bisphosphate breakdown, amino acid synthesis, and secondary metabolites; and SG decreasing genes related to starch and sugar metabolism, but increasing genes involved in oligosaccharide production and sugar modifications. Genes associated with flowering regulation within the photoperiod, vernalization, and meristem identity pathways were altered in these genotypes. Elevated [CO2] may alter carbohydrates to influence transcription in both genotypes and delayed flowering in SG. Changes in the oligosaccharide pool may contribute to delayed flowering in SG. This work extends the literature exploring genotypic-specific flowering responses to elevated [CO2]., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The majority of natural products utilized to treat a diverse array of human conditions and diseases are derived from terrestrial sources. In recent years, marine ecosystems have proven to be a valuable resource of diverse natural products that are generated to defend and support their growth. Such marine sources offer a large opportunity for the identification of novel compounds that may guide the future development of new drugs and therapies. Using the National Oceanic and Atmospheric Administration (NOAA) portal, we explore deep-sea coral and sponge species inhabiting a segment of the U.S. Exclusive Economic Zone, specifically off the western coast of Florida. This area spans ~100,000 km 2 , containing coral and sponge species at sea depths up to 3000 m. Utilizing PubMed, we uncovered current knowledge on and gaps across a subset of these sessile organisms with regards to their natural products and mechanisms of altering cytoskeleton, protein trafficking, and signaling pathways. Since the exploitation of such marine organisms could disrupt the marine ecosystem leading to supply issues that would limit the quantities of bioactive compounds, we surveyed methods and technological advances that are necessary for sustaining the drug discovery pipeline including in vitro aquaculture systems and preserving our natural ecological community in the future. Collectively, our efforts establish the foundation for supporting future research on the identification of marine-based natural products and their mechanism of action to develop novel drugs and therapies for improving treatment regimens of human conditions and diseases.

The aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine the prevalence of known pathogenic variants and to understand the relationship between pathogenic variants and clinical presentation. Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK and underwent whole genome sequencing as part of the National Institute for Health and Care Research Bioresource Rare Diseases project. A multidisciplinary team assessed the pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels. The results include the following: (i) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: SCN9A(ENST00000409672.1): c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and SPTLC1(ENST00000262554.2): c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1. (ii) Clinically relevant variants were most common in voltage-gated sodium channels (Na v ). (iii) SCN9A(ENST00000409672.1): c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls and causes a gain of function of Na V 1.7 after cooling (the environmental trigger for non-freezing cold injury). (iv) Rare variant association testing showed a significant difference in distribution for genes NGF, KIF1A , SCN8A , TRPM8 , KIF1A , TRPA1 and the regulatory regions of genes SCN11A , FLVCR1 , KIF1A and SCN9A between European participants with neuropathic pain and controls. (v) The TRPA1(ENST00000262209.4):c.515C>T, p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain-of-channel function to agonist stimulation. Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to a better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain-of-function Na V 1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction The allied health workforce is a crucial, if at times poorly visible, component of modern healthcare systems. The services provided by allied health professionals may be particularly important for underserved populations, including rural and remote communities. Aim To determine what is currently known through research about the allied health workforce in rural Aotearoa New Zealand. Method A scoping review of diverse sources of literature from Aotearoa New Zealand was obtained from seven databases (July 2011-July 2021). Results Eighty-nine articles were identified, of which 10 met the inclusion criteria; nine empirical studies and one narrative review. The included research fell into two main categories: geographic workforce distribution (n  = 8), and the role of the rural allied health workforce (n  = 2). Discussion The paucity of research that meets the criteria for inclusion makes it difficult to draw conclusions about the allied health workforce in rural Aotearoa New Zealand. There is a focus in both the international rural allied health literature and the Aotearoa New Zealand rural medical and nursing literature on: measuring geographic workforce distribution; and rural-specific training. This suggests that these issues are important to the rural workforce. Similar research is needed in Aotearoa New Zealand to inform policy and ensure the rural allied health workforce reaches its full potential in improving health outcomes for rural New Zealanders.

Male mosquitoes detect and localize conspecific females by their flight-tones using the Johnston's organ (JO), which detects antennal deflections under the influence of local particle motion. Acoustic behaviours of mosquitoes and their JO physiology have been investigated extensively within the frequency domain, yet the auditory sensory range and the behaviour of males at the initiation of phonotactic flights are not well known. In this study, we predict a maximum spatial sensory envelope for flying Culex quinquefasciatus by integrating the physiological tuning response of the male JO with female aeroacoustic signatures derived from numerical simulations. Our sensory envelope predictions were tested with a behavioural assay of free-flying males responding to a female-like artificial pure tone. The minimum detectable particle velocity observed during flight tests was in good agreement with our theoretical prediction formed by the peak JO sensitivity measured in previous studies. The iso-surface describing the minimal detectable particle velocity represents the quantitative auditory sensory range of males and is directional with respect to the female body orientation. Our results illuminate the intricacy of the mating behaviour and point to the importance of observing the body orientation of flying mosquitoes to understand fully the sensory ecology of conspecific communication.

Background: There is evidence of altered corticolimbic circuitry in adults with chronic pain, but relatively little is known of functional brain mechanisms in adolescents with neuropathic pain (NeuP). Pediatric NeuP is etiologically and phenotypically different from NeuP in adults, highlighting the need for pediatric-focused research. The amygdala is a key limbic region with important roles in the emotional-affective dimension of pain and in pain modulation., Objective: To investigate amygdalar resting state functional connectivity (rsFC) in adolescents with NeuP., Methods: This cross-sectional observational cohort study compared resting state functional MRI scans in adolescents aged 11-18 years with clinical features of chronic peripheral NeuP ( n = 17), recruited from a tertiary clinic, relative to healthy adolescents ( n = 17). We performed seed-to-voxel whole-brain rsFC analysis of the bilateral amygdalae. Next, we performed post hoc exploratory correlations with clinical variables to further explain rsFC differences., Results: Adolescents with NeuP had stronger negative rsFC between right amygdala and right dorsolateral prefrontal cortex (dlPFC) and stronger positive rsFC between right amygdala and left angular gyrus (AG), compared to controls (P FDR <0.025). Furthermore, lower pain intensity correlated with stronger negative amygdala-dlPFC rsFC in males ( r = 0.67, P = 0.034, n = 10), and with stronger positive amygdala-AG rsFC in females ( r = -0.90, P = 0.006, n = 7). These amygdalar rsFC differences may thus be pain inhibitory., Conclusions: Consistent with the considerable affective and cognitive factors reported in a larger cohort, there are rsFC differences in limbic pain modulatory circuits in adolescents with NeuP. Findings also highlight the need for assessing sex-dependent brain mechanisms in future studies, where possible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Verriotis, Sorger, Peters, Ayoub, Seunarine, Clark, Walker and Moayedi.)

Background: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer., Methods: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures., Results: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression., Conclusions: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming., Trial Registration: Not applicable (non-interventional study). CRUK Internal Database Number 14232., (© 2021. The Author(s).)

The objective was to undertake an early cost-effectiveness assessment of valoctocogene roxaparvovec (valrox; Roctavian) compared to factor (F)VIII prophylaxis or emicizumab (Hemlibra; Roche HQ, Bazel, Switzerland) in patients with severe Hemophilia A (HA) without FVIII-antibodies. We also aimed to incorporate and quantify novel measures of value such as treatment durability, maximum value-based price (MVBP) and break-even time (ie, time until benefits begin to offset upfront payment). We constructed a Markov model to model bleeds over time which were linked to costs and quality-of-life decrements. In the valrox arm, FVIII over time was estimated combining initial effect and treatment waning and then linked to bleeds. In FVIII and emicizumab arms, bleeds were based on trial evidence. Evidence and assumptions were validated using expert elicitation. Model robustness was tested via sensitivity analyses. A Dutch societal perspective was applied with a 10-year time horizon. Valrox in comparison to FVIII, and emicizumab showed small increases in quality-adjusted life years at lower costs, and were therefore dominant. Valrox' base case MVBP was estimated at €2.65 million/treatment compared to FVIII and €3.5 million/treatment versus emicizumab. Mean break-even time was 8.03 years compared to FVIII and 5.68 years to emicizumab. Early modeling of patients with HA in The Netherlands treated with valrox resulted in estimated improved health and lower cost compared to prophylactic FVIII and emicizumab. We also demonstrated feasibility of incorporation of treatment durability and novel outcomes such as value-based pricing scenarios and break-even time. Future work should aim to better characterize uncertainties and increase translation of early modeling to direct research efforts., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Understanding mechanisms that underly the transition from acute to chronic pain and identifying potential targets for preventing or minimizing this progression have specific relevance for chronic postsurgical pain (CPSP). Though it is clear that multiple psychosocial, family, and environmental factors may influence CPSP, this review will focus on parallels between clinical observations and translational laboratory studies investigating the acute and long-term effects of surgical injury on nociceptive pathways. This includes data related to alterations in sensitivity at different points along nociceptive pathways from the periphery to the brain; age- and sex-dependent mechanisms underlying the transition from acute to persistent pain; potential targets for preventive interventions; and the impact of prior surgical injury. Ongoing preclinical studies evaluating age- and sex-dependent mechanisms will also inform comparative efficacy and preclinical safety assessments of potential preventive pharmacological interventions aimed at reducing the risk of CPSP. In future clinical studies, more detailed and longitudinal peri-operative phenotyping with patient- and parent-reported chronic pain core outcomes, alongside more specialized evaluations of somatosensory function, modulation, and circuitry, may enhance understanding of individual variability in postsurgical pain trajectories and improve recognition and management of CPSP., Competing Interests: No potential conflict of interest was reported by the author., (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management., Methods: We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma., Results: Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice., Conclusions: Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies., Competing Interests: Conflict of interest: J. Busby has nothing to disclose. Conflict of interest: J.G. Matthews has nothing to disclose. Conflict of interest: R. Chaudhuri reports grants, personal fees for advisory board work and nonfinancial support for meeting attendance from AstraZeneca, personal fees for advisory board work from GlaxoSmithKline and Novartis, personal fees for advisory board work and nonfinancial support for meeting attendance from Chiesi, nonfinancial support for meeting attendance from Napp Pharmaceuticals, outside the submitted work. Conflict of interest: I.D. Pavord reports personal fees for lectures, advisory board honoraria, sponsorship to attend scientific meetings, and payments for organising educational events from AstraZeneca, personal fees for lectures, advisory board honoraria, and sponsorship to attend scientific meetings from Boehringer Ingelheim and GlaxoSmithKline, personal fees for lectures from Aerocrine and Chiesi, personal fees for lectures and advisory board honoraria from Almirall and Novartis, advisory board honoraria from Genentech, Regeneron, Sanofi, Circassia and Knopp, personal fees for lectures, payments for organising educational events, and sponsorship to attend scientific meetings from Teva, grants from the National Institute for Health Research, outside the submitted work. Conflict of interest: T.C. Hardman has nothing to disclose. Conflict of interest: J.R. Arron has patents “Diagnosis and treatments relating to Th2 inhibition” (US 9,684,000 B2) and “Diagnosis and treatments relating to Th2 inhibition” (US 9,995,755 B2) issued with rights assigned to Genentech, a member of the Roche group, and is an employee of Genentech, Inc. and owns stocks/options in the Roche group. Conflict of interest: P. Bradding reports grants from Genentech, other (consultancy work on behalf of the University of Leicester) from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: C.E. Brightling reports grants and personal fees from GlaxoSmithKline, AstraZeneca, Sanofi, Novartis, Chiesi, Genentech, Gossamer, Mologic and 4D Pharma, all paid to the institution and outside the submitted work. Conflict of interest: D.F. Choy is an employee of Genentech, Inc. and owns stocks/options in the Roche group. Conflict of interest: D.C. Cowan has nothing to disclose. Conflict of interest: R. Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and Teva, consultation for Teva and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline; he is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin-out company. Conflict of interest: C.E. Hanratty has nothing to disclose. Conflict of interest: T.W. Harrison reports grants, personal fees and nonfinancial support from AstraZeneca, grants and personal fees from GlaxoSmithKline, personal fees from Vectura, Synairgen and Chiesi, outside the submitted work. Conflict of interest: C.T. Holweg is an employee and stock owner of Genentech Inc., a member of the Roche Group, outside the submitted work. Conflict of interest: P.H. Howarth reports employment by GlaxoSmithKline. Conflict of interest: S.J. Fowler reports personal fees for lectures and support to attend an international conference from AstraZeneca, grants and personal fees for lectures from Boehringer Ingelheim, personal fees for lectures, participation in an advisory board, and support to attend an national conference from Chiesi, personal fees for lectures from GlaxoSmithKline, Novartis and Teva, outside the submitted work. Conflict of interest: J.L. Lordan has nothing to disclose. Conflict of interest: A.H. Mansur reports personal and institution payment for talks, advisory board meetings, sponsorship to attend conferences and education grants for service developments from GlaxoSmithKline, AstraZeneca, Novartis, Sanofi, Teva and others, outside the submitted work. Conflict of interest: A. Menzies-Gow reports grants and personal fees from AstraZeneca, personal fees from Novartis, GlaxoSmithKline, Sanofi and Vectura, personal fees and nonfinancial support from Teva and Boehringer Ingelheim, outside the submitted work. Conflict of interest: R.M. Niven has received lecture fees, advisory board activity and been supported to attend international meetings/conferences in the last 5 years by the following companies: AstraZeneca, Boehringer, Boston Scientific, Chiesi, Napp, Novartis and Teva. None of these have any relevance to the manuscript; R.M. Niven owns no shares or stocks and is not personally or in any family way connected to any pharmaceutical companies. Conflict of interest: D.S. Robinson has nothing to disclose. Conflict of interest: S.M. Walker has nothing to disclose. Conflict of interest: A. Woodcock reports personal fees for lectures from GlaxoSmithKline, personal fees for lectures and consultancy from Novartis, personal fees for consultancy from Chiesi, other (chairing research projects) from Reacta Biotech, Axalbion and Medicines Evaluation Unit, outside the submitted work. Conflict of interest: L.G. Heaney reports other (sponsorship for meeting attendance) from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline and Napp Pharmaceutical, personal fees for lectures and advisory board work from Novartis, Hoffman la Roche/Genentech Inc., Sanofi, GlaxoSmithKline, AstraZeneca, Teva, Theravance and Circassia, grants from Medimmune, Novartis UK, Roche/Genentech Inc., and GlaxoSmithKline, and is academic lead for the Medical Research Council Stratified Medicine UK Consortium in severe asthma, which involves industrial partnerships with Amgen, Genentech/Hoffman la Roche, AstraZeneca, Medimmune, GlaxoSmithKline, Aerocrine and Vitalograph, outside the submitted work., (Copyright ©The authors 2022.)