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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]

Pain and its effects in the neonatal period are complicated by the immaturity of many important physiological systems. Nociceptive sensory processing is considerably modified in early life such that the mechanisms and consequences of pain very much depend on developmental age, which has important implications for clinical management. The effective treatment of pain also requires an understanding of the substantial changes in pharmacokinetics and pharmacodynamics that are taking place at this time. It is now becoming clear that there may also be long-term consequences of pain that are due to the structural and functional reorganization of nociceptive pathways secondary to activity-dependent factors at this vulnerable time. [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]

Background: Although effects of general anesthesia on neuronal activity in the human neonatal brain are incompletely understood, electroencephalography provides some insight and may identify age-dependent differences., Methods: A systematic search (MEDLINE, Embase, PubMed, and Cochrane Library to November 2023) retrieved English language publications reporting electroencephalography during general anesthesia for cardiac or noncardiac surgery in term neonates (37 to 44 weeks postmenstrual age). Data were extracted, and risk of bias (ROBINS-I Cochrane tool) and quality of evidence (Grading of Recommendations Assessment, Development, and Evaluation [GRADE] checklist) were assessed., Results: From 1,155 abstracts, 9 publications (140 neonates; 55% male) fulfilled eligibility criteria. Data were limited, and study quality was very low. The occurrence of discontinuity, a characteristic pattern of alternating higher and lower amplitude electroencephalography segments, was reported with general anesthesia (94 of 119 neonates, 6 publications) and with hypothermia (23 of 23 neonates, 2 publications). Decreased power in the delta (0.5 to 4 Hz) frequency range was also reported with increasing anesthetic dose (22 neonates; 3 publications)., Conclusion: Although evidence gaps were identified, both increasing sevoflurane concentration and decreasing temperature are associated with increasing discontinuity., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

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.

Background: Age and sex differences may exist in the frequency (incidence, prevalence) or symptoms of neuropathic pain (NP) and complex regional pain syndrome (CRPS) due to biopsychosocial factors (eg, neurodevelopment, physiological and hormonal changes, psychosocial differences) that evolve through childhood and adolescence. Age and sex differences may have implications for evaluating screening and diagnostic tools and treatment interventions., Objective: To map the existing literature on pediatric NP and CRPS with respect to age and sex distributions, and age and sex differences in symptomology and frequency., Methods: A scoping literature review was conducted. Databases were searched from inception to January 2023. Data were collected on study design, setting, demographics, and age and sex differences in frequency and symptoms., Results: Eighty-seven studies were included. Distribution of participants with CRPS (n=37 studies) was predominantly early adolescence (10 to 14 y) and female sex, while NP (n=42 studies) was most commonly reported throughout adolescence (10 to 19 y) in both sexes. Forty-one studies examined age and sex differences in frequency; 6 studies reported higher frequency in adolescence. Very few studies (n=11) examined differences in symptomology., Discussion: Large epidemiological studies are required to further understand age and sex differences in frequency of pediatric NP and CRPS. Age and sex differences must be considered when evaluating screening and diagnostic tools and treatment interventions to ensure relevance and validity to both sexes and across ages. Validated tools will improve understanding of age-dependent and sex-dependent differences in symptoms, pathophysiology, and psychosocial impact of pediatric NP and CRPS., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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.