How to differentiate induced pluripotent stem cells into sensory neurons for disease modelling: a functional assessment.

BACKGROUND: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic disorders. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs remain key challenges to study human nociception in vitro. Here, we report a detailed functional characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Anatomic's commercially available RealDRG™ were further characterized for both functional and expression phenotyping of key nociceptor markers. METHODS: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Manual patch clamp was used to functionally characterize both control and patient-derived neurons. High throughput techniques were further used to demonstrate that RealDRGs™ derived from the Anatomic protocol are amenable to high throughput technologies for disease modelling. RESULTS: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. Chambers protocol results in predominantly tonic firing when compared to Anatomic protocol. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. RealDRG™ sensory neurons show heterogeneity of nociceptive markers indicating that the cells may be useful as a humanized model system for translational studies. CONCLUSIONS: We validated the efficiency of two differentiation protocols and their potential application for functional assessment and thus understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.

Acute and Long-Term Changes in Blood-Borne Biomarkers in Response to Dynamic Standing in Nonambulant Children With Cerebral Palsy.

PURPOSE: To investigate acute and long-term changes in hormonal and inflammatory biomarkers in nonambulant children with cerebral palsy in response to dynamic standing exercise. METHODS: Fourteen children with severe cerebral palsy were recruited. Anthropometrics and body composition measures were obtained. Physical activity levels before the study were assessed using hip-worn accelerometry. All children underwent a 30-minute dynamic standing exercise using the Innowalk standing aid. Respiratory data during exercise were collected using indirect calorimetry. Blood samples were collected before and after exercise. Blood samples were also obtained after two 16-week exercise protocols, in a resting state. Hormonal and inflammatory metabolites were measured from blood serum/plasma, and acute and long-term changes in biomarker levels were assessed using Wilcoxon signed-rank tests. RESULTS: Of the 14 children at baseline, all had slightly/moderately/severely elevated C-reactive protein and cortisol levels. C-reactive protein levels were decreased following a 30-minute bout of dynamic standing (before exercise: 53 mg/L [interquartile range: 40-201]; after exercise: 39 mg/L [interquartile range: 20-107]; P = .04). CONCLUSIONS: We show that several hormonal and inflammatory biomarkers are dysregulated in children with cerebral palsy. Our preliminary results from a small, but deep-phenotyped prospective cohort indicate acute and long-term alterations of several biomarkers in response to exercise.

How to differentiate induced pluripotent stem cells into sensory neurons for disease modelling: a comparison of two protocols.

Background: Human induced pluripotent stem cell (iPSC)-derived peripheral sensory neurons present a valuable tool to model human diseases and are a source for applications in drug discovery and regenerative medicine. Clinically, peripheral sensory neuropathies can result in maladies ranging from a complete loss of pain to severe painful neuropathic symptoms. Sensory neurons are located in the dorsal root ganglion and are comprised of functionally diverse neuronal types. Low efficiency, reproducibility concerns, variations arising due to genetic factors and time needed to generate functionally mature neuronal populations from iPSCs for disease modelling remain key challenges to study human nociception in vitro. Here, we report a detailed characterization of iPSC-derived sensory neurons with an accelerated differentiation protocol ("Anatomic" protocol) compared to the most commonly used small molecule approach ("Chambers" protocol). Methods: Multiple iPSC clones derived from different reprogramming methods, genetics, age, and somatic cell sources were used to generate sensory neurons. Expression profiling of sensory neurons was performed with Immunocytochemistry and in situ hybridization techniques. Manual patch clamp and high throughput cellular screening systems (Fluorescence imaging plate reader, automated patch clamp and multi-well microelectrode arrays recordings) were applied to functionally characterize the generated sensory neurons. Results: The Anatomic protocol rendered a purer culture without the use of mitomycin C to suppress non-neuronal outgrowth, while Chambers differentiations yielded a mix of cell types. High throughput systems confirmed functional expression of Na+ and K+ ion channels. Multi-well microelectrode recordings display spontaneously active neurons with sensitivity to increased temperature indicating expression of heat sensitive ion channels. Patient-derived nociceptors displayed higher frequency firing compared to control subject with both, Chambers and Anatomic differentiation approaches, underlining their potential use for clinical phenotyping as a disease-in-a-dish model. Conclusions: We validated the efficiency of two differentiation protocols and their potential application for understanding the disease mechanisms from patients suffering from pain disorders. We propose that both differentiation methods can be further exploited for understanding mechanisms and development of novel treatments in pain disorders.

Cerebrovascular Hemodynamics in Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Transcranial Doppler Studies.

INTRODUCTION: Transcranial Doppler (TCD) sonography is a noninvasive tool for measuring cerebrovascular hemodynamics. Studies have reported alterations in cerebrovascular hemodynamics in normal aging, mild cognitive impairment (MCI), and dementia, as well as in different etiologies of dementia. This systematic review and meta-analysis was designed to investigate the relationship between cerebral blood velocity (CBv) and pulsatility index (PI) in the middle cerebral artery (MCA) in persons with MCI and dementia. METHODS: A systematic literature search was conducted in Pubmed, Embase, Cochrane Library, Epistemonikos, PsychINFO, and CINAHL. The search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. After screening of 33,439 articles, 86 were reviewed in full-text, and 35 fulfilled the inclusion criteria. RESULTS: CBv was significantly lower and PI significantly higher in MCA in vascular dementia (VaD) and Alzheimer's disease (AD) compared to cognitively normal (CN) older persons. Also, CBv was lower in MCI compared to CN. There were no significant differences in CBv in MCA in AD compared with VaD, although PI was higher in VaD compared to AD. CONCLUSION: Alterations in cerebrovascular hemodynamics are seen in AD, VaD, and MCI. While PI was slightly higher in VaD compared to AD, the reduction in CBv appears to be equally pronounced across neurodegenerative and vascular etiologies of dementia.

Self-assembly of alkylated lysine-dendron oxytocin amphiphiles for enhanced stability and sustained pharmacological activity.

Herein, we designed alkylated lysine-dendron oxytocin amphiphiles (ALOAs) 1G-OTK and 2G-OTK, which were self-assembled into spherical nanoparticles and nanostrips, respectively, and showed superior stability compared to native oxytocin. We found similar trends in the functional activity of ALOAs and native OT for human oxytocin receptor. This work may inspire the development of peptide drugs for clinical applications.

Functional outcome in patients with hip fracture from 2008 to 2018, and the significance of hand-grip strength - a cross-sectional comparative study.

BACKGROUND: Incidence of hip fracture is estimated to rise, increasing demands on healthcare. Our objective was to compare patients with hip fracture, a decade apart, regarding surgical characteristics and functional outcome in relation to morbidity. A secondary aim was to analyse postoperative hand-grip strength (HGS) in relation to walking ability 4 months postoperatively. METHODS: This is a cross-sectional comparative study of patients with hip fracture, included in 2008 (n = 78) and 2018 (n = 76) at Örebro University Hospital. Patient-data (age, gender, morbidity, fall-circumstances, fracture, surgical characteristics, and length of stay) were collected from medical records. HGS was measured postoperatively. Data on functional outcome in terms of housing, walking ability and need of walking aids at 4 months postoperatively was collected from the Swedish Hip Fracture Register RIKSHÖFT. Statistical analyses adapted were hypothesis tests and regression analysis. RESULTS: Patients in 2018 presented a significantly higher morbidity than patients in 2008 and there were significant differences in adapted surgical methods. Functional outcome at 4-months postoperatively was analysed by logistic regression where Cohort 2018 was associated with higher odds of independent walking ability (OR 5.7; 95%CI 1.9-17.2) and not needing any walking aids (OR 5.1; 95%CI 1.9-17.2). Postoperative HGS was higher among patients in 2018 and a multiple regression analysis revealed a significant association between HGS and walking ability at 4 months postoperatively. CONCLUSIONS: This study supports the since previously reported development in hip fracture surgery in Sweden while also presenting that functional outcome seems to have improved despite a concomitant increase in morbidity. Results suggest an improvement in postoperative HGS, predicting walking ability at 4 months postoperatively.

'Working outside the box'-an interview study regarding manipulation of medicines with registered nurses and pharmacists at a Swedish paediatric hospital.

AIM: Studies on frequencies of manipulated medicines in paediatric care are common, but there is little knowledge of experiences of pharmacists and registered nurses in this area. The aim of this study was to explore registered nurses' and pharmacists' reasoning in the manipulation of medicines to paediatric inpatients. METHODS: Semistructured interviews with twelve registered nurses and seven pharmacists were performed at a Swedish paediatric university hospital. The interviews were transcribed verbatim and analysed using content analysis. RESULTS: Four major categories emerged from the analysis of the interviews: medicines management, knowledge, consulting others and organisation. Medicines management involved the process of drug handling, which is prescribing, reconstitution or manipulation and administration. Knowledge concerned both the knowledge base and how healthcare personnel seek information. Consulting others involved colleagues, registered nurses and pharmacists, between registered nurses, pharmacists and physicians and between registered nurses, pharmacists and caregivers. Organisation covered documentation, time and working environment. CONCLUSION: Both pharmacists and registered nurses stated that manipulation of medicines to paediatric patients was often necessary but felt unsafe due to lack of supporting guidelines. Pharmacists were natural members of the ward team, contributing with specific knowledge about medicines and formulations.

GRIN1 variants associated with neurodevelopmental disorders reveal channel gating pathomechanisms.

OBJECTIVE: N-methyl-d-aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor, are associated with severe neurological disorders that include epilepsy, intellectual disability, and developmental delay. Here, we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val (GluN1-3b[I481V]), p.Ala666Ser (GluN1-3b[A666S]), and p.Tyr668His (GluN1-3b[Y668H]). METHODS: Wild-type and variant-containing NMDA receptors were expressed in HEK293 cells and primary hippocampal neurons. Patch-clamp electrophysiology and pharmacology were used to profile the functional properties of the receptors. Receptor surface expression was evaluated using fluorescently tagged receptors and microscopy. RESULTS: Our data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers ketamine and memantine with reduce potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain-of-function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK-801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude, and exhibited impaired block by extracellular magnesium ions, memantine, ketamine, and MK-801. These variant receptors were also activated by either glutamate or glycine alone. Single-receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild-type GluN1/2A receptors. SIGNIFICANCE: Our study reveals a critical functional locus of the receptor (GluN1[Y668]) that couples receptor gating to ion channel conductance, which when mutated may be associated with neurological disorder.

Frequency of paediatric patients administered extemporaneous preparations at a Swedish university hospital: a registry-based study comparing two study-years, 10 years apart.

BACKGROUND: Lack of child-friendly dosage forms and strengths often leads to manipulation of medicines at hospital units or by caregivers in the home setting. One alternative to manipulating dosage forms is the use of extemporaneous preparations. In Sweden, these are produced according to good manufacturing practice by a few extemporaneous pharmacies. OBJECTIVES: To compare frequencies of patients administered extemporaneous preparations in two separate years, 10 years apart. METHODS: This registry-based study describes and compares the frequency of extemporaneous oral preparations administered to paediatric patients in 2009 and 2019 at a Swedish university hospital.The study included 117 023 oral administrations (to 4905 patients) and 128 638 oral administrations (to 4718 patients) from 2009 and 2019, respectively. RESULTS: The frequency of inpatients administered one or more extemporaneous preparations increased from 22% in 2009 to 40% in 2019 (p<0.0001). The increase was observed in all age groups. The use of some active pharmaceutical ingredients increased (eg, captopril, clonidine, hydrocortisone, melatonin and propranolol), and some active pharmaceutical ingredients decreased between the study years (eg, midazolam and sildenafil). CONCLUSIONS: The introduction of new authorised products has decreased the need for manipulation or extemporaneous preparations in some therapeutic groups. There remains, however, a pronounced lack of commercially available child-friendly dosage forms and suitable strengths enabling safe administration of medicines to children, indicated by the large percentage of patients receiving at least one extemporaneous preparation.

A Chemoenzymatic Approach To Produce a Cyclic Analogue of the Analgesic Drug MVIIA (Ziconotide).

Ziconotide (ω-conotoxin MVIIA) is an approved analgesic for the treatment of chronic pain. However, the need for intrathecal administration and adverse effects have limited its widespread application. Backbone cyclization is one way to improve the pharmaceutical properties of conopeptides, but so far chemical synthesis alone has been unable to produce correctly folded and backbone cyclic analogues of MVIIA. In this study, an asparaginyl endopeptidase (AEP)-mediated cyclization was used to generate backbone cyclic analogues of MVIIA for the first time. Cyclization using six- to nine-residue linkers did not perturb the overall structure of MVIIA, and the cyclic analogues of MVIIA showed inhibition of voltage-gated calcium channels (CaV 2.2) and substantially improved stability in human serum and stimulated intestinal fluid. Our study reveals that AEP transpeptidases are capable of cyclizing structurally complex peptides that chemical synthesis cannot achieve and paves the way for further improving the therapeutic value of conotoxins.

Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function.

Voltage-gated sodium (NaV) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived NaV channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons.

Traditional compared to modified method of disinfection before hip fracture surgery - Experiences of nursing personnel.

BACKGROUND: National guidelines in Sweden recommend preoperative full-body disinfection (FBD) with 4% chlorhexidine to prevent surgical-site infection (SSI) after hip fracture surgery, a method causing patients' severe pain. Although, due to little evidence in research, orthopedic clinics in Sweden are wavering in favor of simpler methods such as local disinfection (LD) of the surgical site. PURPOSE: The aim of this study was to describe the experiences of nursing personnel regarding the performance of preoperative LD on patients prior to hip fracture surgery after having switched from FBD. METHODS: This study has a qualitative design where data were collected via focus-group discussions (FGDs) including in total 12 participants and analysed using content analysis. RESULTS: Six categories were identified describing the aim: sparing the patients' physical harm, sparing the patients' psychological distress, involving the patients in the procedure, improving the working environment for personnel, preventing unethical situations and a more adequate utilization of resources. CONCLUSIONS: All participants considered LD of the surgical site as a favorable method to FBD, witnessing of an increased wellbeing in patients and the method facilitating a better involvement of patients in the procedure, findings that are supported by other studies promoting person-centered care.

Description and comparison of postoperative functioning of patients with hip fracture 2018 and 2008 at the Örebro University Hospital - a comparative cross-sectional study.

BACKGROUND: Hip fractures are a global problem, and it will probably increase. Hip fractures impair health aspects which creates demands on postoperative care. This study describes and compares patients with hip fracture in 2008 and in 2018. An increased knowledge of this group could be a basis how to optimize aftercare and dimension rehabilitation. METHODS: Using a comparative cross-sectional study to describe and compare patients with hip fracture from 2018 and 2008 at Örebro University Hospital regarding age, sex, multimorbidity, fracture type, surgical materials, surgery within 24 hours, length of stay, postoperative walking ability, physical activity level and hand grip strength. Data was collected from 76 patients with hip fracture from 2018 and 78 patients from 2008. Outcome measures considering functioning were walking ability (Functional Ambulation Categories), physical activity level (Classification system of physical activity) and hand grip strength (Jamar hand dynamometer). Statistical analyses used were hypothesis tests and regressions analysis. RESULTS: No differences in age, sex, fracture type, proportion of surgery within 24 hours or length of stay between the cohorts. The cohort 2018 had more multimorbidity in number of diagnoses and ASA-classification preoperatively. In 2018 70% of the participants were dependent in walking ability (physical human support) compared to 43% 2008 (p = 0.007). Proportion of physically inactive was 9% in 2018 compared to 21% 2008 (p = 0.047). Hand grip strength was 5.1 kg better in 2018 (p = 0.011). Adjusted for age, sex, ASA-classification (American Society of Anaesthesiologists Classification System), surgical materials and number of days between surgery and testing the cohort of 2018 had a lower odds to have independent walking ability and higher odds to be physical active. Differences in hand grip strength decreased to 4.7 kg. Participants in 2018 suffered significantly more multimorbidity. CONCLUSIONS: Study indicated differences in patients' postoperative functioning between 2018 and 2008 with more impaired walking ability, more multimorbidity, higher proportion of physically active and better hand grip strength 2018. The results are important for future reasoning regarding care needs of patients with hip fracture.

Anti-seizure mechanisms of midazolam and valproate at the ß2(L51M) variant of the GABAA receptor.

Genetic sequencing is identifying an expanding number of variants of GABAA receptors associated with human epilepsies. We identified a new de novo variant of the ß2 subunit (ß2L51M) of the inhibitory GABAA receptor associated with seizures. Our analysis determined the pathogenicity of the variant and the effects of anti-seizure medications. Our data demonstrates that the variant reduced cell surface trafficking and peak GABA-gated currents. Synaptic currents mediated by variant-containing receptors decayed faster than wild-type and single receptor currents showed that the variant shortened the duration of receptor activity by decreasing receptor open times. We tested the effects of the anti-seizure medications, midazolam, carbamazepine and valproate and found that all three enhance variant receptor surface expression. Additionally, midazolam restored receptor function by increasing single receptor active periods and synaptic current decay times towards wild-type levels. By contrast, valproate increased synaptic peak currents, event frequency and promoted synaptic bursting. Our study identifies a new disease-causing variant to the GABAA receptor, profiles its pathogenic effects and demonstrates how anti-seizure drugs correct its functional deficits.

The structural conformation of the tachykinin domain drives the anti-tumoural activity of an octopus peptide in melanoma BRAFV600E.

BACKGROUND AND PURPOSE: Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF-mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF-melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin-peptide from the Octopus kaurna, Octpep-1 in melanoma. EXPERIMENTAL APPROACH: We evaluated the cytotoxicity of Octpep-1 by MTT assay. Mechanistic insights on viability and cellular damage caused by Octpep-1 were gained via flow cytometry and bioenergetics. Structural and pharmacological characterization was conducted by molecular modelling, molecular biology, CRISPR/Cas9 technology, high-throughput mRNA and calcium flux analysis. In vivo efficacy was validated in two independent xerograph animal models (mice and zebrafish). KEY RESULTS: Octpep-1 selectively reduced the proliferative capacity of human melanoma BRAFV600E -mutated cells with minimal effects on fibroblasts. In melanoma-treated cells, Octpep-1 increased ROS with unaltered mitochondrial membrane potential and promoted non-mitochondrial and mitochondrial respiration with inefficient ATP coupling. Molecular modelling revealed that the cytotoxicity of Octpep-1 depends upon the α-helix and polyproline conformation in the C-terminal region of the peptide. A truncated form of the C-terminal end of Octpep-1 displayed enhanced potency and efficacy against melanoma. Octpep-1 reduced the progression of tumours in xenograft melanoma mice and zebrafish. CONCLUSION AND IMPLICATIONS: We unravel the intrinsic anti-tumoural properties of a tachykinin peptide. This peptide mediates the selective cytotoxicity in BRAF-mutated melanoma in vitro and prevents tumour progression in vivo, providing a foundation for a therapy against melanoma.

Surgical-site infection after hip fracture surgery: preoperative full-body disinfection compared to local disinfection of the surgical site-a population-based observational cohort study.

PURPOSE: Swedish national guidelines recommend full-body disinfection (FBD) with 4% chlorhexidine before hip fracture surgery to prevent surgical-site infection (SSI) despite little evidence. Our objective was to compare preoperative FBD with local disinfection (LD) of the surgical site regarding SSI incidence. METHODS: All patients with hip fracture, operated at a hospital in Sweden, January 1, 2018 to December 31, 2019 were included. Patients in 2018 (n = 237) were prepared with FBD and patients in 2019 (n = 259) with LD. Primary outcome was SSI and secondary outcome was SSI and/or death. We adjusted for potential confounders with logistic regression. The adjusted analysis was performed in two models to enable assessment of variables that lacked either outcome; in the first model, these variables were not adjusted, and the second model was restricted to a sub-population not affected by respective variables. RESULTS: There were 16 (6.8%) cases of SSI in 2018 and 8 (3.1%) cases in 2019. FBD (2018) compared to LD (2019) presented an adjusted OR of 1.9 (95%CI 0.8-4.9, P = 0.16) respectively 2.0 (95%CI 0.8-5.1, P = 0.14) in the two models of the logistic regression. In addition, 40 (16.9%) patients in 2018 and 29 (11.2%) patients in 2019 had the combined outcome of SSI and/or death, adjusted OR 1.6 (95% CI 0.9-2.8, P = 0.08) respectively 1.7 (95% CI 0.9-2.9, P = 0.06). CONCLUSION: We found a non-significant increased risk of SSI 2018 compared to 2019 after adjustment. Randomized control trials are needed. Nonetheless, results suggest that LD is not inferior to FBD regarding SSI prevention, meaning patients could potentially be spared substantial pain.

Acute Response to One Bout of Dynamic Standing Exercise on Blood Glucose and Blood Lactate Among Children and Adolescents With Cerebral Palsy Who are Nonambulant.

PURPOSE: To investigate the acute exercise effects of dynamic standing exercise on blood glucose and blood lactate among children and adolescents with cerebral palsy who are nonambulant. METHODS: Twenty-four participants with cerebral palsy who are nonambulant performed 30 minutes of dynamic standing exercise using a motorized device enabling assisted passive movements in an upright weight-bearing position. Capillary blood samples were taken from the fingertip for measurement of blood glucose and blood lactate at rest and at the end of exercise. RESULTS: At rest, the participants had hyperlactatemia that was unaffected after exercise, presented as median and interquartile range at rest 1.8 (1.3:2.7) mmol/L, and after exercise 2.0 (1.1:2.5) mmol/L. Children and adolescents with Gross Motor Function Classification System, level V, had higher lactate levels at rest (2.5 [1.8:2.9] vs 1.4 [1.0:2.0]; P = .030) and after exercise (2.3 [2.0:2.6] vs 1.2 [0.9:2.2]; P = .032) compared with children and adolescents with Gross Motor Function Classification System, level IV, respectively. A statistically significant larger decrease in blood lactate levels after exercise was observed in children and adolescents with higher resting blood lactate levels (ρ = .56; P = .004). There were no statistically significant changes in blood glucose. CONCLUSIONS: Forty percentage of the participants had mild hyperlactatemia at rest and participants with the highest blood lactate levels at rest had the greatest decrease in blood lactate levels after one bout of exercise. Children and adolescents who were classified with the highest level of the Gross Motor Function Classification Scale had higher blood lactate levels. More studies are needed on how to prevent chronically high resting levels of lactate with exercise in children with cerebral palsy who are nonambulant.

Manipulated Oral and Rectal Drugs in a Paediatric Swedish University Hospital, a Registry-Based Study Comparing Two Study-Years, Ten Years Apart.

This is a registry-based study with the aim of describing and comparing the frequency of manipulations of solid oral and rectal medicines in 2009 and 2019 at inpatient units and an emergency department in a paediatric hospital within a Swedish university hospital. All patients aged 1 month−18 years with oral or rectal administrations were included. In total, 140,791 oral and rectal administrations were included in 2009, and 167,945 oral and rectal administrations were included in 2019. The frequency of patients receiving at least one manipulated oral medicine decreased between the study years, both in inpatient units and in the emergency department (from 19% to 17%, p = 0.0029 and from 11% to 5%, p < 0.0001, respectively). The frequency of patients receiving a manipulated rectal medicine also decreased between the study years, both in inpatient units and in the emergency department (from 22% to 10%, p < 0.0001 and from 35% to 7% 2019, p < 0.0001, respectively). The results show a decrease in the manipulation of both oral and rectal medicines to paediatric patients in 2019 compared to 2009. Even though this implies a safer practice, there is still a pronounced lack of child-friendly dosage forms and suitable strengths enabling the safe administration of medicines to sick children.