Phytocannabinoids for the Treatment of Neuropathic Pain: A Scoping Review of Randomised Controlled Trials Published Between 2012 and 2023.

PURPOSE OF REVIEW: Neuropathic pain (NP) remains a challenge to treat, with 50% of patients experiencing limited efficacy from current treatments. Medicinal cannabis, which contains tetrahydrocannabinol (THC), cannabidiol (CBD) and other minor cannabinoids, is garnering attention as an alternative treatment for NP. This paper reviews the clinical evidence for phytocannabinoid treatment of NP. RECENT FINDINGS: Seventeen randomised controlled trials (RCT) were identified for inclusion in this review. Of these, ten studies using phytocannabinoid preparations containing THC alone had the most evidence for pain relief. Four studies investigating THC/CBD combinations showed some reductions in pain scores, although not all findings were statistically significant, whereas studies investigating CBD (two studies) or cannabidivarin (one study) showed no analgesic effect over placebo. However, CBD studies were of small sample size when compared to other studies in the review and short duration. Results for treatment of diabetic peripheral neuropathy patients with THC showed better improvements over those for NP induced by chemotherapy and multiple sclerosis, with these trials using vaporised whole plant cannabis. This formulation may have trace amounts of other minor cannabinoids, compared with synthetic cannabinoids such as dronabinol or nabilone that were investigated in other studies. This review provides an overview of RCTs that have investigated phytocannabinoid use for the treatment of NP. There appears to be evidence to necessitate further high quality RCTs into novel formulations of phytocannabinoids for the treatment of NP.

Using automation to manage donor engagement and fine-tune supply and demand during the first year of the COVID-19 pandemic.

BACKGROUND: COVID-19 disrupted blood center operations starting March 2020 and continues to affect donor presentation and blood availability today. The industry mobilized significant resources to collect COVID-19 convalescent plasma (CCP) to treat COVID-19 patients. At the same time, blood centers continued to collect platelets, plasma, and red blood cells (RBCs) to meet the needs of non-COVID-19 patients. The purpose of this study was to quantify how automation was used to fine-tune supply and demand and increase donor engagement during the first year of the pandemic. METHODS: This was a single-center retrospective study of blood collection and donor presentation at a mid-sized US blood center. Data was evaluated from January 1, 2020 through March 31, 2021. Parameters evaluated included donor presentation, platelets per procedure, concurrent RBC and plasma collections per procedure, operator compliance, total donor appointment count, and donor frequency. RESULTS: With the cancelation of mobile blood drives, fixed sites increased total apheresis procedures by 37% and increased turns per bed by 46% whereas less products were collected per donor. By collecting only what was needed, platelet expiration rate decreased from 6.8% (pre-pandemic) to less than 4%. Donor engagement as measured by donor frequency increased from 1.6 in January 2020 to 1.8 in March 2021. CONCLUSIONS: Using technological advances such as automated blood collection and information systems, the blood center improved donor engagement and avoided collecting a surplus of any one type of blood product over the course of the pandemic.

Changes in plasma unit distributions to hospitals over a 10-year period.

BACKGROUND: There are many influences on a hospital's demand for plasma. Pharmaceuticals are now being administered for many indications instead of plasma, although trauma resuscitation now emphasizes increased and early intervention with plasma. This multinational study evaluated changes in blood center plasma unit distributions over a 10-year period. STUDY DESIGN AND METHODS: Data on the total number and the ABO groups of plasma unit distributions were obtained from nine American blood collectors (ABCs) and nine national or provincial blood services (NPBS) from 2007 through 2016. Plasma distributions to trauma hospitals by five ABCs and four NPBS were also analyzed. RESULTS: The overall number of plasma unit distributions from ABCs decreased by 23.1% from 2007 to 2016, but the relative proportion of distributed AB plasma units increased during the same period. The NPBS (excluding the Japanese Red Cross [JRC]) also had a 35.4% decrease in the overall number of plasma unit distributions with an increase in the relative proportion of AB plasma distributions between 2007 and 2016. The JRC, however, reported an increase in the overall number of plasma distributions by 13.5% in 2016 compared to 2007. The proportion of low-titer A plasma distributions increased to 1.6% of total plasma distributions by ABCs in 2016. There was a trend of distributing increasing proportions of group AB plasma units to trauma hospitals over the 10-year period. CONCLUSION: Although the number of plasma unit distributions has decreased at many blood collectors over time, the proportion of AB units has increased at both ABCs and NPBS.

Maternal Regulation of Daughters' Emotion During Conflicts From Early to Mid-Adolescence.

Primary caregivers play an important role in emotion socialization. Real-time mother-daughter emotion socialization was examined in 45 mother-daughter dyads with early-adolescent daughters (age M = 11.80, SD = .27) at the first observation point. Maternal supportive emotion regulation and daughters' emotions were coded during two conflict discussions, 2 years apart. With multilevel survival analysis, the likelihood of maternal supportiveness was predicted both over time, between early and mid-adolescence, and by daughters' pubertal status. Mothers were more likely to respond to daughters' negative and positive emotions with supportiveness for daughters whose pubertal maturation occurred relatively early. Results suggest that mothers adjust their socialization of daughters' emotions according to their daughters' pubertal development.

Hypervalent Activation as a Key Step for Dehydrogenative ortho C-C Coupling of Iodoarenes.

Building on earlier results, a direct metal-free α-arylation of substituted cyclic 1,3-diones using ArI(O2CCF3)2 reagents has been developed; unlike other arylative approaches, the arylated products retain the iodine substituent ortho to the newly formed C-C bond. The mechanism is explored by using DFT calculations, which show a vanishingly small activation barrier for the C-C bond-forming step. In fact, taking advantage of an efficient in situ hypervalent activation, the iodoarenes are shown to undergo a cross-dehydrogenative C-C coupling at the C-H ortho to the iodine. When Oxone is used as terminal oxidant, the process is found to benefit from a rapid initial formation of the hypervalent ArI(OR)2 species and the sulfate-accelerated final coupling with a ketone. This method complements the ipso selectivity obtained in the metal-catalyzed α-arylation of carbonyl compounds.

Dietary nitrate supplementation improves exercise performance and decreases blood pressure in COPD patients.

Dietary nitrate (NO3(-)) supplementation via beetroot juice has been shown to increase the exercise capacity of younger and older adults. The purpose of this study was to investigate the effects of acute NO3(-) ingestion on the submaximal constant work rate exercise capacity of COPD patients. Fifteen patients were assigned in a randomized, single-blind, crossover design to receive one of two treatments (beetroot juice then placebo or placebo then beetroot juice). Submaximal constant work rate exercise time at 75% of the patient's maximal work capacity was the primary outcome. Secondary outcomes included plasma NO3(-) and nitrite (NO2(-)) levels, blood pressure, heart rate, oxygen consumption (VO2), dynamic hyperinflation, dyspnea and leg discomfort. Relative to placebo, beetroot ingestion increased plasma NO3(-) by 938% and NO2(-) by 379%. Median (+interquartile range) exercise time was significantly longer (p = 0.031) following the ingestion of beetroot versus placebo (375.0 + 257.0 vs. 346.2 + 148.0 s, respectively). Compared with placebo, beetroot ingestion significantly reduced iso-time (p = 0.001) and end exercise (p = 0.008) diastolic blood pressures by 6.4 and 5.6 mmHg, respectively. Resting systolic blood pressure was significantly reduced (p = 0.019) by 8.2 mmHg for the beetroot versus the placebo trial. No other variables were significantly different between the beetroot and placebo trials. These results indicate that acute dietary NO3(-) supplementation can elevate plasma NO3(-) and NO2(-) concentrations, improve exercise performance, and reduce blood pressure in COPD patients.

Interobserver Reliability of Quantitative Muscle Sonographic Analysis in the Critically Ill Population.

OBJECTIVES: There is growing interest in the use of quantitative high-resolution neuromuscular sonography to evaluate skeletal muscles in patients with critical illness. There is currently considerable methodological variability in the measurement technique of quantitative muscle analysis. The reliability of muscle parameters using different measurement techniques and assessor expertise levels has not been examined in patients with critical illness. The primary objective of this study was to determine the interobserver reliability of quantitative sonographic measurement analyses (thickness and echogenicity) between assessors of different expertise levels and using different techniques for selecting the region of interest. METHODS: We conducted a cross-sectional observational study in neurocritical care and mixed surgical-medical intensive care units from 2 tertiary referral hospitals. RESULTS: Twenty diaphragm and 20 quadriceps images were evaluated. Images were obtained by using standardized imaging acquisition techniques. Quantitative sonographic measurements included muscle thickness and echogenicity analysis (either by the trace or square technique). All images were analyzed twice independently by 4 assessors of differing expertise levels. Excellent interobserver reliability was obtained for all measurement techniques regardless of expertise level (intraclass correlation coefficient, >0.75 for all comparisons). There was less variability between assessors for echogenicity values when the square technique was used for the quadriceps muscle and the trace technique for the diaphragm. CONCLUSIONS: Excellent interobserver reliability exists regardless of expertise level for quantitative analysis of muscle parameters on sonography in the critically ill population. On the basis of these findings, it is recommended that echogenicity analysis be performed using the square technique for the quadriceps and the trace technique for the diaphragm.

Developmental change in EEG theta activity in the medial prefrontal cortex during response control.

Cognitive control functions continue to improve from infancy until early adulthood, allowing flexible adaptation to a complex environment. However, it remains controversial how this development in cognitive capabilities is mediated by changes in cortical activity: both age-related increases and decreases of mediofrontal neural activity have been observed and interpreted as neural underpinnings of this functional development. To better understand this developmental process, we examined EEG theta activity in the mediofrontal region using a Go/No-go response control task. We found that both pre-stimulus baseline theta-power and theta-power during the response control task, without baseline-correction, decreased with age. Conversely, when task-related theta-power was baseline corrected (using a ratio method), it exhibited a positive developmental trajectory. The age-related theta-power increase was source-localized to the anterior cingulate cortex. This increase in theta activity also partially mediated age-related improvements in response control and was greatest in a condition that demanded greater effort. Theta activity in older children also showed greater temporal reliability across trials as measured by inter-trial phase-coherence. Interestingly, directly subtracting baseline activity from task-related activity did not yield significant developmental effects, which highlights the necessity of separating and contrasting the pre-stimulus baseline with task-related processing in the understanding of neurodevelopmental changes.

Improving the thermal, radial, and temporal accuracy of the analytical ultracentrifuge through external references.

Sedimentation velocity (SV) is a method based on first principles that provides a precise hydrodynamic characterization of macromolecules in solution. Due to recent improvements in data analysis, the accuracy of experimental SV data emerges as a limiting factor in its interpretation. Our goal was to unravel the sources of experimental error and develop improved calibration procedures. We implemented the use of a Thermochron iButton temperature logger to directly measure the temperature of a spinning rotor and detected deviations that can translate into an error of as much as 10% in the sedimentation coefficient. We further designed a precision mask with equidistant markers to correct for instrumental errors in the radial calibration that were observed to span a range of 8.6%. The need for an independent time calibration emerged with use of the current data acquisition software (Zhao et al., Anal. Biochem., 437 (2013) 104-108), and we now show that smaller but significant time errors of up to 2% also occur with earlier versions. After application of these calibration corrections, the sedimentation coefficients obtained from 11 instruments displayed a significantly reduced standard deviation of approximately 0.7%. This study demonstrates the need for external calibration procedures and regular control experiments with a sedimentation coefficient standard.

Neural mechanisms of emotion regulation in childhood anxiety.

BACKGROUND: The present study was designed to examine the cortical processes that mediate cognitive regulation in response to emotion-eliciting stimuli in anxious children. METHODS: Electroencephalographic (EEG) activity was recorded from clinically anxious children (n = 29) and typically developing children (n = 34). Event-related potential components were recorded while children performed a go/no-go task using facial stimuli depicting angry, calm, and happy expressions. RESULTS: Anxious children had significantly greater posterior P1 and frontal N2 amplitudes, components associated with attention/arousal and cognitive control, respectively, than typically developing children. Anxious children also had significantly greater error-related negativities and correct-response negativities relative to typically developing children. For the anxious group only, there were no differences in neural activation between face (emotion) types or trial (Go vs. No-go) types. A regression analysis revealed that No-go N2 amplitudes for calm faces predicted self-reported anxiety levels. CONCLUSIONS: Anxious children appeared to show increased cortical activation regardless of the emotional content of the stimuli. Anxious children also showed greater medial-frontal activity regardless of task demands and response accuracy. Taken together, these findings suggest indiscriminate cortical processes that may underlie the hypervigilant regulatory style seen in clinically anxious individuals.

Emotion regulation in children with behavior problems: linking behavioral and brain processes.

Past studies have shown that aggressive children exhibit rigid (rather than flexible) parent-child interactions; these rigid repertoires may provide the context through which children fail to acquire emotion-regulation skills. Difficulties in regulating emotion are associated with minimal activity in dorsal systems in the cerebral cortex, for example, the anterior cingulate cortex. The current study aimed to integrate parent-child and neurocognitive indices of emotion regulation and examine their associations for the first time. Sixty children (8-12 years old) referred for treatment for aggression underwent two assessments. Brain processes related to emotion regulation were assessed using dense-array EEG with a computerized go/no-go task. The N2 amplitudes thought to tap inhibitory control were recorded, and a source analysis was conducted. In the second assessment, parents and children were videotaped while trying to solve a conflict topic. State space grids were used to derive two dynamic flexibility parameters from the coded videotapes: (a) the number of transitions between emotional states and (b) the dispersion of emotional states, based on proportional durations in each state. The regression results showed that flexibility measures were not related to N2 amplitudes. However, flexibility measures were significantly associated with the ratio of dorsal to ventral source activation: for transitions, ΔR 2 = .27, F (1, 34) = 13.13, p = .001; for dispersion, ΔR 2 = .29, F (1, 35) = 14.76, p < .001. Thus, in support of our main hypothesis, greater dyadic flexibility was associated with a higher ratio of dorsomedial to ventral activation, suggesting that children with more flexible parent-child interactions are able to recruit relatively more dorsomedial activity in challenging situations.

Magnitude and chronometry of neural mechanisms of emotion regulation in subtypes of aggressive children.

Emotion regulation is a key social skill and children who fail to master it are at risk for clinical disorders. Specific styles of emotion regulation have been associated with particular patterns of prefrontal activation. We investigated whether anxious aggressive children would reveal a different pattern of cortical activation than non-anxious aggressive children and normally-developing children. We examined the magnitude and timing of source activation underlying the N2-an ERP associated with inhibitory control-during a go/nogo task with a negative emotion induction component (loss of earned points). We estimated cortical activation for two regions of interest-a ventral prefrontal and a dorsomedial prefrontal region-for three 100-ms windows over the range of the N2 (200-500 ms). Anxious aggressive children showed high ventral prefrontal activation in the early window; non-anxious aggressive children showed high ventral prefrontal activation in the late window, but only for the duration of the emotion induction; and normally-developing children showed low ventral prefrontal activation throughout. There were no group differences in dorsomedial prefrontal activation. These results suggest that anxious aggressive children recruit ventral prefrontal activation quickly and indiscriminately, possibly giving rise to their rigid, threat-oriented approach to conflict. The late ventral prefrontal activation seen for non-anxious aggressive children may underlie a more delayed, situation-specific, but ineffective response to frustration.

Development of hot and cool executive function during the transition to adolescence.

This study examined the development of executive function (EF) in a typically developing sample from middle childhood to adolescence using a range of tasks varying in affective significance. A total of 102 participants between 8 and 15years of age completed the Iowa Gambling Task, the Color Word Stroop, a Delay Discounting task, and a Digit Span task. Age-related improvements were found on all tasks, but improvements on relatively cool tasks (Color Word Stroop and Backward Digit Span) occurred earlier in this age range, whereas improvements on relatively hot tasks (Iowa Gambling Task and Delay Discounting) were more gradual and occurred later. Exploratory factor analysis indicated that performance on all tasks could be accounted for by a single-factor model. Together, these findings indicate that although similar abilities may underlie both hot and cool EF, hot EF develops relatively slowly, which may have implications for the risky behavior often observed during adolescence. Future work should include additional measures to characterize more intensively the development of both hot and cool EF during the transition to adolescence.

The time course of social-emotional processing in early childhood: ERP responses to facial affect and personal familiarity in a Go-Nogo task.

To date, little is known about the neural underpinnings of social-emotional processes in young children. The present study investigated the time course of children's ERP responses to facial expression and personal familiarity, and the effect of these variables on ERP measures of effortful attention in a Go-Nogo task. Dense-array EEG was collected from 48 4-6-year-old children who were presented with pictures of their mothers' and strangers' happy and angry faces. ERPs were scored following face presentation and following a subsequent cue signaling a Go or Nogo response. Responses to face presentation showed early perceptual components that were larger following strangers' faces, suggesting facilitated rapid processing of personally important faces. A mid-latency frontocentral negativity was greatest following angry mothers' faces, indicating increased attentional monitoring and/or recognition memory evoked by an angry parent. Finally a right-lateralized late positive component was largest following angry faces, suggesting extended processing of negatively valenced social stimuli in general. Following the Go-Nogo response cue, a right-lateralized mid-latency negativity thought to measure effortful attention was larger in Nogo than Go trials, and following angry than happy faces, possibly reflecting increased effortful control required in those conditions. The present study suggests that overlapping but differentiated networks for both rapid and elaborative processing of important socio-affective information are established by 4-6 years. Moreover, the extended spatial and temporal distribution of components suggests a pattern of response to social stimuli in which more rapid processes may index personal familiarity, whereas temporally extended processes are sensitive to affective valence on both familiar and unfamiliar faces.

Grb2 adaptor undergoes conformational change upon dimerization.

Grb2 is an adaptor protein that couples activated receptor tyrosine kinases to downstream effector molecules such as Ras and Akt. Despite being a central player in mitogenic signaling and a target for therapeutic intervention, the role of Grb2 oligomerization in cellular signaling is not well understood. Here, using the techniques of size-exclusion chromatography, mass spectrometry, analytical ultra-centrifugation and isothermal titration calorimetry, we demonstrate that Grb2 exists in monomer-dimer equilibrium in solution and that the dissociation of dimer into monomers is entropically-driven without an unfavorable enthalpic change at physiological temperatures. Our data indicate that enthalpy and entropy of dimer dissociation are highly temperature-dependent and largely compensate each other resulting in negligible effect of temperature on the overall free energy. From the plot of enthalpy change versus temperature, the magnitude of heat capacity change derived is much smaller than that expected from the rather large molecular surfaces becoming solvent-occluded upon Grb2 dimerization, implying that Grb2 monomers undergo conformational rearrangement upon dimerization. 3D structural models of Grb2 dimer and monomers suggest strongly that such conformational rearrangement upon dimerization may arise from domain swapping. Taken together, our study provides novel insights into the role of Grb2 as an adaptor in cellular signaling circuitry and how Grb2 dimerization may impart high fidelity in signal transduction as well as lead to rapid signal amplification upon receptor stimulation.

Changes in the neural bases of emotion regulation associated with clinical improvement in children with behavior problems.

Children's behavior problems may stem from ineffective cortical mechanisms for regulating negative emotions, and the success of interventions may depend on their impact on such mechanisms. We examined neurophysiological markers associated with emotion regulation in children comorbid for externalizing and internalizing problems before and after treatment. We hypothesized that treatment success would correspond with reduced ventral prefrontal activation, and increased dorsomedial prefrontal activation, at the time point of an event-related potential (ERP) associated with inhibitory control. Twenty-seven 8- to 12-year-old children (with usable data) were tested before and after a 14-week community-based treatment program and assessed as to improvement status. Fifteen 8- to 12-year-olds from the normal population (with usable data) were tested over the same interval. All children completed an emotion-induction go/no-go task while fitted with a 128-channel electrode net at each test session. ERP amplitudes, and estimates of cortical activation in prefrontal regions of interest, were measured at the peak of the "inhibitory" N2 and compared between improvers, nonimprovers, and nonclinical children. ERP amplitudes showed no group differences. However, improvers showed an overall reduction in ventral prefrontal activation from pretreatment to posttreatment, bringing them in line with nonclinical children, whereas ventral activation remained high for nonimprovers. Both improvers and nonimprovers showed high dorsal activation relative to nonclinical children. Supplementary analyses indicated that only ventral prefrontal regions, and only within the N2 time window, showed decreased activity from pre- to posttreatment, suggesting changes in regulatory processes rather than in overall emotional arousal. These cortically mediated changes may permit a reduction in the overengaged, rigid style of emotion regulation characteristic of children with behavior problems.

Event-related potential measures of emotion regulation in early childhood.

Emotion regulation in adults may be mediated by frontal cortical activities that adjust attention in response to challenging emotions. We examined event-related potentials across emotional conditions to assess normative patterns and individual differences in cortical mechanisms of emotion regulation in 4-6-year-olds. The children viewed pictures of angry, neutral, and happy faces during a Go/No-go task. Angry faces generated the greatest (frontocentral) N2 amplitudes and fastest N2 latencies, and happy faces produced the smallest amplitudes and slowest latencies. Frontal electrodes showed larger N2s to angry faces in the Go condition. The P3b was also largest for angry faces. More fearful children showed faster latency N2s to angry faces. These results are interpreted in terms of early-developing mechanisms for regulating anxiety and processing emotional information.

A dynamic systems analysis of parent-child changes associated with successful "real-world" interventions for aggressive children.

Studies have shown that improved parenting mediates treatment outcomes for aggressive children, but we lack fine-grained descriptions of how parent-child interactions change with treatment. The current study addresses this gap by applying new dynamic systems methods to study parent-child emotional behavior patterns. These methods tap moment-to-moment changes in interaction processes within and across sessions and quantify previously unmeasured processes of change related to treatment success. Aggressive children and their parents were recruited from combined Parent Management Training and Cognitive-behavioral programs in "real world" clinical settings. Behavioral outcomes were assessed by reports from parents and clinicians. At pre- and post-treatment, home visits were videotaped while parents and children discussed consecutively: a positive topic, a mutually unresolved problem, and another positive topic. Results showed that significant improvements in children's externalizing behavior were associated with increases in parent-child emotional flexibility during the problem-solving discussion. Also, dyads who improved still expressed negative emotions, but they acquired the skills to repair conflicts, shifting out of their negative interactions to mutually positive patterns.