Cannabis and Cannabinoids in Adults With Cancer: ASCO Guideline.

PURPOSE: To guide clinicians, adults with cancer, caregivers, researchers, and oncology institutions on the medical use of cannabis and cannabinoids, including synthetic cannabinoids and herbal cannabis derivatives; single, purified cannabinoids; combinations of cannabis ingredients; and full-spectrum cannabis. METHODS: A systematic literature review identified systematic reviews, randomized controlled trials (RCTs), and cohort studies on the efficacy and safety of cannabis and cannabinoids when used by adults with cancer. Outcomes of interest included antineoplastic effects, cancer treatment toxicity, symptoms, and quality of life. PubMed and the Cochrane Library were searched from database inception to January 27, 2023. ASCO convened an Expert Panel to review the evidence and formulate recommendations. RESULTS: The evidence base consisted of 13 systematic reviews and five additional primary studies (four RCTs and one cohort study). The certainty of evidence for most outcomes was low or very low. RECOMMENDATIONS: Cannabis and/or cannabinoid access and use by adults with cancer has outpaced the science supporting their clinical use. This guideline provides strategies for open, nonjudgmental communication between clinicians and adults with cancer about the use of cannabis and/or cannabinoids. Clinicians should recommend against using cannabis or cannabinoids as a cancer-directed treatment unless within the context of a clinical trial. Cannabis and/or cannabinoids may improve refractory, chemotherapy-induced nausea and vomiting when added to guideline-concordant antiemetic regimens. Whether cannabis and/or cannabinoids can improve other supportive care outcomes remains uncertain. This guideline also highlights the critical need for more cannabis and/or cannabinoid research.Additional information is available at www.asco.org/supportive-care-guidelines.

Vaporized Cannabis versus Placebo for Acute Migraine: A Randomized Controlled Trial.

Background: Preclinical and retrospective studies suggest cannabinoids may be effective in migraine treatment. However, there have been no randomized clinical trials examining the efficacy of cannabinoids for acute migraine. Methods: In this randomized, double-blind, placebo-controlled, crossover trial, adults with migraine treated up to 4 separate migraine attacks, 1 each with vaporized 1) 6% Δ9-tetrahydrocannabinol (THC-dominant); 2) 11% cannabidiol (CBD-dominant); 3) 6% THC+11% CBD; and 4) placebo cannabis flower in a randomized order. Washout period between treated attack was ≥1 week. The primary endpoint was pain relief and secondary endpoints were pain freedom and most bothersome symptom (MBS) freedom, all assessed at 2 hours post-vaporization. Results: Ninety-two participants were enrolled and randomized, and 247 migraine attacks were treated. THC+CBD was superior to placebo at achieving pain relief (67.2% vs 46.6%, Odds Ratio [95% Confidence Interval] 2.85 [1.22, 6.65], p=0.016), pain freedom (34.5% vs. 15.5%, 3.30 [1.24, 8.80], p=0.017) and MBS freedom (60.3% vs. 34.5%, 3.32 [1.45, 7.64], p=0.005) at 2 hours, as well as sustained pain freedom at 24 hours and sustained MBS freedom at 24 and 48 hours. THC-dominant was superior to placebo for pain relief (68.9% vs. 46.6%, 3.14 [1.35, 7.30], p=0.008) but not pain freedom or MBS freedom at 2 hours. CBD-dominant was not superior to placebo for pain relief, pain freedom or MBS freedom at 2 hours. There were no serious adverse events. Conclusions: Acute migraine treatment with 6% THC+11% CBD was superior to placebo at 2 hours post-treatment with sustained benefits at 24 and 48 hours.

Biphasic effects of cannabis and cannabinoid therapy on pain severity, anxiety, and sleep disturbance: a scoping review.

INTRODUCTION: Cannabinoids are being used by patients to help with chronic pain management and to address the 2 primary chronic pain comorbidities of anxiety and sleep disturbance. It is necessary to understand the biphasic effects of cannabinoids to improve treatment of this symptom triad. METHODS: A scoping review was conducted to identify whether biphasic effects of cannabinoids on pain severity, anxiolysis, and sleep disturbance have been reported. The search included the Embase, Biosis, and Medline databases of clinical literature published between 1970 and 2021. The inclusion criteria were (1) adults more than 18 years of age, (2) data or discussion of dose effects associated with U-shaped or linear dose responses, and (3) measurements of pain and/or anxiety and/or sleep disturbance. Data were extracted by 2 independent reviewers (with a third reviewer used as a tiebreaker) and subjected to a thematic analysis. RESULTS: After the database search and study eligibility assessment, 44 publications met the final criteria for review. Eighteen publications that specifically provided information on dose response were included in the final synthesis: 9 related to pain outcomes, 7 measuring anxiety, and 2 reporting sleep effects. CONCLUSIONS: This scoping review reports on biphasic effects of cannabinoids related to pain, sleep, and anxiety. Dose-response relationships are present, but we found gaps in the current literature with regard to biphasic effects of cannabinoids in humans. There is a lack of prospective research in humans exploring this specific relationship.

Neural Plasticity in Tinnitus Mechanisms.

Basic work into neuroplasticity mechanisms in both invertebrate and vertebrate brains, followed by the development of the first animal model of tinnitus, and coupled with clinical studies of tinnitus, meant that, by 1990, Jastreboff [...].

High-frequency spinal cord stimulation (10 kHz) alters sensory function and nerve fiber density in painful diabetic neuropathy: a pilot prospective open-label study.

OBJECTIVE: Spinal cord stimulation at 10 kHz has provided effective pain relief and improved function in painful diabetic peripheral neuropathy. This study aims to confirm the clinical outcomes for 10-kHz spinal cord stimulation treatment of painful diabetic peripheral neuropathy and explore its impact on objective quantitative measures of nerve pathology and function. METHODS: This single-academic center, prospective, open-label, observational study examined the pain relief success of 10-kHz spinal cord stimulation in patients >18 years of age with diabetic peripheral neuropathy. Patients underwent skin biopsies to measure intra-epidermal nerve fiber densities and corneal confocal microscopy measurements before implantation and at the 3-, 6-, and 12-month follow-up visits. Numerical rating scale for pain, visual analog scale, neuropathy pain scale, Short Form-36, and Neuropen (pin prick and monofilament) assessments were also conducted. RESULTS: Eight patients met the criteria and were enrolled in the study. A successful trial was achieved in 7 subjects, and 6 completed the study. Significant pain relief (P < .001) was achieved at all follow-up visits. Neurological assessments showed reduced numbers of "absent" responses and increased "normal" responses from baseline to 12 months. Both proximal and distal intra-epidermal nerve fiber densities were higher at 12 months than at baseline (P < .01). Confocal microscopy measurements showed a steady increase in nerve density from baseline (188.8% increase at 12 months; P = .029). CONCLUSIONS: We observed pain relief and improvements in sensory function after stimulation that were accompanied by increases in lower-limb intra-epidermal nerve fiber density and corneal nerve density. Further evaluation with a blinded and controlled study is needed to confirm the preliminary findings in this study.

Road pavement upgrade scheduling accounting for minimizing congestion.

Road pavement maintenance and upgrades (RPU) need to be scheduled in a way that minimises congestion across the road network and matches the schedule with the availability of equipment and skilled labourers to ensure that they are completed on time. RPU should not introduce unbearable congestion around blocked lanes or roads, and increased traffic due to ongoing road upgrades needs to be transferred to alternative routes. In situations where multiple upgrades are planned together, the scheduled road closures should be coordinated to not block alternative routes. While extensive studies have been conducted separately on scheduling and routing, limited research has linked these processes together, and only in restricted scenarios. In this paper, we investigate how to minimise the disruption of a set of road maintenance tasks based on their interaction with other tasks. We propose a new approach for scheduling a set of road maintenance tasks, some at the same time and others at different times, to minimise overall disruption. The proposed approach has two phases: (1) identify the local area affected by the RPU, and (2) determine which upgrades can be planned together to minimise congestion. The comparison of the results shows how the novel optimized approach identifies a better schedule to minimise congestion.

Examining the latent structure and correlates of sensory reactivity in autism: a multi-site integrative data analysis by the autism sensory research consortium.

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these "supra-modal" traits in the autistic population. METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a "general response pattern" factor for each supra-modal construct and determine the added value of "modality-specific response pattern" scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. RESULTS: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ωH = .800) but not a supra-modal HYPO construct (ωH = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ωH = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations). LIMITATIONS: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many "real-world" sensory experiences. CONCLUSION: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.

Physicians differ in their perceptions of sensitive medical records: Survey and interview study.

Physician categorizations of electronic health record (EHR) data (e.g., depression) into sensitive data categories (e.g., Mental Health) and their perspectives on the adequacy of the categories to classify medical record data were assessed. One thousand data items from patient EHR were classified by 20 physicians (10 psychiatrists paired with ten non-psychiatrist physicians) into data categories via a survey. Cluster-adjusted chi square tests and mixed models were used for analysis. 10 items were selected per each physician pair (100 items in total) for discussion during 20 follow-up interviews. Interviews were thematically analyzed. Survey item categorization yielded 500 (50.0%) agreements, 175 (17.5%) disagreements, 325 (32.5%) partial agreements. Categorization disagreements were associated with physician specialty and implied patient history. Non-psychiatrists selected significantly (p = .016) more data categories than psychiatrists when classifying data items. The endorsement of Mental Health and Substance Use categories were significantly (p = .001) related for both provider types. During thematic analysis, Encounter Diagnosis (100%), Problems (95%), Health Concerns (90%), and Medications (85%) were discussed the most when deciding the sensitivity of medical information. Most (90.0%) interview participants suggested adding additional data categories. Study findings may guide the evolution of digital patient-controlled granular data sharing technology and processes.

Multi-environment association study highlights candidate genes for robust agronomic quantitative trait loci in a novel worldwide Capsicum core collection.

Investigating crop diversity through genome-wide association studies (GWAS) on core collections helps in deciphering the genetic determinants of complex quantitative traits. Using the G2P-SOL project world collection of 10 038 wild and cultivated Capsicum accessions from 10 major genebanks, we assembled a core collection of 423 accessions representing the known genetic diversity. Since complex traits are often highly dependent upon environmental variables and genotype-by-environment (G × E) interactions, multi-environment GWAS with a 10 195-marker genotypic matrix were conducted on a highly diverse subset of 350 Capsicum annuum accessions, extensively phenotyped in up to six independent trials from five climatically differing countries. Environment-specific and multi-environment quantitative trait loci (QTLs) were detected for 23 diverse agronomic traits. We identified 97 candidate genes potentially implicated in 53 of the most robust and high-confidence QTLs for fruit flavor, color, size, and shape traits, and for plant productivity, vigor, and earliness traits. Investigating the genetic architecture of agronomic traits in this way will assist the development of genetic markers and pave the way for marker-assisted selection. The G2P-SOL pepper core collection will be available upon request as a unique and universal resource for further exploitation in future gene discovery and marker-assisted breeding efforts by the pepper community.

The Processing of Audiovisual Speech Is Linked with Vocabulary in Autistic and Nonautistic Children: An ERP Study.

Explaining individual differences in vocabulary in autism is critical, as understanding and using words to communicate are key predictors of long-term outcomes for autistic individuals. Differences in audiovisual speech processing may explain variability in vocabulary in autism. The efficiency of audiovisual speech processing can be indexed via amplitude suppression, wherein the amplitude of the event-related potential (ERP) is reduced at the P2 component in response to audiovisual speech compared to auditory-only speech. This study used electroencephalography (EEG) to measure P2 amplitudes in response to auditory-only and audiovisual speech and norm-referenced, standardized assessments to measure vocabulary in 25 autistic and 25 nonautistic children to determine whether amplitude suppression (a) differs or (b) explains variability in vocabulary in autistic and nonautistic children. A series of regression analyses evaluated associations between amplitude suppression and vocabulary scores. Both groups demonstrated P2 amplitude suppression, on average, in response to audiovisual speech relative to auditory-only speech. Between-group differences in mean amplitude suppression were nonsignificant. Individual differences in amplitude suppression were positively associated with expressive vocabulary through receptive vocabulary, as evidenced by a significant indirect effect observed across groups. The results suggest that efficiency of audiovisual speech processing may explain variance in vocabulary in autism.

Real-Time Monitoring and Control of Nanoparticle Formation.

Methods capable of controlling synthesis at the level of an individual nanoparticle are a key step toward improved reproducibility and scalability in engineering complex nanomaterials. To address this, we combine the spatially patterned activation of the photoreductant sodium pyruvate with interferometric scattering microscopy to achieve fast, label-free monitoring and control of hundreds of gold nanoparticles in real time. Individual particle growth kinetics are well-described by a two-step nucleation-autocatalysis model but with a distribution of individual rate constants that change with reaction conditions.

Sound Level Changes the Auditory Cortical Activation Detected with Functional Near-Infrared Spectroscopy.

BACKGROUND: Functional near-infrared spectroscopy (fNIRS) is a viable non-invasive technique for functional neuroimaging in the cochlear implant (CI) population; however, the effects of acoustic stimulus features on the fNIRS signal have not been thoroughly examined. This study examined the effect of stimulus level on fNIRS responses in adults with normal hearing or bilateral CIs. We hypothesized that fNIRS responses would correlate with both stimulus level and subjective loudness ratings, but that the correlation would be weaker with CIs due to the compression of acoustic input to electric output. METHODS: Thirteen adults with bilateral CIs and 16 with normal hearing (NH) completed the study. Signal-correlated noise, a speech-shaped noise modulated by the temporal envelope of speech stimuli, was used to determine the effect of stimulus level in an unintelligible speech-like stimulus between the range of soft to loud speech. Cortical activity in the left hemisphere was recorded. RESULTS: Results indicated a positive correlation of cortical activation in the left superior temporal gyrus with stimulus level in both NH and CI listeners with an additional correlation between cortical activity and perceived loudness for the CI group. The results are consistent with the literature and our hypothesis. CONCLUSIONS: These results support the potential of fNIRS to examine auditory stimulus level effects at a group level and the importance of controlling for stimulus level and loudness in speech recognition studies. Further research is needed to better understand cortical activation patterns for speech recognition as a function of both stimulus presentation level and perceived loudness.

Cholinergic modulation of sensory perception and plasticity.

Sensory systems are highly plastic, but the mechanisms of sensory plasticity remain unclear. People with vision or hearing loss demonstrate significant neural network reorganization that promotes adaptive changes in other sensory modalities as well as in their ability to combine information across the different senses (i.e., multisensory integration. Furthermore, sensory network remodeling is necessary for sensory restoration after a period of sensory deprivation. Acetylcholine is a powerful regulator of sensory plasticity, and studies suggest that cholinergic medications may improve visual and auditory abilities by facilitating sensory network plasticity. There are currently no approved therapeutics for sensory loss that target neuroplasticity. This review explores the systems-level effects of cholinergic signaling on human visual and auditory perception, with a focus on functional performance, sensory disorders, and neural activity. Understanding the role of acetylcholine in sensory plasticity will be essential for developing targeted treatments for sensory restoration.

Visually biased Perception in Cochlear Implant Users: A Study of the McGurk and Sound-Induced Flash Illusions.

The reduction in spectral resolution by cochlear implants oftentimes requires complementary visual speech cues to facilitate understanding. Despite substantial clinical characterization of auditory-only speech measures, relatively little is known about the audiovisual (AV) integrative abilities that most cochlear implant (CI) users rely on for daily speech comprehension. In this study, we tested AV integration in 63 CI users and 69 normal-hearing (NH) controls using the McGurk and sound-induced flash illusions. To our knowledge, this study is the largest to-date measuring the McGurk effect in this population and the first that tests the sound-induced flash illusion (SIFI). When presented with conflicting AV speech stimuli (i.e., the phoneme "ba" dubbed onto the viseme "ga"), we found that 55 CI users (87%) reported a fused percept of "da" or "tha" on at least one trial. After applying an error correction based on unisensory responses, we found that among those susceptible to the illusion, CI users experienced lower fusion than controls-a result that was concordant with results from the SIFI where the pairing of a single circle flashing on the screen with multiple beeps resulted in fewer illusory flashes for CI users. While illusion perception in these two tasks appears to be uncorrelated among CI users, we identified a negative correlation in the NH group. Because neither illusion appears to provide further explanation of variability in CI outcome measures, further research is needed to determine how these findings relate to CI users' speech understanding, particularly in ecological listening conditions that are naturally multisensory.

Near-field potentials index local neural computations more accurately than population spiking.

Local field potentials (LFP) are low-frequency extracellular voltage fluctuations thought to primarily arise from synaptic activity. However, unlike highly localized neuronal spiking, LFP is spatially less specific. LFP measured at one location is not entirely generated there due to far-field contributions that are passively conducted across volumes of neural tissue. We sought to quantify how much information within the locally generated, near-field low-frequency activity (nfLFP) is masked by volume-conducted far-field signals. To do so, we measured laminar neural activity in primary visual cortex (V1) of monkeys viewing sequences of multifeatured stimuli. We compared information content of regular LFP and nfLFP that was mathematically stripped of volume-conducted far-field contributions. Information content was estimated by decoding stimulus properties from neural responses via spatiotemporal multivariate pattern analysis. Volume-conducted information differed from locally generated information in two important ways: (1) for stimulus features relevant to V1 processing (orientation and eye-of-origin), nfLFP contained more information. (2) in contrast, the volume-conducted signal was more informative regarding temporal context (relative stimulus position in a sequence), a signal likely to be coming from elsewhere. Moreover, LFP and nfLFP differed both spectrally as well as spatially, urging caution regarding the interpretations of individual frequency bands and/or laminar patterns of LFP. Most importantly, we found that population spiking of local neurons was less informative than either the LFP or nfLFP, with nfLFP containing most of the relevant information regarding local stimulus processing. These findings suggest that the optimal way to read out local computational processing from neural activity is to decode the local contributions to LFP, with significant information loss hampering both regular LFP and local spiking. Author's Contributions: Conceptualization, D.A.T., J.A.W, and A.M.; Data Collection, J.A.W., M.A.C., K.D.; Formal Analysis, D.A.T. and J.A.W.; Data Visualization, D.A.T. and J.A.W.; Original Draft, D.A.T., J.A.W., and A.M.; Revisions and Final Draft, D.A.T., J.A.W., M.A.C., K.D., M.T.W., A.M.B., and A.M. Competing Interests: The authors declare no conflicts of interest.

Combination therapy with simultaneous delivery of spinal cord stimulation modalities: COMBO randomized controlled trial.

Aim: The Combining Mechanisms for Better Outcomes randomized controlled trial assessed the effectiveness of various spinal cord stimulation (SCS) modalities for chronic pain. Specifically, combination therapy (simultaneous use of customized sub-perception field and paresthesia-based SCS) versus monotherapy (paresthesia-based SCS) was evaluated. Methods: Participants were prospectively enrolled (key inclusion criterion: chronic pain for ≥6 months). Primary end point was the proportion with ≥50% pain reduction without increased opioids at the 3 month follow-up. Patients were followed for 2 years. Results: The primary end point was met (n = 89; p < 0.0001) in 88% of patients in the combination-therapy arm (n = 36/41) and 71% in the monotherapy arm (n = 34/48). Responder rates at 1 and 2 years (with available SCS modalities) were 84% and 85%, respectively. Sustained functional outcomes improvement was observed out to 2 years. Conclusion: SCS-based combination therapy can improve outcomes in patients with chronic pain. Clinical Trial Registration: NCT03689920 (ClinicalTrials.gov), Combining Mechanisms for Better Outcomes (COMBO).

Spinal cord stimulation (SCS) is a device-based therapy for chronic pain that delivers electrical impulses to the spinal cord, disrupting pain signals to the brain. Pain relief can be achieved using different SCS techniques that use or do not use paresthesia (stimulation that produces a tingling sensation). These approaches affect patients in different ways, suggesting that different biological processes are involved in enabling pain relief. Research also suggests that better long-term results occur when patients can choose the therapy that is best for their own needs. This clinical study compared pain relief and other functional activities in those receiving combination therapy (simultaneous use of SCS that does and does not produce tingling sensation) against those receiving monotherapy (only SCS therapy producing tingling sensation) for 3 months. In the study, 88% of those receiving combination therapy and 71% with monotherapy alone reported a 50% (or greater) decrease in overall pain (the 'responder rate') without an increased dose of opioid drugs at 3 months after the start of therapy. This responder rate was found to be 84% at 1 year and 85% at 2 years (with all SCS therapy options available). Analysis of functional activities or disability showed that patients improved from 'severely disabled' at study start to 'moderately disabled' after 2 years, indicating that effective long-term (2 year) improvement can be achieved using SCS-based combination therapy for chronic pain.

Neural Correlates of Audiovisual Speech Processing in Autistic and Non-Autistic Youth.

Autistic youth demonstrate differences in processing multisensory information, particularly in temporal processing of multisensory speech. Extensive research has identified several key brain regions for multisensory speech processing in non-autistic adults, including the superior temporal sulcus (STS) and insula, but it is unclear to what extent these regions are involved in temporal processing of multisensory speech in autistic youth. As a first step in exploring the neural substrates of multisensory temporal processing in this clinical population, we employed functional magnetic resonance imaging (fMRI) with a simultaneity-judgment audiovisual speech task. Eighteen autistic youth and a comparison group of 20 non-autistic youth matched on chronological age, biological sex, and gender participated. Results extend prior findings from studies of non-autistic adults, with non-autistic youth demonstrating responses in several similar regions as previously implicated in adult temporal processing of multisensory speech. Autistic youth demonstrated responses in fewer of the multisensory regions identified in adult studies; responses were limited to visual and motor cortices. Group responses in the middle temporal gyrus significantly interacted with age; younger autistic individuals showed reduced MTG responses whereas older individuals showed comparable MTG responses relative to non-autistic controls. Across groups, responses in the precuneus covaried with task accuracy, and anterior temporal and insula responses covaried with nonverbal IQ. These preliminary findings suggest possible differences in neural mechanisms of audiovisual processing in autistic youth while highlighting the need to consider participant characteristics in future, larger-scale studies exploring the neural basis of multisensory function in autism.