Canadians' use of cannabis for therapeutic purposes since legalization of recreational cannabis: a cross-sectional analysis by medical authorization status.

BACKGROUND: There has been a precipitous decline in authorizations for medical cannabis since non-medical cannabis was legalized in Canada in 2018. This study examines the demographic and health- and medical cannabis-related factors associated with authorization as well as the differences in medical cannabis use, side effects, and sources of medical cannabis and information by authorization status. METHODS: Individuals who were taking cannabis for therapeutic purposes completed an online survey in early 2022. Multivariable logistic regression was used to determine odds ratios (OR) and 95% confidence intervals (CI) of demographic and health- and medical cannabis-related variables associated with holding medical cannabis authorization. The differences in medical cannabis use, side effects, and sources of information by authorization status were determined via t-tests and chi-squared analysis. RESULTS: A total of 5433 individuals who were currently taking cannabis for therapeutic purposes completed the study, of which 2941 (54.1%) currently held medical authorization. Individuals with authorization were more likely to be older (OR ≥ 70 years vs. < 30 years, 4.85 (95% CI, 3.49-6.76)), identify as a man (OR man vs. woman, 1.53 (1.34-1.74)), have a higher income (OR > $100,000/year vs. < $50,000 year, 1.55 (1.30-1.84)), and less likely to live in a small town (OR small town/rural vs. large city, 0.69 (0.59-0.81)). They were significantly more likely to report not experiencing any side effects (29.9% vs. 23.4%; p < 0.001), knowing the amount of cannabis they were taking (32.1% vs. 17.7%; p < 0.001), obtaining cannabis from regulated sources (74.1% vs. 47.5%; p < 0.001), and seeking information about medical cannabis from healthcare professionals (67.8% vs. 48.2%; p < 0.01) than individuals without authorization. CONCLUSIONS: These findings offer insight into the possible issues regarding equitable access to medical cannabis and how authorization may support and influence individuals in a jurisdiction where recreational cannabis is legalized, highlighting the value of a formal medical cannabis authorization process.

Five-Year Longitudinal Follow-up of Restorative Neurostimulation Shows Durability of Effectiveness in Patients With Refractory Chronic Low Back Pain Associated With Multifidus Muscle Dysfunction.

BACKGROUND: Adults with refractory, mechanical chronic low back pain associated with impaired neuromuscular control of the lumbar multifidus muscle have few treatment options that provide long-term clinical benefit. This study hypothesized that restorative neurostimulation, a rehabilitative treatment that activates the lumbar multifidus muscles to overcome underlying dysfunction, is safe and provides relevant and durable clinical benefit to patients with this specific etiology. MATERIALS AND METHODS: In this prospective five-year longitudinal follow-up of the ReActiv8-B pivotal trial, participants (N = 204) had activity-limiting, moderate-to-severe, refractory, mechanical chronic low back pain, a positive prone instability test result indicating impaired multifidus muscle control, and no indications for spine surgery. Low back pain intensity (10-cm visual analog scale [VAS]), disability (Oswestry Disability Index), and quality of life (EuroQol's "EQ-5D-5L" index) were compared with baseline and following the intent-to-treat principle, with a supporting mixed-effects model for repeated measures that accounted for missing data. RESULTS: At five years (n = 126), low back pain VAS had improved from 7.3 to 2.4 cm (-4.9; 95% CI, -5.3 to -4.5 cm; p < 0.0001), and 71.8% of participants had a reduction of ≥50%. The Oswestry Disability Index improved from 39.1 to 16.5 (-22.7; 95% CI, -25.4 to -20.8; p < 0.0001), and 61.1% of participants had reduction of ≥20 points. The EQ-5D-5L index improved from 0.585 to 0.807 (0.231; 95% CI, 0.195-0.267; p < 0.0001). Although the mixed-effects model attenuated completed-case results, conclusions and statistical significance were maintained. Of 52 subjects who were on opioids at baseline and had a five-year visit, 46% discontinued, and 23% decreased intake. The safety profile compared favorably with neurostimulator treatments for other types of back pain. No lead migrations were observed. CONCLUSION: Over a five-year period, restorative neurostimulation provided clinically substantial and durable benefits with a favorable safety profile in patients with refractory chronic low back pain associated with multifidus muscle dysfunction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02577354; registration date: October 15, 2016; principal investigator: Christopher Gilligan, MD, Brigham and Women's Hospital, Boston, MA, USA. The study was conducted in Australia (Broadmeadow, New South Wales; Noosa Heads, Queensland; Welland, South Australia; Clayton, Victoria), Belgium (Sint-Niklaas; Wilrijk), The Netherlands (Rotterdam), UK (Leeds, London, Middlesbrough), and USA (La Jolla, CA; Santa Monica, CA; Aurora, CO; Carmel, IN; Indianapolis, IN; Kansas City, KS; Boston, MA; Royal Oak, MI; Durham, NC; Winston-Salem, NC; Cleveland, OH; Providence, RI; Spartanburg, SC; Spokane, WA; Charleston, WV).

Treating Chronic, Intractable Pain with a Miniaturized Spinal Cord Stimulation System: 1-Year Outcomes from the AUS-nPower Study During the COVID-19 Pandemic.

Purpose: Spinal cord stimulation (SCS) is a highly effective treatment for chronic neuropathic pain. Despite recent advances in technology, treatment gaps remain. A small SCS system with a miniaturized implantable pulse generator (micro-IPG; <1.5 cm3 in volume) and an externally worn power source may be preferred by patients who do not want a large, implanted battery. We report here the long-term outcomes from the first-in-human study evaluating the safety and performance of a new neurostimulation system. Patients and Methods: This was a prospective, multi-center, open-label, single-arm study to evaluate this SCS system, in the treatment of chronic, intractable leg and low-back pain. Consented subjects who passed screening continued on to the long-term phase of the study. One-year, patient-reported outcomes (PRO's) such as pain (Numeric Rating Scale, NRS), functional disability, quality of life, and mood were captured. Results: Twenty-six (26) evaluable subjects with permanent implants were included in this analysis. The average leg pain NRS score decreased from 6.8 ± 1.2 at baseline to 1.1 ± 1.2 at the end of the study (p < 0.001), while the average low-back pain NRS score decreased from 6.8 ± 1.2 to 1.5 ± 1.2 (p < 0.001). The responder rate (proportion with ≥50% pain relief) was 91% in the leg(s) and 82% in the low back. There were significant improvements in functional disability (Oswestry Disability Index) and in mood (Beck Depression Inventory), demonstrating a 46% and 62% improvement, respectively (p < 0.001). Eleven-point Likert scales demonstrated the wearable to be very comfortable and very easy to use. Conclusion: There were considerable challenges conducting a clinical study during the COVID-19 pandemic, such as missed study programming visits. Nevertheless, subjects had significant PRO improvements through 1-year. The small size of the implanted device, along with a proprietary waveform, may allow for improved SCS outcomes and a drop in incidence of IPG-pocket pain.

Single-Nucleus Transcriptional Profiling of GAD2-Positive Neurons From Mouse Lateral Habenula Reveals Distinct Expression of Neurotransmission- and Depression-Related Genes.

Background: Glutamatergic projection neurons of the lateral habenula (LHb) drive behavioral state modulation by regulating the activity of midbrain monoaminergic neurons. Identifying circuit mechanisms that modulate LHb output is of interest for understanding control of motivated behaviors. Methods: A small population of neurons within the medial subnucleus of the mouse LHb express the GABAergic (gamma-aminobutyric acidergic)-synthesizing enzyme GAD2, and they can inhibit nearby LHb projection neurons; however, these neurons lack markers of classic inhibitory interneurons, and they coexpress the vesicular glutamate transporter VGLUT2. To determine the molecular phenotype of these neurons, we genetically tagged the nuclei of GAD2-positive cells and used fluorescence-activated nuclear sorting to isolate and enrich these nuclei for single-nucleus RNA sequencing. Results: Our data confirm that GAD2+/VGLUT2+ neurons intrinsic to the LHb coexpress markers of both glutamatergic and GABAergic transmission and that they are transcriptionally distinct from either GABAergic interneurons or habenular glutamatergic neurons. We identify gene expression programs within these cells that show sex-specific differences in expression and that are implicated in major depressive disorder, which has been linked to LHb hyperactivity. Finally, we identify the Ntng2 gene encoding the cell adhesion protein netrin-G2 as a marker of LHb GAD2+/VGLUT2+ neurons and a gene product that may contribute to their target projections. Conclusions: These data show the value of using genetic enrichment of rare cell types for transcriptome studies, and they advance understanding of the molecular composition of a functionally important class of GAD2+ neurons in the LHb.

Succinate in the tumor microenvironment affects tumor growth and modulates tumor associated macrophages.

Succinate is an important metabolite that modulates metabolism of immune cells and cancer cells in the tumor microenvironment (TME). Herein, we report that polyethylene succinate (PES) microparticles (MPs) biomaterial mediated controlled delivery of succinate in the TME modulates macrophage responses. Administering PES MPs locally with or without a BRAF inhibitor systemically in an immune-defective aging mice with clinically relevant BRAFV600E mutated YUMM1.1 melanoma decreased tumor volume three-fold. PES MPs in the TME also led to maintenance of M1 macrophages with up-regulation of TSLP and type 1 interferon pathway. Impressively, this led to generation of pro-inflammatory adaptive immune responses in the form of increased T helper type 1 and T helper type 17 cells in the TME. Overall, our findings from this challenging tumor model suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.

A rotating white dwarf shows different compositions on its opposite faces.

White dwarfs, the extremely dense remnants left behind by most stars after their death, are characterized by a mass comparable to that of the Sun compressed into the size of an Earth-like planet. In the resulting strong gravity, heavy elements sink towards the centre and the upper layer of the atmosphere contains only the lightest element present, usually hydrogen or helium1,2. Several mechanisms compete with gravitational settling to change a white dwarf's surface composition as it cools3, and the fraction of white dwarfs with helium atmospheres is known to increase by a factor of about 2.5 below a temperature of about 30,000 kelvin4-8; therefore, some white dwarfs that appear to have hydrogen-dominated atmospheres above 30,000 kelvin are bound to transition to be helium-dominated as they cool below it. Here we report observations of ZTF J203349.8+322901.1, a transitioning white dwarf with two faces: one side of its atmosphere is dominated by hydrogen and the other one by helium. This peculiar nature is probably caused by the presence of a small magnetic field, which creates an inhomogeneity in temperature, pressure or mixing strength over the surface9-11. ZTF J203349.8+322901.1 might be the most extreme member of a class of magnetic, transitioning white dwarfs-together with GD 323 (ref. 12), a white dwarf that shows similar but much more subtle variations. This class of white dwarfs could help shed light on the physical mechanisms behind the spectral evolution of white dwarfs.

Zwitterionic Copolymers for Anti-Scaling Applications in Simulated Spaceflight Wastewater Scenarios.

Water reclamation in spaceflight applications, such as those encountered on the International Space Station (ISS), requires complex engineering solutions to ensure maximum water recovery. Current vapor compression distillation (VCD) technologies are effective but produce highly concentrated brines and often cause scaling within a separation system. This work evaluates initial steps toward integrating pervaporation, a membrane separation process, as a brine management strategy for ISS wastewaters. Pervaporation performs separations driven by a chemical potential difference across the membrane created by either a sweep gas or a vacuum pull. Pervaporation membranes, as with most membrane processes, can be subject to scaling. Therefore, this work studies the anti-scaling properties of zwitterions (polymeric molecules with covalently tethered positive and negative ions) coated onto sulfonated pentablock terpolymer block polymer (Nexar) pervaporation membrane surfaces. We report a method for applying zwitterions to the surface of pervaporation membranes and the effect on performance parameters such as flux and scaling resistance. Membranes with zwitterions had up to 53% reduction in permeance but reduced scaling. The highest amount of scaling occurred in the samples exposed to calcium chloride, and uncoated membranes had weight percent increases as high as 1617 ± 241%, whereas zwitterion-coated membranes experienced only about 317 ± 87% weight increase in the presence of the same scalant.

Long transients and dendritic network structure affect spatial predator-prey dynamics in experimental microcosms.

Spatial dynamics can promote persistence of strongly interacting predators and prey. Theory predicts that spatial predator-prey systems are prone to long transients, meaning that the dynamics leading to persistence or extinction manifest over hundreds of generations. Furthermore, the form and duration of transients may be altered by spatial network structure. Few empirical studies have examined the importance of transients in spatial food webs, especially in a network context, due to the difficulty in collecting the large scale and long-term data required. We examined predator-prey dynamics in protist microcosms using three experimental spatial structures: isolated, river-like dendritic networks and regular lattice networks. Densities and patterns of occupancy were followed for both predators and prey over a time scale that equates to >100 predator and >500 prey generations. We found that predators persisted in dendritic and lattice networks whereas they went extinct in the isolated treatment. The dynamics leading to predator persistence played out over long transients with three distinct phases. The transient phases showed differences between dendritic and lattice structures, as did underlying patterns of occupancy. Spatial dynamics differed among organisms in different trophic positions. Predators showed higher local persistence in more connected bottles while prey showed this in more spatially isolated ones. Predictions based on spatial patterns of connectivity derived from metapopulation theory explained predator occupancy, while prey occupancy was better explained by predator occupancy. Our results strongly support the hypothesized role of spatial dynamics in promoting persistence in food webs, but that the dynamics ultimately leading to persistence may occur with long transients which in turn may be influenced by spatial network structure and trophic interactions.

Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy.

Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses. Administration of poly(ethylene succinate) (PES MP)-based vaccines and glutaminase inhibitor to young immunocompetent mice with aggressive and large, established B16F10 melanoma tumors increased their survival three-fold, a result of increased cytotoxic T cells expressing RORγT (Tc17). Mechanistically, PES MPs directly modulate glutamine and glutamate metabolism, upregulate succinate receptor SUCNR1, activate antigen presenting cells through and HIF-1alpha, TNFa and TSLP-signaling pathways, and are dependent on alpha-ketoglutarate dehydrogenase for their activity, which demonstrates correlation of succinate delivery and these pathways. Overall, our findings suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.

Colorectal Cancer Screening Decisions From Student-Led Telemedicine Initiative During COVID-19.

Background and Objectives: With the onset of the COVID-19 pandemic, there has been a significant decrease in colorectal cancer (CRC) screening leading to delayed diagnoses and increased cancer deaths. To mitigate these burgeoning gaps in care, we developed a medical student-led service learning project aimed at improving rates of colorectal cancer screening at the Farrell Health Center (FHC), a primary care practice within the Ambulatory Care Network (ACN) at New York-Presbyterian Hospital. Methods: A cohort of 973 FHC patients aged 50-75 years were identified as possibly overdue for screening. Student volunteers reviewed patient charts to confirm screening eligibility and then contacted patients to offer colonoscopy or stool DNA test. Following the patient outreach intervention, medical student volunteers completed a questionnaire to assess the educational value for the service-learning experience. Results: Fifty-three percent of identified patients were due for CRC screening; 67.8% of eligible patients were reached by volunteers. Among the patients reached, 47.0% were referred for CRC screening. No statistical significance was observed between likelihood of CRC screening acceptance and patient age or sex; 87% of medical student volunteers felt that the service-learning project was a valuable educational experience. Conclusion: The student-led patient telehealth outreach program is an effective model for identifying and referring patients overdue for CRC screening and an enriching educational experience for preclinical medical students. The structure provides a valuable framework to address gaps in health care maintenance.

Long-term safety of spinal cord stimulation systems in a prospective, global registry of patients with chronic pain.

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration: NCT01719055 (ClinicalTrials.gov).

Early Experience With a Novel Miniaturized Spinal Cord Stimulation System for the Management of Chronic Intractable Pain of the Back and Legs.

INTRODUCTION: A novel, spinal cord stimulation (SCS) system with a battery-free miniaturized implantable pulse generator (IPG) was used in this feasibility study. The system uses an external power source that communicates bidirectionally with the IPG (< 1.5 cm3). Human factors, subject comfort, and effects on low back and leg pain were evaluated in this first-in-human study. MATERIALS AND METHODS: A prospective, multicenter, open-label clinical trial was initiated to evaluate the safety and performance of a novel miniaturized stimulator in the treatment of chronic, intractable leg and low-back pain. Eligible subjects were recruited for the study and gave consent. Subjects who passed the screening/trial phase (defined as ≥ 50% decrease in pain) continued to the long-term implant phase and were followed up at predefined time points after device activation. Interim clinical and usability outcomes were captured and reported at 90 days. RESULTS: Results of 22 subjects who chose a novel pulsed stimulation pattern therapy using the battery-free IPG (< 1.5 cm3) are described here. At 90-days follow-up, the average pain reduction was 79% in the leg (n = 22; p < 0.0001) and 76% in the low back (n = 21; p < 0.0001) compared with baseline. Responder rates (≥ 50% pain relief) at 90 days were 86% in leg pain (19/22) and 81% in low-back pain (17/21). Subjects rated the level of comfort of the external wearable power source to be 0.41 ± 0.73 at 90 days on an 11-point rating scale (0 = very comfortable, 10 = very uncomfortable). DISCUSSION: These interim results from the ongoing study indicate the favorable efficacy and usability of a novel, externally powered, battery-free SCS IPG (< 1.5 cm3) for leg and low-back pain. Study subjects wore the external power source continuously and found it comfortable, and the system provided significant pain relief. These preliminary findings warrant further investigation. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is ACTRN12618001862235.

Single-nucleus transcriptional profiling of GAD2-positive neurons from mouse lateral habenula reveals distinct expression of neurotransmission- and depression-related genes.

Glutamatergic projection neurons of the lateral habenula (LHb) drive behavioral state modulation by regulating the activity of midbrain monoaminergic neurons. Identifying circuit mechanisms that modulate LHb output is of interest for understanding control of motivated behaviors. A small population of neurons within the medial subnucleus of the mouse LHb express the GABAergic synthesizing enzyme GAD2, and they can inhibit nearby LHb projection neurons; however, these neurons lack markers of classic inhibitory interneurons and they co-express the vesicular glutamate transporter VGLUT2. To determine the molecular phenotype of these neurons, we genetically tagged the nuclei of GAD2-positive cells and used fluorescence-activated nuclear sorting to isolate and enrich these nuclei for single nuclear RNA sequencing (FANS-snRNAseq). Our data confirm that GAD2+/VGLUT2+ neurons intrinsic to the LHb co-express markers of both glutamatergic and GABAergic transmission and that they are transcriptionally distinct from either GABAergic interneurons or habenular glutamatergic neurons. We identify gene expression programs within these cells that show sex-specific differences in expression and that are implicated in major depressive disorder (MDD), which has been linked to LHb hyperactivity. Finally, we identify the Ntng2 gene encoding the cell adhesion protein Netrin-G2 as a marker of LHb GAD2+/VGLUT+ neurons and a gene product that may contribute to their target projections. These data show the value of using genetic enrichment of rare cell types for transcriptome studies, and they advance understanding of the molecular composition of a functionally important class of GAD2+ neurons in the LHb.

Long-Term Outcomes of Restorative Neurostimulation in Patients With Refractory Chronic Low Back Pain Secondary to Multifidus Dysfunction: Two-Year Results of the ReActiv8-B Pivotal Trial.

BACKGROUND: Impaired neuromuscular control and degeneration of the multifidus muscle have been linked to the development of refractory chronic low back pain (CLBP). An implantable restorative-neurostimulator system can override the underlying multifidus inhibition by eliciting episodic, isolated contractions. The ReActiv8-B randomized, active-sham-controlled trial provided effectiveness and safety evidence for this system, and all participants received therapeutic stimulation from four months onward. OBJECTIVE: This study aimed to evaluate the two-year effectiveness of this restorative neurostimulator in patients with disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. MATERIALS AND METHODS: Open-label follow-up of 204 participants implanted with a restorative neurostimulation system (ReActiv8, Mainstay Medical, Dublin, Ireland) was performed. Pain intensity (visual analog scale [VAS]), disability (Oswestry disability index [ODI]), quality-of-life (EQ-5D-5L), and opioid intake were assessed at baseline, six months, one year, and two years after activation. RESULTS: At two years (n = 156), the proportion of participants with ≥50% CLBP relief was 71%, and 65% reported CLBP resolution (VAS ≤ 2.5 cm); 61% had a reduction in ODI of ≥20 points, 76% had improvements of ≥50% in VAS and/or ≥20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 87% of participants had continued device use during the second year for a median of 43% of the maximum duration, and 60% (34 of 57) had voluntarily discontinued (39%) or reduced (21%) opioid intake. CONCLUSIONS: At two years, 76% of participants experienced substantial, clinically meaningful improvements in pain, disability, or both. These results provide evidence of long-term effectiveness and durability of restorative neurostimulation in patients with disabling CLBP, secondary to multifidus muscle dysfunction. CLINICAL TRIAL REGISTRATION: The study is registered on clinicaltrials.gov with identifier NCT02577354.

Time to change direction in training load monitoring in elite football? The application of MEMS accelerometers for the evaluation of movement requirements.

In elite football, the emphasis is placed on monitoring the output from the Global Positioning Systems (GPS) component of a Micro-Electro-Mechanical Systems (MEMS) device; however, this does not comprehensively overview the total demands due to the intermittent multidirectional nature. The aim of the study was to investigate the application of accelerometer data provided by MEMS, to evaluate movement requirements in elite football. A two-staged research approach, involving an effectiveness and efficacy stage, was deployed. The effectiveness stage examined two MEMS-accelerometer variables (PlayerLoadTM (PL) and PlayerLoadTM per meter (PL.m-1)) for four years and four months. Ninety-nine English Premier League outfield football players' participated. In the efficacy stage, 26 elite outfield football players completed three different training modalities (running, possession and dribbling) and a range of MEMS-accelerometer variables were analysed. In the effectiveness stage, the mean difference in PL for all training activities other than Set Pieces were similar to Matches (-283 to -246au). Model coefficients for PL.m-1 were smallest in Team Shape (-0.00114au), Attacking (0.00025au) and Games (0.00196au), and largest for Possession (0.03356AU), Defending (0.03182au) and Skills Games (0.03106au) compared to Matches. The findings suggest that PL.m-1 but not PL may be effective at describing differences in movement requirements. In the efficacy stage, PL.m-1 and inertial movement analysis (IMA) efforts were the only variables that had greater mean differences in the smaller conditions, confirming PL.m-1's suitability in evaluating movement requirements of different training activities and pitch dimensions. The findings suggest such a variable offers value in a monitoring strategy in football.

Three-Year Durability of Restorative Neurostimulation Effectiveness in Patients With Chronic Low Back Pain and Multifidus Muscle Dysfunction.

BACKGROUND: Restorative neurostimulation is a rehabilitative treatment for patients with refractory chronic low back pain (CLBP) associated with dysfunction of the lumbar multifidus muscle resulting in impaired neuromuscular control. The ReActiv8-B randomized, sham-controlled trial provided evidence of the effectiveness and safety of an implanted, restorative neurostimulator. The two-year analysis previously published in this journal demonstrated accrual of clinical benefits and long-term durability. OBJECTIVE: Evaluation of three-year effectiveness and safety in patients with refractory, disabling CLBP secondary to multifidus muscle dysfunction and no indications for spine surgery. MATERIALS AND METHODS: Prospective, observational follow-up of the 204 implanted trial participants. Low back pain visual analog scale (VAS), Oswestry Disability Index (ODI), EuroQol quality of life survey, and opioid intake were assessed at baseline, six months, and one, two, and three years after activation. The mixed-effects model repeated measures approach was used to provide implicit imputations of missing data for continuous outcomes and multiple imputation for proportion estimates. RESULTS: Data were collected from 133 participants, and 16 patients missed their three-year follow-up because of coronavirus disease restrictions but remain available for future follow-up. A total of 62% of participants had a ≥ 70% VAS reduction, and 67% reported CLBP resolution (VAS ≤ 2.5cm); 63% had a reduction in ODI of ≥ 20 points; 83% had improvements of ≥ 50% in VAS and/or ≥ 20 points in ODI, and 56% had these substantial improvements in both VAS and ODI. A total of 71% (36/51) participants on opioids at baseline had voluntarily discontinued (49%) or reduced (22%) opioid intake. The attenuation of effectiveness in the imputed (N = 204) analyses was relatively small and did not affect the statistical significance and clinical relevance of these results. The safety profile remains favorable, and no lead migrations have been observed to date. CONCLUSION: At three years, 83% of participants experienced clinically substantial improvements in pain, disability, or both. The results confirm the long-term effectiveness, durability, and safety of restorative neurostimulation in patients with disabling CLBP associated with multifidus muscle dysfunction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT02577354.

A case report of primary meningococcal pericarditis secondary to Neisseria meningitidis in a young female patient.

Pericarditis is responsible for approximately 5 % of emergency admissions due to chest pain. Pericarditis secondary to Neisseria meningitidis (meningococci) was originally reported in 1918, and remains a rare diagnosis. We report a case of primary meningococcal pericarditis presenting with non-specific symptoms, illustrating the importance of considering rarer causes of pericardial effusion. A previously fit and well 23-year-old female presented to her local hospital with a 2-day history of feeling generally unwell with myalgia and fevers and was initially discharged. Four days following discharge the patient re-presented with worsening symptoms. A Computed Tomography Pulmonary Angiogram (CTPA) demonstrated a large pericardial effusion with subsequent bedside echocardiogram confirming a global pericardial effusion of up to 3 cm. This required drainage, with blood cultures and pericardial fluid showing polymerase chain reaction positivity for Neisseria meningitidis, serogroup B. Our report describes a rare case of Primary Meningococcal Pericarditis secondary to serotype B meningococcal infection. The European Society of Cardiology propose criteria that warrant hospital admission and an aetiology search for certain patients with pericardial disease. These criteria provide a useful framework to help select those minority of patients in whom a more serious underlying cause is present. Blood cultures provide vital information to allow us to complete a thorough aetiological search and empirical antibiotics can cloud the clinical picture, making it harder to identify causative organisms. To aid the early administration of appropriate therapy, it may be pertinent to recommend a low threshold for taking blood cultures in patients with pyrexia and pericarditis or pericardial effusion.

KCa3.1 potentiation stimulates Cl- secretion in F508del and G551D CFTR-corrected primary human bronchial epithelial cells.

We previously identified potentiators of KCa3.1 (5,6-dichloro-1-ethyl-1,3-dihydro-2H-benzimidazol-2-one; DCEBIO) that stimulate Cl- secretion across human bronchial epithelial cells (HBEs) expressing wild-type (WT) cystic fibrosis transmembrane conductance regulator (CFTR). However, these compounds failed to stimulate Cl- secretion in F508del CFTR HBEs. Drug discovery efforts identified CFTR potentiators (VX-770) and correctors (VX-445, VX-661) for cystic fibrosis (CF) disease-causing mutations, including F508del and G551D. Herein, we evaluated the effect of KCa3.1 potentiation on Cl- equivalent current (ICl) across primary HBEs expressing WT, F508del, and G551D CFTR. Transepithelial impedance analysis was used to obtain estimates of apical (Ra) and basolateral membrane (BLM; Rb) resistances. In WT CFTR HBEs, DCEBIO stimulated ICl, which was increased by forskolin. Similarly, forskolin stimulated ICl, and this was increased by DCEBIO. The KCa3.1 blocker, TRAM-34 inhibited ICl. DCEBIO decreased Rb, whereas TRAM-34 increased Rb, consistent with BLM localization of KCa3.1. Following correction of F508del CFTR with VX-445 + VX-661, DCEBIO failed to stimulate ICl, although the subsequent addition of forskolin + VX-770 increased ICl. Importantly, following stimulation of ICl with forskolin + VX-770, DCEBIO induced a further significant increase in ICl. As above, DCEBIO reduced Rb, whereas TRAM-34 increased Rb, consistent with BLM localized KCa3.1. Finally, we assessed KCa3.1 potentiation on ICl in G551D/F508del CFTR HBEs in the absence or presence of VX-445 + VX-661. In both cases, DCEBIO failed to stimulate ICl. However, following stimulation with forskolin + VX-770, DCEBIO nearly doubled ICl. Our results demonstrate that following correction/potentiation of F508del and G551D CFTR, potentiation of KCa3.1 increases the Cl- secretory response, suggesting this class of compounds may represent a novel means of further increasing Cl- secretion across CF airway.

Genome-Wide Association and Genomic Prediction of Growth Traits in the European Flat Oyster (Ostrea edulis).

The European flat oyster (Ostrea edulis) is a bivalve mollusc that was once widely distributed across Europe and represented an important food resource for humans for centuries. Populations of O. edulis experienced a severe decline across their biogeographic range mainly due to overexploitation and disease outbreaks. To restore the economic and ecological benefits of European flat oyster populations, extensive protection and restoration efforts are in place within Europe. In line with the increasing interest in supporting restoration and oyster farming through the breeding of stocks with enhanced performance, the present study aimed to evaluate the potential of genomic selection for improving growth traits in a European flat oyster population obtained from successive mass-spawning events. Four growth-related traits were evaluated: total weight (TW), shell height (SH), shell width (SW) and shell length (SL). The heritability of the growth traits was in the low-moderate range, with estimates of 0.45, 0.37, 0.22, and 0.32 for TW, SH, SW and SL, respectively. A genome-wide association analysis revealed a largely polygenic architecture for the four growth traits, with two distinct QTLs detected on chromosome 4. To investigate whether genomic selection can be implemented in flat oyster breeding at a reduced cost, the utility of low-density SNP panels was assessed. Genomic prediction accuracies using the full density panel were high (> 0.83 for all traits). The evaluation of the effect of reducing the number of markers used to predict genomic breeding values revealed that similar selection accuracies could be achieved for all traits with 2K SNPs as for a full panel containing 4,577 SNPs. Only slight reductions in accuracies were observed at the lowest SNP density tested (i.e., 100 SNPs), likely due to a high relatedness between individuals being included in the training and validation sets during cross-validation. Overall, our results suggest that the genetic improvement of growth traits in oysters is feasible. Nevertheless, and although low-density SNP panels appear as a promising strategy for applying GS at a reduced cost, additional populations with different degrees of genetic relatedness should be assessed to derive estimates of prediction accuracies to be expected in practical breeding programmes.

Migration of retained tarsal bee stinger onto the ocular surface causing superficial keratopathy.

We report a case of keratopathy due to retained stinger elements following a bee sting and envenomation of the ocular adnexa. A 48-year-old woman presented with a 2-day history of right-sided eye pain, photophobia, and reduced visual acuity. Six days prior to presentation, she had been stung on the right upper eyelid by a bee. Her usual practitioner had removed the stinger and commenced a course of oral antibiotics. Anterior segment examination revealed coarse linear abrasions and superficial punctate keratitis with associated epithelial edema. Eversion of the right upper eyelid revealed the presence of retained stinger lancets near the medial eyelid margin. The retained stinger was removed, and the patient responded well to treatment with topical antibiotics, steroids, and cycloplegia.