Evaluating change in diet with pegvaliase treatment in adults with phenylketonuria: Analysis of phase 3 clinical trial data.

Phenylketonuria (PKU), a genetic disorder characterized by phenylalanine hydroxylase (PAH) deficiency and phenylalanine (Phe) accumulation, is primarily managed with a protein-restricted diet and PKU-specific medical foods. Pegvaliase is an enzyme substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 µmol/L) despite prior management. This analysis assessed the effect of pegvaliase on dietary intake using data from the Phase 3 PRISM-1 (NCT01819727), PRISM-2 (NCT01889862), and 165-304 (NCT03694353) clinical trials. Participants (N = 250) had a baseline diet assessment, blood Phe ≥600 µmol/L, and had discontinued sapropterin; they were not required to follow a Phe-restricted diet. Outcomes were analyzed by baseline dietary group, categorized as >75%, some (>0% but ≤75%), or no protein intake from medical food. At baseline, mean age was 29.1 years, 49.2% were female, mean body mass index was 28.4 kg/m2, and mean blood Phe was 1237.0 µmol/L. Total protein intake was stable up to 48 months for all 3 baseline dietary groups. Over this time, intact protein intake increased in all groups, and medical protein intake decreased in those who consumed any medical protein at baseline. Of participants consuming some or >75% medical protein at baseline, 49.1% and 34.1% were consuming no medical protein at last assessment, respectively. Following a first hypophenylalaninemia (HypoPhe; 2 consecutive blood Phe measurements <30 µmol/L) event, consumption of medical protein decreased and consumption of intact protein increased. Substantial and sustained Phe reductions were achieved in all 3 baseline dietary groups. The probability of achieving sustained Phe response (SPR) at ≤600 µmol/L was significantly greater for participants consuming medical protein versus no medical protein in an unadjusted analysis, but no statistically significant difference between groups was observed for probability of achieving SPR ≤360 or SPR ≤120 µmol/L. Participants with alopecia (n = 49) had longer pegvaliase treatment durations, reached HypoPhe sooner, and spent longer in HypoPhe than those who did not have alopecia. Most (87.8%) had an identifiable blood Phe drop before their first alopecia episode, and 51.0% (n = 21/41) of first alopecia episodes with known duration resolved before the end of the HypoPhe episode. In conclusion, pegvaliase treatment allowed adults with PKU to lower their blood Phe, reduce their reliance on medical protein, and increase their intact and total protein intake. Results also suggest that HypoPhe does not increase the risk of protein malnutrition in adults with PKU receiving pegvaliase.

Best practice recommendations for the management of anxiety during the pegvaliase journey.

BACKGROUND: Pegvaliase, an enzyme substitution therapy, is a treatment option for phenylketonuria (PKU). Due to the neuropathophysiology and disease burden of PKU, individuals can experience baseline anxiety unrelated to pegvaliase therapy. In addition, there are aspects of pegvaliase therapy that may be anxiety-inducing for those considering or receiving treatment. The aim of this manuscript is to present best practice recommendations for the identification and management of anxiety symptoms that can occur along the pegvaliase journey. METHODS: A modified Delphi approach was used to seek consensus among a multidisciplinary panel of experts. To this end, an in-person meeting was held that was preceded by a medical specialist- and patient-specific survey to develop preliminary recommendations on ways to address anxiety along the pegvaliase journey. After the meeting, an additional survey was conducted to rank the proposed solutions and mitigation strategies from which a set of recommendations was developed. All recommendations were voted on with the aim of consensus generation, defined as achieving ≥75% agreement among experts. RESULTS: The panel reached consensus on a total of 28 best practice recommendations for the management of anxiety during the pre-treatment, induction and titration, early maintenance (pre-efficacy), and late maintenance (post-efficacy) stages. The recommendations offer strategies to identify and address the most common causes of pegvaliase-related anxiety, including self-injection, side effects, the titration schedule, prescribed dietary changes, and variable time to efficacy. Overall, managing anxiety in those considering or receiving pegvaliase involves patient-centered communication, shared decision-making, and personalized treatment plans. CONCLUSIONS: The best practice recommendations described herein can guide healthcare providers in proactively addressing anxiety during the different stages of pegvaliase treatment, and support providers with initiating and managing pegvaliase in individuals who may experience baseline and treatment-related anxiety.

Updates in the management of relapsed/refractory multiple myeloma.

Multiple myeloma, a malignant neoplasm of plasma cells that accumulate in bone marrow, accounts for approximately 18% of hematologic malignancies in the United States. Patients are often treated with triplet therapy and may undergo stem cell transplantation. Despite effective therapies, multiple myeloma remains incurable. Patients often require maintenance therapy, and many will progress or relapsed following upfront treatment. Selection of treatment in the relapse/refractory setting is complex due numerous active therapeutic agents and combinations. Treatment is often tailored to prior exposure and duration. In 2020, three novel pharmacological agents were approved in the relapsed setting. We highlight the clinical safety and efficacy of selinexor, isatuximab-irfc, and belantamab mafodotin for patients with multiple myeloma.

Subacute administration of both methcathinone and manganese causes basal ganglia damage in mice resembling that in methcathinone abusers.

An irreversible extrapyramidal syndrome occurs in man after intravenous abuse of "homemade" methcathinone (ephedrone, Mcat) that is contaminated with manganese (Mn) and is accompanied by altered basal ganglia function. Both Mcat and Mn can cause alterations in nigrostriatal function but it remains unknown whether the effects of the 'homemade' drug seen in man are due to Mcat or to Mn or to a combination of both. To determine how toxicity occurs, we have investigated the effects of 4-week intraperitoneal administration of Mn (30 mg/kg t.i.d) and Mcat (100 mg/kg t.i.d.) given alone, on the nigrostriatal function in male C57BL6 mice. The effects were compared to those of the 'homemade' mixture which contained about 7 mg/kg of Mn and 100 mg/kg of Mcat. Motor function, nigral dopaminergic cell number and markers of pre- and postsynaptic dopaminergic neuronal integrity including SPECT analysis were assessed. All three treatments had similar effects on motor behavior and neuronal markers. All decreased motor activity and induced tyrosine hydroxylase positive cell loss in the substantia nigra. All reduced 123I-epidepride binding to D2 receptors in the striatum. Vesicular monoamine transporter 2 (VMAT2) binding was not altered by any drug treatment. However, Mcat treatment alone decreased levels of the dopamine transporter (DAT) and Mn alone reduced GAD immunoreactivity in the striatum. These data suggest that both Mcat and Mn alone could contribute to the neuronal damage caused by the 'homemade' mixture but that both produce additional changes that contribute to the extrapyramidal syndrome seen in man.

Defining and Applying Locally Relevant Benchmarks for the Adenoma Detection Rate.

INTRODUCTION: The adenoma detection rate (ADR) is the best validated colonoscopy performance quality indicator. The ASGE/ACG Task Force on Colonoscopy Quality set an ADR benchmark of ≥25% in a mixed male/female population. We propose a novel means for defining locally relevant ADR benchmarks using data from the population of interest and for applying ADR benchmarks using 95% confidence intervals (CIs) of an endoscopist's ADR. We further propose that ADR benchmarks should be raised to reflect what can be achieved by high-performing endoscopists. METHODS: We used endoscopists' performance in a baseline year to develop and apply benchmarks in an assessment year. We defined assessment year benchmarks (Minimally Acceptable, Standard of Care, and Aspirational) based on the average ADR of performance groups defined by baseline year ADR quartiles. We demonstrated the use of these benchmarks in endoscopists performing screening colonoscopies by determining if the upper bound of the 95% CI of the endoscopist's ADR included the ADR benchmark. RESULTS: The study included 8,492 colonoscopies (mean ADR 29%) in 2014 and 5,193 colonoscopies (mean ADR 32%) in 2015, completed at a regional screening center in Calgary, Canada. The Minimally Acceptable, Standard of Care, and Aspirational benchmarks for 2015 were 25%, 30%, and 39%, respectively. The 95% CI of the ADR of 1 (3%), 3 (10%), and 12 (39%) endoscopists did not include the benchmark. DISCUSSION: We have proposed methods for defining and applying benchmarks for ADR in average-risk patients that go beyond the "minimally acceptable" threshold currently recommended.

Hypophosphatemia is Prevalent among Preterm Infants Less than 1,500 Grams.

OBJECTIVE: This article identifies the prevalence and associated factors of hypophosphatemia (HP) in very low birth weight (VLBW) infants in the first week of life. STUDY DESIGN: Prospective exploratory cohort study of 106 consecutive VLBW infants admitted to neonatal intensive care at Foothills Hospital, Calgary, Canada. HP was defined as at least one measurement of serum phosphate < 1.5 mmol/L (4.5 mg/dL). RESULTS: Seventy-seven percent (82/106) of the VLBW infants had HP, with significantly higher prevalence in infants < 1,000 g (94%) compared to infants ≥ 1,000 g (61%) (p < 0.001). Hypophosphatemic infants had lower birth weight (p < 0.001), gestational age (p < 0.001), and their increase in phosphate intake was slower (p = 0.003). Respiratory distress syndrome (RDS) (p = 0.002), intraventricular hemorrhage (IVH) ≥ grade III (p = 0.020), and hyperglycemia (p = 0.013) were more frequent among hypophosphatemic infants, especially among those < 1,000 g. Mortality, seizures, arrhythmias, and need for transfusion were not different between groups. Birth weight modified the association between RDS, IVH, hyperglycemia, and HP. CONCLUSION: HP was ubiquitous among infants < 1,000 g and highly prevalent among those weighing 1,000 to 1,500 g. While the direction of effect was not clear, RDS, IVH, and hyperglycemia were associated with HP. Prevention of HP in these physiologically immature neonates might improve neonatal outcomes.

The effect of Banisteriopsis caapi (B. caapi) on the motor deficits in the MPTP-treated common marmoset model of Parkinson's disease.

Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4-113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4-7 mg/kg). L-DOPA reversed motor disability, increased locomotor activity, and induced moderate dyskinesia. B. caapi did not increase locomotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved motor disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in motor disability without affecting locomotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.

Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial.

BACKGROUND: Observational reports suggest that supplementation that increases citric acid cycle intermediates via anaplerosis may have therapeutic advantages over traditional medium-chain triglyceride (MCT) treatment of long-chain fatty acid oxidation disorders (LC-FAODs) but controlled trials have not been reported. The goal of our study was to compare the effects of triheptanoin (C7), an anaplerotic seven-carbon fatty acid triglyceride, to trioctanoin (C8), an eight-carbon fatty acid triglyceride, in patients with LC-FAODs. METHODS: A double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long-chain acylCoA dehydrogenase, trifunctional protein or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) who were randomly assigned a diet containing 20% of their total daily energy from either C7 or C8 for 4 months was conducted. Primary outcomes included changes in total energy expenditure (TEE), cardiac function by echocardiogram, exercise tolerance, and phosphocreatine recovery following acute exercise. Secondary outcomes included body composition, blood biomarkers, and adverse events, including incidence of rhabdomyolysis. RESULTS: Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p = 0.046) while experiencing a 20% (p = 0.041) decrease in LV wall mass on their resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared to patients taking C8. There was no difference in TEE, phosphocreatine recovery, body composition, incidence of rhabdomyolysis, or any secondary outcome measures between the groups. CONCLUSIONS: C7 improved LV ejection fraction and reduced LV mass at rest, as well as lowering heart rate during exercise among patients with LC-FAODs. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01379625.

Patient satisfaction and regret with decision differ between outcomes in the composite definition of success after reconstructive surgery.

INTRODUCTION AND HYPOTHESIS: To evaluate patient satisfaction and regret with their decision for reconstructive surgery, and determine if they valued each item equally in the composite definition of success after making the decision for surgery. METHODS: A list was created including all patients who underwent laparoscopic sacral colpopexy or laparoscopic uterosacrocolpopexy. Patients were placed in mutually exclusive outcome categories (retreatment, symptomatic failure, anatomic failure, and surgical success). Retreatment included any postoperative treatment for urinary incontinence, pelvic organ prolapse including pessary use, or surgery for mesh complications. The validated modified Decision Regret Scale (DRS) and the Satisfaction Decision Scale (SDS) questionnaires were administered by telephone. Higher DRS scores indicate greater regret and higher SDS scores indicate greater satisfaction with the decision for surgery. RESULTS: Of 715 patients, 197 were successfully contacted by telephone following reconstructive surgery and surveyed as study participants. Composite surgical outcomes were available for 150. Information on the need for retreatment was available for all the study participants. Surgery was successful in 101 (67.3 %) of the study participants. Anatomic failure occurred in 14, symptomatic failure occurred in 10, and retreatment was required in 25 of the study participants. Overall, the study participants were more satisfied than regretful with their decision for reconstructive surgery. Regret and satisfaction with their decision differed between outcomes in the composite definition of success after reconstructive surgery. CONCLUSIONS: Surgeons and patients should focus on retreatment rates during preoperative outcome discussions because retreatment will result in the least satisfaction and greatest regret with the decision for reconstructive surgery.

Defining Benchmarks for Adenoma Detection Rate and Adenomas Per Colonoscopy in Patients Undergoing Colonoscopy Due to a Positive Fecal Immunochemical Test.

OBJECTIVES: Although there is an accepted benchmark for adenoma detection rate (ADR) in average risk screening colonoscopy, a benchmark for ADR or the associated quality indicator, adenomas per colonoscopy (APC), for colonoscopies performed for a positive fecal immunochemical test (FIT+) has not been established. The purpose of this study was to propose methods for establishing a benchmark ADR and APC for FIT+ patients. METHODS: In this historical cohort study, we included 15,329 patients aged 50-74 years who underwent a colonoscopy at Alberta Health Services' Colon Cancer Screening Centre, Calgary, Canada, from 1 January 2014 to 30 June 2015 for either investigation of a positive FIT or average risk screening. Using meta-regression, we estimated for FIT+ patients the ADR and APC that corresponded to (Method #1: minimally acceptable) an ADR of 25% in average risk individuals, (Method #2: standard of care) the average ADR or APC in all FIT+ patients, and (Method #3: aspirational) the average FIT+ ADR or APC in colonoscopies performed by endoscopists with an ADR of ≥35% in average risk patients. RESULTS: At least one adenoma was detected in 30% of average risk patients and 58% of FIT+ patients. The calculated benchmark FIT+ ADRs for the three methods were 55, 60, and 65%, respectively. The calculated benchmarks for FIT+ APC were 1.2, 1.4, and 1.7, respectively. To account for expected random variation in individual endoscopists' ADR or APC, we propose using the upper bound of the 95% confidence interval of an endoscopist's ADR or APC to determine if they fall below a given benchmark. CONCLUSIONS: We have proposed methods of defining benchmarks for ADR and APC in FIT+ patients that go beyond the current "minimally acceptable" threshold currently recommended in average risk patients. These new thresholds represent results obtained by all peers and by a group of expert adenoma detectors defined in an independent patient cohort (average risk). Because the true adenoma burden in FIT+ patients could vary based on factors such as the threshold used to define a positive FIT, screening programs or endoscopy units may need to calculate their own benchmarks using local data.

Oral r-(-)-11-o-valeryl-n-n-propylnoraporphine reverses motor deficits in mptp-treated marmosets.

BACKGROUND: The D1/D2 dopamine agonist apomorphine has poor oral bioavailability, necessitating subcutaneous administration in the treatment of Parkinson's disease (PD). Acute subcutaneous injection is used as rescue therapy from "off" periods, whereas continuous subcutaneous infusion is used to increase "on" periods and to reduce dyskinesia when oral treatment fails. An orally active derivative of apomorphine would avoid the need for parenteral administration. We now describe the effects of the orally active compound R-(-)-11-O-valeryl-N-n-propylnoraporphine (11-OH-NPa valerate) on reversal of motor disability and expression of dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, l-dopa-primed dyskinetic common marmosets. METHODS: Locomotor activity, motor disability, and dyskinesia were assessed in MPTP-treated marmosets following the administration of apomorphine (0.075 mg/kg, subcutaneous and 0.28 to 1.12 mg/kg, oral) and 11-OH-NPa valerate (0.19, 0.38, and 0.75mg/kg, oral). RESULTS: Subcutaneous administration of apomorphine (0.075 mg/kg) produced a short-lasting reversal of motor disability and the expression of established dyskinesia, but when administered orally (0.28-1.12 mg/kg) it had no effect. In contrast, oral treatment with 11-OH-NPa valerate (0.19 and 0.75 mg/kg) induced a dose-related reversal of motor disability and increased locomotor activity with only mild to moderate dyskinesia. Only at the highest dose (0.75 mg/kg) was marked dyskinesia seen accompanying an extended period of motor disability reversal and increased locomotor activity. CONCLUSION: Oral administration of 11-OH-NPa valerate produced a rapid reversal of motor disability and, at effective dose levels, had a limited propensity to induce dyskinesia. 11-OH-NPa valerate is the first orally active derivative of apomorphine with potential for use in PD. © 2016 International Parkinson and Movement Disorder Society.

Inhibition of i-NOS but not n-NOS protects rat primary cell cultures against MPP(+)-induced neuronal toxicity.

Nitrative stress is a key component of the pathogenic process in Parkinson's disease (PD), but the relative roles of constitutive neuronal nitric oxide synthase (n-NOS) and inducible nitric oxide synthase (i-NOS) in glial cells remain unresolved. We have investigated the effects of a range of concentrations of the selective n-NOS inhibitor ARR17477, and the selective i-NOS inhibitor 1400W, on MPP(+)-induced cell death in foetal ventral mesencephalic (VM) dopaminergic cultures. MPP(+) induced a loss of TH-positive neurones accompanied by an increase in immunoreactivity for GFAP and OX-6 as markers of astrocytes and activated microglia, respectively, and induced i-NOS immunoreactivity. Unexpectedly, MPP(+) treatment did not induce 3-NT immunoreactivity in the cultures. ARR17477 and 1400W alone had no effect on the number of TH-positive cells or on the number of GFAP or OX-6 positive cells. ARR17477 did not prevent the MPP(+)-induced decrease in TH-positive neurones and had no effect on the increased number of GFAP- and OX-6-positive cells. By contrast, 1400W caused a concentration-dependent preservation of TH-positive neurones in the presence of MPP(+). It also significantly reduced the number of OX-6-immunoreactive cells and there was a small reduction in GFAP immunoreactivity. The results suggest a major role for i-NOS-mediated nitrative stress in microglia in MPP(+)-induced dopaminergic cell death and this may have important implications for developing neuroprotective strategies for PD.

Loss of locus coeruleus noradrenergic neurons alters the inflammatory response to LPS in substantia nigra but does not affect nigral cell loss.

In Parkinson's disease (PD), destruction of noradrenergic neurons in the locus coeruleus (LC) may precede damage to nigral cells and subsequently exaggerate dopaminergic cell loss. We examine if destruction of the locus coeruleus with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) alters dopaminergic cell loss in substantia nigra (SN) initiated by lipopolysaccharide (LPS) in the rat through an effect on glial cell activation. In rats, a single intraperitoneal dose of DSP-4 administered 8 days previously, caused a marked loss of tyrosine hydroxylase positive neurons in LC but no change in dopaminergic cell number in SN. Unilateral nigral LPS administration resulted in marked dopaminergic cell death with reactive microgliosis associated with enhanced p47 phox in OX-6 and OX-42 positive microglia. There was proliferation of inducible nitric oxide synthase (iNOS)-positive cells, formation of 3-nitrotyrosine (3-NT) and proliferation of astrocytes that expressed glial cell line-derived neurotrophic factor (GDNF). Following combined DSP-4 treatment and subsequent administration of LPS, unexpectedly, no further loss of tyrosine hydroxylase (TH)-immunoreactivity (-ir) occurred in the SN compared to the effects of LPS alone. However, there was a marked alteration in the morphology of microglial cell and a reduction of 3-NT- and iNOS-ir was evident. Expression of p47 phox was downregulated in microglia but up-regulated in TH-ir neurons. No further change in GFAP-ir was observed compared to that produced by DSP-4 alone or LPS alone, but the expression of GDNF was markedly reduced. This study suggests that in contrast to previous reports, prior LC damage does not influence subsequent nigral dopaminergic cell degeneration induced by LPS. Rather it appears to attenuate the microglial response thought to contribute to disease progression in PD.

The impact of relative age effects on psychosocial development: A systematic review.

BACKGROUND: Within the same school class, it is usual to find children who differ in age by almost a full calendar year. Although associations between being relatively young and poor academic outcomes are well documented, and relatively consistent, the associations between being relatively young and psychosocial outcomes are less clearly documented. AIMS: To review research which presents data relating to associations between a child's relative age and their psychosocial development. METHODS: A systematic review was conducted and reported in accordance with PRISMA guidelines. RESULTS: Fifty-nine papers met the inclusion criteria. The outcomes of the narrative synthesis and three meta-analyses found consistent, but very small, associations with relative age indicating that those who are relatively young are more likely to have more negative behaviour, mental well-being, and social experiences. CONCLUSIONS: Although being relatively young is associated with more negative psychosocial outcomes, the magnitude of these associations is consistently small. Furthermore, many of the outcome measures used are likely to be the result of multiple influences, not limited to the effects of relative age. Therefore, the findings are reassuring as they suggest that relative age itself is unlikely to substantially increase an individual's risk of poor psychosocial development.

A cross-cultural study of children's graphic representations of men- and women-dominated occupations.

Occupational gender stereotypes develop from early age and contribute to occupational gender imbalance. Previous research used questionnaires or interviews to investigate children's explicit stereotypes and where drawings have been used, mostly men-dominated occupations have been considered. This study used drawings and interviews to assess implicit stereotypes of both men and women-dominated occupations and whether children's sex, age and cultural background predicted these stereotypes. Two hundred and forty-three 6-to-7-year-olds and 10-to-11-year-olds in Britain and Argentina-encompassing both Global South and Global North perspectives- drew five human figures: (i) person of their choice, (ii) dancer, (iii) nanny (iv) firefighter and (v) pilot. In interviews, children confirmed and justified their gender choices for each drawing. Results indicate gender stereotypes in children from both countries, especially towards women-dominated occupations. Girls exhibited more rigid gender views than boys. These findings suggest widespread and culturally consistent occupational gender stereotypes, potentially limiting children's future job choices.

Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia.

Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson's disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release. Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.

Cannabidiol for moderate-severe insomnia: a randomized controlled pilot trial of 150 mg of nightly dosing.

STUDY OBJECTIVES: Low-dose cannabidiol (CBD) has become readily available in numerous countries; however, little consensus exists on its efficacy as a sleep aid. This trial explored the efficacy of 150 mg of CBD (n = 15) compared with placebo (n = 15) as a sleep aid in primary insomnia. CBD supplementation was hypothesized to decrease insomnia symptoms and improve aspects of psychological health, relative to placebo. METHODS: Using a randomized, placebo-controlled, parallel design featuring a single-blind placebo run-in week followed by a 2-week double-blind randomized dosing phase, participants consumed the assigned treatment sublingually 60 minutes before bed nightly. Wrist-actigraphy and sleep diaries measured daily sleep. Sleep quality, sleep effort, and well-being were measured weekly over 4 in-laboratory visits. Insomnia severity and trait anxiety were measured at screening and study conclusion. RESULTS: Insomnia severity, self-reported sleep-onset latency, sleep efficiency, and wake after sleep onset did not differ between treatments throughout the trial (all P > .05). Compared with placebo, the CBD group reported greater well-being scores throughout the trial (trial end mean difference = 2.60; standard error: 1.20), transient elevated behavior following wakefulness scores after 1 week of treatment (mean difference = 3.93; standard error: 1.53), and had superior objective sleep efficiency after 2 weeks of treatment (mean difference = 6.85; standard error: 2.95) (all P < .05). No other significant treatment effects were observed. CONCLUSIONS: Nightly supplementation of 150 mg CBD was similar to placebo regarding most sleep outcomes while sustaining greater well-being, suggesting more prominent psychological effects. Additional controlled trials examining varying treatment periods and doses are crucial. CLINICAL TRIAL REGISTRATION: Registry: Australian New Zealand Clinical Trials Registry; Name: Cannabidiol (CBD) treatment for insomnia; URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000070932; Identifier: ACTRN12620000070932. CITATION: Narayan AJ, Downey LA, Rose S, Di Natale L, Hayley AC. Cannabidiol for moderate-severe insomnia: a randomized controlled pilot trial of 150 mg of nightly dosing. J Clin Sleep Med. 2024;20(5):753-763.

Intracranial Efficacy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel in Real-World Patients with Non-Small-Cell Lung Cancer and EGFR or ALK Alterations.

Contrary to Pemetrexed-containing chemo-immunotherapy studies, Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel (ABCP) treatment has consistently shown clinical benefit in prospective studies in patients with lung cancer and actionable mutations, where intracranial metastases are common. Here, we aimed to describe the real-life population of patients fit to receive ABCP after targeted therapy and quantify its clinical effect in patients with brain metastases. Patients treated in Cheshire and Merseyside between 2019 and 2022 were identified. Data were collected retrospectively. A total of 34 patients with actionable EGFR or ALK alterations had treatment with a median age of 59 years (range 32-77). The disease control rate was 100% in patients with PDL1 ≥ 1% (n = 10). In total, 19 patients (56%) had brain metastases before starting ABCP, 17 (50%) had untreated CNS disease, and 4 (22%) had PDL1 ≥ 1%. The median time to symptom improvement was 12.5 days (range 4-21 days), with 74% intracranial disease control rates and 89.5% synchronous intracranial (IC) and extracranial (EC) responses. IC median Progression Free Survival (mPFS) was 6.48 months, EC mPFS was 10.75 months, and median Overall Survival 11.47 months. ABCP in real-life patients with brain metastases (treated or untreated) was feasible and showed similar efficacy to that described in patients without actionable mutations treated with upfront chemo-immunotherapy.

Expression of integrin and CD44 receptors recognising osteopontin in the normal and LPS-lesioned rat substantia nigra.

The multifunctional protein osteopontin (OPN) is expressed in the substantia nigra (SN) and protects nigral dopaminergic neurones against toxic insult in animal models of Parkinson's disease, although the mechanisms involved are uncertain. In the periphery, OPN regulates inflammatory processes by interacting with integrin and CD44 receptors but the presence and distribution of these sites in SN is unknown. We investigated the expression of integrin receptor subunits and CD44 receptors in the normal SN and after induction of inflammation by lipopolysaccharide (LPS), and their interaction with OPN. In normal rat SN, integrin αv , ß3 and ß1 , and CD44, receptors were expressed on neurones including TH-positive cells but not on glia. LPS administration induced a loss of TH-positive neurones in SN and increased expression of glial cells as shown by GFAP, OX-6 and ED-1 immunoreactivity. In LPS-lesioned SN, there was up-regulation of the expression of integrin ß3 and CD44 receptors. Co-localisation studies showed that this related to their increased expression on OX-6-, ED-1- and GFAP-positive cells. Furthermore, OPN interacted with integrin and CD44 receptors in the normal rat SN as demonstrated by co-immunoprecipitation and pull-down techniques. These data show that integrin and CD44 receptors are present on neurones in normal rat SN and that they are up-regulated on glial cells following LPS-mediated inflammation in SN, suggesting that they are functionally important in the inflammatory process. The interaction of OPN with these receptors suggests a role in the neuroprotective effect of this protein in the LPS model of Parkinson's disease.

Levodopa infusion does not decrease the onset of abnormal involuntary movements in parkinsonian rats.

The short duration of effect of levodopa is linked to pulsatile stimulation of striatal dopamine receptors and dyskinesia induction. However, the recent introduction of intraduodenal (i.d.) infusions and novel oral controlled release formulations of l-dopa may prevent dyskinesia induction and reduce the severity of established involuntary movements. We have compared the effects of twice-daily intraperitoneal (i.p.) administration and daily i.d. infusion of l-dopa on the induction and expression of abnormal involuntary movements in 6-hydroxydopamine (6-OHDA)-lesioned rats. Animals were treated with either twice-daily i.p. administration of l-dopa/carbidopa (7.85/12.5 mg/kg) or an 8-hour i.d. infusion of l-dopa/carbidopa (20/5 mg/mL; infusion rate: 0.04 mL/h) for 14 days, after which treatments were switched between groups and continued for a further 14 days. Pulsatile i.p. administration of l-dopa induced moderate to severe abnormal involuntary movements, which gradually increased in severity over the 14 days, but i.d. infusion of l-dopa induced abnormal involuntary movements of a similar severity. Switching from continuous i.d. to pulsatile i.p. administration of l-dopa continued to provoke severe abnormal involuntary movements expression. Switching from pulsatile i.p. to continuous i.d. l-dopa administration did not alter the peak abnormal involuntary movement severity but tended to reduce their duration. Treatment with less pulsatile l-dopa administration using i.d. infusion does not reduce the risk of the appearance of dyskinesia. By contrast, the duration of established dyskinesia can be reduced by more continuous l-dopa delivery in agreement with clinical experience.