Feasibility and Acceptability of a Videoconferencing CBT Intervention for Anxiety in People with Parkinson's Disease.

OBJECTIVES: In people with Parkinson's disease (PwPD), non-motor symptoms such as anxiety are common and have negative impacts on their quality of life. There are currently few interventions that address anxiety in PwPD, and access to diagnosis and treatment is often limited for those living in rural areas. The aim of this study was to evaluate the feasibility and acceptability of a telehealth videoconferencing CBT intervention for anxiety in PwPD. METHODS: A pre- and post-test feasibility study (N = 10) was conducted and evaluated utilizing the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance). RESULTS: Lack of access to the internet and videoconferencing technology were identified as barriers to participation. Physical health issues also impacted recruitment and retention. Non-completers were significantly older and less likely to have a carer involved in the intervention. Clinician adoption of the intervention was low while participant acceptability of videoconferencing technology varied and required carer support. CONCLUSIONS: Providing access to technology and support to overcome technological issues, as well as telehealth training for clinicians, are recommended in future studies to improve recruitment, retention, and implementation. CLINICAL IMPLICATIONS: Identification of barriers and facilitators provides future studies with the knowledge to tailorize their program to better suit PwPD.

Global assessment, cognitive profile, and characteristics of mild cognitive impairment in Parkinson's disease.

BACKGROUND: Cognitive deficits are evident throughout the course of Parkinson's disease (PD), with 24% of patients experiencing subtle cognitive disturbances at the time of diagnosis, and with up to 80% of patients developing PD dementia (PDD) at advanced stages of the disease PD patients with mild cognitive impairment (MCI), an at-risk phenotype of PDD, present with heterogeneous clinical characteristics that complicate the management of PD. OBJECTIVES: This study aims to examine the characteristics of PD-MCI by using the Movement Disorder Society (MDS) diagnostic criteria and evaluate the validity of global cognitive scales in identifying PD-MCI. METHODS: Seventy-nine (79) PD patients completed neuropsychological assessments and a comprehensive cognitive battery. PD-MCI was classified according to the level 2 MDS task force criteria. Mini-Mental State Examination (sMMSE), Montreal Cognitive Assessment (MoCA) and Parkinson's Disease Cognitive Rating Scale (PDCRS) were examined against a level 2 dichotomised PD-MCI diagnosis. Characteristics of PD-MCI were evaluated using logistic regression analysis. RESULTS: Twenty-seven patients met criteria for PD-MCI (34%). The MoCA and PDCRS demonstrated high validity to screen for PD-MCI. Impairments in multiple cognitive domains were observed in 77.8% of PD-MCI patients. There were significantly more males in the PD-MCI group compared to PD patients without MCI (p < 0.01). CONCLUSIONS: PD patients with MCI exhibited impairments in the attention/working memory, executive function and memory domains. Heterogeneous cognitive characteristics in PD warrant further investigation into specific cognitive subtypes to advance understanding and effective evaluation of PD-MCI.

Caring for a loved one with Parkinson's disease: the role of coping styles and relationship quality.

OBJECTIVE: Informal carers play an essential role in the care of individuals with Parkinson's disease (PD). This role, however, is often fraught with difficulties, including emotional, physical, and financial. Coping styles and relationship quality have been hypothesized to influence the impact of stressors. The aim of this study is to examine the relationship between carers' coping style, relationship quality, and carer burden. DESIGN: Cross-sectional. PARTICIPANTS: Thirty-nine PD patient carer dyads were included in the study. MEASUREMENTS: Participants completed self-rated questionnaires including the Dyadic Adjustment Scale, Zarit Burden Interview, and Brief Coping Orientation to Problems Experienced Inventory. RESULTS: Correlational analyses found significant and positive correlation between carer burden and all three coping styles (problem-focused, emotion-focused, and dysfunctional). There was also a moderate association between carers' perceived relationship quality and satisfaction and carer burden. Regression analyses found that carer's gender, severity of PD, relationship quality, emotion-focused, and dysfunctional coping styles did not predict carer burden. Conversely, problem-focused coping style predicted carer burden. CONCLUSION: The results highlight that there is no perfect way to react and care for a loved one and serves as important information for practitioners who design and implement interventions.

Updates and advances in the treatment of Parkinson disease.

Parkinson disease (PD) is a complex neurodegenerative disorder that can present heterogeneously with a combination of motor and non-motor symptoms. α-synuclein, a neuronal protein, can undergo aberrant conformational change resulting in the intra-neuronal accumulation of toxic oligomers that form Lewy bodies, the pathological hallmark of PD. There is evidence that pathological α-synuclein exhibits prion-like behaviour in its mode of transmission through the nervous system. The choice of initial dopaminergic treatments should be individually tailored but long term outcomes appear to be equivalent. There is level A evidence supporting the benefit of three different device-assisted therapies in treating troublesome motor fluctuations and dyskinesias. Stem cell transplantation as currently being trialled is predominantly a symptomatic therapy targeting only limited regions of the brain affected by PD, and will need to be proven to be not only as effective but as safe as currently available device-assisted therapies. New modes of treatment including active immunisation against oligomeric α-synuclein and drugs that alter cellular metabolism show some promise. The inability to effectively treat a range of non-motor, non-dopaminergic symptoms remains a major therapeutic challenge.

An overview of sleep and circadian dysfunction in Parkinson's disease.

Sleep and circadian alterations are amongst the very first symptoms experienced in Parkinson's disease, and sleep alterations are present in the majority of patients with overt clinical manifestation of Parkinson's disease. However, the magnitude of sleep and circadian dysfunction in Parkinson's disease, and its influence on the pathophysiology of Parkinson's disease remains often unclear and a matter of debate. In particular, the confounding influences of dopaminergic therapy on sleep and circadian dysfunction are a major challenge, and need to be more carefully addressed in clinical studies. The scope of this narrative review is to summarise the current knowledge around both sleep and circadian alterations in Parkinson's disease. We provide an overview on the frequency of excessive daytime sleepiness, insomnia, restless legs, obstructive apnea and nocturia in Parkinson's disease, as well as addressing sleep structure, rapid eye movement sleep behaviour disorder and circadian features in Parkinson's disease. Sleep and circadian disorders have been linked to pathological conditions that are often co-morbid in Parkinson's disease, including cognitive decline, memory impairment and neurodegeneration. Therefore, targeting sleep and circadian alterations could be one of the earliest and most promising opportunities to slow disease progression. We hope that this review will contribute to advance the discussion and inform new research efforts to progress our knowledge in this field.

How Well Do Caregivers Detect Depression and Anxiety in Patients With Parkinson Disease?

Depression and anxiety are prevalent in Parkinson disease (PD) yet underrecognized in clinical practice. Caregiver reports are frequently utilized to aid in the assessment of neuropsychiatric symptoms but little is known about caregivers' ability to recognize them in patients with PD. This study sought to examine the accuracy of caregiver reports. Eighty patient-caregiver dyads were involved. Accuracy of caregiver recognition was assessed by examining the level of agreement between caregiver ratings on the Neuropsychiatric Inventory and patients' diagnosis of depression and anxiety on the Mini-International Neuropsychiatric Interview (MINI)-Plus. The agreement between caregiver report and MINI-Plus diagnosis was low for both depression (6.3%) and anxiety (17.5%). The presence of depression was overreported, while anxiety was largely underestimated by caregivers. Caregiver distress significantly predicted inaccurate caregiver identification of depression ( R2 = .51, P < .001) and anxiety ( R2 = .08, P < .05). Results indicate that caregivers may be poor at recognizing depression and anxiety in patients with PD. Utilization of caregiver report should take into account potential biases that affect caregiver judgment.

Stepwise partitioning of Xp21: a profiling method for XK deletions causative of the McLeod syndrome.

BACKGROUND: McLeod syndrome (MLS) is hematologically defined by the absence of the red blood cell (RBC) antigen Kx on the transmembrane RBC protein, XK, representing a highly specific diagnostic marker. Direct molecular assessment of XK therefore represents a desirable diagnostic tool. Whereas pathogenic point mutations may be simply identified, partial and complete deletions of XK on Xp21.1, eventually covering adjacent genes and causing multifaceted "continuous gene syndromes," are difficult to localize. STUDY DESIGN AND METHODS: Three different McLeod patient samples were tested using 16 initial positional polymerase chain reaction (PCR) procedures distributed over an approximately 2.8-Mbp Xp-chromosomal region, ranging telomeric from MAGEB16 to OTC, centromeric of XK. The molecular breakpoint of one sample with an apparent large Xp deletion was iteratively narrowed down by stepwise positioning further PCR procedures and sequenced. Two mutant XK genes, one previously published and serving as a positive control, were also sequenced. RESULTS: We confirmed the positive control as previously published and listed as XK*N.20 by the International Society of Blood Transfusion (ISBT). The other XK showed a novel four-nucleotide deletion in Exon 1, 195-198delCCGC (newly listed as XK*N.39 by the ISBT). The third sample had an approximately 151-kbp X-chromosomal deletion, reaching from Exon 2 of LANCL3, across XK to Exon 3 of CYBB (newly listed as XK*N.01.016 by the ISBT). Carrier status of the patients' sister was diagnosed using a diagnostic "gap-PCR." CONCLUSIONS: The stepwise partitioning of Xp21.1 is pragmatic and cost-efficient in comparison to other diagnostic techniques such as "massive parallel sequencing" given the rarity of MLS. All males with suspected MLS should be considered for molecular XK profiling.

Practical approaches to commencing device-assisted therapies for Parkinson disease in Australia.

In Australia 1% of individuals aged over 50 years have Parkinson disease (PD). Guidance for commencing device-assisted therapies (DAT) for PD in Australia was developed based on a review of European recommendations and their relevance to the local clinical setting. An online survey and teleconference discussions were held by a group of eight local movement disorder experts to develop consensus. Referral to a movement disorder specialist and consideration of DAT is appropriate when motor fluctuations cause disability or reduced quality of life, response to treatment is inconsistent or motor fluctuations and dyskinesias require frequent treatment adjustment without apparent benefit and levodopa is required four or more times daily. Three types of DAT are available in Australia for patients with PD: continuous subcutaneous apomorphine; continuous levodopa-carbidopa intestinal gel infusion; and deep brain stimulation. All improve consistency of motor response. The most important aspects when considering which DAT to use are the preferences of the patient and their carers, patient comorbidities, age, cognitive function and neuropsychiatric status. Patients and their families need to be provided with treatment options that are suitable to them, with adequate explanations regarding the recommendations and comparison of potential device-related complications. DAT are best managed, where possible, in a specialist centre with experience in all three types of therapy. Proactive and early management of symptoms during disease progression is essential to maintain optimally motor responses and quality of life in patients with PD.

Cognitive Behavior Therapy for Anxiety in Parkinson's Disease: Outcomes for Patients and Caregivers.

OBJECTIVE: Anxiety negatively impacts the quality of life of Parkinson's disease (PD) patients and caregivers. Despite high prevalence, there is a paucity of trials investigating effective treatments for anxiety in PD. This uncontrolled study investigated the use of a manualized and tailored Cognitive Behavior Therapy (CBT) for anxiety in PD. METHODS: Participants completed 6 weekly CBT sessions. Pre-, post- and follow-up (3 and 6 months) assessments were made. Change in outcomes were analysed using t-tests and Reliability Change Index. Of 17 PD patients who agreed to CBT, 12 completed the intervention. RESULTS: This study showed a significant reduction in Hamilton Anxiety Rating Scale scores in PD immediately post CBT (t(11) = 3.59, p < .01), maintained at 3-month (t(8) = 2.83, p = .02) and 6-month (t(7) = 2.07, p = .04) follow-up. A reduction in caregiver burden (t(11) = 2.68, p = .03) was observed post intervention. Improvements in motor disability (t(11) = 2.41, p = .04) and cognitive scores (t(11) = -2.92, p = .01) were also observed post intervention and at follow-up. CONCLUSIONS: Tailored CBT can be used to treat anxiety in PD. CLINICAL IMPLICATIONS: This study provides preliminary evidence suggesting that tailored CBT reduces anxiety in PD with persisting benefits, and lowers caregiver burden.

Management of impulse control disorders in Parkinson's disease.

BACKGROUND: Impulse control disorders (ICDs) have become a widely recognized non-motor complication of Parkinson's disease (PD) in patients taking dopamine replacement therapy (DRT). There are no current evidence-based recommendations for their treatment, other than reducing their dopaminergic medication. METHODS: This study reviews the current literature of the treatment of ICDs including pharmacological treatments, deep brain stimulation, and psychotherapeutic interventions. RESULTS: Dopamine agonist withdrawal is the most common and effective treatment, but may lead to an aversive withdrawal syndrome or motor symptom degeneration in some individuals. There is insufficient evidence for all other pharmacological treatments in treating ICDs in PD, including amantadine, serotonin selective reuptake inhibitors, antipsychotics, anticonvulsants, and opioid antagonists (e.g. naltrexone). Large randomized control trials need to be performed before these drugs can be routinely used for the treatment of ICDs in PD. Deep brain stimulation remains equivocal because ICD symptoms resolve in some patients after surgery but may appear de novo in others. Cognitive behavioral therapy has been shown to improve ICD symptoms in the only published study, although further research is urgently needed. CONCLUSIONS: Further research will allow for the development of evidence-based guidelines for the management of ICDs in PD.

Disease-specific anxiety symptomatology in Parkinson's disease.

BACKGROUND: Symptoms of anxiety relating to Parkinson's disease (PD) occur commonly and include symptomatology associated with motor disability and complications arising from PD medication. However, there have been relatively few attempts to profile such disease-specific anxiety symptoms in PD. Consequently, anxiety in PD is underdiagnosed and undertreated. The present study characterizes PD-related anxiety symptoms to assist with the more accurate assessment and treatment of anxiety in PD. METHODS: Ninety non-demented PD patients underwent a semi-structured diagnostic assessment targeting anxiety symptoms using relevant sections of the Mini International Neuropsychiatric Interview (MINI-plus). In addition, they were assessed for the presence of 30 PD-related anxiety symptoms derived from the literature, the clinical experience of an expert panel and the PD Anxiety-Motor Complications Questionnaire (PDAMCQ). The onset of anxiety in relation to the diagnosis of PD was determined. RESULTS: Frequent (>25%) PD-specific anxiety symptoms included distress, worry, fear, agitation, embarrassment, and social withdrawal due to motor symptoms and PD medication complications, and were experienced more commonly in patients meeting DSM-IV criteria for an anxiety disorder. The onset of common anxiety disorders was observed equally before and after a diagnosis of PD. Patients in a residual group of Anxiety Not Otherwise Specified had an onset of anxiety after a diagnosis of PD. CONCLUSION: Careful characterization of PD-specific anxiety symptomatology provides a basis for conceptualizing anxiety and assists with the development of a new PD-specific measure to accurately assess anxiety in PD.

A mutation in the Golgi Qb-SNARE gene GOSR2 causes progressive myoclonus epilepsy with early ataxia.

The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi.

The clinical spectrum of anxiety in Parkinson's disease.

Anxiety is common in Parkinson's disease (PD), and contributes to increased disability and poorer quality of life. In spite of its significant impact, the symptomatology, chronology, and neurobiology of anxiety in PD are all poorly understood, and this hinders accurate diagnosis and development of effective treatment strategies. This review investigates and updates literature related to the clinical spectrum of anxiety in PD. The reported prevalence of anxiety in PD varies considerably, with emerging interest in the frequency of the DSM-IV residual category of "Anxiety disorder, not otherwise specified" (Anxiety disorder NOS), which is observed in up to 25% of PD patients. By design, there are no standardized diagnostic criteria for Anxiety disorder NOS, because this is the category applied to individuals who do not meet diagnostic criteria for any other current anxiety disorder. Anxiety rating scales incompletely capture anxiety symptoms that relate specifically to PD symptoms and the complications arising from PD therapy. Consequently, these scales have been deemed inappropriate for use in PD, and there remains a need for the development of a new PD-specific anxiety scale. Research establishing accurate symptom profiles of anxiety in PD is sparse, although characterizing such symptomatology would likely improve clinical diagnosis and facilitate targeted treatment strategies. Research into the neurobiological and psychological underpinnings of anxiety in PD remains inconclusive. Anxiety can precede the onset of PD motor symptoms or can develop after a diagnosis of PD. Further investigations focused on the chronology of anxiety and its relationship to PD diagnosis are required.

'North Sea' progressive myoclonus epilepsy: phenotype of subjects with GOSR2 mutation.

We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.

A physiotherapy group exercise and self-management approach to improve physical activity in people with mild-moderate Parkinson's disease: a randomized controlled trial.

BACKGROUND: Physical activity levels are low in people with Parkinson's disease (PD) and have proved difficult to increase with exercise programs alone. Intervention approaches that address both the capacity to engage in physical activity and self-management strategies to change and maintain exercise behaviours are needed to address this intractable issue. METHODS: This will be an assessor-blinded, randomized controlled trial performed in Brisbane, Australia. Ninety-two people with mild-moderate PD will be randomly allocated to two groups: usual care, and a physiotherapy-led group exercise program combined with self-management strategies. In the intervention group, twelve, 80-min sessions will be conducted over 4 weeks in groups of up to 4 participants. The intervention will consist of circuit training including treadmill walking to target aerobic fitness, and activities targeting strength, balance, and gait performance. In addition, each session will also incorporate strategies focusing on self-management and behaviour change, augmented by the provision of a fitness activity tracker. Outcome measures will be collected at baseline (T1), immediately post intervention (T2) and at 6 months follow-up (T3). The primary outcome measure is free-living physical activity (average daily step count over 7 days) at pre (T1) and post (T2) intervention measured using an activPAL™ device. Secondary outcome measures captured at all time points include time spent walking, sedentary and in moderate intensity exercise over 7 days; spatiotemporal gait performance (step length, gait speed, endurance); health-related quality of life; and outcome expectations and self-efficacy for exercise. DISCUSSION: Sustainability of gains in physical activity following exercise interventions is a challenge for most populations. Our incorporation of a chronic disease self-management approach into the exercise program including fitness tracking extends previous trials and has potential to significantly improve free-living physical activity in people with PD. TRIAL REGISTRATION: This study has been prospectively registered in Australian and New Zealand Clinical Trial Registry (ACTRN12617001057370), registered on 19/07/2017. Available from www.anzctr.org.au/ACTRN12617001057370.aspx .

Hippocampal resting-state connectivity is associated with posterior-cortical cognitive impairment in Parkinson's disease.

AIM: Frontal and posterior-cortical cognitive subtypes in Parkinson's disease (PD) present with executive/attention and memory/visuospatial deficits, respectively. As the posterior-cortical subtype is predicted to progress rapidly toward dementia, the present study aimed to explore biological markers of this group using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: K-means cluster analysis delineated subtypes (cognitively intact, frontal, posterior-cortical, and globally impaired) among 85 people with PD. A subset of PD participants (N = 42) and 20 healthy controls (HCs) underwent rs-fMRI. Connectivity of bilateral hippocampi with regions of interest was compared between posterior-cortical, cognitively intact, and HC participants using seed-based analysis, controlling for age. Exploratory correlations were performed between areas of interest from the group analysis and a series of cognitive tests. RESULTS: The posterior-cortical subtype (N = 19) showed weaker connectivity between the left hippocampus and right anterior temporal fusiform cortex compared to the cognitively intact (N = 11) group, p-false discovery rate (FDR) = .01, and weaker connectivity between bilateral hippocampi and most fusiform regions compared to HCs (N = 20). No differences were found between HCs and cognitively intact PD. Exploratory analyses revealed strongest associations between connectivity of the right anterior temporal fusiform cortex and left hippocampus with category fluency (p-FDR = .01). CONCLUSION: Results suggest that weakened connectivity between the hippocampus and fusiform region is a unique characteristic of posterior-cortical cognitive deficits in PD. Further exploration of hippocampal and fusiform functional integrity as a marker of cognitive decline in PD is warranted.

Pareidolias are a function of visuoperceptual impairment.

Pareidolias, or the misperception of ambiguous stimuli as meaningful objects, are complex visual illusions thought to be phenomenologically similar to Visual Hallucination (VH). VH are a major predictor of dementia in Parkinson's Disease (PD) and are included as a core clinical feature in Dementia with Lewy Bodies (DLB). A newly developed Noise Pareidolia Test (NPT) was proposed as a possible surrogate marker for VH in DLB patients as increased pareidolic responses correlated with informant-corroborated accounts of VH. This association could, however, be mediated by visuoperceptual impairment. To understand the drivers of performance on the NPT, we contrasted performances in patient groups that varied both in terms of visuoperceptual ability and rates of VH. N = 43 patients were studied of whom n = 13 had DLB or PD with Dementia (PDD); n = 13 had PD; n = 12 had typical, memory-onset Alzheimer's Disease (tAD); and n = 5 had Posterior Cortical Atrophy (PCA) due to Alzheimer's disease. All patient groups reported pareidolias. Within the Lewy body disorders (PD, DLB, PDD), there was no significant difference in pareidolic response rates between hallucinating and non-hallucinating patients. Visuoperceptual deficits and pareidolic responses were most frequent in the PCA group-none of whom reported VH. Regression analyses in the entire patient cohort indicated that pareidolias were strongly predicted by visuoperceptual impairment but not by the presence of VH. These findings suggest that pareidolias reflect the underlying visuoperceptual impairment of Lewy body disorders, rather than being a direct marker for VH.

A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation.

Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1ß and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.