ALSUntangled #75: Portable neuromodulation stimulator therapy.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

Common practices for sociodemographic data reporting in digital mental health intervention research: a scoping review.

BACKGROUND: The ability of digital mental health interventions (DMHIs) to reduce mental health disparities relies on the recruitment of research participants with diverse sociodemographic and self-identity characteristics. Despite its importance, sociodemographic reporting in research is often limited, and the state of reporting practices in DMHI research in particular has not been comprehensively reviewed. OBJECTIVES: To characterise the state of sociodemographic data reported in randomised controlled trials (RCTs) of app-based DMHIs published globally from 2007 to 2022. METHODS: A scoping review of RCTs of app-based DMHIs examined reporting frequency for 16 sociodemographic domains (eg, gender) and common category options within each domain (eg, woman). The search queried five electronic databases. 5079 records were screened and 299 articles were included. RESULTS: On average, studies reported 4.64 (SD=1.79; range 0-9) of 16 sociodemographic domains. The most common were age (97%) and education (67%). The least common were housing situation (6%), residency/location (5%), veteran status (4%), number of children (3%), sexual orientation (2%), disability status (2%) and food security (<1%). Gender or sex was reported in 98% of studies: gender only (51%), sex only (28%), both (<1%) and gender/sex reported but unspecified (18%). Race or ethnicity was reported in 48% of studies: race only (14%), ethnicity only (14%), both (10%) and race/ethnicity reported but unspecified (10%). CONCLUSIONS: This review describes the widespread underreporting of sociodemographic information in RCTs of app-based DMHIs published from 2007 to 2022. Reporting was often incomplete (eg, % female only), unclear (eg, the conflation of gender/sex) and limited (eg, only options representing majority groups were reported). Trends suggest reporting has somewhat improved in recent years. Diverse participant populations must be welcomed and described in DMHI research to broaden learning and the generalisability of results, a prerequisite of DMHI's potential to reduce disparities in mental healthcare.

ALSUntangled #74: Withania Somnifera (Ashwagandha).

ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS (PALS) who ask about them. Here, we review withania somnifera (WS) commonly known as ashwagandha or winter cherry. WS has plausible mechanisms for slowing ALS progression because of its effects on inflammation, oxidative stress, autophagy, mitochondrial function, and apoptosis. Preclinical trials demonstrate that WS slows disease progression in multiple different animal models of ALS. Of the five individuals we found who described using WS for their ALS, two individuals reported moderate benefit while none reported experiencing any significant side effects. There is currently one clinical trial using WS to treat PALS; the results are not yet published. There are no serious side effects associated with WS and the associated cost of this treatment is low. Based on the above information, WS appears to us to be a good candidate for future ALS trials.

ALSUntangled #72: Insulin.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review insulin, which has at least one plausible mechanism for slowing ALS progression. However, pre-clinical studies are limited and there have been no trials in PALS yet. Insulin use in patients without a metabolic need may cause very serious and potentially lethal side effects. While further studies to evaluate potential benefits may be warranted, at this time we cannot endorse insulin treatment to slow ALS progression.

ALSUntangled #71: Nuedexta.

Nuedexta is a combination of dextromethorphan hydrobromide and quinidine sulfate and was approved by the Food and Drug Administration (FDA) in 2010 to treat pseudobulbar affect (PBA). There have since been anecdotal case reports of bulbar function improvements after Nuedexta treatment. Here, we review the off-label use of Nuedexta for improving bulbar function in people with ALS. Nuedexta has plausible mechanisms for protecting brain stem motor neurons via its effects on S1R and glutamate excitotoxicity. Recent clinical trials support that Nuedexta can improve bulbar function in PALS, with or without PBA. Nuedexta causes mild to moderate side effects. Based on this information, we support considering Nuedexta treatment for bulbar dysfunction in ALS patients with or without PBA.

ALSUntangled #73: Lion's Mane.

Lion's Mane (Hericium erinaceus) has historically been used as traditional medicine in Asia and Europe for its potential benefits in fighting infection and cancer. It has gained interest in the neurodegenerative disease field because of its mechanisms of action; these include anti-inflammation, neuroprotection, and promoting neurite growth demonstrated in various cell and animal models. A very small, double-blind, placebo-controlled trial in patients with mild cognitive impairment showed a temporary improvement in cognitive function; this finding has yet to be replicated. However, there have been no studies in ALS cell or animal models or in humans with ALS. Lion's Mane appears safe and inexpensive when consumed in powder or capsule, but one anaphylactic case was reported after a patient consumed fresh Lion's Mane mushroom. Currently, we do not have enough information to support the use of Lion's Mane for treating ALS. We support further research in ALS disease models and clinical trials to study its efficacy.

Anatomy of a Woebot® (WB001): agent guided CBT for women with postpartum depression.

INTRODUCTION: Postpartum depression (PPD) is common, persistent, and stigmatized. There are insufficient trained professionals to deliver appropriate screening, diagnosis, and treatment. AREAS COVERED: WB001 is a Software as a Medical Device (SaMD) based Agent-Guided Cognitive-Behavioral Therapy (AGCBT) program for the treatment of PPD, for which Breakthrough Device Designation was recently granted by the US Food and Drug Administration. WB001 combines therapeutic alliance, human-centered design, machine learning techniques, and established principles from CBT and interpersonal therapy (IPT). We introduce AGCBT as a new model of service delivery, whilst describing Woebot, the agent technology that enables guidance through the replication of some elements of human relationships. The profile describes the device's design principles, enabling technology, risk handling, and efficacy data in PPD. EXPERT OPINION: WB001 is a dynamic and personalized tool with which patients may establish a therapeutic bond. Woebot is designed to augment (rather than replace) human healthcare providers, unlocking the therapeutic potency associated with guidance, whilst retaining the scalability and agency that characterizes self-help approaches. WB001 has the potential to improve both the quality and the scalability of care through providing support to patients on waiting lists, in between clinical encounters, and enabling automation of measurement-based-care.

ALSUntangled #70: caffeine.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here, we review caffeine which has plausible mechanisms for slowing ALS progression. However, pre-clinical studies are contradictory, and a large case series showed no relationship between caffeine intake and ALS progression rate. While low doses of caffeine are safe and inexpensive, higher doses can cause serious side effects. At this time, we cannot endorse caffeine as a treatment to slow ALS progression.

Online randomised trials with children: A scoping review.

BACKGROUND: Paediatric trials must contend with many challenges that adult trials face but often bring additional obstacles. Decentralised trials, where some or all trial methods occur away from a centralised location, are a promising strategy to help meet these challenges. This scoping review aims to (a) identify what methods and tools have been used to create and conduct entirely online-decentralised trials with children and (b) determine the gaps in the knowledge in this field. This review will describe the methods used in these trials to identify their facilitators and the gaps in the knowledge. METHODS: The methods were informed by guidance from the Joanna Briggs Institute and the PRISMA extension for scoping reviews. We systematically searched MEDLINE, CENTRAL, CINAHL, and Embase databases, trial registries, pre-print servers, and the internet. We included randomised and quasi-randomised trials conducted entirely online with participants under 18 published in English. A risk of bias assessment was completed for all included studies. RESULTS: Twenty-one trials met our inclusion criteria. The average age of participants was 14.6 years. Social media was the most common method of online recruitment. Most trials employed an external host website to store and protect their data. Duration of trials ranged from single-session interventions up to ten weeks. Fourteen trials compensated participants. Eight trials involved children in their trial design process; none reported compensation for this. Most trials had a low risk of bias in "random sequence generation", "selective reporting", and "other". Most trials had a high risk of bias in "blinding participants and personnel", "blinding of outcome assessment", and "incomplete outcome data". "Allocation concealment" was unclear in most studies. CONCLUSIONS: There was a lack of transparent reporting of the recruitment, randomisation, and retention methods used in many of the trials included in this review. Patient and public involvement (PPI) was not common, and the compensation of PPI partners was not reported in any study. Consent methods and protection against fraudulent entries to trials were creative and thoroughly discussed by some trials and not addressed by others. More work and thorough reporting of how these trials are conducted is needed to increase their reproducibility and quality. ETHICS AND DISSEMINATION: Ethical approval was not necessary since all data sources used are publicly available.

Rigorous and rapid evidence assessment in digital health with the evidence DEFINED framework.

Dozens of frameworks have been proposed to assess evidence for digital health interventions (DHIs), but existing frameworks may not facilitate DHI evidence reviews that meet the needs of stakeholder organizations including payers, health systems, trade organizations, and others. These organizations may benefit from a DHI assessment framework that is both rigorous and rapid. Here we propose a framework to assess Evidence in Digital health for EFfectiveness of INterventions with Evaluative Depth (Evidence DEFINED). Designed for real-world use, the Evidence DEFINED Quick Start Guide may help streamline DHI assessment. A checklist is provided summarizing high-priority evidence considerations in digital health. Evidence-to-recommendation guidelines are proposed, specifying degrees of adoption that may be appropriate for a range of evidence quality levels. Evidence DEFINED differs from prior frameworks in its inclusion of unique elements designed for rigor and speed. Rigor is increased by addressing three gaps in prior frameworks. First, prior frameworks are not adapted adequately to address evidence considerations that are unique to digital health. Second, prior frameworks do not specify evidence quality criteria requiring increased vigilance for DHIs in the current regulatory context. Third, extant frameworks rarely leverage established, robust methodologies that were developed for non-digital interventions. Speed is achieved in the Evidence DEFINED Framework through screening optimization and deprioritization of steps that may have limited value. The primary goals of Evidence DEFINED are to a) facilitate standardized, rapid, rigorous DHI evidence assessment in organizations and b) guide digital health solutions providers who wish to generate evidence that drives DHI adoption.

So You Want to Build Your Disease's First Online Patient Registry: An Educational Guide for Patient Organizations Based on US and European Experience.

Patient registries fulfill a number of key roles for clinicians, researchers, non-profit organizations, payers, and policy makers. They can help the field understand the natural history of a condition, determine the effectiveness of interventions, measure safety, and audit the quality of care provided. Successful registries in cystic fibrosis, Duchenne's muscular dystrophy, and other rare diseases have become a model for accelerating progress. However, the complex tasks required to develop a modern registry can seem overwhelming, particularly for those who are not from a technical background. In this Education article, a team of co-authors from across patient advocacy, technology, privacy, and commercial perspectives who have worked on a number of such projects offer a "Registry 101" primer to help get started. We will outline the promise and potential of patient registries with worked case examples, identify some of the key technical considerations you will need to consider, describe the type of data you might want to collect, consider privacy risks to protect your users, sketch out some of the paths towards long-term financial sustainability we have observed, and conclude with plans to mitigate some of the challenges that can occur and signpost interested readers to further resources. While rapid growth in the digital health market has presented numerous opportunities to those at the beginning of their journey, it is important to start with the long-term goals in mind and to benefit from the learnings of those who have walked this path before.

ALSUntangled # 69: astaxanthin.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review astaxanthin which has plausible mechanisms for slowing ALS progression including antioxidant, anti-inflammatory, and anti-apoptotic effects. While there are no ALS-specific pre-clinical studies, one verified "ALS reversal" occurred in a person using a combination of alternative therapies which included astaxanthin. There have been no trials of astaxanthin in people living with ALS. Natural astaxanthin appears to be safe and inexpensive. Based on the above information, we support further pre-clinical and/or clinical trials of astaxanthin in disease models and PALS, respectively, to further elucidate efficacy.

ALSUntangled #68: ozone therapy.

ALSUntangled reviews alternative and off-label treatments for people living with amyotrophic lateral sclerosis (PALS). Here we review ozone therapy. Ozone therapy has possible mechanisms for slowing ALS progression based on its antioxidant, anti-inflammatory, and mitochondrial effects. A non-peer-reviewed report suggests that ozone treatment may slow progression in a mTDP-43 mouse model of ALS. One verified "ALS reversal" occurred on a cocktail of alternative treatments including ozone. There are no ALS trials using ozone to treat PALS. There can be potentially serious side effects associated with ozone therapy, depending on the dose. Based on the above information, we support an investigation of ozone therapy in ALS cell or animal models but cannot yet recommend it as a treatment in PALS.

Comparison Of King's Clinical Staging In Multinational Amyotrophic Lateral Sclerosis Cohorts.

Background: Amyotrophic lateral sclerosis (ALS) shows considerable clinical heterogeneity, which affects clinical trials. A clinical staging system has been proposed for ALS with potential applications in patient care, research, trial design and health economic analyses. The King's system consists of five stages. We have previously shown that progressive clinical stages were reached at predictable proportions through the disease course, but this needs to be validated in other independent samples. Objectives: We aimed to compare King's clinical staging in ALS in four patient groups, located in different regions and countries and using different health care systems from the original study population in South London. Methods: Clinical data were extracted from two European phase 3 randomized controlled trials (MitoTarget and LiCALS) and from two databases predominately from the United States: the PRO-ACT Consortium Database and a database of patients from the PatientsLikeMe website. Clinical stage was estimated using an algorithm, and standardized time to each clinical stage was calculated in deceased patients. Results: 8,796 patients were included, of whom 1,959 had died by the end of follow-up. Stages occurred in the same order as in the original study for all cohorts. Median standardized times to stages (interquartile range) were Stage 2: 0.61 (0.47-0.75), Stage 3: 0.68 (0.56-0.81), Stage 4A: 0.82 (0.71-0.91), Stage 4B: 0.82 (0.69-0.92) and Stage 4 0.80 (0.67-0.91). Discussion: Timings for all stages were similar to those reported in the original study, except Stage 2 which occurred later in the clinical trial databases due to recruitment occurring after diagnosis.

ALSUntangled #67: rituximab.

ALSUntangled reviews alternative and off-label treatments on behalf of people with ALS who ask about them. Here we review rituximab, a drug which specifically depletes B lymphocytes. We show a current lack of evidence for a role of these cells in ALS progression. The one patient we found who described using Rituximab for their ALS found no benefit. Given all this, and the known serious risks of rituximab, we advise against its use as an ALS treatment.

ALSUntangled #65: glucocorticoid corticosteroids.

ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (PALS). Here we review glucocorticoids. Neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis, so some hypothesize that glucocorticoids might be an effective ALS therapy through their immunosuppressive effects. In this paper, we review the available evidence for glucocorticoids in ALS, including one pre-clinical study with a genetic mouse model of ALS, nine case reports (ranging from 1 to 26 patients each), and four clinical trials. We also review the possible side effects (including steroid myopathy) and the costs of therapy. We graded the level of evidence as follows: Mechanism, D; Pre-Clinical, F; Cases, B; Trials, F; Risks, C. Our review of the current evidence concludes that glucocorticoids do not offer clinical benefit in ALS and confer serious risks. Thus, ALSUntangled does not recommend glucocorticoids as a treatment for ALS.

ALSUntangled #66: antimycobacterial antibiotics.

Several infections have been associated with motor neuron diseases resembling ALS, including species of viruses, bacteria, and parasites. Mycobacterium avium subspecies paratuberculosis (MAP), most known for its probable etiologic association with Crohn's disease, has been suggested as another possible infectious cause of motor neuron disease. Two published case reports describe the successful treatment of ALS-like symptoms with antimycobacterial antibiotics. Both cases had atypical features. Based on these, we believe it would be reasonable to begin performing chest imaging in PALS who have features of their history or exam that are atypical for ALS such as pain, fevers, or eye movement abnormalities. If the chest imaging is abnormal, more specific testing for mycobacteria may be indicated. Until there is more clear evidence of an association between mycobacteria and ALS, we cannot endorse the widespread use of potentially toxic antimycobacterial antibiotics for PALS.