Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Factors associated with adherence to noninvasive positive pressure ventilation in amyotrophic lateral sclerosis.

INTRODUCTION: This cohort study aimed to investigate the factors associated with noninvasive positive pressure ventilation adherence and assess the long-term effects of noninvasive positive pressure ventilation adherence in patients with amyotrophic lateral sclerosis (ALS). METHODS: The medical records of patients with ALS admitted to a tertiary hospital for noninvasive positive pressure ventilation initiation were retrospectively reviewed. Pulmonary function parameters, variables of blood gas analysis, the site of symptom onset, the time from onset and diagnosis to noninvasive positive pressure ventilation application, ALS Functional Rating Scale-Revised, neurophysiological index, and the length of hospital stay were evaluated. The adherence to noninvasive positive pressure ventilation was defined as the use of noninvasive positive pressure ventilation for ≥ 2 h/day or ≥ 4 h/day. The correlations between noninvasive positive pressure ventilation adherence or length of hospital stay and other clinical parameters were analyzed. RESULTS: Fifty-one patients with ALS were included in the study. The time from onset and diagnosis to NIPPV application was reduced by 16 months in the adherent group than that in the non-adherent group; however, the parameters of blood gas analysis and pulmonary function tests did not differ significantly between the groups. Furthermore, the neurophysiological index of the abductor digiti minimi muscle was higher by 4.05 in the adherent group than that in the non-adherent group. The adherence to noninvasive positive pressure ventilation prolonged tracheostomy-free survival compared to that of non-adherence. Desaturation events, lower forced vital capacity, last pCO2, bicarbonate, and base excess, and higher differences in pCO2, were associated with an increase in the length of hospital stay. CONCLUSIONS: Noninvasive positive pressure ventilation application shortly after symptom onset and ALS diagnosis in patients with CO2 retention and reduced forced vital capacity can be considered for successful adherence. Adherence to noninvasive positive pressure ventilation may result in reduced tracheostomy conversion rates and prolonged tracheostomy-free survival.

Efficacy of non-pharmacological interventions for individuals with amyotrophic lateral sclerosis: systematic review and network meta-analysis of randomized control trials.

This network meta-analysis (NMA) aimed to compare the efficacy of five non-pharmacological interventions, including exercise intervention (EI), nutritional intervention (NI), respiratory intervention (RI), psychological intervention (PSI), and integrated physical intervention (IPI), on functional status, quality of life, muscle strength, pulmonary function, and safety in patients with amyotrophic lateral sclerosis (ALS). We searched nine databases, PubMed, Cochrane, Embase, Scopus, Web of Science, CNKI, CBM, WFPD, and CSTJ, for randomized controlled trials of ALS patients. The primary outcome was the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. Secondary outcomes were the McGill Quality of Life Questionnaire (McGill-QoL), Medical Research Council (MRC)-sum score, Forced Vital Capacity (FVC), and Fatigue Severity Scale (FSS) score. This NMA was conducted using random-effect models to calculate the standard mean difference (SMD) and 95% confidence interval (CI). All types of supplemental interventions had some benefit for patients with ALS. EI had a beneficial effect on the ALSFRS-R score (SMD: 1.01; 95% CI 0.50-1.51), FVC (SMD: 0.78; 95% CI 0.02-1.55), McGill-QoL (SMD: 0.71 95% CI 0.33-1.08), and MRC (SMD: 1.11; 95% CI 0.08-2.14). RI had a beneficial effect on the ALSFRS-R score (SMD: 0.83 95% CI 0.12-1.55). IPI had a beneficial effect on the ALSFRS-R score (SMD: 0.65 95% CI 0.06-1.24). NI had a beneficial effect on the McGill-QoL (SMD: 0.63 95% CI 0.02-1.23). The current study findings support a multimodal intervention strategy with an emphasis on EI for slowing disease progression in patients with ALS.

Optimizing breathlessness management in amyotrophic lateral sclerosis: insights from a comprehensive systematic review.

BACKGROUND: Breathlessness is a prevalent symptom affecting the quality of life (QOL) of Amyotrophic Lateral Sclerosis (ALS) patients. This systematic review explored the interventions for controlling breathlessness in ALS patients, emphasizing palliative care (PALC), non-invasive ventilation (NIV), opioids, and non-pharmacological strategies. METHODS: A comprehensive search of PubMed, Cochrane Library, and Web of Science databases was conducted. Eligibility criteria encompassed adults with ALS or motor neuron disease experiencing breathlessness. Outcomes included QOL and symptom control. Study designs comprised qualitative studies, cohort studies, and randomized controlled trials. RESULTS: Eight studies were included, most exhibiting low bias risk, comprising one randomized controlled trial, three cohort studies, two comparative retrospective studies, and two qualitative studies (interviews). Most studies originated from Europe, with one from the United States of America. The participants totaled 3423, with ALS patients constituting 95.6%. PALC consultations significantly improved symptom assessment, advance care planning, and discussions about goals of care. NIV demonstrated efficacy in managing breathlessness, with considerations for device limitations. Opioids were effective, though predominantly studied in non-ALS patients. Non-pharmacological strategies varied in efficacy among patients. CONCLUSION: The findings underscore the need for individualized approaches in managing breathlessness in ALS. PALC, NIV, opioids, and non-pharmacological strategies each play a role, with unique considerations. Further research, especially ALS-specific self-management studies, is warranted.

Biomarkers for Managing Neurodegenerative Diseases.

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD).

Experiences with advance care planning in amyotrophic lateral sclerosis: Qualitative longitudinal study with people with amyotrophic lateral sclerosis and their family carers.

BACKGROUND: It is unclear when people with amyotrophic lateral sclerosis and their family carers think about their future, what they would prefer in terms of care, and how their ideas change over time. AIM: Understanding experiences with advance care planning of persons with amyotrophic lateral sclerosis and their family carers-and if, when, how, and why these experiences change over time. DESIGN: A qualitative longitudinal interview study. Analysis involved content analysis, followed by a two-step timeline method to describe changes in advance care planning experiences within and across participants. SETTING/PARTICIPANTS: Nine persons with amyotrophic lateral sclerosis and nine family carers who were interviewed three times over a 9-month period. RESULTS: All participants thought about future care, but few talked about it. Over time, advance care planning experiences were influenced by intertwined elements: (1) experienced physical decline and related future care needs; (2) how persons with amyotrophic lateral sclerosis identify themselves as patients; (3) obtaining information about diagnosis and prognosis; (4) professionals initiating conversations about medical aspects of end-of-life decisions; (5) balancing between hope to remain stable and worry about the future; and (6) protecting themselves and each other from worries about the future. CONCLUSION: This study emphasizes how factors such as coping with the disease and relational dynamics shape individuals' thoughts about future care over time and how psychological, social, and medical factors are interwoven in advance care planning. The findings advocate for a process-oriented perspective, portraying advance care planning as an ongoing dialog, encompassing the needs, concerns, and emotions of both people with amyotrophic lateral sclerosis and their family carers.

Online speech synthesis using a chronically implanted brain-computer interface in an individual with ALS.

Brain-computer interfaces (BCIs) that reconstruct and synthesize speech using brain activity recorded with intracranial electrodes may pave the way toward novel communication interfaces for people who have lost their ability to speak, or who are at high risk of losing this ability, due to neurological disorders. Here, we report online synthesis of intelligible words using a chronically implanted brain-computer interface (BCI) in a man with impaired articulation due to ALS, participating in a clinical trial (ClinicalTrials.gov, NCT03567213) exploring different strategies for BCI communication. The 3-stage approach reported here relies on recurrent neural networks to identify, decode and synthesize speech from electrocorticographic (ECoG) signals acquired across motor, premotor and somatosensory cortices. We demonstrate a reliable BCI that synthesizes commands freely chosen and spoken by the participant from a vocabulary of 6 keywords previously used for decoding commands to control a communication board. Evaluation of the intelligibility of the synthesized speech indicates that 80% of the words can be correctly recognized by human listeners. Our results show that a speech-impaired individual with ALS can use a chronically implanted BCI to reliably produce synthesized words while preserving the participant's voice profile, and provide further evidence for the stability of ECoG for speech-based BCIs.

[Promising approaches to the pathogenetic therapy of amyotrophic lateral sclerosis]. / Perspektivnye podkhody k patogeneticheskoi terapii bokovogo amiotroficheskogo skleroza.

Amyotrophic lateral sclerosis is a severe incurable disease of the nervous system. Currently only methods of palliative care for the patients with this disease are available. Few medications for the pathogenetic therapy are registered in some countries, i.e. riluzole, edaravon, sodium phenylbutyrate/taurursodiol as well as tofersen (conditionally). Their efficacy is relatively low. The main directions in the development of pathogenetic therapy of ALS include gene therapy, use of stem cells, immunomodulators, agents affecting gut microbiota. A search is also underway for low-molecular compounds with neuroprotective and antioxidant properties. Perspective direction is prevention of ALS. This will be possible when biomarkers for identification of patients in pre-manifest/prodromal stage are detected.

[SOD1 gene therapy delays ALS disease progression]. / Precisionsmedicinsk genterapi har bromsat utveckling av ALS.

We present a patient with familial amyotrophic lateral sclerosis caused by an aggressive A4S mutation in the SOD1 gene. In 2020, the patient was enrolled in the VALOR SOD1 gene therapy phase-3 trial. At screening, the ALSFRS-R score was 41 (48 is normal) and the level of CSF-neurofilament L (an indicator of ongoing neuronal damage) was 11 000 ng/L (ref <650 ng/L). In the four years following enrollment, the patient received monthly intrathecal treatment with tofersen, an antisense oligonucleotide compound that inhibits SOD1 protein expression and hence lowers the synthesis of toxic SOD1 protein species. Side effects have been minimal and mostly attributed to the spinal taps. The patient remains ambulatory with an active social lifestyle. The ALSFRS-R score has in the past 18 months stabilized around 35-37, CSF-NfL is 1 290 ng/L and plasma-NfL is 12 (reference <13). This is the first documented arresting intervention in a patient with ALS in Sweden.

Astrocytes: The Stars in Neurodegeneration?

Today, neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases.

The clinical practice guideline for the management of amyotrophic lateral sclerosis in Japan-update 2023.

Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.

European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).

BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management. CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.

Remote pulmonary function testing allows for early identification of need for non-invasive ventilation in a subset of persons with ALS.

The traditional ALS multidisciplinary clinical practice of quarterly respiratory assessment may leave some individuals in danger of developing untreated respiratory insufficiency between visits or beginning non-invasive ventilation (NIV) later than would be optimal. Remote, or home-based, pulmonary function testing (rPFT) allows patients with ALS to perform regular respiratory testing at more frequent intervals in the home. The aim of this study was to determine the clinical benefit of weekly rPFT compared to standard, quarterly in-clinic respiratory assessments: the number of individuals with earlier identification of NIV need, the magnitude of this advance notice, and the individual factors predicting benefit. Participants with ALS (n = 39) completed rPFT training via telemedicine and then completed one year of weekly self-guided assessments in the home. Over this period, 17 individuals exhibited remotely-measured FVC dropping below 50% of predicted, the value often used for recommendation of NIV initiation. In 13 individuals with clinical detection of this event, the median and range of advance notice of need for NIV was 53 (-61-294) days. Prescription of NIV occurred for 21 individuals on the study, six of whom began NIV as a result of remote testing, prior to indication of need as determined by in-person assessments. Weekly home assessments appeared to be of greatest clinical value in a subset of patients with low baseline respiratory test values and rapid respiratory decline. This has potential implications for clinical management of ALS as well as the conduct of clinical trials that rely on respiratory endpoints.

Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis: Clinical Protocol and Evaluation of Microbiota Immunity Axis.

The fecal microbial transplantation (FMT) is a therapeutic transplant of fecal microbiota from healthy donors to patients. This practice is aimed at restoring eubiosis and rebalancing the enteric and systemic immune responses, and then eliminating pathogenic triggers of multiple disease, including neurodegenerative diseases. Alterations of gut microbiota (GM) affect the central nervous system (CNS) health, impacting neuro-immune interactions, synaptic plasticity, myelination, and skeletal muscle function. T-regulatory lymphocytes (Treg) are among the most important players in the pathogenesis of amyotrophic lateral sclerosis (ALS), altering the disease course. Along with circulating neuropeptides, other immune cells, and the gut-brain axis, the GM influences immunological tolerance and controls Treg's number and suppressive functions. A double-blind, controlled, multicenter study on FMT in ALS patients has been designed to evaluate if FMT can modulate neuroinflammation, by restoring Treg number, thus modifying disease activity and progression.

The Role of Human Pluripotent Stem Cells in Amyotrophic Lateral Sclerosis: From Biological Mechanism to Practical Implications.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, characterized by progressive loss of both upper and lower motor neurons, resulting in clinical features such as muscle weakness, paralysis, and ultimately, respiratory failure. Nowadays, there is not effective treatment to reverse the progression of the disease, that leads to death within 3-5 years after the onset. Nevertheless, the induced pluripotent stem cells (iPS) technology could be the answer, providing disease modelling, drug testing, and cell-based therapies for this pathology. The aim of this work was to conduct a literature review of the past 5 years about the role of iPS in ALS, to better define the neurobiological mechanisms involved in the pathogenesis and the potential future therapies. The review also deals with advanced and currently available technologies used to reprogram cell lines and generate human motor neurons in vitro, which represent the source to study the pathological processes, the relationship between phenotype and genotype, the disease progression and the potential therapeutic targets of these group of disorders. Specific treatment options with stem cells involve Advance Gene Editing Technology, neuroprotective agents, and cells or exosomes transplantation, aimed to replace dead or damaged nerve cells. In summary, this review comprehensively addresses the role of human pluripotent stem cells (hPSCs) in motor neuron diseases (MND), with a focus on physiopathology, diagnostic and prognostic implications, specific and potential future treatment options. Understanding the biological mechanisms and practical implications of hPSCs in MND is crucial for advancing therapeutic strategies and improving outcomes for patients affected by these devastating diseases.

Geographical distribution of clinical trials in amyotrophic lateral sclerosis: a scoping review.

Introduction: Clinical trials location is determined by many factors, including the availability of patient populations, regulatory environment, scientific expertise, and cost considerations. In clinical drug development of amyotrophic lateral sclerosis (ALS), where genetic differences have been described and may be related to geographic setting, this could have implications for the clinical interpretation of results in underrepresented geographic settings. Objective: The aim of this study was to review country participation in ALS clinical research based on available data from clinical trial registries and databases. Methods: We performed a scoping review with available information about clinical trials on ALS in ClinicalTrials.gov (CT), EU clinical trials register (EudraCT), WHO International Clinical Trials Registry Platform (ICTRP) and Web of Science (WOS). Inclusion criteria were clinical trials in phase 2 and 3 to treat ALS, recruiting or active not recruiting, from 23/06/2018 to 23/06/2023. Results: The total number of clinical trials identified were 188; 54 studies in CT, 38 in EudraCT, 47 in ICTRP and 49 in WOS. We identified 77 clinical trials after deleting duplicates and applying exclusion criteria. The countries with most studies conducted were the US with 35 studies (10.9%), followed by the United Kingdom, Belgium, France and Germany with 21 studies each one of them (6.5%). Conclusion: The data obtained in our review showed a non-homogeneous distribution in clinical trials at the international level, which may influence the interpretation of the results obtained.

Trends in Specialty Palliative Care Service Utilization and In-Hospital Outcomes for Patients With Amyotrophic Lateral Sclerosis.

Background: Hospitalized people with amyotrophic lateral sclerosis (ALS) may benefit from specialty palliative care services (sPCS). Objective: To describe access to in-hospital sPCS for people with ALS (pALS). Methods: We compared years 2010-2011 to 2018-2019, and conducted trend analyses of sPCS from 2010 to 2019 stratified by race. Results: Of 103,193 pALS admitted during the study period, 13,885 (13.4%) received sPCS. Rates of sPCS increased over time (2010-2011: 8.9% vs. 2018-2019: 16.6%; p < 0.01). From 2010 to 2019, there was an increase in sPCS (p-trend<0.01) for all studied racial groups. Conclusions: Access to palliative care has increased over time for pALS admitted to hospitals in the United States.

Partly unequal receipt of healthcare in last month of life in amyotrophic lateral sclerosis: a retrospective cohort study of the Stockholm region.

Context: In amyotrophic lateral sclerosis (ALS), equal care is important, given that the disease often has complex symptoms at the end of life. Objectives: The aim was to study the possible associations between demographic and clinical factors, including age, sex, and frailty, with acute healthcare utilization in the last month of life, measured by emergency room (ER) visits, admissions to acute hospitals and, acute hospitals as place of death, among patients with ALS. A second aim was to study whether receipt of specialized palliative care (SPC) affects above-mentioned healthcare utilization. Methods: Observational, retrospective study based on Region Stockholm's administrative data warehouse (VAL) in Sweden. Data were retrieved for 2015-2021 and analyzed with descriptive statistics and logistic regression models. Results: All deceased patients (n = 448) ≥18 years with ALS were included. The mean age was 70.5 years, 46% were women and 58% had risk of frailty according to Hospital Frailty Risk Score (HFRS). Ninety-nine (22%) were nursing home residents and 49% received SPC. The receipt of SPC in patients with ALS was equal in relation to gender, socio-economic standing, frailty, and age <75 years. Patients ≥75 years, those with dementia and/or residing in nursing homes (NH) were less likely to receive SPC (P = 0.01, P = 0.03 and P = 0.002, respectively). Receipt of SPC reduced ER visits (29% vs. 48%, P < 0.001) and deaths at hospital (12% vs. 48%, P <0.001). Patients who were frail, had a higher risk of ER visits and were more likely to die at an acute hospital setting (P < 0.001 and P = 0.004). NH residents were less likely to have ER visits and to die in hospital (P = 0.002 and P = 0.005). Conclusions: The results indicate partly unequal distribution of palliative care, however the actual, individual preferences cannot be deducted from registry studies. All patients with ALS should be offered SPC when needed. Key message: This register study shows that receipt of SPC in patients with ALS is equal in relation to gender, socioeconomic standing, frailty, and age <75 years, while those ≥75 years, with dementia, or residing in NH were somewhat less likely to receive SPC. Receipt of SPC reduces ER visits and acute hospital admissions.