Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein.

Mutant KRAS is a major driver of oncogenesis in a multitude of cancers but remains a challenging target for classical small molecule drugs, motivating the exploration of alternative approaches. Here, we show that aggregation-prone regions (APRs) in the primary sequence of the oncoprotein constitute intrinsic vulnerabilities that can be exploited to misfold KRAS into protein aggregates. Conveniently, this propensity that is present in wild-type KRAS is increased in the common oncogenic mutations at positions 12 and 13. We show that synthetic peptides (Pept-ins™) derived from two distinct KRAS APRs could induce the misfolding and subsequent loss of function of oncogenic KRAS, both of recombinantly produced protein in solution, during cell-free translation and in cancer cells. The Pept-ins exerted antiproliferative activity against a range of mutant KRAS cell lines and abrogated tumor growth in a syngeneic lung adenocarcinoma mouse model driven by mutant KRAS G12V. These findings provide proof-of-concept that the intrinsic misfolding propensity of the KRAS oncoprotein can be exploited to cause its functional inactivation.

A gain-of-function HCN4 mutant in the HCN domain is responsible for inappropriate sinus tachycardia in a Spanish family.

In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (If) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (IHCN4) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. IHCN4 generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases If and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.

Continuous Positive Airway Pressure Effect on Albuminuria Progression in Patients with Obstructive Sleep Apnea and Diabetic Kidney Disease: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic kidney disease (DKD). However, the effect of apnea-hypopnea suppression on DKD progression is unclear. Objectives: To assess the effect of continuous positive airway pressure (CPAP) on the urinary albumin-to-creatinine ratio (UACR) in patients with DKD and OSA. Methods: In a 52-week, multicentric, open-label, parallel, and randomized clinical trial, 185 patients with OSA and DKD were randomized to CPAP and usual care (n = 93) or usual care alone (n = 92). Measurements and Main Results: UACR, estimated glomerular filtration rate, serum concentrations of creatinine and glycated hemoglobin, insulin resistance, lipid concentrations, sleepiness, and quality of life. A 52-week change in UACR from baseline did not differ significantly between the CPAP group and the usual-care group. However, in per-protocol analyses that included 125 participants who met prespecified criteria for adherence, CPAP treatment was associated with a great reduction in UACR (mean difference, -10.56% [95% confidence interval, -19.06 to -2.06]; P = 0.015). CPAP effect on UACR was higher in nonsleepy patients with more severe OSA, worse renal function, and a more recent diagnosis of DKD. CPAP treatment also improved glycemic control and insulin resistance, as well as sleepiness and health-related quality of life. Conclusions: In patients with OSA and DKD, the prescription of CPAP did not result in a statistically significant reduction in albuminuria. However, good adherence to CPAP treatment in addition to usual care may result in long-term albuminuria reduction compared with usual care alone. Clinical trial registered with www.clinicaltrials.gov (NCT02816762).

Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes.

Diabetes mellitus (DM) is a highly prevalent disease worldwide, estimated to affect 1 in every 11 adults; among them, 90-95% of cases are type 2 diabetes mellitus. This is partly attributed to the surge in the prevalence of obesity, which has reached epidemic proportions since 2008. In these patients, cardiovascular (CV) risk stands as the primary cause of morbidity and mortality, placing a substantial burden on healthcare systems due to the potential for macrovascular and microvascular complications. In this context, leptin, an adipocyte-derived hormone, plays a fundamental role. This hormone is essential for regulating the cellular metabolism and energy balance, controlling inflammatory responses, and maintaining CV system homeostasis. Thus, leptin resistance not only contributes to weight gain but may also lead to increased cardiac inflammation, greater fibrosis, hypertension, and impairment of the cardiac metabolism. Understanding the relationship between leptin resistance and CV risk in obese individuals with type 2 DM (T2DM) could improve the management and prevention of this complication. Therefore, in this narrative review, we will discuss the evidence linking leptin with the presence, severity, and/or prognosis of obesity and T2DM regarding CV disease, aiming to shed light on the potential implications for better management and preventive strategies.

Can Oncologists Prompt Patient Prognostic Awareness to Enhance Decision-Making? Data From the NEOetic Study.

INTRODUCTION: Anti-neoplastic therapy improves the prognosis for advanced cancer, albeit it is not curative. An ethical dilemma that often arises during patients' first appointment with the oncologist is to give them only the prognostic information they can tolerate, even at the cost of compromising preference-based decision-making, versus giving them full information to force prompt prognostic awareness, at the risk of causing psychological harm. METHODS: We recruited 550 participants with advanced cancer. After the appointment, patients and clinicians completed several questionnaires about preferences, expectations, prognostic awareness, hope, psychological symptoms, and other treatment-related aspects. The aim was to characterize the prevalence, explanatory factors, and consequences of inaccurate prognostic awareness and interest in therapy. RESULTS: Inaccurate prognostic awareness affected 74%, conditioned by the administration of vague information without alluding to death (odds ratio [OR] 2.54; 95% CI, 1.47-4.37, adjusted P = .006). A full 68% agreed to low-efficacy therapies. Ethical and psychological factors oriented first-line decision-making, in a trade-off in which some lose quality of life and mood, for others to gain autonomy. Imprecise prognostic awareness was associated with greater interest in low-efficacy treatments (OR 2.27; 95% CI, 1.31-3.84; adjusted P = .017), whereas realistic understanding increased anxiety (OR 1.63; 95% CI, 1.01-2.65; adjusted P = 0.038), depression (OR 1.96; 95% CI, 1.23-3.11; adjusted P = .020), and diminished quality of life (OR 0.47; 95% CI, 0.29-0.75; adjusted P = .011). CONCLUSION: In the age of immunotherapy and targeted therapies, many appear not to understand that antineoplastic therapy is not curative. Within the mix of inputs that comprise inaccurate prognostic awareness, many psychosocial factors are as relevant as the physicians' disclosure of information. Thus, the desire for better decision-making can actually harm the patient.

Transglenoidal Approach in Pigmented Villonodular Synovitis of the Temporomandibular Joint.

Pigmented villonodular synovitis is a benign pathology with locally aggressive behavior caused by an uncontrolled proliferation of the articular synovial membranes. Here the authors present a case of pigmented villonodular synovitis of the temporomandibular joint with middle cranial fossa extension and review the different management options including surgery, which have been proposed to target this condition in the recent literature.

Asbestos exposure and small cell lung cancer: Systematic review and meta-analysis.

Asbestos is a mineral that is carcinogenic to humans. Its use has been banned in many occidental countries yet it is still produced in the United States, and materials that contain asbestos remain in many occupational settings and indoor environments. Even though asbestos carcinogenicity is well known, there is scant literature on its specific effects regarding small cell lung cancer (SCLC). We therefore conducted a systematic review and meta-analysis to determine SCLC risk among workers exposed to asbestos. A systematic search of the literature was conducted to identify studies which reported occupational exposure to asbestos and SCLC-related deaths and/or incidence. We identified seven case-control studies that included 3,231 SCLC cases; four studies reported smoking-adjusted risks. A significantly increased risk of SCLC (pooled OR 1.89; 95% CI, 1.25-2.86) was observed on pooling studies on men (six studies) that displayed moderate heterogeneity (I2 = 46.0%). Overall, our synthesis suggests that occupational exposure to asbestos significantly increases the risk of SCLC on men.

Non-tuberculous mycobacteria: clinical and laboratory characterisation (2009 and 2019).

A cross-sectional and retrospective study of patients with Mycobacterium spp. in a Portuguese tertiary hospital, in 2009 and 2019, was performed to understand better the rise in isolations of nontuberculous mycobacteria (NTM). The number of patients with positive samples for Mycobacterium spp. grew from 56 in 2009 to 83 in 2019. The proportion of NTM rose from 39.3% to 49.4% (P = 0.240), with Mycobacterium avium complex being more frequent in 2009 and Mycobacterium gordonae in 2019, and Mycobacterium tuberculosis complex decreased from 60.7% to 50.6%. Higher age was associated with NTM in both years, and pulmonary disease and immunosuppression were associated with NTM in 2019 (P < 0.05), with weak to moderate correlation (V = 0.231-0.343). The overall rise of NTM, allied to their known capacity to resist antimicrobial therapy, alerts clinicians to the importance of recognising potential risk factors for infection and improving future prevention strategies.

Early Experiences in Switching between Monoclonal Antibodies in Patients with Nonresponsive Migraine in Spain: A Case Series.

Monoclonal antibodies targeting the calcitonin gene-related peptide have been introduced into the therapeutic arsenal of migraine prophylaxis. Clinical trials report similar efficacy between them, and there is no evidence of switching to another one after failure. We aim to describe our experience in switching from erenumab to galcanezumab after therapeutic failure. We retrospectively reviewed 30 migraine patients who received monoclonal antibodies, with 15 of them switched after failure to achieve reduction in migraine days per month ≥30%. A ≥30% reduction in migraine days per month compared to baseline was observed in 8/15 (4/15 ≥ 50%) patients after switch. Some nonresponsive patients may benefit from switching between monoclonal antibodies with different therapeutic targets.

Dignity and psychosocial related variables in elderly advanced cancer patients.

INTRODUCTION: Most cancers occur in older individuals, who are more vulnerable due to functional impairment, multiple comorbidities, cognitive impairment, and lack of socio-familial support. These can undermine patients' sense of dignity. This study seeks to compare dignity scores in older patients with advanced cancer on sociodemographic and clinical variables and analyze the predictive value of anxiety, depression, functional limitations, and social support on dignity scores. METHODS: A prospective, multicenter, observational study conducted with participation of 15 hospitals in Spain from February 2020 to October 2021. Patients with newly-diagnosed, advanced cancer completed the dignity (PPDS), anxiety and depression (BSI), Social Support (Duke-UNC-11), and functional limitations (EORTC-C30) scales. Lineal regression analyses explored the effects of anxiety, depression, functional status, and social support on dignity, adjusting for sociodemographic and clinical variables. RESULTS: A total of 180 subjects participated in this study. The results of the correlation analysis revealed that dignity correlated negatively with anxiety, depression, and sex, and positively with social support, functional status, and longer estimated survival. Thus, women, and more anxious and depressed individuals scored lower on the dignity scale, whereas patients with more social support, fewer functional limitations, and longer estimated survival scored higher. CONCLUSION: In conclusion, being female, having a lower educational level, lower estimated survival, depression, anxiety, less social support, and limited functionality are correlated with less dignity in the elderly with advanced cancer. It is a priority to manage both physical and psychological symptoms in patients with unresectable advanced cancer to mitigate psychological distress and increase their sense of dignity.

Obesity and Risk for Lymphoma: Possible Role of Leptin.

Obesity, which is considered a pandemic due to its high prevalence, is a risk factor for many types of cancers, including lymphoma, through a variety of mechanisms by promoting an inflammatory state. Specifically, over the last few decades, obesity has been suggested not only to increase the risk of lymphoma but also to be associated with poor clinical outcomes and worse responses to different treatments for those diseases. Within the extensive range of proinflammatory mediators that adipose tissue releases, leptin has been demonstrated to be a key adipokine due to its pleotropic effects in many physiological systems and diseases. In this sense, different studies have analyzed leptin levels and leptin/leptin receptor expressions as a probable bridge between obesity and lymphomas. Since both obesity and lymphomas are prevalent pathophysiological conditions worldwide and their incidences have increased over the last few years, here we review the possible role of leptin as a promising proinflammatory mediator promoting lymphomas.

Impact of Obesity on Quality of Life, Psychological Distress, and Coping on Patients with Colon Cancer.

BACKGROUND: Despite the causal relationship between obesity and colon cancer being firmly established, the effect of obesity on the course of cancer calls for further elucidation. The objective of this study was to assess differences in clinical-pathological and psychosocial variables between obese and nonobese individuals with colon cancer. MATERIALS AND METHODS: This was a prospective, multicentric, observational study conducted from 2015-2018. The sample comprised patients with stage II-III, resected colon cancer about to initiate adjuvant chemotherapy with fluoropyrimidine in monotherapy or associated with oxaliplatin and grouped into nonobese (body mass index <30 kg/m2 ) or obese (≥30 kg/m2 ). Subjects completed questionnaires appraising quality of life (European Organization for Research and Treatment of Cancer Quality of Life Core questionnaire), coping (Mini-Mental Adjustment to Cancer), psychological distress (Brief Symptom Inventory 18), perceived social support (Multidimensional Scale of Perceived Social Support), personality (Big Five Inventory 10), and pain (Brief Pain Inventory). Toxicity, chemotherapy compliance, 12-month recurrence, and mortality rate data were recorded. RESULTS: Seventy-nine of the 402 individuals recruited (19.7%) were obese. Obese subjects exhibited more comorbidities (≥2 comorbidities, 46.8% vs. 30.3%, p = .001) and expressed feeling slightly more postoperative pain (small size-effect). There was more depression, greater helplessness, less perceived social support from friends, and greater extraversion among the obese versus nonobese subjects (all p < .04). The nonobese group treated with fluoropyrimidine and oxaliplatin suffered more grade 3-4 hematological toxicity (p = .035), whereas the obese had higher rates of treatment withdrawal (17.7% vs. 7.7%, p = .033) and more recurrences (10.1% vs. 3.7%, p = .025). No differences in sociodemographic, quality of life, or 12-month survival variables were detected. CONCLUSION: Obesity appears to affect how people confront cancer, as well as their tolerance to oncological treatment and relapse. IMPLICATIONS FOR PRACTICE: Obesity is a causal factor and affects prognosis in colorectal cancer. Obese patients displayed more comorbidities, more pain after cancer surgery, worse coping, and more depression and perceived less social support than nonobese patients. Severe hematological toxicity was more frequent among nonobese patients, whereas rates of withdrawal from adjuvant chemotherapy were higher in the obese cohort, and during follow-up, obese patients presented greater 12-month recurrence rates. With the growing and maintained increase of obesity and the cancers associated with it, including colorectal cancer, the approach to these more fragile cases that have a worse prognosis must be adapted to improve outcomes.

Echocardiographic Changes with Positive Airway Pressure Therapy in Obesity Hypoventilation Syndrome. Long-Term Pickwick Randomized Controlled Clinical Trial.

Rationale: Obesity hypoventilation syndrome (OHS) has been associated with cardiac dysfunction. However, randomized trials assessing the impact of long-term noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) on cardiac structure and function assessed by echocardiography are lacking.Objectives: In a prespecified secondary analysis of the largest multicenter randomized controlled trial of OHS (Pickwick Project; N = 221 patients with OHS and coexistent severe obstructive sleep apnea), we compared the effectiveness of three years of NIV and CPAP on structural and functional echocardiographic changes.Methods: At baseline and annually during three sequential years, patients underwent transthoracic two-dimensional and Doppler echocardiography. Echocardiographers at each site were blinded to the treatment allocation. Statistical analysis was performed using a linear mixed-effects model with a treatment group and repeated measures interaction to determine the differential effect between CPAP and NIV.Measurements and Main Results: A total of 196 patients were analyzed: 102 were treated with CPAP and 94 were treated with NIV. Systolic pulmonary artery pressure decreased from 40.5 ± 1.47 mm Hg at baseline to 35.3 ± 1.33 mm Hg at three years with CPAP, and from 41.5 ± 1.56 mm Hg to 35.5 ± 1.42 with NIV (P < 0.0001 for longitudinal intragroup changes for both treatment arms). However, there were no significant differences between groups. NIV and CPAP therapies similarly improved left ventricular diastolic dysfunction and reduced left atrial diameter. Both NIV and CPAP improved respiratory function and dyspnea.Conclusions: In patients with OHS who have concomitant severe obstructive sleep apnea, long-term treatment with NIV and CPAP led to similar degrees of improvement in pulmonary hypertension and left ventricular diastolic dysfunction.Clinical trial registered with www.clinicaltrials.gov (NCT01405976).

Ischemic Cerebellar Stroke in a 4-Year-Old Boy After Chickenpox: An Atypical Vascular Involvement.

Cerebrovascular events in pediatric population are very rare. Up to 30% may result from varicella zoster (VZV) arteriopathy, usually as a delayed complication of varicella primary infection. The most typical pattern includes involvement of anterior brain circulation arteries, probably by VZV migration from the trigeminal ganglia. Strokes related with VZV usually have a good prognosis, but risk of recurrence is greater when compared to other stroke etiologies in this age group. We report the case of a 4-year-old boy, immunocompetent, who presented a basilar artery stenosis and a cerebellar stroke, an extremely rare presentation of VZV arteriopathy. The investigation workup and treatment are detailed, as the clinical and imaging follow-up after one year.

Zfhx3 Transcription Factor Represses the Expression of SCN5A Gene and Decreases Sodium Current Density (INa).

The ZFHX3 and SCN5A genes encode the zinc finger homeobox 3 (Zfhx3) transcription factor (TF) and the human cardiac Na+ channel (Nav1.5), respectively. The effects of Zfhx3 on the expression of the Nav1.5 channel, and in cardiac excitability, are currently unknown. Additionally, we identified three Zfhx3 variants in probands diagnosed with familial atrial fibrillation (p.M1260T) and Brugada Syndrome (p.V949I and p.Q2564R). Here, we analyzed the effects of native (WT) and mutated Zfhx3 on Na+ current (INa) recorded in HL-1 cardiomyocytes. ZFHX3 mRNA can be detected in human atrial and ventricular samples. In HL-1 cardiomyocytes, transfection of Zfhx3 strongly reduced peak INa density, while the silencing of endogenous expression augmented it (from -65.9 ± 8.9 to -104.6 ± 10.8 pA/pF; n ≥ 8, p < 0.05). Zfhx3 significantly reduced the transcriptional activity of human SCN5A, PITX2, TBX5, and NKX25 minimal promoters. Consequently, the mRNA and/or protein expression levels of Nav1.5 and Tbx5 were diminished (n ≥ 6, p < 0.05). Zfhx3 also increased the expression of Nedd4-2 ubiquitin-protein ligase, enhancing Nav1.5 proteasomal degradation. p.V949I, p.M1260T, and p.Q2564R Zfhx3 produced similar effects on INa density and time- and voltage-dependent properties in WT. WT Zfhx3 inhibits INa as a result of a direct repressor effect on the SCN5A promoter, the modulation of Tbx5 increasing on the INa, and the increased expression of Nedd4-2. We propose that this TF participates in the control of cardiac excitability in human adult cardiac tissue.

Cost-effectiveness of positive airway pressure modalities in obesity hypoventilation syndrome with severe obstructive sleep apnoea.

BACKGROUND: Obesity hypoventilation syndrome (OHS) is treated with either non-invasive ventilation (NIV) or CPAP, but there are no long-term cost-effectiveness studies comparing the two treatment modalities. OBJECTIVES: We performed a large, multicentre, randomised, open-label controlled study to determine the comparative long-term cost and effectiveness of NIV versus CPAP in patients with OHS with severe obstructive sleep apnoea (OSA) using hospitalisation days as the primary outcome measure. METHODS: Hospital resource utilisation and within trial costs were evaluated against the difference in effectiveness based on the primary outcome (hospitalisation days/year, transformed and non-transformed in monetary term). Costs and effectiveness were estimated from a log-normal distribution using a Bayesian approach. A secondary analysis by adherence subgroups was performed. RESULTS: In total, 363 patients were selected, 215 were randomised and 202 were available for the analysis. The median (IQR) follow-up was 3.01 (2.91-3.14) years for NIV group and 3.00 (2.92-3.17) years for CPAP. The mean (SD) Bayesian estimated hospital days was 2.13 (0.73) for CPAP and 1.89 (0.78) for NIV. The mean (SD) Bayesian estimated cost per patient/year in the NIV arm, excluding hospitalisation costs, was €2075.98 (91.6), which was higher than the cost in the CPAP arm of €1219.06 (52.3); mean difference €857.6 (105.5). CPAP was more cost-effective than NIV (99.5% probability) because longer hospital stay in the CPAP arm was compensated for by its lower costs. Similar findings were observed in the high and low adherence subgroups. CONCLUSION: CPAP is more cost-effective than NIV; therefore, CPAP should be the preferred treatment for patients with OHS with severe OSA. TRIAL REGISTRATION NUMBER: NCT01405976.

Young Children Are Wishful Thinkers: The Development of Wishful Thinking in 3- to 10-Year-Old Children.

Previously, research on wishful thinking has found that desires bias older children's and adults' predictions during probabilistic reasoning tasks. In this article, we explore wishful thinking in children aged 3- to 10-years-old. Do young children learn to be wishful thinkers? Or do they begin with a wishful thinking bias that is gradually overturned during development? Across five experiments, we compare low- and middle-income United States and Peruvian 3- to 10-year-old children (N = 682). Children were asked to make predictions during games of chance. Across experiments, preschool-aged children from all backgrounds consistently displayed a strong wishful thinking bias. However, the bias declined with age.

Children in Critical Care Due to Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Experience in a Spanish Hospital.

OBJECTIVES: Spain has been one of the countries most severely affected by the coronavirus disease 2019. This study aims to describe a series of children admitted to a PICU due to coronavirus disease 2019 infection. DESIGN: Prospective observational study. SETTING: Tertiary hospital in Madrid, Spain. PATIENTS: Children admitted to the PICU with severe acute respiratory syndrome coronavirus 2 (severe acute respiratory syndrome coronavirus 2) infection, from March 1, 2020, to April 15, 2020. INTERVENTIONS: Observational study. MEASUREMENTS AND MAIN RESULTS: Epidemiologic data, previous clinical characteristics, support therapy needed, imaging tests, laboratory observations on admission, and pharmacologic therapy. Eleven children were admitted to the PICU, with suspected coronavirus disease 2019; the polymerase chain reaction test was positive in seven. The median age was 100.7 months (range, 0.5-162). Five were admitted from the emergency department and two from the ward. The Pediatric Sequential Organ Failure Assessment score was 3 (range, 0-9), and Pediatric Risk of Mortality II score was 4 (range, 0-16). All children were previously healthy except one (allogeneic hematopoietic stem cell transplantation). Respiratory symptoms and fever were prevalent. A chest radiograph led to a pneumonia diagnosis. Not all patients presented with lymphopenia on admission. D-Dimer and ferritin were elevated. All patients needed oxygen therapy through a nasal cannula; five patients received high-flow nasal cannula therapy, which was later substituted with noninvasive ventilation in four. Mechanical ventilation was necessary in two patients on the first day of PICU admission. Two children required mechanical ventilation and inotropic support. Tocilizumab was applied in two intubated children. Also, four children received heparin. No patients died. CONCLUSIONS: On the whole, the children were previously healthy and are more than 1 year old. Respiratory symptoms were the leading cause of PICU admission, making respiratory support the principal therapy. Patients requiring mechanical ventilation showed deterioration on the first day of admission. These children seemed to require close monitoring, and multicenter studies are necessary.

Social value of a set of proposals for the ideal approach of multiple sclerosis within the Spanish National Health System: a social return on investment study.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease that in many cases produces disability, having a high impact in patients' lives, reducing significantly their quality of life. The aim of this study was to agree on a set of proposals to improve the current management of MS within the Spanish National Health System (SNHS) and apply the Social Return on Investment (SROI) method to measure the potential social impact these proposals would create. METHODS: A Multidisciplinary Working Team of nine experts, with representation from the main stakeholders regarding MS, was set up to agree on a set of proposals to improve the management of MS. A forecast SROI analysis was carried out, with a one-year timeframe. Data sources included an expert consultation, a narrative literature review and a survey to 532 MS patients. We estimated the required investment of a hypothetical implementation, as well as the potential social value that it could create. We calculated outcomes in monetary units and we measured intangible outcomes through financial proxies. RESULTS: The proposed ideal approach revealed that there are still unmet needs related to MS that can be addressed within the SNHS. Investment would amount to 148 million € and social return to 272 million €, so each euro invested could yield almost €2 of social return. CONCLUSIONS: This study could guide health interventions, resulting in money savings for the SNHS and increases in patients' quality of life.