Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update.

ABSTRACT: Tisagenlecleucel is approved for adults with relapsed/refractory (r/r) follicular lymphoma (FL) in the third- or later-line setting. The primary analysis (median follow-up, 17 months) of the phase 2 ELARA trial reported high response rates and excellent safety profile in patients with extensively pretreated r/r FL. Here, we report longer-term efficacy, safety, pharmacokinetic, and exploratory biomarker analyses after median follow-up of 29 months (interquartile range, 22.2-37.7). As of 29 March 2022, 97 patients with r/r FL (grades 1-3A) received tisagenlecleucel infusion (0.6 × 108-6 × 108 chimeric antigen receptor-positive viable T cells). Bridging chemotherapy was allowed. Baseline clinical factors, tumor microenvironment, blood soluble factors, and circulating blood cells were correlated with clinical response. Cellular kinetics were assessed by quantitative polymerase chain reaction. Median progression-free survival (PFS), duration of response (DOR), and overall survival (OS) were not reached. Estimated 24-month PFS, DOR, and OS rates in all patients were 57.4% (95% confidence interval [CI], 46.2-67), 66.4% (95% CI, 54.3-76), and 87.7% (95% CI, 78.3-93.2), respectively. Complete response rate and overall response rate were 68.1% (95% CI, 57.7-77.3) and 86.2% (95% CI, 77.5-92.4), respectively. No new safety signals or treatment-related deaths were reported. Low levels of tumor-infiltrating LAG3+CD3+ exhausted T cells and higher baseline levels of naïve CD8+ T cells were associated with improved outcomes. Tisagenlecleucel continued to demonstrate highly durable efficacy and a favorable safety profile in this extended follow-up of 29 months in patients with r/r FL enrolled in ELARA. This trial was registered at www.clinicaltrials.gov as #NCT03568461.

Environmental DNA reveals the genetic diversity and population structure of an invasive species in the Laurentian Great Lakes.

Environmental DNA (eDNA) has been established as a noninvasive and efficient approach to sample genetic material from aquatic environments. Although most commonly used to determine species presence and measure biodiversity, eDNA approaches also hold great potential to obtain population-level genetic information from water samples. In this study, we sequenced a panel of multiallelic microsatellite markers from filtered water and fish tissue samples to uncover patterns of intraspecific diversity in the freshwater Round Goby (Neogobius melanostomus) across their invaded range in the Laurentian Great Lakes region. Although we found that the concentration of nuclear eDNA is lower than mitochondrial eDNA, we nonetheless detected over two-thirds of all nuclear alleles identified from genotyped tissues in our eDNA samples, with the greatest recovery of common alleles in the population. Estimates of allele frequencies and genetic variability within and between populations were detected from eDNA in patterns that were consistent with individual tissue-based estimates of genetic diversity and differentiation. The strongest genetic differentiation in both eDNA and tissues exists in an isolation by distance pattern. Our study demonstrates the potential for eDNA-based approaches to characterize key population parameters required to effectively monitor, manage, or sustain aquatic species.

Primary central nervous system marginal zone lymphoma.

Marginal zone lymphoma (MZL) is the most common indolent lymphoma primarily arising in the central nervous system (CNS). To date, 207 cases of primary CNS MZL (PCNSMZL) were published, mostly as single case reports or small case series. It most commonly presents as extra-axial dural-based masses, more frequently in middle-aged women, displaying an insidious onset, with a long history of symptoms preceding the diagnosis. PCNSMZL can be radiographically mistaken for meningioma. PCNSMZL consists of CD20+ , CD3- small B lymphocytes with varying degrees of plasmacytic differentiation and low proliferation index. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality. Other recurrent genetic abnormalities involve TNFAIP3 and NOTCH2. Ethiopathogenesis was poorly investigated. Due to its rarity, standard of care remains to be defined; it exhibits an excellent prognosis after varied treatments, such as surgery, radiotherapy, chemotherapy or their combinations. Nevertheless, each treatment should be considered after an accurate analysis of overtreatment risk. Short follow-up is a major limitation in reported PCNSMZL cases, which restrains our knowledge on long-term results and iatrogenic sequels. This review was focussed on presentation, differential diagnoses, pathological findings, treatment options and clinical outcomes of PCNSMZL; recommendations for best clinical practice are provided.

Enantioselective Amination of 4-Substituted Pyrazolones Catalyzed by Oxindole-Containing Thioureas and by a Recyclable Linear-Polymer-Supported Analogue in a Continuous Flow Process.

A highly efficient organocatalytic amination of 4-substituted pyrazolones with azodicarboxylates mediated by a novel quinine-derived thiourea with a 3,3-diaryl-oxindole scaffold is reported. This synthetic method furnished 4-amino-5-pyrazolones in high yields and with excellent enantioselectivities (up to 97:3 er) at room temperature in short reaction times. Moreover, a linear-polymer-supported bifunctional thiourea, synthesized by reacting a bifunctional aromatic monomer (biphenyl) with isatin in superacidic media and further derivatization, was proven to be also an efficient heterogeneous organocatalyst for this α-amination reaction. The practical value of this process was demonstrated by the use of the immobilized catalyst in recycling experiments, maintaining the activity without additional reactivation, and in flow processes, allowing the synthesis of 4-amino-pyrazolone derivatives in a gram scale with high yield and enantioselectivity.

The Polyanalgesic Consensus Conference (PACC)®: Intrathecal Drug Delivery Guidance on Safety and Therapy Optimization When Treating Chronic Noncancer Pain.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians and scientists based on expertise with international representation to establish evidence-based guidance on intrathecal drug delivery in treating chronic pain. This Polyanalgesic Consensus Conference (PACC)® project, created more than two decades ago, intends to provide evidence-based guidance for important safety and efficacy issues surrounding intrathecal drug delivery and its impact on the practice of neuromodulation. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when PACC® last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence is scant. RESULTS: The PACC® examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The PACC® recommends best practices regarding intrathecal drug delivery to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate.

The Neurostimulation Appropriateness Consensus Committee (NACC)®: Recommendations for the Mitigation of Complications of Neurostimulation.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise and international representation to establish evidence-based guidance on the mitigation of neuromodulation complications. This Neurostimulation Appropriateness Consensus Committee (NACC)® project intends to update evidence-based guidance and offer expert opinion that will improve efficacy and safety. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to October 2023. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant. RESULTS: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The NACC recommends best practices regarding the mitigation of complications associated with neurostimulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate.

Detecting and analysing intraspecific genetic variation with eDNA: From population genetics to species abundance.

Advancements in environmental DNA (eDNA) approaches have allowed for rapid and efficient species detections in diverse environments. Although most eDNA research is focused on leveraging genetic diversity to identify taxa, some recent studies have explored the potential for these approaches to detect within-species genetic variation, allowing for population genetic assessments and abundance estimates from environmental samples. However, we currently lack a framework outlining the key considerations specific to generating, analysing and applying eDNA data for these two purposes. Here, we discuss how various genetic markers differ with regard to genetic information and detectability in environmental samples and how analysis of eDNA samples differs from common tissue-based analyses. We then outline how it may be possible to obtain species absolute abundance estimates from eDNA by detecting intraspecific genetic variation in mixtures of DNA under multiple scenarios. We also identify the major causes contributing to allele detection and frequency errors in eDNA data, discuss their consequences for population-level analyses and outline bioinformatic approaches to detect and remove erroneous sequences. This review summarizes the key advances required to harness the full potential of eDNA-based intraspecific genetic variation to inform population-level questions in ecology, evolutionary biology and conservation management.

Environment and shipping drive environmental DNA beta-diversity among commercial ports.

The spread of nonindigenous species by shipping is a large and growing global problem that harms coastal ecosystems and economies and may blur coastal biogeographical patterns. This study coupled eukaryotic environmental DNA (eDNA) metabarcoding with dissimilarity regression to test the hypothesis that ship-borne species spread homogenizes port communities. We first collected and metabarcoded water samples from ports in Europe, Asia, Australia and the Americas. We then calculated community dissimilarities between port pairs and tested for effects of environmental dissimilarity, biogeographical region and four alternative measures of ship-borne species transport risk. We predicted that higher shipping between ports would decrease community dissimilarity, that the effect of shipping would be small compared to that of environment dissimilarity and shared biogeography, and that more complex shipping risk metrics (which account for ballast water and stepping-stone spread) would perform better. Consistent with our hypotheses, community dissimilarities increased significantly with environmental dissimilarity and, to a lesser extent, decreased with ship-borne species transport risks, particularly if the ports had similar environments and stepping-stone risks were considered. Unexpectedly, we found no clear effect of shared biogeography, and that risk metrics incorporating estimates of ballast discharge did not offer more explanatory power than simpler traffic-based risks. Overall, we found that shipping homogenizes eukaryotic communities between ports in predictable ways, which could inform improvements in invasive species policy and management. We demonstrated the usefulness of eDNA metabarcoding and dissimilarity regression for disentangling the drivers of large-scale biodiversity patterns. We conclude by outlining logistical considerations and recommendations for future studies using this approach.

Access to Spiropyrazolone-butenolides through NHC-Catalyzed [3 + 2]-Asymmetric Annulation of 3-Bromoenals and 1H-Pyrazol-4,5-diones.

The stereoselective synthesis of spirocyclic pyrazolin-5-ones by N-heterocyclic carbene (NHC) organocatalysis has been less studied so far. For this reason and considering the interest of this class of compounds, here, we present the NHC-catalyzed [3 + 2]-asymmetric annulation of ß-bromoenals and 1H-pyrazol-4,5-diones that achieves to produce chiral spiropyrazolone-butenolides. The synthesis is general for aryl and heteroaryl ß-bromo-α,ß-unsaturated aldehydes and 1,3-disubstituted pyrazolones. The spirobutenolides have been obtained in good yields (up to 88%) and enantioselectivities (up to 97:3 er). This constitutes the first described example using pyrazoldiones as the starting materials for this class of spiro compounds.

Organocatalytic asymmetric synthesis of oxazolidino spiropyrazolinones via N,O-acetalization/aza Michael addition domino reaction between N-Boc pyrazolinone ketimines and γ-hydroxyenones.

A squaramide-catalyzed asymmetric N,O-acetalization/aza Michael addition domino reaction between N-Boc ketimines derived from pyrazolin-5-ones and γ-hydroxyenones has been developed for the construction of pyrazolinone embedded spirooxazolidines. A hydroquinine derived bifunctional squaramide catalyst was found to be the most effective for this cascade spiroannulation. This new protocol allows the generation of two stereocenters and the desired products are obtained in good yields with moderate to good diastereoselectivities (up to 3.3 : 1 dr) and high enantioselectivities (up to >99% ee) from a range of substituted N-Boc pyrazolinone ketimines and γ-hydroxyenones. The developed protocol is amenable for a scale-up reaction.

Effect of Conventional Spinal Cord Stimulation on Serum Protein Profile in Patients With Persistent Spinal Pain Syndrome: A Case-Control Study.

BACKGROUND: Spinal cord stimulation (SCS) provides pain relief for most patients with persistent spinal pain syndrome type 2 (PSPS 2). Evidence is mounting on molecular changes induced by SCS as one of the mechanisms to explain pain improvement. We report the SCS effect on serum protein expression in vivo in patients with PSPS 2. MATERIALS AND METHODS: Serum proteins were identified and quantified using mass spectrometry. Proteins with significantly different expression among patients with PSPS 2 relative to controls, responders, and nonresponders to SCS, or significantly modulated by SCS relative to baseline, were identified. Those most correlated with the presence and time course of pain were selected using multivariate discriminant analysis. Bioinformatic tools were used to identify related biological processes. RESULTS: Thirty patients with PSPS 2, of whom 23 responded to SCS, were evaluated, together with 14 controls with no pain who also had undergone lumbar spinal surgery. A significant improvement in pain intensity, disability, and quality of life was recorded among responders. Five proteins differed significantly at baseline between patients with PSPS 2 and controls, with three proteins, mostly involved in immune processes and inflammation, being downregulated and two, mostly involved in vitamin metabolism, synaptic transmission, and restorative processes, being upregulated. In addition, four proteins, mostly related to immune processes and inflammation, decreased significantly, and three, mostly related to iron metabolism and containment of synaptic sprouting, increased significantly during SCS. CONCLUSION: This study identifies various biological processes that may underlie PSPS 2 pain and SCS therapeutic effects, including the modulation of neuroimmune response and inflammation, synaptic sprouting, vitamin and iron metabolism, and restorative processes.

Clinical results of lumbar sympathetic blocks in lower limb complex regional pain syndrome using infrared thermography as a support tool.

AIM: To describe the clinical outcomes for a group of complex regional pain syndrome patients using infrared thermography as an intraprocedural support tool when undertaking fluoroscopy-guided lumbar sympathetic blocks. SUBJECTS: 27 patients with lower limb complex regional pain syndrome accompanied by severe pain and persistent functional impairment. METHODS: A series of three fluoroscopic-guided lumbar sympathetic blocks with local anesthetic and corticoids using infrared thermography as an intraprocedural support tool were performed. Clinical variables were collected at baseline, prior to each block, and one, three, and six months after blocks in a standardized checklist assessing each of the clinical categories of complex regional pain syndrome stipulated in the Budapest criteria. RESULTS: 23.75% of the blocks required more than one chance to achieve the desired thermal pattern and therefore to be considered as successful. A decrease in pain measured on a visual analogic scale was observed at all time points compared to pre-blockade data, but only 37% of the cases were categorized as responders, representing a ≥ 30% decrease in VAS, with the disappearance of pain at rest. An improvement of most of the clinical variables recorded was observed, such as tingling, edema, perception of thermal asymmetry, difference in coloring and sweating. There was a significant decrease of neuropathic pain and improvement of functional limitation. Logistic regression analysis showed the main variable to explain the probability of being a responder was immobilization time (odds ratio of 0.89). CONCLUSION: A series of fluoroscopy-guided lumbar sympathetic blocks controlled by infrared thermography in the treatment of lower limb CRPS showed a responder rate of 37%.

Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study.

BACKGROUND AND AIMS: Data regarding outcome of COVID-19 in patients with autoimmune hepatitis (AIH) are lacking. APPROACH AND RESULTS: We performed a retrospective study on patients with AIH and COVID-19 from 34 centers in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes, defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity score-matched cohort of patients without AIH but with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase > 2 × the upper limit of normal) during COVID-19 was also evaluated. We included 110 patients with AIH (80% female) with a median age of 49 (range, 18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (P = 0.041; OR, 3.36; 95% CI, 1.05-10.78), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (P = 0.009; OR, 0.26; 95% CI, 0.09-0.71). The rates of severe COVID-19 (15.5% versus 20.2%, P = 0.231) and all-cause mortality (10% versus 11.5%, P = 0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (P < 0.001; OR, 17.46; 95% CI, 4.22-72.13). Continuation of immunosuppression or presence of liver injury during COVID-19 was not associated with severe COVID-19. CONCLUSIONS: This international, multicenter study reveals that patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of CLD. Cirrhosis was the strongest predictor for severe COVID-19 in patients with AIH. Maintenance of immunosuppression during COVID-19 was not associated with increased risk for severe COVID-19 but did lower the risk for new-onset liver injury during COVID-19.

COVID-19 psychological impact in 3109 healthcare workers in Spain: The PSIMCOV group.

BACKGROUND: The current coronavirus disease (COVID-19) has a great impact worldwide. Healthcare workers play an essential role and are one of the most exposed groups. Information about the psychosocial impact on healthcare workers is limited. METHODS: 3109 healthcare workers completed a national, internet-based, cross-sectional 45-item survey between 9 and 19 April 2020. The objective is to assess the psychological impact of the COVID-19 pandemic in Spanish healthcare workers. A Psychological Stress and Adaptation at work Score (PSAS) was defined combining four modified versions of validated psychological assessment tests (A) Healthcare Stressful Test, (B) Coping Strategies Inventory, (C) Font-Roja Questionnaire and (D) Trait Meta-Mood Scale. RESULTS: The highest psychosocial impact was perceived in Respiratory Medicine, the mean (S.D.) PSAS was 48.3 (13.6) and Geriatrics 47.6 (16.4). Higher distress levels were found in the geographical areas with the highest incidence of COVID-19 (>245.5 cases per 100 000 people), PSAS 46.8 (15.2); p < 0.001. The least stress respondents were asymptomatic workers PSAS, 41.3 (15.4); p < 0.001, as well as those above 60 years old, PSAS, 37.6 (16); p < 0.001. Workers who needed psychological therapy and did not receive it, were more stressed PSAS 52.5 (13.6) than those who did not need it PSAS 39.7 (13.9); p < 0.001. CONCLUSIONS: The psychological impact in healthcare workers in Spain during COVID-19 emergency has been studied. The stress perceived is parallel to the number of cases per 100 000 people. Psychotherapy could have a major role to mitigate the experimented stress level.

Effectiveness of Caplacizumab Nanobody in Acquired Thrombotic Thrombocytopenic Purpura Refractory to Conventional Treatment.

Acquired thrombocytopenic thrombotic purpura (aTTP) is an autoantibody-mediated disease against the enzyme A Disintegrin and Metalloprotease domain with ThromboSpondin-1 type motif 13, which until now has been treated with plasma exchange (PEX) and corticosteroids. A 29-year-old female patient, who presented with aTTP in the context of pregnancy, has developed multiple relapses after treatment with PEX, corticosteroids, and rituximab. Recently, caplacizumab, a nanobody against von Willebrand factor, has been approved for the treatment of aTTP. In our patient, caplacizumab achieved better disease control, with a lower platelet count restoration time, days of PEX and hospitalization duration, as compared to standard therapy, reproducing the results of clinical trials. Caplacizumab represents a significant advance in the treatment of aTTP, especially in cases of recurrent relapses.

The association of salivary caffeine levels with serum concentrations in premature infants with apnea of prematurity.

The purpose of this paper is to verify whether the concentrations of caffeine in saliva are comparable to serum concentrations in preterm infants who are treated with caffeine for apnea of prematurity. This is a prospective observational study. Eligible participants were newborn infants < 37 weeks of gestational age treated with oral or intravenous caffeine for apnea of prematurity. Two paired samples of saliva and blood were collected per patient. Tube solid-phase microextraction coupled online to capillary liquid chromatography with diode array detection was used for analysis. A total of 47 infants with a median gestational age of 28 [26-30] weeks and a mean of 1.11 ± 0.4 kg of birth weight. Median postmenstrual age, when samples were collected, was 31 [29-33] weeks. Serum caffeine median levels of 19.30 µg/mL [1.9-53.90] and salivary caffeine median levels of 16.36 µg/mL [2.20-56.90] were obtained. There was a strong positive Pearson's correlation between the two variables r = 0.83 (p < 0.001). CONCLUSION: The measurement of salivary caffeine concentrations after intravenous or oral administration offers an alternative to serum caffeine monitoring in apnea of prematurity. Measurement of salivary concentration minimizes blood draws, improves blood conservation, and subsequently minimizes painful procedures in premature infants. WHAT IS KNOWN: • Salivary sampling may be useful when is applied to extremely low birth weight infant, in whom blood sampling must be severely restricted. WHAT IS NEW: • The measurement of caffeine salivary concentrations after intravenous or oral administration offers an alternative to serum caffeine monitoring in apnoea of prematurity. • Salivary sampling may be a valid non-invasive alternative that could be used to individualize and optimize caffeine dose.

Analysis of chemical contamination by hazardous drugs with BD HD Check® system in a tertiary hospital.

The presence of contamination in the healthcare work environment by one of the types of hazardous drugs, cytostatics, has been found in multiple international studies. Recent studies and guidelines recommend surface monitoring for risk assessment of healthcare professionals' exposure. The availability of detection techniques is critical to successfully carry out this type of monitoring. The use of new semi-quantitative techniques allows quicker results. The main objective of this study was to determine the existence of hazardous drugs on the working surfaces in different locations of a tertiary hospital using the BD HD Check® semi-quantitative device. The presence of methotrexate, doxorubicin and cyclophosphamide was analysed at 80, 89 and 82 locations in 10, 13 and 11 clinical units, respectively. A total of 251 samples were analysed. The monitoring results were positive for 13.1% of the analysed samples, with 36.3% of the methotrexate samples, 0% of the doxorubicin samples and 4.9% of the cyclophosphamide samples. Mapping the presence of HD in our hospital has allowed us to evaluate the effectiveness of controls established in the hospital to minimise the exposure of healthcare professionals to hazardous drugs. The speed in obtaining results has enabled immediate corrective actions in cases where contaminated surfaces were detected.

Tall man lettering application in medication information systems as a quality and safety strategy in hospital organization.

WHAT IS KNOWN AND OBJECTIVE: The technique of highlighted capital letters, Tall Man lettering, is a tool that allows differentiating the names of similar drugs in a way that contributes to reduce medication errors related to the drug identification. The objective was to implement and monitor the application protocol of the Tall Man lettering tool in drug information systems in the healthcare environment to improve the quality of care and patient safety in the pharmacy service and the medical institution. METHODS: Scope: Tertiary general hospital with 1000 beds in which a Tall Man lettering application protocol was approved in the pharmacy service information systems. DESIGN: Retrospective observational study. PERIOD: 2019-2021. POPULATION: Information systems and databases used in the pharmacy service. Working group: Made up of people in charge of information areas and systems. IMPLEMENTATION: Five phases were defined: organization of the working group, selection of drug names and information systems, establishment of actions, their execution, and results monitoring. VARIABLES: Number of pharmaceutical specialties, names of active ingredient and brands incorporated in the information systems. RESULTS AND DISCUSSION: The application of Tall Man lettering was authorized in 13/13 information systems, six have been fully implemented and seven are in the database update phase. Of the implanted systems, a total of 210 drug names have been modified (168/210 active ingredient and 42/210 brand names), corresponding to 659 pharmaceutical specialties. WHAT IS NEW AND CONCLUSION: The application of Tall Man lettering in hospital information systems is a tool for improving the quality of the pharmacy service and guarantees the safety of medicines in the hospital.

A multi-criteria decision analysis on the value of nintedanib for interstitial lung diseases.

OBJECTIVES: Our aim was to assess the value of nintedanib for non-idiopathic progressive fibrosing interstitial lung disease (non-IPF PF-ILD) and systemic sclerosis-associated ILD (SSc-ILD) in the Spanish context, using a multi-criteria decision analysis (MCDA). METHODS: Following an adaptation of the Evidence and Value: Impact on DEcision Making (EVIDEM) MCDA methodology, the estimated value of nintedanib was obtained by means of an additive linear model that combined individual weights (100-points distribution) of criteria with the individual scoring of nintedanib in each criterion for every indication, assigned by a multidisciplinary committee of twelve clinicians, patients, pharmacists, and decision-makers. To assess the reproducibility, an alternative weighting method was applied, as well as a re-test of weights and scores at a different moment of time. RESULTS: The experts committee recognized nintedanib as an intervention with a positive value contribution in comparison to placebo for the treatment of non-IPF PF-ILD (0.50 ± 0.16, on a scale from -1 to 1) and SSc-ILD (0.40 ± 0.12), diseases which were considered as very severe and with high unmet needs. The drug was perceived as a treatment that provides an added therapeutic benefit for patients (0.06-0.07), given its proven clinical efficacy (0.05-0.06), slight improvements in patient-reported outcomes (0.01-0.02), and similar safety profile than placebo (-0.04-0.00), which will likely be positioned as a recommended therapy in the next clinical practice guidelines updates. CONCLUSIONS: Under this increasingly used methodology, nintedanib has shown to provide a positive value estimate for non-IPF PF-ILD and SSc-ILD when compared to placebo in Spain.

Effect of Lead Position and Polarity on Paresthesia Coverage in Spinal Cord Stimulation Therapy: A Computational Study.

OBJECTIVES: The effect of lead placement and programming strategies on spinal cord stimulation (SCS) therapy has been widely studied; however, there is a need to optimize these parameters to favor dorsal column (DC) over dorsal root (DR) stimulation in complex pain treatment. This study aimed to determine the optimal lateral distance between two leads and the effect of transverse stimulation using a mathematical model. MATERIALS AND METHODS: A three-dimensional computational SCS and a nerve fiber model were used to determine the effect of the lateral distance between two leads at the same vertebral level T8 and the effect of the addition of anodes with two parallel leads at T8 and three different lateral distances on the model-based results (perception thresholds, activated DC fiber area and depth, and position of the first stimulated fiber). RESULTS: With two parallel leads programmed with symmetrical polarities, the maximal DC fiber area stimulated was found for a lateral distance of 5 mm. The results also show a higher preference for DR stimulation as the lateral distance increased. The addition of positive contacts at the same level of active contacts in the second lead produces a displacement of the first stimulated fiber laterally. CONCLUSIONS: A lateral distance of 5 mm shows a DC stimulated fiber area greater than when leads are placed contiguously. The addition of anodes creates an effect whereby the area of paresthesia is not displaced to the midline, but in the opposite direction. This may be useful when the leads are too close and stimulation of one of the sides is compromised.