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Competing Interests: DISCLOSURE: No conflicts of interest to be declared.

Background: Few studies have examined the prevalence of cancer worry in the general and at-risk population. The objective of this study was to describe the prevalence of cancer worry in a sample of individuals at increased risk of developing hereditary cancer, determine differences in cancer worry by socio-demographic characteristics and assess the relationship between cancer worry and psychological distress., Methods: A cross-sectional study was designed with 895 patients. The Cancer Worry Scale (CWS), Hospital Anxiety and Depression Scale (HADS) for psychological distress and sociodemographic characteristics were examined. The multiple linear regression model was developed to explore what variables were predicted for cancer worry. To identify variables associated with higher cancer worry scores, a logistic model was fitted., Results: In the at-higher-risk sample of hereditary cancer, the mean of CWS was 10.20 (SD: 3.70). The significant predictors for cancer worry were gender, age, previous psychiatric treatment, patients affected by cancer and having children. In the sample, 38% of patients had higher scores on cancer worry, the variables associated were patients affected by cancer compared, women, widow/divorced participants, less than secondary school, patients with previous psychiatric treatment and patients less than 55 years old. Using the HADS cutoff score 29% of the sample showed significant psychological distress, more anxiety (35%) than depressive (22%) symptomatology. Psychological distress showed a higher variability (36%) on cancer worry., Conclusion: Findings highlighted distinctive profiles in socio-demographic characteristics according to the degree of cancer worry; therefore, genetic counseling should continue to be provided to address cancer worry and relieve psychological distress., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined., Methods: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain., Results: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections., Discussion: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world., Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions., Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA., Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future., Competing Interests: V.D. Armengol reports no disclosures relevant to the manuscript; B.T. Darras reports grants and non-financial support from, and being the FIREFISH Study Steering Committee Chair and an ad hoc scientific advisory board member for Roche/Genentech, which manufactures risdiplam, grant support from and being an ad hoc scientific board member for Biogen, which manufactures nusinersen; non-financial support from and being an ad hoc scientific board member for Novartis Gene Therapies (AveXis), which manufactures onasemnogene abeparvovec, grant support for the ENDEAR, CHERISH, and CS2/CS12 studies from Ionis Pharmaceuticals, grants from and being an ad hoc scientific board member for Sarepta Pharmaceuticals, grants from PTC Therapeutics, Fibrogen, Summit, the US NIH and National Institute of Neurological Disorders and Stroke, Slaney Family Fund for SMA, Spinal Muscular Atrophy Foundation, CureSMA, and Working on Walking Fund, being an ad hoc scientific board member for Vertex, and a data and safety monitoring board member for Amicus Inc; A.A. Abulaban reports no disclosures relevant to the manuscript; A. Alshehri reports no disclosures relevant to the manuscript; N. Barišić is investigator for Roche clinical trials, served as advisor or consultant, speaker or member of Advisory Boards for: Roche, Novartis, PTC, and Biogen/Medis-Adria; T. Ben-Omran reports no disclosures relevant to the manuscript; G. Bernert has served on Advisory boards for Avexis/Novartis Gene Therapies, Biogen, PTC, Roche, Pfizer and Santhera, he has received funding for travel or speaker honoraria for Biogen, Novartis, Pfizer, PTC, Roche, Santhera, and Merz, he has served as PI for DELOS, SIDEROS (SANTHERA), LELANTOS 1 + 2 (Fibrogen), and STRIDE Registry (PTC); C. Castiglioni has participated in advisory and educational activities by Biogen, Roche and Novartis and received honoraria for these activities; Y.H. Chien has served on advisory boards for Biogen and Novartis Gene Therapies and received honoraria for educational activities; M.A. Farrar is funded by a National Health and Medical Research Council of Australia Investigator grant (APP1194940), she has served on advisory boards for Biogen, Roche and Novartis Gene Therapies and received honoraria for educational activities; G. Kandawasvika reports no disclosures relevant to the manuscript; S. Khadilkar reports no disclosures relevant to the manuscript; J.K. Mah received research grants as PI in studies sponsored by Biogen, Roche, and the Alberta Children's Hospital Foundation; C. Marini-Bettolo reports participation in Scientific Advisory boards and teaching initiatives for Avexis, Biogen, and Roche, she is involved as an investigator in clinical trials from Avexis, and she is principal investigator for the UK SMA patient registry funded by SMA UK; D. Osredkar reports participation in scientific advisory boards and teaching initiatives for Biogen, Medis, Novartis Gene Therapies, PTC, Roche, and Serapta, and he is PI in studies sponsored partly by Biogen and PTC; G. Pfeffer reports no disclosures relevant to the manuscript; F. Piazzon reports no disclosures relevant to the manuscript; I. Pitarch-Castellano has participated in advisory and educational activities by Biogen, Roche and Novartis; S. Quijano-Roy is PI for clinical trials of Biogen (DEVOTE), Novartis Gene Therapies (SMART), and Roche (OLEOS), has served on advisory boards for Biogen, Novartis GT and Roche, and has received travel and speaker honoraria from Biogen Novartis and Roche; K. Saito is funded by the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development, AMED (grant number: 22ek0109472h0003), and she is Principal Investigator for clinical trials of Biogen (DEVOTE), Novartis Gene Therapies, Inc./Novartis (SPR1NT, LT-002), and Chugai (Roche) (SUNFISH), has served on advisory boards for Biogen, Novartis Gene Therapies, Inc./Novartis, and Chugai (Roche), and has received honoraria from Biogen, Novartis and Chugai; J.H. Shin reports no disclosures relevant to the manuscript; J.F. Vázquez-Costa is funded by grants of the Instituto de Salud Carlos III (JR19/00030, PI Vázquez), served on advisory boards for Biogen and Roche and received travel and speaker honoraria from Biogen and Roche; M.C. Walter has served on advisory boards for Avexis, Biogen, Novartis, Roche, Santhera, Sarepta, PTC Therapeutics, Ultragenyx, Wave Sciences, received funding for Travel or Speaker Honoraria from Novartis, Biogen, Ultragenyx, Santhera, PTC Therapeutics, and worked as an ad hoc consultant for AskBio, Audentes Therapeutics, Biogen Pharma GmbH, Fulcrum Therapeutics, Novartis, PTC Therapeutics, Roche; J. Wanigasinghe receives support as principal investigator from NIH grant 1R21HD093563-01; H. Xiong is one of the investigators of Biogen (DEVOTE), Roche (FIREFISH, SUNFISH) and Novartis (STEER), but has no conflicts of interest related to this study; R.C. Griggs serves as Co-PI of a training grant from the NINDS for the Experimental Therapeutics of Neurological Diseases. He receives grant funding from the NIH, the Muscular Dystrophy Association, and the Parent Project for Muscular Dystrophy in support of clinical trials, and he also receives support from PTC Therapeutics, Sarepta Pharmaceuticals and Santhera Pharmaceutics for clinical trial data, and he serves as Chair of a DSMB for Solid Pharmaceuticals, Chair of the Research Advisory Committee of the American Brain Foundation, inaugural Chair of the American Academy of Neurology Section on Experimental Neurotherapeutics, and he receives compensation as an Editor of Cecil Textbook of Medicine; B. Roy has served as a consultant for Alexion Pharmaceuticals (now part of AstraZeneca), Takeda Pharmaceuticals, and argenx, but he has no conflicts directly related to this work. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. TAKE-HOME POINTS → Stark global disparities in access to disease-modifying therapy (DMT) for spinal muscular atrophy (SMA) currently exist, and these disparities are not driven simply by differences in countries' wealth.→ The economic burden of DMT was identified by a majority of survey respondents as a barrier to treatment of SMA, with several other barriers also noted.→ Most respondents reported access to genetic testing, but newborn screening is unavailable in several countries included in this survey and is only implemented regionally in others.→ Increased awareness of unequal access to treatment is the first step toward mitigating inequities in rare neurologic diseases., (© 2023 American Academy of Neurology.)

Background: Left bundle branch area pacing (LBBAP) may be associated with greater improvement in left ventricular ejection fraction and reduction in death or heart failure hospitalization compared with biventricular pacing (BVP) in patients requiring cardiac resynchronization therapy. We sought to compare the occurrence of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) and new-onset atrial fibrillation (AF) in patients undergoing BVP and LBBAP., Methods: The I-CLAS study (International Collaborative LBBAP Study) included patients with left ventricular ejection fraction ≤35% who underwent BVP or LBBAP for cardiac resynchronization therapy between January 2018 and June 2022 at 15 centers. We performed propensity score-matched analysis of LBBAP and BVP in a 1:1 ratio. We assessed the incidence of VT/VF and new-onset AF among patients with no history of AF. Time to sustained VT/VF and time to new-onset AF was analyzed using the Cox proportional hazards survival model., Results: Among 1778 patients undergoing cardiac resynchronization therapy (BVP, 981; LBBAP, 797), there were 1414 propensity score-matched patients (propensity score-matched BVP, 707; propensity score-matched LBBAP, 707). The occurrence of VT/VF was significantly lower with LBBAP compared with BVP (4.2% versus 9.3%; hazard ratio, 0.46 [95% CI, 0.29-0.74]; P <0.001). The incidence of VT storm (>3 episodes in 24 hours) was also significantly lower with LBBAP compared with BVP (0.8% versus 2.5%; P =0.013). Among 299 patients with cardiac resynchronization therapy pacemakers (BVP, 111; LBBAP, 188), VT/VF occurred in 8 patients in the BVP group versus none in the LBBAP group (7.2% versus 0%; P <0.001). In 1194 patients with no history of VT/VF or antiarrhythmic therapy (BVP, 591; LBBAP, 603), the occurrence of VT/VF was significantly lower with LBBAP than with BVP (3.2% versus 7.3%; hazard ratio, 0.46 [95% CI, 0.26-0.81]; P =0.007). Among patients with no history of AF (n=890), the occurrence of new-onset AF >30 s was significantly lower with LBBAP than with BVP (2.8% versus 6.6%; hazard ratio, 0.34 [95% CI, 0.16-0.73]; P =0.008). The incidence of AF lasting >24 hours was also significantly lower with LBBAP than with BVP (0.7% versus 2.9%; P =0.015)., Conclusions: LBBAP was associated with a lower incidence of sustained VT/VF and new-onset AF compared with BVP. This difference remained significant after adjustment for differences in baseline characteristics between patients with BVP and LBBAP. Physiological resynchronization by LBBAP may be associated with lower risk of arrhythmias compared with BVP., Competing Interests: Disclosures Dr Herweg is a speaker and consultant for Abbott; is a speaker and receives fellowship support from Medtronic. Dr Sharma has received honoraria from Medtronic and Biotronik, and is a consultant for Medtronic, Abbott, and Biotronik. Dr Cano has received honoraria from and is a consultant for Medtronic, Biotronik, and Boston Scientific. Dr Ponnusamy has received honoraria from Medtronic. Dr Zanon has received honoraria from Abbott, Biotronik, Boston Scientific, Medtronic, and Microport. Dr Jastrzebski has received honoraria and is a consultant for Medtronic and Abbott. Dr Chelu has received research support from Patient-Centered Outcomes Research Institute (PCORI), National Institutes of Health (NIH), Abbott, Impulse Dynamics, and an honorarium from Impulse Dynamics. Dr Vernooy has been a consultant for Biosense Webster, Philips, Medtronic, Abbott, and Boston Scientific; his institution has received research and educational grants from Philips, Abbott, Medtronic, and Biosense Webster. Dr Whinnett has received honoraria from Medtronic and Boston Scientific and is a consultant for Medtronic and Abbott. Dr Nair has received grants in aid from Biosense Webster, Medtronic Inc., CIHR, and Heart and Stroke Foundation of Canada, and honoraria and consulting fees from Medtronic, Biosense Webster, and Boston Scientific. Dr Curila is a consultant for and has received honoraria from Medtronic, Biotronik, and Abbott. Dr Subzposh has received honoraria from Medtronic. Dr Ellenbogen is a consultant for Medtronic, Boston Scientific, Abbott, and Biotronik, and has received honoraria from Medtronic, Boston Scientific, and Biotronik. Dr Vijayaraman has received honoraria and consultant, research, and fellowship support from Medtronic; he is a consultant for Abbott, Eaglepoint LLC, and has received honoraria from Boston Scientific, Biotronik, and holds a patent for a His bundle pacing delivery tool. The remaining authors report no conflicts of interest.

Objectives: The worldwide practice and impact of noninvasive ventilation (NIV) in pediatric acute respiratory distress syndrome (PARDS) is unknown. We sought to describe NIV use and associated clinical outcomes in PARDS., Design: Planned ancillary study to the 2016/2017 prospective Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study., Setting: One hundred five international PICUs., Patients: Patients with newly diagnosed PARDS admitted during 10 study weeks., Interventions: None., Measurements and Main Results: Children were categorized by their respiratory support at PARDS diagnosis into NIV or invasive mechanical ventilation (IMV) groups. Of 708 subjects with PARDS, 160 patients (23%) received NIV at PARDS diagnosis (NIV group). NIV failure rate (defined as tracheal intubation or death) was 84 of 160 patients (53%). Higher nonrespiratory pediatric logistic organ dysfunction (PELOD-2) score, Pa o2 /F io2 was less than 100 at PARDS diagnosis, immunosuppression, and male sex were independently associated with NIV failure. NIV failure was 100% among patients with nonrespiratory PELOD-2 score greater than 2, Pa o2 /F io2 less than 100, and immunosuppression all present. Among patients with Pa o2 /F io2 greater than 100, children in the NIV group had shorter total duration of NIV and IMV, than the IMV at initial diagnosis group. We failed to identify associations between NIV use and PICU survival in a multivariable Cox regression analysis (hazard ratio 1.04 [95% CI, 0.61-1.80]) or mortality in a propensity score matched analysis ( p = 0.369)., Conclusions: Use of NIV at PARDS diagnosis was associated with shorter exposure to IMV in children with mild to moderate hypoxemia. Even though risk of NIV failure was high in some children, we failed to identify greater hazard of mortality in these patients., Competing Interests: Dr. Emeriaud’s institution received funding from Fonds de recherche du Quebec Santé (research public agency award) and Maquet. Dr. Pons-Òdena’s institution received funding from Medtronic; he received funding from Philips Respironics. Drs. Bhalla and Killien received support for article research from the National Institutes of Health. Dr. Shein received funding from Hill Ward Henderson. Dr. Killien’s institution received funding from the National Institutes of Child Health and Human Development. Dr. Rowan’s institution received funding from the National Heart, Lung, and Blood Institute (K23). Dr. Lin received funding from ROMTech. Dr. Napolitano’s institution received funding from Drager, Actuated Medical, Philips/Respinronics, and VeroBiotech. Dr. Khemani received funding from Orange Med and Bayer. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background and Importance: Deterioration of renal function with respect to baseline during an acute heart failure (AHF) episode is frequent, but impact on outcomes is still a matter of debate., Objective: To investigate the association of creatinine deterioration detected at emergency department (ED) arrival and short-term outcomes in patients with AHF., Design: Secondary analysis of a large multipurpose registry., Settings and Participants: Patients with AHF were diagnosed in 10 Spanish ED for whom a previous baseline creatinine was available., Exposure: Difference between creatinine at ED arrival and at baseline was calculated (∂-creatinine)., Outcome Measures and Analysis: Primary outcome was 30-day all-cause death, and secondary outcomes were inhospital all-cause death, prolonged hospitalization (>7 days) and 7-day postdischarge adverse events. Associations between ∂-creatinine and outcomes were explored using logistic regression by restricted cubic spline (RCS) curves and expressed as odds ratio (OR) with 95% confidence interval (CI), taking ∂-creatinine = 0 mg/dl as reference. Curves were adjusted by age, sex, comorbidities, patient baseline status, chronic treatments, and vitals and laboratory results at ED arrival. Interactions for the primary outcome also were investigated., Main Results: We analyzed 3036 patients (median age = 82 years; IQR = 75-87; women = 55%), with ∂-creatinine ranged from -0.3 to 3 mg/dl. The 30-day mortality was 11.6%. Increments of ∂-creatinine were associated with progressive increase in risk of 30-day death, although adjustment attenuated this association: ∂-creatinine of 0.3/1/2/3 mg/dl were, respectively, associated with adjusted OR of 1.41 (1.02-1.95), 1.69 (1.02-2.80), 1.46 (0.56-3.80) and 1.27 (0.27-5.83). Distinctively significant higher risk was found for patients over 80 years old, female, nondiabetic, functionally disabled and on digoxin therapy. With respect to secondary outcomes, inhospital mortality was 8.1%, prolonged hospitalization was 33.6% and 7-day postdischarge adverse event was 9.7%. Inhospital death steadily increased with increments in ∂-creatinine [from 1.50 (1.04-2.17) with ∂-creatinine = 0.3 to 3.78 (0.78-18.3) with ∂-creatinine = 3], as well as prolonged hospitalization did [from 1.41 (1.11-1.77) to 2.24 (1.51-3.33), respectively]. Postdischarge adverse events were not associated with ∂-creatinine., Conclusion: WRF detected at ED arrival has prognostic value in AHF, being associated with increased risk of death and prolonged hospitalization. These associations showed different patterns of risk but, remarkably, risk started with increments as low as 0.3 mg/dl., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Acute nontraumatic chest pain is a frequent reaso n for consultation in emergency departments and represents a diagnostic challenge. The objective is to estimate the risk of significant coronary artery disease (CAD) in patients with cardiogenic acute chest pain for whom the diagnosis of infarction was ruled out in the emergency department with a nondiagnostic ECG and negative high-sensitivity troponins. We prospectively recruited 1625 patients from emergency departments of seven Spanish hospitals. The outcome was presence of significant CAD determined by presence of ischaemia in functional tests or more than 70% stenosis in imaging tests. In this study, we developed a predictive model and evaluated its performance and clinical utility. The prevalence of significant CAD was 14% [227/1625; 95% confidence interval (CI), 12-16]. MAPAC Cardio-PreTest model included seven predictors: age, sex, smoking, history of hypertension, family history of CAD, history of hyperuricaemia, and type of chest pain. The optimism-adjusted model discrimination was C-statistic 0.654 (95% CI, 0.618-0.693). Calibration plot showed good agreement between the predicted and observed risks, and calibration slope was 0.880 (95% CI, 0.731-1.108) and calibration-in-the-large -0.001 (95% CI, -0.141 to 0.132). The model increased net benefit and improved risk classification over the recommended approach by the European Society of Cardiology [Net Reclassification Index (NRI) of events = 5.3%, NRI of nonevents = 7.0%]. MAPAC Cardio-PreTest model is an online prediction tool to estimate the individualised probability of significant CAD in patients with acute chest pain without a diagnosis of infarction in emergency department. The model was more useful than the current alternatives in helping patients and clinicians make individually tailored choices about the intensity of monitoring or additional coronary tests., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed., Design: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science., Setting: Not applicable., Patients: Patients with or at risk for PARDS., Interventions: None., Measurements and Main Results: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%., Conclusions: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients., Competing Interests: Dr. Barbaro is currently receiving grant support (R01 HL153519; R01 HD015434) from the National Institutes of Health (NIH); he is currently Chair of the Extracorporeal Life Support Organization Registry. Dr. Bembea receives research funding to her institution from the NIH/National Institute of Neurological Disorders and Stroke (R01NS106292) and the Grifols Investigator Sponsored Research Grant. She serves as Chair of the Scientific Committee of the Pediatric Acute Lung Injury and Sepsis Investigators Research Network. Dr. Cheifetz is a medical consultant for Phillips and Medtronic. His institution receives research grant funding from the NIH. Dr. Cruces received funding from the Chilean Ministry of Sciences (Fondecyt 1220322). Dr. Curley received funding from the NIH (UH3HL141736, R01HD098269, R01HL149910, R01HL153519, R01HD104618). Dr. Dahmer received funding from the NIH (National Institute of Child Health and Human Development [NICHD], R21 HD097387; National Heart, Lung and Blood Institute [NHLBI] R01 HL149910). Dr. Dalton received funding from the Department of Defense (No. 13363072). She is a consultant for Innovative Extracorporeal Membrane Oxygenation Concepts, Hemocue, Entegrion, Medtronic, and advisory board member for Abiomed. Dr. Emeriaud’s research program is supported by the Fonds de Recherche du Québec-Santé and the Quebec Respiratory Health Network. Dr. Emeriaud is leading a study, which is financially supported by Maquet. Dr. Jouvet’s research program and salary is supported by the Fonds de Recherche du Québec-Santé and the Quebec Respiratory Health Network. Dr. Jouvet is leading studies, which is financially supported by VitalTracer, Dymedso and public financial agencies (Canadian Foundation for innovation, Institut TransMedTech, Quebec Ministry of Health, Sainte-Justine Hospital). Dr. Killien received funding from the NIH (NICHD K23HD100566). Dr. Kneyber received research funding from the NIH/NICHD (UG3 HL141736-01/U24 HL141723-01) and ZorgOnderzoek Nederland and the area Medical (848041002), Stichting Vrienden Beatrix Kinderziekenhuis, Fonds NutsOhra, University Medical Center Groningen, VU University Medical Center, and the Royal Academy of Dutch Sciences (TerMeulen stipend). Dr. Kneyber’s research program is technically supported by Vyaire, Applied Biosignals, and Timpl. Dr. Kneyber received honoraria from Vyaire. Dr. Kneyber serves as consultant for Metran and served as consultant for Vyaire. Dr. Kudchadkar received funding to her institution from the NIH/NICHD (R01HD103811 & R21HD093369) and the Donaghue Foundation. Dr. López-Fernández is funded by an academic grant from the Instituto de Salud Carlos III, Madrid, Spain (PI19/00141). Dr. Maddux received funding to her institution from the NIH/NICHD (K23HD096018). Dr. Morrow has received honoraria for Continuing Medical Education presentations from EduPro Health. Her research is part-funded by the National Research Foundation of South Africa, through the Incentive Funding for Rated Researchers program. Dr. Nadkarni receives unrestricted research grants to his institution from the NIH, U.S. Department of Defense, Agency for Healthcare Research and Quality, Laerdal Foundation, RQI Partners, Zoll Medical, Defibtech, HeartHero, and Nihon-Kohden. Dr. Nadkarni is an elected member of the Executive Committee (Council) of the Society of Critical Care Medicine. Dr. Napolitano research and consulting relationships with: Drager, Timpel, VERO-Biotech, Actuated Medical, and Philips/Respironics. Dr. Pons has been on the speaker’s bureau of Philips, ResMed and Fisher & Paykel; Hospital Sant Joan de Déu has received disposable material from these companies. Dr. Randolph receives funding from the Centers for Disease Control and Prevention, NIH (National Institute of Allergy and Infectious Diseases AI154470). Dr. Rowan receives funding from the NHLBI (NHLBI K23HL150244). Dr. Sanchez-Pinto received funding from the NIH (NICHD R01 HD105939). Dr. Sauthier research program and salary is supported by the Fonds de Recherche du Québec-Santé. Dr. Takeuchi receives funding from Japan Society for the Promotion of Science grant (KAKENHI 21K09063). Dr. Tse receives research funding to her institution from the Canadian Institute of Health Research and salary support from the Fonds de Recherche du Québec—Santé. Dr. Watson receives research funding to his institution from the NIH. Dr. Zimmerman received research funding from NIH and Biomedical Advanced Research and Development Authority; royalties from Elsevier Publishing. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Purpose of Review: The development of high-throughput techniques like next-generation sequencing (NGS) has unraveled the genetic profile of cancer. In this review, we discuss the role of NGS on the diagnostic, risk stratification, and follow-up of patients with acute myeloid leukemia (AML)., Recent Findings: NGS has become an essential tool in clinical practice for AML management. Therefore, efforts are being made to improve its applications, automation, and turnaround time. Other high-throughput techniques, such as whole genome sequencing or RNA-sequencing, can be also used to this end. However, not all institutions may be able to implement these approaches. NGS is being investigated for measurable residual disease (MRD) assessment, especially with the development of error-correction NGS. New data analysis approaches like machine learning are being investigated in order to integrate genomic and clinical data and develop comprehensive classifications and risk scores., Summary: NGS has proven to be a useful approach for the analysis of genomic alterations in patients with AML, which aids patient management. Current research is being directed at reducing turnaround time and simplifying processes so that these techniques can be universally integrated into clinical practice., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Distal hereditary motor neuropathies (dHMN) are a clinically and genetically diverse group of disorders that are characterized by length-dependent axonal degeneration of lower motor neurons. In this review, we will provide an overview of dHMN, and we will correlate the distinct clinical subtypes with their causative genes, focusing on the most recent advances in the field., Recent Findings: Despite the massive use of new-generation sequencing (NGS) and the discovery of new genes, only a third of dHMN patients receive a molecular diagnosis. Thanks to international cooperation between researchers, new genes have been implicated in dHMN, such as SORD and VWA1 . Mutations in SORD are the most frequent cause of autosomal recessive forms of dHMN. As a result of these findings, the potential benefits of some pharmacological compounds are being studied in cell and animal models, mainly targeting axonal transport and metabolic pathways., Summary: Despite the wide use of NGS, the diagnosis of dHMN remains a challenge. The low prevalence of dHMN makes international cooperation necessary in order to discover new genes and causal mechanisms. Genetic diagnosis of patients and identification of new pathomechanism are essential for the development of therapeutical clinical trials., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: To evaluate long-term efficacy (percent seizure frequency reduction and responder rates), safety, and tolerability of adjunctive cenobamate (CNB) in an open-label extension (OLE) of the randomized, double-blind, placebo-controlled study., Methods: Patients (aged 18-70 years) with uncontrolled focal seizures despite treatment with 1-3 antiseizure medications who completed the 18-week double-blind study (n = 360) could enter the OLE, where they underwent a 2-week blinded conversion to CNB (target dose, 300 mg/d; min/max, 50/400 mg/d)., Results: Three hundred fifty-five patients were included in the OLE safety population (265 originally randomized to CNB, 90 originally randomized to placebo), and 354 were included in the OLE modified intent-to-treat population. As of July 2019, 58.9% of patients (209/355) were continuing CNB treatment and 141 had discontinued, including 16.6% (59/355) because of lack of efficacy, 8.7% (31/355) because of withdrawal by patient, and 7.6% (27/355) because of adverse events. The median (range) duration of OLE exposure was 53.9 (1.1-68.7) months. Retention rates at 12, 24, 36, and 48 months were 83%, 71%, 65%, and 62%, respectively. Median percent seizure frequency reduction over baseline increased with each 6-month OLE interval, up to 76.1% at months 43-48. Among observed patients, 16.4% (36/220) achieved 100% and 39.1% (86/220) achieved ≥90% seizure reduction during >36-48 months. Among the initial OLE modified intent-to-treat population, 10.2% of patients (36/354) achieved 100% and 24.3% (86/354) achieved ≥90% seizure reduction during >36-48 months. Similar to the double-blind study, adverse events (AEs) included dizziness, somnolence, fatigue, and headache. Serious AEs occurred in 20.3% of patients (72/355)., Discussion: Long-term efficacy, including 100% and ≥90% seizure reduction, was sustained during 48 months of CNB treatment, with 71% retention at 24 months. No new safety issues were identified. These results confirm the findings of the double-blind study and support the potential long-term clinical benefit of CNB., Classification of Evidence: This study provides Class IV evidence that oral CNB 50-400 mg/d is effective as an adjunctive treatment for the long-term management of patients with uncontrolled focal seizures previously treated with 1-3 ASMs., Trial Registration Information: ClinicalTrials.gov NCT01866111 (clinicaltrials.gov/ct2/show/results/NCT01866111)., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: This study aims to explore the impact of Charcot-Marie-Tooth disease type 1A (CMT1A) and its treatment on patients in European (France, Germany, Italy, Spain, and the United Kingdom) and US real-world practice., Methods: Adults with CMT1A (n = 937) were recruited to an ongoing observational study exploring the impact of CMT. Data were collected via CMT&Me, an app through which participants completed patient-reported outcome measures., Results: Symptoms ranked with highest importance were weakness in the extremities, difficulty in walking, and fatigue. Almost half of participants experienced a worsening of symptom severity since diagnosis. Anxiety and depression were each reported by over one-third of participants. Use of rehabilitative interventions, medications, and orthotics/walking aids was high., Conclusions: Patient-reported burden of CMT1A is high, influenced by difficulties in using limbs, fatigue, pain, and impaired quality of life. Burden severity appears to differ across the population, possibly driven by differences in rehabilitative and prescription-based interventions, and country-specific health care variability., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: Although future treatments may speciically target the tumour phenotype, other factors should be included to confirm the efficacy of treatment and prevention strategies. The objective of this study was to compare sociodemographic characteristics and psychological distress for breast, ovarian and colorectal cancer predisposition syndrome in a sample at high risk of hereditary cancer., Methods: A cross-sectional study was designed with 799 patients. The nonparametric test, with Kruskal-Wallis test, was used to compare three genetic cancer syndromes, with significant differences in sample size., Results: There were no differences in cancer hereditary syndromes related to sociodemographic characteristics except sex, as breast/ovarian cancer mainly affects women. No group differences were observed for cancer worry (P = 0.17). Breast/ovarian cancer syndrome showed significantly higher scores in cognitive distress compared to colorectal cancer (P = 0.01)., Conclusion: The differences in the distribution of sociodemographic characteristics in these hereditary cancer syndromes can help to better plan resources for patient care in genetic counselling units., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Anticoagulation and antiplatelet therapies are increasingly used in liver transplant (LT) candidates and recipients due to cardiovascular comorbidities, portal vein thrombosis, or to manage posttransplant complications. The implementation of the new direct-acting oral anticoagulants and the recently developed antiplatelet drugs is a great challenge for transplant teams worldwide, as their activity must be monitored and their complications managed, in the absence of robust scientific evidence. In this changing and clinically heterogeneous scenario, the Spanish Society of Liver Transplantation and the Spanish Society of Thrombosis and Haemostasis aimed to achieve consensus regarding the indications, drugs, dosing, and timing of anticoagulation and antiplatelet therapies initiated from the inclusion of the patient on the waiting list to post-LT surveillance. A multidisciplinary group of experts composed by transplant hepatologists, surgeons, hematologists, transplant-specialized anesthesiologists, and intensivists performed a comprehensive review of the literature and identified 21 clinically relevant questions using the patient-intervention-comparison-outcome format. A preliminary list of recommendations was drafted and further validated using a modified Delphi approach by a panel of 24 transplant delegates, each representing a LT institution in Spain. The present consensus statement contains the key recommendations together with the core supporting scientific evidence, which will provide guidance for improved and more homogeneous clinical decision making., Competing Interests: A.B. has received a lecture fee from Octapharma. The remaining authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Anti-IgLON5 disease is a recently described neurologic disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are underreported. We describe the frequency and types of movement disorders in a series of consecutive patients with this disease., Methods: In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by 3 experts in movement disorders., Results: Seventy-two patients were included. In 41 (57%), the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least 1 movement disorder with a median of 3 per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients [72%]), chorea (24 [33%]), bradykinesia (20 [28%]), dystonia (19 [26%]), abnormal body postures or rigidity (18 [25%]), and tremor (15 [21%]). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients [32%]) including dystonia (13), myorhythmia (6), chorea (4), or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31 (43%) patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only 7 (13%) cases., Discussion: Movement disorders are a frequent and leading cause of initial neurologic consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment., (© 2021 American Academy of Neurology.)

Objectives: Genetic variability in anthracycline metabolism could modify the response and safety of acute myeloid leukemia (AML) induction., Methods: Polymorphisms in genes that encodes enzymes of anthracyclines metabolic pathway (CBR3: rs1056892, rs8133052, NQO1: rs1800566, NQO2: rs1143684, NOS3: rs1799983, rs2070744) were evaluated in 225 adult de novo AML patients., Results: The variant CBR3 rs8133052 was associated with lower hepatotoxicity (P = 0.028). Wild-type genotype of NQO2 rs1143684 was related to higher complete remission (P = 0.014), and the variant allele with greater gastrointestinal toxicity (P = 0.024). However, the variant genotype of NQO1 rs1800566 was associated with mucositis (P = 0.018), but heterozygous genotype showed less gastrointestinal toxicity (P = 0.028) and thrombocytopenia (P = 0.009). Protective effects against nephrotoxicity and thrombocytopenia were reported with variant NOS3 rs1799983 (P = 0.006, P = 0.014), whereas carriers of NOS3 rs2070744 showed higher hepatotoxicity and thrombocytopenia (P = 0.017, P = 0.013)., Conclusions: This study supports the influence of genetic variability of idarubicin metabolizing could be critical in predicting anthracycline-induced toxicities., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN)., Recent Findings: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases., Summary: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Platelet-rich plasma (PRP) has demonstrated efficacy as submucosal injection before endoscopic mucosal resection or local injection after endoscopic submucosal dissection of nonpedunculated colorectal lesions., Methods: The EndoPRP study was a prospective single-center study to analyze the efficacy of PRP shield after endoscopic mucosal resection of large nonpedunculated colorectal lesio with impossible clip closure, assessed by the incidence of delayed bleeding (DB) and delayed perforation, and percentage of mucosal restoration after 4 weeks (mucosal healing rate)., Results: Shielding technique with PRP was performed in 4 patients, aged 52 to 80, with 4 lesions at rectum (mean size 53.7±20.6 mm, range 35 to 80 mm). DB occurred in 1 lesion (25% of all lesions), no required blood transfusion or endoscopic treatment. No postoperative delayed perforation occurred. Mucosal healing rate was of 78.6% after 4 weeks., Conclusions: PRP shield failed in prevent DB, probably due to migration and failure in the adherence in large wounds. Future comparative studies are needed to confirm these data., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To describe the clinical, genetic, and disability profile of pediatric distal hereditary motor neuropathy (dHMN) and to determine the utility of an outcome measure validated for children with Charcot-Marie-Tooth disease (CMT) in assessing disability in this cohort., Methods: We reviewed the clinical, neurophysiologic, and disability data on individuals with dHMN, evaluated before the age of 20 years, at 2 tertiary neuromuscular clinics in Australia and Spain. Disability was assessed annually with the CMT Pediatric Scale (CMTPedS) in a subset of individuals., Results: Twenty-two children (13 female) from 19 families were included. Fourteen individuals were symptomatic in the first year of life. Intellectual disability was present in 6 individuals; upper motor neuron signs were seen in 8. Pathogenic variants were found in 9 families, more frequently in BICD2 ( BICD2 -4, DYNC1H1 -2, MFN2 -2, GARS -1). A novel pathogenic variant in the GARS gene was detected and characterized phenotypically. Disability was moderate on the CMTPedS (mean [SD] 18.2 [6.3], n = 16), with balance and long jump being the most affected and sensation items and grip strength the least affected. Over 1 year, the CMTPedS total score deteriorated, on average 1.5 points (SD 3.7) or 9% (n = 12), with significant variability in the rate of progression within the cohort., Conclusions: The genetic profile of pediatric dHMN is different from that identified in adult cohorts. This study has identified distinct functional limitations for the CMTPedS in children and adolescents with dHMN., (© 2020 American Academy of Neurology.)

Background: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe., Methods: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries., Results: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P <0.003). Heart failure was the leading cause of death (10 of 17; 59%), and LV systolic dysfunction predicted an adverse outcome. Eight men and 8 women (28%) underwent heart transplantation or received an LV assist device. Our cohort suggests better prognosis of female compared with male heart transplant recipients., Conclusions: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.

Objective: To study the presence of nodal and paranodal immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in patients with genetic neuropathies., Methods: A total of 108 patients with genetic neuropathies from 3 different centers were included. The presence of IgG and IgM antibodies against neurofascin-155 (NF155), nodal neurofascin (NF186 and NF140), and contactin-1 (CNTN1) were investigated with a cell-based assay (CBA) using immunocytochemistry in transfected HEK293 cells. Sera with positive or uncertain results were further tested by ELISA and immunohistochemistry in pig teased-nerve fibers., Results: Six patients with Charcot-Marie-Tooth disease (CMT) had an uncertain staining pattern for IgM against nodal neurofascin that was not confirmed by ELISA. Two patients with CMT had an uncertain staining pattern for IgG against nodal neurofascin that was not confirmed by ELISA or immunohistochemistry. One patient with CMT with a confirmed GJB1 mutation tested positive for IgG against NF155 by CBA and ELISA (1/900), but was not confirmed by immunohistochemistry and was ultimately classified as negative., Conclusions: Antibodies against nodal or paranodal antigens were not detected in our cohort of patients with CMT, as previously reported. Some patients may falsely test positive for any of the techniques; confirmatory techniques should be incorporated into the routine testing., (© 2020 American Academy of Neurology.)

Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.

Objective: To describe the characteristics of patients with very-late-onset myasthenia gravis (MG)., Methods: This observational cross-sectional multicenter study was based on information in the neurologist-driven Spanish Registry of Neuromuscular Diseases (NMD-ES). All patients were >18 years of age at onset of MG and onset occurred between 2000 and 2016 in all cases. Patients were classified into 3 age subgroups: early-onset MG (age at onset <50 years), late-onset MG (onset ≥50 and <65 years), and very-late-onset MG (onset ≥65 years). Demographic, immunologic, clinical, and therapeutic data were reviewed., Results: A total of 939 patients from 15 hospitals were included: 288 (30.7%) had early-onset MG, 227 (24.2%) late-onset MG, and 424 (45.2%) very-late-onset MG. The mean follow-up was 9.1 years (SD 4.3). Patients with late onset and very late onset were more frequently men ( p < 0.0001). Compared to the early-onset and late-onset groups, in the very-late-onset group, the presence of anti-acetylcholine receptor (anti-AChR) antibodies ( p < 0.0001) was higher and fewer patients had thymoma ( p < 0.0001). Late-onset MG and very-late-onset MG groups more frequently had ocular MG, both at onset (<0.0001) and at maximal worsening ( p = 0.001). Although the very-late-onset group presented more life-threatening events (Myasthenia Gravis Foundation of America IVB and V) at onset ( p = 0.002), they required fewer drugs ( p < 0.0001) and were less frequently drug-refractory ( p < 0.0001)., Conclusions: Patients with MG are primarily ≥65 years of age with anti-AChR antibodies and no thymoma. Although patients with very-late-onset MG may present life-threatening events at onset, they achieve a good outcome with fewer immunosuppressants when diagnosed and treated properly., (© 2020 American Academy of Neurology.)

We present a case of a preteen with autism spectrum disorder and severe self-injurious behavior who developed neuroleptic malignant syndrome on antipsychotics and required urgent electroconvulsive therapy and continued maintenance electroconvulsive therapy for ongoing clinical stability.

Objective: The aim of this study was to compare and validate the different classifications of severity in acute pancreatitis (AP) and to investigate which characteristics of the disease are associated with worse outcomes., Summary of Background Data: AP is a heterogeneous disease, ranging from uneventful cases to patients with considerable morbidity and high mortality rates. Severity classifications based on legitimate determinants of severity are important to correctly describe the course of disease., Methods: A prospective multicenter cohort study involving patients with AP from 23 hospitals in Spain. The Atlanta Classification (AC), Revised Atlanta Classification (RAC), and Determinant-based Classification (DBC) were compared. Binary logistic multivariate analysis was performed to investigate independent determinants of severity., Results: A total of 1655 patients were included; 70 patients (4.2%) died. RAC and DBC were equally superior to AC for describing the clinical course of AP. Although any kind of organ failure was associated with increased morbidity and mortality, persistent organ failure (POF) was the most significant determinant of severity. All local complications were associated with worse outcomes. Infected pancreatic necrosis correlated with high morbidity, but in the presence of POF, it was not associated to higher mortality when compared with sterile necrotizing pancreatitis. Exacerbation of previous comorbidity was associated with increased morbidity and mortality., Conclusion: The RAC and DBC both signify an advance in the description and differentiation of AP patients. Herein, we describe the complications of the disease independently associated to morbidity and mortality. Our findings are valuable not only when designing future studies on AP but also for the improvement of current classifications.

Background: The incidence of invasive cervical cancer and its mortality have been reduced through primary and secondary prevention. Screening rates tend to be lower in vulnerable groups, such as people with severe mental disorders, who have a later detection of cancer and a higher mortality. The access of these women to cervical cancer screening is uncertain in our context., Objective: The aim of this study was to determine the cervical cancer screening rates in women with severe mental disorders., Methods: This was a descriptive cross-sectional study. Women 25 to 65 years old who were admitted during 2016 to the psychiatric unit of a public hospital in Spain were included in the study, and it was determined if they had had cervical cancer screening., Results: A total of 103 eligible women, with a mean age of 45.6 years, were enrolled. Only 28 of the participants (27.2%) had had a cervical cancer screening done in the last 5 years. By age groups, statistically significant differences were found, with women between 35 and 44 years of age having higher rates of cervical cancer screening (41.9%) and the oldest, between 55 and 65 years of age, having the lowest (5%)., Conclusions: Women with severe mental health disorders who were admitted to acute psychiatric care units had much lower cervical cancer screening rates compared with the general population., Implications for Practice: Mental health nurses could be the optimum professionals to promote cancer primary and secondary prevention in women with mental disorders.

Objective: To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified., Methods: Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed., Results: Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma., Conclusion: We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain., (© 2018 American Academy of Neurology.)

Background: Frailty is a syndrome of decreased physiologic reserve that results from compromise of multiple physiologic systems including cardiovascular system. We aimed to determine the association between the frail phenotype and cardiac abnormalities in liver transplant (LT) candidates through evaluation of transthoracic echocardiography (TTE) indices., Methods: Included were consecutive outpatients listed for LT who underwent a frailty assessment from January 1, 2014, to June 30, 2016 (using the Liver Frailty Index) and a 2-dimensional/Doppler TTE examination. Patients were categorized as robust, intermediate frail, or frail by the Liver Frailty Index based on scores of less than 3.2, between 3.2 and 4.5, or 4.5 or greater. Linear regression assessed associations between the Liver Frailty Index and TTE indices., Results: Of 335 patients, 19% were robust, 65% intermediate frail, and 16% frail. TTE indices of left atrial (LA) dilatation differed significantly by frailty status: median LA dimension (P = 0.03), LA volume index (LAVI mL/m; P < 0.001) and %LAVI > 34 mL/m (P = 0.001). In linear regression adjusted for age, sex, hypertension, and diabetes, the Liver Frailty Index was positively associated with LA dimension (coeff, 0.20; 95% confidence interval [CI], 0.07-0.34), LAVI mL/m (coeff, 0.01; 95% CI, 0.005-0.02), ejection fraction (coeff, 1.59; 95% CI, 0.32-2.85), and pulmonary artery systolic pressure (coeff, 0.01; 95% CI, 0.003-0.02), and negatively associated with LV hypertrophy (coeff, -0.22; 95% CI, -0.37 to -0.06)., Conclusions: In LT candidates, frailty is associated with cardiac structural and functional changes, independent of known risk factors. Our study provides evidence to support that measures of frailty in cirrhotic patients encompass abnormalities of the cardiovascular system and may inform assessments of cardiovascular reserve in this population.

Background: Pulmonary vein isolation is the cornerstone of ablation for persistent atrial fibrillation (AF). The role of balloon catheters in this patient population remains ill defined. We sought to compare efficacy and safety of the laser balloon (LB) with wide-area circumferential pulmonary vein isolation using irrigated radiofrequency current (RF) ablation and 3-dimensional mapping., Methods and Results: In 6 European centers, patients with persistent AF were prospectively randomized. Follow-up included 3-day Holter ECG recordings and office visits at 3, 6, and 12 months. The primary efficacy end point was freedom from AF between 90 and 365 days after a single ablation. The primary safety end point was the incidence of any periprocedural complications. Of 152 enrolled patients, 134 (n=68 LB and 66 RF; 63% men; mean age, 66+10 years) with persistent AF (median AF history, 14 months; Q1-Q3, 7-36 months) underwent pulmonary vein isolation and completed the entire follow-up. Baseline parameters were similar in both groups. Procedure and fluoroscopy times were similar in both groups (135±38 and 14±9 minutes (LB) versus 128±51 and 11±9 minutes). The primary efficacy end point was met by 71.2% versus 69.3%, in the LB and RF groups, respectively ( P =0.40). In the LB group, stroke (n=1), a false aneurysm (n=1), and phrenic nerve palsy (n=1) were observed. In the RF group, 2 patients developed a false aneurysm, and 1 patient needed surgical repair., Conclusions: An LB-guided strategy was associated with similar efficacy as wide-area circumferential pulmonary vein isolation using irrigated RF in patients with persistent AF., Clinical Trial Registration: https://www.clinicaltrials.org. Unique identifier: NCT01863472., (© 2017 American Heart Association, Inc.)

Objective: To report the presentation, main syndromes, human leukocyte antigen (HLA) association, and immunoglobulin G (IgG) subclass in the anti-IgLON5 disease: a disorder with parasomnias, sleep apnea, and IgLON5 antibodies., Methods: This was a retrospective clinical analysis of 22 patients. The IgG subclass was determined using reported techniques., Results: Patients' median age was 64 years (range 46-83). Symptoms that led to initial consultation included sleep problems (8 patients; 36%), gait abnormalities (8; 36%), bulbar dysfunction (3; 14%), chorea (2; 9%), and cognitive decline (1; 5%). By the time of diagnosis of the disorder, 4 syndromes were identified: (1) a sleep disorder with parasomnia and sleep breathing difficulty in 8 (36%) patients; (2) a bulbar syndrome including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency in 6 (27%); (3) a syndrome resembling progressive supranuclear palsy (PSP-like) in 5 (23%); and (4) cognitive decline with or without chorea in 3 (14%). All patients eventually developed parasomnia, sleep apnea, insomnia, or excessive daytime sleepiness. HLA-DRB1*10:01 and HLA-DQB1*05:01 were positive in 13/15 (87%) patients; the DRB1*10:01 allele was 36 times more prevalent than in the general population. Among 16 patients with paired serum and CSF samples, 14 had IgLON5 antibodies in both, and 2 only in serum (both had a PSP-like syndrome). Twenty of 21 patients had IgG1 and IgG4 antibodies; the latter predominated in 16., Conclusions: Patients with IgLON5 antibodies develop a characteristic sleep disorder preceded or accompanied by bulbar symptoms, gait abnormalities, oculomotor problems, and, less frequently, cognitive decline. IgG4 subclass antibodies predominate over IgG1; we confirm a strong association with the HLA-DRB1*10:01 allele., (© 2017 American Academy of Neurology.)

Objectives: Positive autoantibody (AAB) titres are commonly encountered in autoimmune hepatitis (AIH) and in a proportion of drug-induced liver injury (DILI) patients. The underlying mechanism for selective AAB occurrence in DILI is unknown, but could be associated with variations in immune-associated genes. Hence, we aimed to analyse human leucocyte antigen (HLA) allele compositions in DILI with positive (+) and negative (-) AAB titres and in AIH patients., Methods: High-resolution genotyping of HLA class I (A, B, C) and II (DRB1, DQB1) loci was performed on 207 DILI and 50 idiopathic AIH patients and compared with 885 healthy Spanish controls., Results: Compared with controls, HLA-B*08:01 [44 vs. 9.7%, P=3.7E-13/corrected P-value (Pc)=1.0E-11], C*07:01 (46 vs. 24%, P=6.4E-04/Pc=0.012), DRB1*03:01 (58 vs. 21.5%, P=5.0E-09/Pc=1.0E-07) and DQB1*02:01 (56 vs. 22%, P=6.8E-08/Pc=9.0E-07) were significantly more frequent in AIH patients. The HLA-A*01:01 frequency was increased in the same population, but did not reach significance after Bonferroni's correction (34 vs. 19%, P=0.02/Pc=0.37). Fifty-eight of 207 DILI patients presented positive titres for at least one AAB (predominantly antinuclear antibody 76% and antismooth muscle antibody 28%). There was a tendency towards higher representation of DRB1*14:01 and DQB1*05:03 in DILI AAB+ compared with DILI AAB- (13.8 vs. 4.0%, P=0.02/Pc=0.5; 13.8 vs. 4.7%, P=0.04/Pc=0.5)., Conclusion: The presence of HLA alleles B*08:01, C*07:01, DRB1*03:01, DQB1*02:01 and possibly A*01:01 enhances the risk of AIH (type 1) in Spanish patients. These alleles form part of the ancestral haplotype 8.1. HLA-DRB1*14:01 and DQB1*05:03 could potentially increase the risk of positive AAB (particularly antinuclear antibody) in Spanish DILI patients.

Background: Subcutaneous administration of hepatitis B immunoglobulin (HBIg) is effective in preventing hepatitis B virus (HBV) recurrence after liver transplantation, but early conversion to subcutaneous administration is undocumented., Methods: In a prospective study, patients transplanted for terminal liver disease due to HBV infection who were HBV DNA-negative at transplant were switched by week 3 posttransplantation from intravenous to subcutaneous HBIg (500 or 1000 IU weekly or fortnightly, adjusted according to serum anti-HBs trough level) if they were HBsAg- and HBV-DNA negative at time of switch. All patients concomitantly received nucleos(t)ide analogue antiviral therapy. Primary endpoint was failure rate by month 6, defined as serum anti-HBs of 100 IU/L or less or HBV reinfection despite serum anti-HBs greater than 100 IU/L., Results: Of 49 patients treated, 47 (95.9%) continued treatment until month 6. All patients achieved administration by a caregiver or self-injection by week 14. No treatment failures occurred. Mean anti-HBs declined progressively to month 6, plateauing at a protective titer of approximately 290 IU/L. All patients tested for HBV DNA remained negative (45/45). Only 1 adverse event (mild injection site hematoma) was assessed as treatment-related., Conclusions: Introduction of subcutaneous HBIg administration by week 3 posttransplantation, combined with HBV virostatic prophylaxis, is effective and convenient for preventing HBV recurrence.

This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m/2day divided into three doses, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle-dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5-15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2-35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle-related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB.

Background: We sought to evaluate the safety and feasibility of a minimally fluoroscopic approach using the CARTOUNIVU module during scar-related ventricular tachycardia (VT) ablation., Methods and Results: Consecutive patients with structural heart disease undergoing VT ablation using the CARTOUNIVU module were prospectively included and classified depending on their VT substrate: (1) ischemic VT (IVT) and (2) nonischemic VT and depending on the presence of an epicardial access. Radiation exposure parameters and major and minor procedure-related complications were registered. A near-zero fluoroscopy exposure was defined as those procedures with an effective dose ≤1 mSv. A total of 44 VT ablation procedures were performed in 41 patients (22 IVT and 19 nonischemic VT). The use of the CARTOUNIVU module resulted in low levels of radiation exposure: median total fluoroscopy time and effective dose of 6.08 (1.51-12.36) minutes and 2.15 (0.58-8.22) mSv, respectively. Patients with IVT had lower radiation exposure than patients with nonischemic VT (total fluoroscopy time, 2.53 [1.22-11.22] versus 8.51 [5.55-17.34] minutes; P=0.016). Epicardial access was associated with significantly higher levels of radiation exposure. Complications occurred in 4.9% patients, none of them being related to the use of the image integration tool. A near-zero fluoroscopy ablation could be performed in 14 of 44 procedures (32%), 43% of IVT procedures, and 50% of procedures with endocardial access only., Conclusions: The use of the CARTOUNIVU module during scar-related VT ablation resulted in low levels of radiation exposure. A near-zero fluoroscopy approach can be achieved in up to half of the procedures, especially in IVT patients with endocardial ablation., (© 2016 American Heart Association, Inc.)

Purpose of Review: Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder is an increasingly life-threatening complication after allogeneic stem cell transplantation with the use of more complex transplant procedures., Recent Findings: Reduced intensity conditioning regimens in combination with in-vivo or ex-vivo T-cell depletion are particularly important risk factors. Prospective monitoring of EBV viremia by real-time quantitative polymerase-chain reaction (PCR) should be performed after high-risk allogeneic stem cell transplantation. However, lack of standardization and concerns about sensitivity and low positive-predictive value challenge the interpretation of PCR monitoring. Preemptive treatment is feasible and can reduce EBV-related mortality but may lead to overtreatment in some patients. Readily available rituximab and methods of adoptive transfer of T-cells are valuable tools. Rituximab is probably the most attractive agent showing the most robust data in this setting. Rituximab seems to offer a good balance between efficacy and toxicity for the treatment of established EBV-associated posttransplant lymphoproliferative disorder. But most often there is a need to combine with adoptive immunotherapy with T-cells to maintain long-term disease control, with either simple unmanipulated donor lymphocyte infusion or more specific and complex adoptive EBV-specific cytotoxic T-cells., Summary: EBV-associated posttransplant lymphoproliferative disorder can often be prevented or treated, especially in earlier stages. The specific role and timing of the different treatment strategies need to be defined.

To determine the maximum tolerated dose of irinotecan administered every 2 weeks, in combination with a fixed and continuous administration of temozolomide, in patients with glioblastoma at first relapse. Patients received oral temozolomide at a fixed and continuous dose of 50 mg/m divided into three daily doses, except for a single 100 mg/m dose, administered before every irinotecan infusion. Irinotecan was given intravenously on days 8 and 22 of 28-day cycles. The starting dose of irinotecan was 100 mg/m, and this was escalated by increments of 15 mg/m in cohorts of 3-6 evaluable patients. Determination of the dose-limiting toxicity was based on toxicities recorded from day 1 of the first cycleto day 8 of the third cycle. Enzyme-inducing antiepileptic drugs were not allowed. Tumor response was assessed by MRI every 8 weeks. Twelve patients were enrolled in this phase I study. The three patients enrolled at dose level 1 and six of nine patients enrolled at dose level 2 were evaluable for toxicity. The maximum tolerated dose of irinotecan was 100 mg/m. The dose-limiting toxicities were hematologic and gastrointestinal. Nine patients were evaluable for response: one patient achieved a partial response, four patients remained stable, and four patients had disease progression. The combination of metronomic temozolomide and irinotecan every 2 weeks can be safely administered at the recommended doses; a phase II study with this combination was started and has completed accrual.

Interpatient variability in drug response can be widely explained by genetically determined differences in metabolizing enzymes, drug transporters, and drug targets, leading to different pharmacokinetic and/or pharmacodynamic behaviors of drugs. Genetic variations affect or do not affect drug responses depending on their influence on protein activity and the relevance of such proteins in the pathway of the drug. Also, the frequency of such genetic variations differs among populations, so the clinical relevance of a specific variation is not the same in all of them. In this study, a panel of 33 single nucleotide polymorphisms in 14 different genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP2C19, CYP2C9, CYP3A4, CYP3A5, MTHFR, NOD2/CARD15, SLCO1A2, SLCO1B1, TPMT, and UGT1A9), encoding for the most relevant metabolizing enzymes and drug transporters relating to immunosuppressant agents, was analyzed to determine the genotype profile and allele frequencies in comparison with HapMap data. A total of 570 Spanish white recipients and donors of solid organ transplants were included. In 24 single nucleotide polymorphisms, statistically significant differences in allele frequency were observed. The largest differences (>100%) occurred in ABCB1 rs2229109, ABCG2 rs2231137, CYP3A5 rs776746, NOD2/CARD15 rs2066844, TPMT rs1800462, and UGT1A9 rs72551330. In conclusion, differences were recorded between the Spanish and other white populations in terms of allele frequency and genotypic distribution. Such differences may have implications in relation to dose requirements and drug-induced toxicity. These data are important for further research to help explain interindividual pharmacokinetic and pharmacodynamic variability in response to drug therapy.

Objective: A meta-analysis was carried out of published studies on the effect of the CYP3A5 6986A>G polymorphism in liver donors and transplant recipients on tacrolimus pharmacokinetics., Methods: Cohort studies that evaluated the relationship between the CYP3A5 polymorphism in liver donors and transplant recipients and tacrolimus, trough blood concentration normalized for the daily dose (C) per kilogram body weight (D) (C/D, ng/ml/mg/kg/day) up to 1 year after transplantation, were included. Data were not restricted by patient age or the language or journal of publication. A literature search was conducted using the Cochrane Library, MEDLINE, EMBASE, and grey literature, and articles published up to 24 April 2013 were selected. Data were pooled (random-effects model), and the results were expressed as the mean difference of the corresponding C/D ratios and 95% confidence intervals., Results: Six studies involving donor genotypes (254 patients) and four involving recipient genotypes (180 patients) were ultimately included. The meta-analysis showed the C/D ratio to be significantly higher in recipients with nonexpresser donor variants at all time points. In recipients, the variant did not influence the C/D ratio., Conclusion: The presence of the CYP3A5 6986A>G polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although only the evidence available for the first month after transplantation was of adequate quality for demonstrating a significant difference. The evidence provided here shows no effect of the recipient genotype; however, the quality of the evidence was low, thereby precluding the drawing of firm conclusions.

Canavan disease is a rare autosomal recessive leukodystrophy characterized by abnormal accumulation of N-acetyl aspartate (NAA) in brain white matter. Currently, there is no cure for this disease, and management of patients consists mainly of treating symptoms. We describe a 3-month-old girl who was hospitalized for poor head control and decreased muscle tone. A battery of laboratory and genetic (homozygous mutation p.C218X) analysis revealed the presence of Canavan disease. Lithium citrate was initiated at a dosage of 45 mg/kg per day after diagnosis. Periodic controls of thyroid and liver function, and lithium levels in blood showed that this drug was sure and well tolerated. After 1 year of treatment, NAA levels decreased by approximately 20% in the brain region, urinary NAA levels showed a reduction of 80%, and patient improved alertness and visual tracking but continued with no heat support, axial hypotonia, and spastic diplegia. In our patient, the results obtained after drug administration are important with respect to the decrease in NAA and more discreet in clinical improvement. However, given the absence of adverse effects and limited treatment options, lithium citrate may be a good alternative to stop the progression of the disease and improve the quality of life of patients.