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Familial hypokalaemic periodic paralysis (FHPP) is an uncommon genetic disease characterized by muscle weakness associated with hypokalaemia. Episodes are precipitated by drugs, stress, metabolic diseases, hypothermia or infection. We report the case of a 38-year-old pregnant women with FHPP who underwent epidural analgesia for labour. Pregnant women with FHPP require multidisciplinary management involving an anaesthesiologist, a gynaecologist and a paediatrician. It is important to maintain normothermia, prevent hyperventilation, monitor electrolytes, avoid glucose infusions and medications that cause hypokalaemia, and administer potassium supplements when required. Locoregional techniques should be preferred over general anaesthesia. Early epidural analgesia reduces the risk of pain that could trigger an episode of FHPP. In the case of general anaesthesia, drugs that can cause malignant hyperthermia should be avoided, and short-acting non-depolarizing neuromuscular blockers with blockade-depth monitoring should be used.

This paper examines the behavior of job seekers and recruiters in the labor market for software engineers. I obtained data from a recruiting platform where individuals can self-report their computer programming skills and recruiters can message individuals they wish to contact about job opportunities. I augment this data set with measures of each individual’s previous programming experience based on analysis of actual computer source code they wrote and shared within the open-source software community. This novel data set reveals that candidates’ self-reported technical skills are quantitatively important predictors of recruiter interest. Consistent with social psychology and behavioral economics studies, I also find female programmers with previous experience in a programming language are 11.07% less likely than their male counterparts to self-report knowledge of that programming language on their resume. Despite public pronouncements, however, recruiters do not appear more inclined toward recruiting female candidates who self-report knowing programming languages. Indeed, recruiters are predicted to be 6.47% less likely to express interest in a female candidate than a male candidate with comparable observable qualifications even if those qualifications are very strong. Ultimately, a gender gap in the self-reporting of skills on resumes exists; but recruiters do not appear to be adjusting their response to such signals in ways that could increase the representation of women among software engineering recruits. This paper was accepted by Yan Chen, behavioral economics and decision analysis.

Sierra Leone is one of the least developed countries in the world, with an economy strangled by the necessity of importing rice to feed the population. In part, this deficit results from domestic farmers rarely using inorganic fertilizer, which is synthesized from fossil fuels internationally. Here, we evaluate the economic benefits of producing green ammonia from renewable local hydropower for low-carbon cost-effective fertilizer production. Its use as fertilizer estimates a 30-year net present value (NPV) of ∼$230M (∼165% return of investment) compared with simply importing fertilizers, which would already save at least $50M a year compared with the current situation of importing rice, but hinges on additional external factors related to implementing modern agriculture. In addition, green ammonia can buffer seasonal fluctuations of hydroelectricity from 900 MW to 50 MW and produce a consistently available 370 MW of power. Although this study presents an initial analysis of Sierra Leone as a case study, it exemplifies the possible economic and social benefits of green ammonia in developing countries. The use of ammonia-based fertilizers is estimated to feed ∼80% of the current world's population through the high-energy and capital-intensive Haber-Bosch process, using methane or coal as feedstock. Current research is developing technologies for the distributed production of green ammonia using solely renewable energy, opening new opportunities to those countries with access to solar, wind, and hydro power. This paper explores the implications of such green ammonia in sub-Saharan Africa, taking Sierra Leone as an example because of its high hydropower capability. It illustrates the economic and social benefits of locally produced fertilizers using their own renewable energy resources versus importing fertilizers or other agricultural products. In addition, green ammonia can also be used to buffer the seasonal variations of renewable energy, leading to a consistently available power to serve as the foundation for development. Green ammonia from renewable resources has the potential to transform the economies of sub-Saharan African countries such as Sierra Leone with high hydropower potential. Here, we show that the use of green ammonia is economically viable and will not only provide fertilizers to feed the population and modernize agriculture but also produce a consistently available power, buffering the seasonal fluctuations of renewable energy.

PURPOSEAlthough NRG1 fusions are oncogenic drivers across multiple tumor types including lung cancers, these are difficult to study because of their rarity. The global eNRGy1 registry was thus established to characterize NRG1 fusion–positive lung cancers in the largest and most diverse series to date.METHODSFrom June 2018 to February 2020, a consortium of 22 centers from nine countries in Europe, Asia, and the United States contributed data from patients with pathologically confirmed NRG1 fusion–positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed.RESULTSAlthough the typified never smoking (57%), mucinous adenocarcinoma (57%), and nonmetastatic (71%) phenotype predominated in 110 patients with NRG1 fusion–positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5′ partners, 20 unique epidermal growth factor domain–inclusive chimeric events, and heterogeneous 5′/3′ breakpoints were found. Platinum-doublet and taxane-based (post–platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS.CONCLUSIONNRG1 fusion–positive lung cancers were molecularly, pathologically, and clinically more heterogeneous than previously recognized. The activity of cytotoxic, immune, and targeted therapies was disappointing. Further research examining NRG1-rearranged tumor biology is needed to develop new therapeutic strategies.

The association between mature B-cell phenotype and KMT2A rearrangements in acute lymphoblastic leukemia is a very rare finding. It identifies a group of patients with similar clinical and biologic...

Background The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death. Methods Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected. Results In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA-4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA-4 plus PD-1 combination therapy recipients (OR, 1.88; p < .001), relative to PD-1/PD-L1 monotherapy recipients, and patients with multiple toxicity had a 5-fold increase in inpatient mortality. Conclusion This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA-4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi-organ involvement is common and those patients are at highest risk of inpatient mortality. Implications for Practice The number of patients admitted to Massachusetts General Hospital for immune-related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.

Summary After a century of status quo in the Haber-Bosch process for synthesizing ammonia, the prospect for green ammonia derived from renewable energy has reinvigorated the development of novel catalysts, but a holistic approach considering both reaction and separation is required. Lower operating pressures—the principal target for process innovations—are constrained by the thermodynamic and practical limitations imposed by the reaction equilibrium and separation characteristics. Both conventional condensation separation and emerging technologies, such as absorption display, lower limits on the operating pressure of the catalyst. As such, the separation techniques should guide the targeting of catalyst design for moderate pressures (10–30 bar) as opposed to atmospheric pressures prevalent in the literature. Under such conditions, removing hydrogen and ammonia inhibition becomes crucial. In describing the constraints imposed by process design, this work provides direction for the development of catalysts for green ammonia production as both a fertilizer and a renewable energy vector.

Purpose: KRAS G12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRASG12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRASG12C-mutant lung adenocarcinoma. Experimental Design: Patients who underwent resection of stage I–III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRASwt), G12C (KRASG12C), or non-G12C (KRASother). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed. Results: In total, 604 patients were included: 374 KRASwt (62%), 95 KRASG12C (16%), and 135 KRASother (22%). Three-year DFS was not different between KRAS-mutant and KRASwt tumors. However, 3-year DFS was worse in patients with KRASG12C than KRASother tumors (log-rank P = 0.029). KRASG12C tumors had more lymphovascular invasion (51% vs. 37%; P = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3–10.8) vs. 6.1 (3.5–9.7); P = 0.021], compared with KRASother tumors. KRASG12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort. Conclusions: KRAS G12C mutations are associated with worse DFS after complete resection of stage I–III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identified a high-risk group for whom KRASG12C inhibitors may be investigated to improve survival.

Sedation can be challenging in critically ill children. Inhaled anesthetics such as sevoflurane have proved to be useful in difficult or long-term sedation. However, its use in children out of the operating room is still limited and little is yet known about its use in patients undergoing ECMO with no previous reports in children. The objective is to assess the effectiveness and safety of sevoflurane during ECMO in two pediatric patients. Sedation was successfully achieved in both patients, and patients' contribution to breathing was possible even with deep sedation. There were not any side effects during sevoflurane treatment or after withdrawal.

Aim To analyse the effect of oxygen fraction reduction (O2 14%, equivalent to 3250 m) on Q-CPR and rescuers' physiological demands. Methodology A quasi-experimental study was carried out in a sample of 9 Q-CPR proficient health care professionals. Participants, in teams of 2 people, performed 10 min CPR on a Laerdal ResusciAnne mannequin (30:2 compression/ventilation ratio and alternating roles between rescuers every 2 min) in two simulated settings: T21-CPR at sea level (FiO2 of 21%) and T14 – CPR at 3250 m altitude (FiO2 of 14%). Effort self-perception was rated from 0 (no effort) to 10 (maximum demand) points. Results Quality of chest compressions was good and similar in both conditions (T21 vs T14). However, the percentage of ventilations with adequate tidal volume was lower in altitude than at sea level conditions (35.9 ± 25.2% vs. 54.7 ± 23.2%, p = 0.035). The subjective perception of effort was significantly higher at simulated altitude (5 ± 2) than at sea level (3 ± 2) (p = 0.038). Maximum heart rate during the tests was similar in both conditions; however, mean oxygen saturation was significantly lower in altitude conditions (90.5 ± 2.5% vs. 99.3 ± 0.5%, p Conclusion Although performing CPR under simulated hypoxic altitude conditions significantly increases the physiological demands and subjective feeling of tiredness compared to sea level CPR, trained rescuers are able to deliver good Q-CPR in such conditions, at least in the first 10 min of resuscitation.

PURPOSECoronavirus-2019 (COVID-19) mortality is higher in patients with cancer than in the general population, yet the cancer-associated risk factors for COVID-19 adverse outcomes are not fully characterized.PATIENTS AND METHODSWe reviewed clinical characteristics and outcomes from patients with cancer and concurrent COVID-19 at Memorial Sloan Kettering Cancer Center until March 31, 2020 (n = 309), and observed clinical end points until April 13, 2020. We hypothesized that cytotoxic chemotherapy administered within 35 days of a COVID-19 diagnosis is associated with an increased hazard ratio (HR) of severe or critical COVID-19. In secondary analyses, we estimated associations between specific clinical and laboratory variables and the incidence of a severe or critical COVID-19 event.RESULTSCytotoxic chemotherapy administration was not significantly associated with a severe or critical COVID-19 event (HR, 1.10; 95% CI, 0.73 to 1.60). Hematologic malignancy was associated with increased COVID-19 severity (HR, 1.90; 95% CI, 1.30 to 2.80). Patients with lung cancer also demonstrated higher rates of severe or critical COVID-19 events (HR, 2.0; 95% CI, 1.20 to 3.30). Lymphopenia at COVID-19 diagnosis was associated with higher rates of severe or critical illness (HR, 2.10; 95% CI, 1.50 to 3.10). Patients with baseline neutropenia 14-90 days before COVID-19 diagnosis had worse outcomes (HR, 4.20; 95% CI, 1.70 to 11.00). Findings from these analyses remained consistent in a multivariable model and in multiple sensitivity analyses. The rate of adverse events was lower in a time-matched population of patients with cancer without COVID-19.CONCLUSIONRecent cytotoxic chemotherapy treatment was not associated with adverse COVID-19 outcomes. Patients with active hematologic or lung malignancies, peri–COVID-19 lymphopenia, or baseline neutropenia had worse COVID-19 outcomes. Interactions among antineoplastic therapy, cancer type, and COVID-19 are complex and warrant further investigation.

Background and objective Patients with thalassaemia major (TM) and sickle cell disease (SCD) in Spain have been counted since the creation of the Spanish registry of haemoglobinopathies (REHem). The objective of this paper is to update the published data after the increase in cases due to the inclusion of adults and introduction of new-born screening in almost the whole country. Material and methods An observational, descriptive, multicentre and ambispective study that included patients with haemoglobinopathies registered in the REHem, started in January 2014 and followed up annually. The data presented correspond until December 31, 2017. Results Nine hundred and fifty-nine patients were collected. There were 75 cases of thalassaemia (62 TM), 826 of ECF and 58 of other types of haemoglobinopathies. The main diagnostic reason in the TM cohort was anaemia symptoms (70.6%), with a mean age at diagnosis of .7 years; in the SCD cohort it was neonatal screening (33.1%), with a mean age at diagnosis of 2.7 years; 26 patients with TM (41.9%) and 30 with SCD (3.6%) underwent a transplant. There were 2 deaths (3.2%) with TM and 19 (2.3%) with SCD. Overall survival was 96.7% in the TM and 97.5% in the SCD cases at 15 years. Conclusions Since the previous publication and after the diffusion of new-born screening, the most frequent diagnostic method, to the majority of autonomous regions, and the inclusion of adult patients to the registry, the REHem has increased by more than 240 cases, reaching a total of 959 records.

Resumen Antecedentes y objetivo Los pacientes con talasemia mayor (TM) y enfermedad de celulas falciformes (ECF) en Espana se han empezado a contabilizar desde la creacion del registro espanol de hemoglobinopatias (REHem). El objetivo del trabajo es actualizar los datos publicados previamente, tras el aumento de casos por la inclusion de adultos y la introduccion del cribado neonatal en casi todo el pais. Material y metodos Estudio observacional, descriptivo, multicentrico y ambispectivo, que incluye pacientes con hemoglobinopatias registrados en REHem, iniciado en enero de 2014 y de seguimiento anual. Los datos presentados corresponden hasta el 31 de diciembre de 2017. Resultados Se recogieron 959 pacientes. Se registraron 75 casos de talasemia (62 TM), 826 de ECF y 58 de otro tipo de hemoglobinopatias. El motivo de diagnostico principal en la TM fue la clinica de anemia (70,6%), con una media de edad al diagnostico de 0,7 anos; en la ECF fue el cribado neonatal (33,1%), con una media de edad al diagnostico de 2,7 anos; 26 pacientes con TM (41,9%) y 30 con ECF (3,6%) fueron sometidos a trasplante. Hubo 2 fallecimientos (3,2%) con TM y 19 (2,3%) con ECF. La supervivencia global fue del 96,7% en la TM y del 97,5% en la ECF a los 15 anos. Conclusiones Desde la publicacion previa y tras la difusion del cribado neonatal, el metodo diagnostico mas frecuente, en la mayoria de comunidades autonomas, y la inclusion de pacientes adultos al registro, el REHem se ha visto incrementado en mas de 240 casos, llegando hasta un total de 959 registros.

This study focuses on the characteristics (feasibility, resuscitation quality, and physical demands) of infant cardiopulmonary resuscitation (CPR) on the forearm during fast walking, performed by a trained lay rescuer.Twenty-one university students from the infant education degree participated in a randomized crossover simulation study to compare a standard pediatric CPR versus a walking pediatric CPR with a manikin on the rescue forearm. Each rescuer performed 2 resuscitation tests of 2 minutes on the infant manikin. Cardiopulmonary resuscitation, physiological, and perceived effort variables were measured.The quality of chest compressions was higher in standard pediatric CPR than in walking pediatric CPR (72% vs 51%; P0.001) and overall CPR quality (59% vs 49%; P = 0.02). There were no differences between ventilation quality (47% vs 46%). Walking pediatric CPR presented a higher percentage of maximum heart rate (52% vs 69%; P0.001) and perceived exertion rate (2 vs 5; P0.001). Participants walked an average of 197 m during the test.In conclusion, pediatric walking CPR is feasible although it represents a slight quality decrease in a simulation infant CPR setting. The option "CPR while walking fast to a safe place" seems to be suitable in terms of safety both for the victim and the rescuer, as well as CPR quality in special circumstances.

SARS-CoV-2 infection causes COVID-19, ranging from mild to critical disease in symptomatic subjects. It is essential to better understand the immunologic responses occurring in patients with the most severe outcomes. In this study, parameters related to the humoral immune response elicited against SARS-CoV-2 were analysed in 61 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centres in Madrid, Spain, during the first pandemic peak between April and June 2020. Subjects were allocated as mild patients without hospitalization, severe patients hospitalized or critical patients requiring ICU assistance. Critical patients showed significantly enhanced levels of B cells with memory and plasmablast phenotypes, as well as higher levels of antibodies against SARS-CoV-2 with neutralization ability, which were particularly increased in male gender. Despite all this, antibody-dependent cell-mediated cytotoxicity was defective in these individuals. Besides, patients with critical COVID-19 also showed increased IgG levels against herpesvirus such as CMV, EBV, HSV-1 and VZV, as well as detectable CMV and EBV viremia in plasma. Altogether, these results suggest an enhanced but ineffectual immune response in patients with critical COVID-19 that allowed latent herpesvirus reactivation. These findings should be considered during the clinical management of these patients due to the potential contribution to the most severe disease during SARS-CoV-2 infection. This work was supported by the Coordinated Research Activities at the Centro Nacional de Microbiología (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr Inmaculada Casas (WHO National Influenza Center of the CNM) and a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. This work was also supported by the Spanish Ministry of Economy and Competitiveness (PID2019 110275RB-I00); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF); Miguel Servet - AESI, MPY 341/21. The work of ML-H and SR is financed by NIH grant R01AI143567. The work of MT is supported by Instituto de Salud Carlos III (COV20_00679). The work of LV is supported by a predoctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). Sí

The NCI-MATCH is a national master protocol trial, published in the Journal of Clinical Oncology, in which diverse tumors are sequenced and patients assigned to treatment. The trial demonstrates the feasibility of identifying rare and common actionable genetic alterations and underscores the strength of academic/community partnerships for improving trial access.

The future of a carbon-free society relies on the alignment of the intermittent production of renewable energy with our continuous and increasing energy demands. Long-term energy storage in molecules with high energy content and density such as ammonia can act as a buffer versus short-term storage (e.g. batteries). In this paper, we demonstrate that the Haber–Bosch ammonia synthesis loop can indeed enable a second ammonia revolution as energy vector by replacing the CO2 intensive methane-fed process with hydrogen produced by water splitting using renewable electricity. These modifications demand a redefinition of the conventional Haber–Bosch process with a new optimisation beyond the current one which was driven by cheap and abundant natural gas and relaxed environmental concerns during the last century. Indeed, the switch to electrical energy as fuel and feedstock to replace fossil fuels (e.g. methane) will lead to dramatic energy efficiency improvements through the use of high efficiency electrical motors and complete elimination of direct CO2 emissions. Despite the technical feasibility of the electrically-driven Haber–Bosch ammonia, the question still remains whether such revolution will take place. We reveal that its success relies on two factors: increased energy efficiency and the development of small-scale, distributed and agile processes that can align to the geographically isolated and intermittent renewable energy sources. The former requires not only higher electrolyser efficiencies for hydrogen production but also a holistic approach to the ammonia synthesis loop with the replacement of the condensation separation step by alternative technologies such as absorption and catalysis development. Such innovations will open the door to moderate pressure systems, the development and deployment of novel ammonia synthesis catalysts, and even more importantly, the opportunity for integration of reaction and separation steps to overcome equilibrium limitations. When realised, green ammonia will reshape the current energy landscape by directly replacing fossil fuels in transportation, heating, electricity, etc., and as done in the last century, food.

Background Cystic fibrosis (CF) is one of the most frequent genetic diseases and the median survival of these patients has improved in the last few decades, therefore it becomes necessary to evaluate the long-term complications as renal and cardiovascular risk factors. Aim of the study To evaluate the incidence, the manifestations of renal disease and the possible association with metabolic and endothelial dysfunction markers in the CF population. Materials and methods We performed a cross-sectional, observational study on 226 CF patients. Clinical and laboratory instrumental parameters (metabolic, inflammatory and endothelial dysfunction markers) were evaluated. Results We showed 65 patients with chronic kidney disease (CKD) and 158 patients with a reduced value of forced expiratory volume in 1 s (FEV1), of which 58 patients with a severe reduction of FEV1. Moreover 28 patients had undergone lung transplantation and them had a significant lower estimated Glomerular Filtration Rate (eGFR) with respect to the non-transplanted patients (p Conclusions Our study showed a high prevalence of CKD in CF patients. Moreover we showed an increase of endothelial dysfunction and metabolic indexes in patients with reduced renal function, as SUA, serum triglycerides and LDL, suggesting the need for an early and complete screening of the main metabolic indexes to reduce cardiovascular risk and progression of renal damage, in particular in patients with lung transplant.

To investigate long-term effect (96 months) of intravitreal ranibizumab administered for exudative age-related macular degeneration (AMD) on retinal nerve fiber layer (RNFL) thickness when used following a pro re nata regimen. In this prospective study, 20 eyes of 20 patients diagnosed with exudative AMD were included. Contralateral non-exudative AMD eyes of nine of these patients were included as controls. Data on intraocular pressure (IOP) and number of injections were recorded. Spectralis optic coherence tomography (OCT) of the circumpapillary RNFL was performed under dilation when diagnosis was made and before the three loading injections. “Follow-up” software was selected to accurately compare baseline with subsequent images through the 8 years of the study. Baseline IOP was 14.1 mmHg both in study (standard deviation, SD: 0.8) and control eyes (SD: 0.9) and remained unchanged during the study. Mean number of injections was 21 (SD: 2.8) at the end of the study. Mean average thickness of RNFL in the study eye group at the end of the study was 96.5 μm (SD: 2.1). Mean loss for the study period was 5.3 μm (SD: 0.7; p

This is a retrospective single-center study of patients with neovascular age-related macular degeneration whose follow-up was delayed due to COVID-19 pandemic with at least three months between visits in Madrid, Spain. The purpose of the study was to evaluate best corrected visual acuity (BCVA) changes and try to identify features in optical coherence tomography (OCT) that could be related to more profound visual loss. It included 270 eyes. The two last visits before lockdown were used for comparison with the visit after lockdown. BCVA changed from 60.2 ± 18.2 to 55.9 ± 20.5 ETDRS letters. 29% of the eyes lost more than 5 letters. OCT was active in 67% of eyes before lockdown and in 80.4% after lockdown. Multiple lineal analysis showed that patients whose OCT before lockdown presented with a combination of intra and subretinal fluid were more likely to suffer a greater visual loss (p = 0.002). These patients should be encouraged to not miss any visits in case a new lockdown is imposed.

OBJECTIVES: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. MATERIALS AND METHODS: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. RESULTS: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p

Objective:Pediatric acute-onset neuropsychiatric syndrome (PANS) is a condition defined by sudden onset of obsessive–compulsive symptoms and/or severe eating restrictions, along with at least two other cognitive, behavioral, or neurological symptoms. Its pathogenesis is unknown but it seems triggered by infections, metabolic disturbances, and other inflammatory reactions. PANS represents a neurodevelopmental problem and infant feeding can play a role. Breast milk is the ideal food for infants and influences children's brain, cognitive, and socio-emotional development.Methods:We enrolled 52 children diagnosed with PANS. We interviewed their parents in order to investigate perinatal history, infant feeding, neurologic development, and confounding factors like socio-economic status and region of origin. We subgrouped PANS patients into three subsets: those who only received human milk (HMO), those who only received infant formula, and those who received mixed feeding.Results:The cohort is composed of 78.9% males, with a median age of 11 years (range 7–17). We found some neurodevelopmental problems (13.5%): walking disorders, ASD, ADHD, oppositional attitude, and delayed psychomotor development. We found scholar performance deficits (25%), including language problems like dysgraphia, dyslexia, and dyscalculia. The achievement of some milestones in the development of the infant is affected in 73.1% of cases. Breastfeeding is not homogeneously practiced in Italy because of social, economic, and cultural phenomena. The richest and the poorest families (100%) in the sample choose breastfeeding, probably with a different approach and for different reasons (awareness or need). In the group of PANS patients fed with HMO, compared to the rest of the patients, we registered fewer cases of growth problems (0 vs. 12.9%;p= 0.14), school performance problems or the need for school support (19.1% vs. 29%;p= 0.42), and a delay in the age of babbling/speaking (range 4–20 vs. 7–36 months;p= 0.066).Conclusion:This is the first study that investigates the role of breastfeeding in the development of PANS. Promoting breastfeeding is important in the general population and also in PANS patients because it has an important social and global health impact, also during adult life. Further studies with a bigger population are needed to investigate the mechanisms underlying PANS and the role that breastfeeding may play in their short- and long-term neurodevelopment.

Infection by novel coronavirus SARS-CoV-2 causes different presentations of COVID-19 and some patients may progress to a critical, fatal form of the disease that requires their admission to ICU and invasive mechanical ventilation. In order to predict in advance which patients could be more susceptible to develop a critical form of COVID-19, it is essential to define the most adequate biomarkers. In this study, we analyzed several parameters related to the cellular immune response in blood samples from 109 patients with different presentations of COVID-19 who were recruited in Hospitals and Primary Healthcare Centers in Madrid, Spain, during the first pandemic peak between April and June 2020. Hospitalized patients with the most severe forms of COVID-19 showed a potent inflammatory response that was not translated into an efficient immune response. Despite the high levels of effector cytotoxic cell populations such as NK, NKT and CD8+ T cells, they displayed immune exhaustion markers and poor cytotoxic functionality against target cells infected with pseudotyped SARS-CoV-2 or cells lacking MHC class I molecules. Moreover, patients with critical COVID-19 showed low levels of the highly cytotoxic TCRγδ+ CD8+ T cell subpopulation. Conversely, CD4 count was greatly reduced in association to high levels of Tregs, low plasma IL-2 and impaired Th1 differentiation. The relative importance of these immunological parameters to predict COVID-19 severity was analyzed by Random Forest algorithm and we concluded that the most important features were related to an efficient cytotoxic response. Therefore, efforts to fight against SARS-CoV-2 infection should be focused not only to decrease the disproportionate inflammatory response, but also to elicit an efficient cytotoxic response against the infected cells and to reduce viral replication. This work was supported by the Coordinated Research Activities at the Centro Nacional de Microbiología (CNM, Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr. Inmaculada Casas (WHO National Influenza Center of the CNM); a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain); the Spanish Ministry of Economy and Competitiveness (PID2019-110275RB-I00); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acciόn Estratégica en Salud, Plan Nacional de Investigaciόn Científica, Desarrollo e Innovaciόn Tecnolόgica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF). The work of ML-H and SR-M is financed by NIH grant R01AI143567. The work of LH is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). Sí

An indirect fuel cell concept is presented herein where a palladium-based membrane (either pure Pd with 25 m thickness or Pd75Ag25 alloy with 10 m thickness) is used to separate the electrochemical cell compartment from a catalysis compartment. In this system, hydrogen is generated from a hydrogen-rich molecule, such as formic acid, and selectively permeated through the membrane into the electrochemical compartment where it is then converted into electricity. In this way, hydrogen is generated and converted in situ, overcoming the issues associated with hydrogen storage and presenting chemical hydrogen storage as an attractive and feasible alternative with potential application in future micro- and macro-power devices for a wide range of applications and fuels.

How do you measure the value of a commodity that transacts at a price of zero from an economic standpoint? This study examines the potential for and extent of omission and misattribution in standard approaches to economic accounting with regards to open source software, an unpriced commodity in the digital economy. The study is the first to follow usage and upgrading of unpriced software over a long period of time. It finds evidence that software updates mislead analyses of sources of firm productivity and identifies several mechanisms that create issues for mismeasurement. To illustrate these mechanisms, this study closely examines one asset that plays a critical role in the digital economic activity, web server software. We analyze the largest dataset ever compiled on web server use in the United States and link it to disaggregated information on over 200,000 medium to large organizations in the United States between 2001 and 2018. In our sample, we find that the omission of economic value created by web server software is substantial and that this omission indicates there is over $4.5 billion dollars of mismeasurement of server software across organizations in the United States. This mismeasurement varies by organization age, geography, industry and size. We also find that dynamic behavior, such as improvements of server technology and entry of new products, further exacerbates economic mismeasurement.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by a state of hyperinflammation. Blood purification techniques can blunt the inflammatory process with a rapidly relevant nonselective effect on the cytokine storm, thus potentially translating into survival benefit for these patients. In this cohort, we evaluated the impact of hemoadsorption with CytoSorb combined with continuous kidney replacement therapy used as adjunctive therapy in 6 critically ill children with multiple organ dysfunction due to HLH. In our series, we found a reduction in inflammatory biomarkers in patients with HLH secondary to infection. Ferritin, one of the most important bedside biomarkers of HLH, showed a reduction in most of the treated patients. The same results were found measuring interleukin-6 and interleukin-10. The same patients showed hemodynamic stabilization measured by the Vasopressor-Inotropic-Score, and reduction in the organ disease score measured with the Pediatric Logistic Organ Dysfunction score. In our cohort, mortality was less than expected based on the Pediatric Index of Mortality 3 score at pediatric intensive care unit admission. Our study shows that hemoperfusion could be a valuable therapeutic option in HLH: stronger scientific evidence is needed to confirm our preliminary experience.

It has been suggested that 1–2% of acute promyelocytic leukemia (APL) patients present variant rearrangements of retinoic acid receptor alpha (RARα) fusion gene, with the promyelocytic leukaemia zinc finger (PLZF)/RARα being the most frequent. Resistance to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested in PLZF/RARα and other variant APLs. Herein, we analyze the incidence, characteristics, and outcomes of variant APLs reported to the multinational PETHEMA (Programa para el Tratamiento de Hemopatias Malignas) registry, and we perform a systematic review in order to shed light on strategies to improve management of these extremely rare diseases. Of 2895 patients with genetically confirmed APL in the PETHEMA registry, 11 had variant APL (0.4%) (9 PLZF-RARα and 2 NPM1-RARα), 9 were men, with median age of 44.6 years (3 months to 76 years), median leucocytes (WBC) 16.8 × 109/L, and frequent coagulopathy. Eight patients were treated with ATRA plus chemotherapy-based regimens, and 3 with chemotherapy-based. As compared to previous reports, complete remission and survival was slightly better in our cohort, with 73% complete remission (CR) and 73% survival despite a high relapse rate (43%). After analyzing our series and performing a comprehensive and critical review of the literature, strong recommendations on appropriate management of variant APL are not possible due to the low number and heterogeneity of patients reported so far.

Background: Ultrasound (US)-guided techniques for peripheral nerve blockade have revealed that intraneural injections are relatively frequent and not necessarily associated with neurological deficits.Objectives: To evaluate the short-term effects of deliberate injections performed under direct vision in two different sites of the sciatic nerve (ScN).Material and Methods: Seventy-two New Zealand white rabbits randomly assigned to one of four experimental groups (n = 18) were employed. All procedures were conducted at a proximal femoral level where the ScN incorporates the common peroneal nerve and the tibial nerve (TN). Fixed volumes of 0.5 ml of saline solution (ES group) or bupivacaine 0.75% (EB group) were administered extrafascicularly inside the paraneurium of the ScN or intrafascicularly (IS and IB groups) under the epineurium of the TN. Cross-sectional area (CSA) and relative echogenicity (RE) of the entire ScN were determined by US before injections, after injections, and at 3 and 7 days. ScN samples were obtained for structural and ultrastructural histopathological studies. Proprioceptive, sensorial, and motor function were clinically evaluated on a daily basis.Results: The CSA of the ScN increased significantly immediately after injections when compared with pre-injection values in all groups (p < 0.05). The RE of the ScN decreased in relation to pre-injection values in all groups (p < 0.05). The CSA and RE of the ScN returned to normal values 7 days after injections in almost all groups. Injected nerves showed histological signs of mild perineural inflammation. Histopathological scores were not significantly different between groups (p > 0.05). The architecture of the ScN was preserved in all rabbits at 3 days and in 31/32 rabbits at 7 days. A focal area of damaged nerve fibers with degeneration of the axons and myelin sheath affecting the TN was observed in one rabbit of the IB group. Nerve function was not clinically impaired in any case.Conclusion: Despite the lack of severe nerve disruption observed in most rabbits, the evidence of a focal area of damaged nerve fibers in one rabbit injected intrafascicularly with bupivacaine confirms that intrafascicular injections should be avoided as they may increase the risk of nerve damage.

The diffusion of genomic testing is critical to the success of precision medicine, but there is limited information on oncologists’ uptake of genetic technology. We aimed to assess the frequency with which medical oncologists and surgeons order BRCA 1/2 and Oncotype DX testing for breast cancer patients. We surveyed 732 oncologists and surgeons treating breast cancer patients. Physicians were from Florida, New York, New Jersey, and Pennsylvania, and were listed in the 2010 AMA Masterfile or identified by patients. 80.6% of providers ordered BRCA 1/2 testing at least sometimes and 85.4% ordered Oncotype DX (p = 0.01). More frequent ordering of BRCA 1/2 was associated with more positive attitudes toward genetic innovation (OR 1.14, p = 0.001), a belief that testing was likely to be covered by patients’ insurance (OR 2.84, p

Background : Oncohematological patients may have a lower immune response against SARS-CoV-2, both to natural infection and to vaccines. Most studies have focused on the analysis of the humoral response, which means that the information available on the cellular response against SARS-CoV-2 in these patients is limited. Current recommendations include vaccination against SARS-CoV-2 in patients undergoing autologous hematopoietic stem cell transplantation (AHSTC), regardless of whether they have been previously exposed to the virus. These recommendations are based on previous studies with other vaccines. Therefore, it is necessary to analyze the immune response that is developed in these patients in order to make specific recommendations for COVID-19 vaccination. Objective : To study the humoral and cellular immune response before and after AHSTC in patients with oncohematological neoplasms who were exposed to SARS-CoV-2 before the transplantation. Materials & methods : Nine patients with previous exposure to SARS-CoV-2 who underwent AHSTC (Table 1) and 8 healthy donors who recovered from mild COVID-19 were recruited from Hospital Ramón y Cajal and Primary Healthcare Center Pedro Laín Entralgo (Madrid, Spain), respectively. Specific direct cellular cytotoxicity (DCC) of PBMCs from these patients against Vero E6 cells infected with pseudotyped SARS-CoV-2 was determined. The activation of caspase-3 in Vero cells was measured after 1 hour of co-culture with PBMCs, in which cytotoxic cell populations were analyzed by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) was analyzed by quantifying the binding of Annexin V to rituximab-coated Raji cells as targets of PBMCs. Results : 1) 66% of AHSTC patients did not develop detectable levels of IgGs against SARS-CoV-2 (Fig. 1). In 33% of these patients with detectable IgG, the titers decreased after AHSTC, as well as their neutralizing capacity (Fig. 1B and C). 2) AHSTC patients showed increased levels of immature B cells (9.5-fold; p=0.0586) and plasmablasts (28.8-fold), in comparison with healthy donors who had mild COVID-19, while naive and resting memory B cells decreased 1.7- and 6.9-fold, respectively. 3) Specific DCC against SARS-CoV-2-infected cells increased 1.5-fold in comparison with healthy donors (Fig. 2A). Cytotoxic populations with NK phenotypes (CD3-CD56+CD16+), NKT (CD3+CD56+CD16+), and CD8+ T cells (CD3+CD8+TCRγδ+) increased 1.9- (p=0.0311), 1.9- (p=0.0592), and 1.6-fold, respectively (Fig. 2B). ADCC increased 2.1-fold in PBMCs from AHSTC patients in comparison with healthy donors (p = 0.0592). Conclusions : Our data show for the first time how the humoral and cellular immune response against the natural infection by SARS-Cov-2 may be modified in patients who were subsequently subjected to AHSTC. Although the humoral response may be reduced after AHSTC, the specific cellular response showed an increased cytotoxic activity. These results could be extrapolated to patients who were vaccinated against COVID-19 prior to AHSTC. Therefore, this information could be useful to define the recommendations for COVID-19 vaccination after AHSTC. Figure 1 Figure 1. Disclosures Garcia-Gutiérrez: Pfizer: Research Funding; Incyte: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy.

The 2018 Faraday Discussion on "Designing Nanoparticle Systems for Catalysis" brought together leading scientists to discuss the current state-of-the-art in the fields of computational chemistry, characterization techniques, and nanomaterial synthesis, and to debate the challenges and opportunities going forward for rational catalyst design. The meeting was a vivid discussion of how the communities accummulate knowledge and on how innovativeness can be combined to have a stronger scientific impact. In the following, we provide an overview of the meeting structure, including plenaries, papers, discussion points and breakout sessions, and we hope to show, to the wider scientific community, that there is great value in continued international discussion and scientific collaboration in these fields.

Background: Oncohematological patients present a variable immune response against many vaccines, due to the immunodeficiency caused by the disease and its treatment. The experience of vaccination against COVID-19 in oncohematological patients is low and mostly limited to studies of humoral immunity. However, the humoral and cellular immune responses between different oncohematological diseases (OHD) have not been compared. Objective: To compare the humoral and cellular immune responses in four groups of patients with OHD after receiving the first dose of one COVID-19 vaccine. Materials & methods: We recruited 53 patients in four groups according to diagnosis: Chronic Lymphatic Leukemia (CLL) (n=14), Chronic Myeloid Leukemia (CML) (n=11), Multiple Myeloma (MM) (n=15), and Allogeneic Hematopoietic Stem Cell Transplantation (ASCT) (n=13) (Table 1). Samples were collected prior to vaccination and 3 weeks after receiving one dose of COMIRNATY (BioNTech-Pzifer), mRNA-1273 (Moderna), or AZD1222 (AstraZeneca). Twenty-six healthy donors with similar vaccination pattern were recruited. IgG titers against SARS-CoV-2 were quantified by Euroimmun-Anti-SARS-CoV-2 ELISA. Direct cellular cytotoxicity (DCC) was determined against Vero E6 cells infected with pseudotyped SARS-CoV-2, measuring caspase-3 activation after co-culture with PBMCs, in which cytotoxic populations were phenotyped by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) analyses were performed using Annexin V on Raji cells as a target. Results: 1) Early humoral response against COVID-19 vaccination in patients with CML was 5.1- (p Conclusions: We found significant differences in the early humoral immune response after one single dose of COVID-19 vaccine depending on the OHD analyzed. It was observed for the first time that the early cytotoxic immune response is efficient in all groups of patients, although superior in those who were not exposed to ASCT. Most cytotoxic activity relied on CD8+ T cells. These data can be useful to determine the efficacy of COVID-19 vaccines in patients with OHD. Figure 1 Figure 1. Disclosures Garcia Gutierrez: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

Background The tropomyosin receptor kinase (TRK) pathway controls appetite, balance, and pain sensitivity. While these functions are reflected in the on-target adverse events (AEs) observed with TRK inhibition, these AEs remain under-recognized, and pain upon drug withdrawal has not previously been reported. As TRK inhibitors are approved by multiple regulatory agencies for TRK or ROS1 fusion-positive cancers, characterizing these AEs and corresponding management strategies is crucial. Patients and methods Patients with advanced or unresectable solid tumors treated with a TRK inhibitor were retrospectively identified in a search of clinical databases. Among these patients, the frequency, severity, duration, and management outcomes of AEs including weight gain, dizziness or ataxia, and withdrawal pain were characterized. Results Ninety-six patients with 15 unique cancer histologies treated with a TRK inhibitor were identified. Weight gain was observed in 53% [95% confidence interval (CI), 43%–62%] of patients and increased with time on TRK inhibition. Pharmacologic intervention, most commonly with glucagon-like peptide 1 analogs or metformin, appeared to result in stabilization or loss of weight. Dizziness, with or without ataxia, was observed in 41% (95% CI, 31%–51%) of patients with a median time to onset of 2 weeks (range, 3 days to 16 months). TRK inhibitor dose reduction was the most effective intervention for dizziness. Pain upon temporary or permanent TRK inhibitor discontinuation was observed in 35% (95% CI, 24%–46%) of patients; this was more common with longer TRK inhibitor use. TRK inhibitor reinitiation was the most effective intervention for withdrawal pain. Conclusions TRK inhibition-related AEs including weight gain, dizziness, and withdrawal pain occur in a substantial proportion of patients receiving TRK inhibitors. This safety profile is unique relative to other anticancer therapies and warrants careful monitoring. These on-target toxicities are manageable with pharmacologic intervention and dose modification.

A 3-month-old, 18 kg, female St Bernard breed dog was presented with recurrent left forelimb lameness and painful swelling of the antebrachium. A large expansile lytic lesion within the left ulna was observed on radiographs. Ultrasound examination revealed a cyst-like structure. Sanguineous fluid was obtained in association with ultrasound guidance. A presumptive diagnosis of aneurysmal bone cyst (ABC) was made. Percutaneous sclerotherapy (PS) with ethanol 95 per cent was performed. Follow-up radiographic examinations showed progressive remodelling. Limb function was normal after 9 months. PS with ethanol was a safe alternative to conventional surgery for the treatment of an ABC in this case.

Background. Cystic fibrosis (CF) is one of the most frequent genetic diseases. The discovery and implementation of new therapies prolonged the survival of CF patients in the last years. Evaluation of long-term complications could be useful to improve the outcome of these patients. Aim of the Study. To evaluate renal function, metabolic, nutritional, and inflammatory status in CF patients on cystic fibrosis transmembrane regulator (CFTR) modulators therapy as well as lung transplant recipients (LRs) and patients on conservative therapy (control group). Materials and Methods. We performed a prospective, longitudinal study on 69 CF patients. Clinical and laboratory parameters (metabolic and nutritional indices and inflammatory markers) were evaluated in all patients before starting CFTR therapy or transplant (T0) and after 3 years (T1). Results. We enrolled 69 CF patients (42 males). Patients were distributed into three groups. The average age was 35.01 ± 10.57 years for the control group (group 0), 32.47 ± 9.40 years for patients on CFTR modulators therapy (group 1), and 38.93 ± 7.14 years for LRs (group 2). At T1, we showed a significant difference among the three groups in terms of renal function indices: creatinine, eGFR, serum nitrogen as well as serum uric acid, sodium, and potassium ( p < 0.001 , p < 0.001 , p < 0.001 , p < 0.001 , p < 0.001 , and p < 0.001 , respectively), particularly in LRs patients. Significant differences were found in nutritional status parameters among the three groups: total protein, serum albumin, serum fibrinogen, serum transferrin, and white blood cell counts ( p < 0.001 , p = 0.037 , p = 0.04 , p = 0.003 , and p = 0.007 , respectively), particularly in LRs compared with other groups. Moreover, we found significant differences in metabolic profile (HbA1c, p = 0.026 ) and inflammatory status, with a significant difference in C-reactive protein values, neutrophil counts, and neutrophil-lymphocyte ratio (NLR) among the three groups ( p < 0.001 , p = 0.005 , and p = 0.026 , respectively). Conclusions. Our study showed a reduced renal function and poor nutritional status in LRs, along with worse metabolic control. Moreover, we showed a lower inflammatory status in patients on CFTR modulators therapy. Therefore, we suggest early and careful monitoring of renal function, metabolic, and nutritional parameters in CF patients, whether they are on conservative therapy, CFTR modulators therapy, and LRs patients.

Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer. Significance: The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors. See related commentary by Koleilat and Kwong, p. 1094. This article is highlighted in the In This Issue feature, p. 1079

Internet gaming disorder (IGD) has been recognized by the American Psychiatric Association (APA) as a tentative disorder in the latest (fifth) revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, psychometric evaluation of the nine IGD criteria remains necessary to further enhance its assessment. Therefore, the objective of this study was to evaluate the psychometric properties of the Spanish version of the Internet Gaming Disorder Scale-Short Form (IGDS9-SF). The internal structure, internal consistency, temporal stability, and relationships with other variables were assessed. Furthermore, a polytomous item response theory (IRT) approach was used to evaluate the performance of each item and the test as a whole. A sample of 388 online gamers (53.61% women, mean age 25.45 years, standard deviation (SD) = 9.62) was recruited for this study. Similar to previous research, the results supported a one-factor structure for the IGDS9-SF, adequate internal consistency and temporal stability of scores, goodness of fit of the items to the graded response model (GRM), and more precise scores at high trait levels to assess IGD in Spanish populations. These findings corroborate the suitability of the Spanish IGDS9-SF for clinical assessment and research within Spanish-speaking populations.

Objective: Cardiac involvement in PANS has not been clarified relying on the scientific literature available until today. It is known that streptococcal infections play a role in the etiology of a great number of diseases including Sydenham chorea and rheumatic fever, among others. Based on the suspected pathogenesis of PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) reported in the medical literature, we decided to investigate the cardiologic involvement in children with a recent PANS/PANDAS diagnosis. Methods: The study population satisfies PANS (1) and PANDAS (2) criteria of diagnoses. Cardiologic assessment was performed through clinical examination, electrocardiography, and echocardiography. Results: In the selected pediatric population, a significant number of children presented mitral valve involvement, systolic murmurs and electrocardiographic abnormalities. High ASLOT levels did not seem to be associated to a cardiac involvement. Conclusions: Often PANS is difficult to diagnose because it is little known by physicians and most of the cardiologic findings described in this study are common among the healthy pediatric population. Also, ASLOT levels seems not to be predictive of cardiac involvement. Furthermore, the existence of PANDAS as a clinical entity is associated with a group of anti-neuronal autoantibodies found in Sydenham chorea is still controversial. We recommend a complete cardiologic evaluation in those children who meet the PANS/PANDAS diagnostic criteria.

Introduction: Extensive research has made it possible to conclude that dysfunctions in serotoninergic transmission are associated with a tendency toward violence and behavioral dysregulations in humans. In this regard, it has been suggested that selective serotonin reuptake inhibitors (SSRIs), such as sertraline, which regulate the serotonin system, might reduce proneness to violence. Aims: This review aims to explore changes in feelings of anger-state (e.g., irritability and hostility) and anger expression as primary outcomes after sertraline treatment. Methods: Based on PRISMA quality criteria for reviews, a literature search was carried out through PubMed, PsycINFO, Dialnet, Psicodoc, Web of Knowledge, and the Cochrane Library. Results: Initially, 605 publications were identified, removing 219 duplicate manuscripts and screening the titles and abstracts of the remaining 386 records. This process left 248 articles for full-text reading, finally including 15 entries. Thus, several empirical studies were included that employed different research designs. In this regard, we considered 3 case reports, 5 open clinical trials, and 7 randomized placebo-controlled trials. The majority of the studies were unanimous in concluding that a large percentage of patients with high irritability levels responded satisfactorily to sertraline treatment. In fact, their mood improved, and they experienced a reduction in irritability and anger expression after a few weeks of treatment (approximately two weeks). However, it was necessary to increase the sertraline dose after months of treatment to avoid exhaustion effects. Moreover, not all the patients responded to the treatment and it is particularly interesting that a small percentage of patients were refractory to treatment or even showed an increase in irritability after a few weeks of treatment. In those cases, it was necessary to discontinue the treatment or reduce the dose to the initial levels. Discussion: Although it is necessary to be cautious about the benefits of sertraline as a way to control anger and irritability, it is relevant to consider pharmacological strategies to reduce anger-state as coadjutant treatments to psychotherapy in order to promote lasting changes in violent populations.

Telephone helplines is an effective method for helping patients with chronic diseases, including inflammatory bowel disease (IBD). The objective of this cross-sectional multicenter study was to assess reasons for consultation by patients with IBD to a nurse-led telephone service. The sample included 7,273 IBD patients from 6 public hospitals in Barcelona, Spain. Data collected included calls registered during 50 working days including caller characteristics, reason for consultation, patient's diagnosis, and action recommended. The most common reasons for consultation were suspicion of relapse, doubts regarding medication, drug monitoring, side effects, visit appointment, and request of test results. In 63.7% of cases, telephone calls were solved solely by nurses, and in 35.9% in collaboration with a physician. Patient's questions were resolved via telephone in 89.3%. Findings from this study add support of the nurse's role for providing an effective telephone service for resolution of a wide range of patient queries in IBD. Helplines managed by IBD nurses may be a key element for patient-centered care.

3012 Background: Loss of BRCA1/2 function leads to homologous recombination deficiency (HRD) and can enhance platinum and PARP inhibitor sensitivity in breast, pancreas, prostate, and ovarian cancers. In BRCA-associated cancers, resistance can result from the development of BRCA1/2 reversion mutations, which restore BRCA1/2 function. By contrast, a BRCA mutation may be an incidental finding in other tumor histologies. Methods: To determine the distribution of reversion mutations in a pan-cancer cohort, the MSK-IMPACT clinical sequencing cohort was mined to identify patients who had both a germline BRCA1/2 mutation and a frameshift somatic reversion mutation that restored BRCA1/2 function. Whole exome resequencing was used to detect HRD signatures. Chart review enabled collection of data on treatment history in patients consented to germline testing. Results: Of the 33,277 patients with matched tumor and normal sequencing profiled in this study, 861 patients were found to have germline pathogenic BRCA1/2 alterations, including 347 (40%) in BRCA1 and 514 (60%) in BRCA2. Somatic BRCA1/2 driver alterations were also found in tumor tissue from an additional 447 patients, with 156 (35%) having BRCA1 mutations, and the remainder having alterations in BRCA2 (65%) . Among the 1,308 germline or somatic BRCA1/2 mutant tumors, we identified reversion mutations in 12 patients, all of whom were germline carriers of BRCA1/2, comprising 3 BRCA1 and 9 BRCA2 tumors. 7 patients consented to germline testing enabling review of clinical characteristics and treatment history, 5 of whom received PARP inhibitor or platinum-therapy prior to reversion detection. Ten of 12 tumors with reversion mutations were in canonical BRCA-associated cancers. Interestingly, reversion mutations were also found in patients with lung adenocarcinoma (n=1) and gastroesophageal junction adenocarcinoma (n=1). In both these non-canonical histologies, the reversion was detected following progression on platinum-based therapy. Whole exome resequencing of the lung tumor revealed the classic somatic molecular phenotypes of HRD that are characteristic of BRCA-dependent tumors, including in terms of large-scale transitions, HRD-loss of heterozygosity, signature 3, and the number of telomeric allelic imbalance score. Conclusions: Matched tumor and normal sequencing from a large cohort of patients with diverse cancer histologies reveals that reversion mutations are found across BRCA-associated cancer types. In rare cases, reversion mutations in BRCA1/2 following platinum-based therapy may be indicative of prior BRCA-dependence in select non-canonical tumor histologies.

8533 Background: Lung cancer is the leading cause of cancer death world-wide, and chemotherapy and radiation remain backbones of therapy for patients with locoregionally advanced and metastatic disease. However, the genetic mechanisms that mediate resistance to chemotherapy and radiation are largely unclear due to a lack of available tissue at the time of relapse. We hypothesized that circulating tumor DNA (ctDNA) analysis could identify emergent mutations after chemotherapy and radiation that may lead to treatment resistance. Methods: To identify emergent mutations at the time of progression following an initial response to chemotherapy and/or radiation therapy for lung cancer, we utilized CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) to analyze plasma samples and matched leukocytes collected pre-treatment and at the time of relapse. We analyzed a targeted panel enriched for lung cancer drivers and recurrently mutated genes for 27 patients treated with chemoradiation therapy for locoregionally advanced lung cancer. In addition, we performed ultra-deep whole exome sequencing ( > 2000X deduped depth) of pre-treatment and relapse cell-free DNA for 5 patients treated with combination chemotherapy for metastatic lung cancer. Functional enrichment analysis was performed on emergent mutation gene lists to identify significantly enriched pathways. Results: We identified emergent variants in 6 out of 27 patients using targeted sequencing after chemoradiation therapy. Emergent mutations after chemoradiation were enriched for plasma membrane adhesion molecules such as PCDH17, PCDH10, and FAT3 (adjusted P = 0.03). Using ultra-deep whole exome sequencing, we observed emergent mutations in 3 out of 5 patients treated with combination chemotherapy. After combination chemotherapy, there was a trend towards enrichment in mutations in ATP-binding cassette transporters, including ABCA13 and ABCB4 (adjusted P = 0.057). Notably, there were no recurrent emergent mutations within our cohort. Conclusions: Our results suggest that ultra-deep whole exome sequencing can non-invasively identify emergent mutations at the time of progression. Resistance to cytotoxic therapy is likely multi-factorial and analysis in expanded cohorts will be helpful to identify recurrently mutated pathways that may contribute to disease progression after an initial response to therapy.