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PURPOSE: To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and homeostatic plasticity in human-induced pluripotent stem cell-derived neurons. METHODS: We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human-induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated into excitatory neurons, and we measured their spontaneous electrophysiological responses using micro-electrode arrays (MEAs). We also characterized their somatodendritic morphology and axon initial segment (AIS) structure and plasticity. RESULTS: We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation. CONCLUSIONS: Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.
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Segmento Inicial del Axón , Epilepsia , Células Madre Pluripotentes Inducidas , Humanos , Segmento Inicial del Axón/metabolismo , Ancirinas/genética , Ancirinas/metabolismo , Neuronas/metabolismo , Epilepsia/genética , Epilepsia/metabolismoRESUMEN
BACKGROUND: Inflammation could be related to cancer-related cognitive impairment (CRCI) and might be used as a predictive marker of long-term CRCI. We evaluated associations between inflammatory markers assessed at diagnosis of breast cancer and CRCI two years afterwards. METHODS: Newly diagnosed stage I-III patients with breast cancer from the French CANTO-Cog (Cognitive sub-study of CANTO, NCT01993498) were included at diagnosis (baseline). Serum inflammatory markers (IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, CRP) were assessed at baseline. Outcomes at year 2 post-baseline included overall cognitive impairment (≥ 2 impaired domains) and the following domains: episodic memory, working memory, attention, processing speed, and executive functions. Multivariable logistic regression models evaluated associations between markers and outcomes, controlling for age, education, and baseline cognitive impairment. RESULTS: Among 200 patients, the mean age was 54 ± 11 years, with 127 (64%) receiving chemotherapy. Fifty-three (27%) patients had overall cognitive impairment at both timepoints. Overall cognitive impairment at year 2 was associated with high (> 3 mg/L) baseline CRP (OR = 2.84, 95%CI: 1.06-7.64, p = 0.037). In addition, associations were found between high CRP and processing speed impairment (OR = 2.47, 95%CI:1.05-5.87, p = 0.039), and between high IL-6 and episodic memory impairment (OR = 5.50, 95%CI:1.43-36.6, p = 0.010). CONCLUSIONS: In this cohort, high levels of CRP and IL-6 assessed at diagnosis were associated with overall CRCI, processing speed and episodic memory impairments two years later. These findings suggest a potential inflammatory basis for long-term CRCI. CRP may represent an easily measurable marker in clinical settings and be potentially used to screen patients at greater risk of persistent CRCI.
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Neoplasias de la Mama , Disfunción Cognitiva , Inflamación , Humanos , Femenino , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico , Persona de Mediana Edad , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Inflamación/sangre , Adulto , Anciano , Biomarcadores/sangre , Pruebas Neuropsicológicas , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Citocinas/sangreRESUMEN
BACKGROUND: Prediction of outcomes remains an unmet need in candidates for LVADs. The development of right-heart failure portends an excess in mortality rates, but imaging parameters of right ventricular systolic function have failed to demonstrate a prognostic role. By integrating pulmonary pressure, right ventriculoarterial coupling could fill this gap. METHODS: The ASSIST-ICD registry was used to test right ventriculoarterial coupling as a surrogate parameter at implantation for the prediction of all-cause mortality. RESULTS: The ratio of the tricuspid annular-plane systolic excursion over the estimated systolic pulmonary pressure (TAPSE/sPAP) was not associated with long-term survival in univariate analysis (Pâ¯=â¯0.89), nor was the pulmonary artery pulsatility index (PAPi) (Pâ¯=â¯0.13). Conversely, the ratio of the right atrial pressure over the pulmonary capillary wedge pressure (RAP/PCWP) was associated with all-cause mortality (P < 0.01). After taking tricuspid regurgitation severity, LVAD indication, LVAD model, age, blood urea nitrogen levels, and pulmonary vascular resistance into account, RAP/PCWP remained associated with survival (HR 1.35 [1.10 - 1.65]; P < 0.01). CONCLUSION: Among pre-implant RVAC surrogates, only RAP/PCWP was associated with long-term all-cause mortality in LVAD recipients. This association was independent of established risk factors.
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We report the mechanism of the iron-catalyzed oxidative α-amination of ketones with sulfonamides. Using linear free energy relationships, competition experiments, and identification of reaction intermediates, we have found that the mechanism of this reaction proceeds through rate-limiting electron transfer to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) from an iron enolate in the process of forming an α-DDQ adduct. The adduct then serves as the electrophile for substitution with sulfonamide nucleophiles, accelerated by iron and additional DDQ. This mechanistic study rules out formation of an α-carbocation intermediate and purely radical mechanistic hypotheses.
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Self-regulatory skills are increasingly recognized as critical early education goals, but few efforts have been made to identify all the features of the classroom that actually promote such skills. This study experiments with a new observational measure capturing three dimensions of the classroom environment hypothesized to influence self-regulation: classroom management, emotionally supportive interactions, and direct promotion of self-regulatory skills. These classroom dimensions were tested as predictors of change over the kindergarten year in both self-regulatory and academic skills in a sample of racially/ethnically-diverse low-income children in Tulsa, OK. Results showed that classroom management was associated with small gains in one of four measures of self-regulation, and four of six measures of academic skills. The other dimensions of the environment had weak or no associations with outcomes. These results indicate that further work is needed to refine both models and measures of the self-regulatory environment.
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When the COVID-19 pandemic forced school closures in the U.S. in March 2020, children's learning moved home and online, making school participation a challenge for many families, particularly those with low incomes. Although there is not a clear and agreed-upon digital analog for in-person school participation for young elementary students, existing research on young children's school attendance and engagement in non-pandemic times suggests that family characteristics broadly recognized to shape child development (e.g., parental depressive symptoms, household chaos), children's own characteristics (e.g., pre-COVID-19 academic skills; demographics), and logistical barriers with particular relevance to remote learning (e.g., internet access) may be determinants of remote learning participation. The current study explores the extent to which student participation during COVID-induced remote learning was predicted by family and child characteristics and logistical barriers by drawing on an existing study of diverse low-income students in Tulsa, OK who were in 1st grade when the pandemic emerged. We capitalize on unique, comprehensive, multi-informant data collected before and during COVID-19 to examine young children's participation in remote learning while controlling for pre-existing differences that might otherwise be confounded with both COVID-related stressors and obstacles to remote learning participation. Both family characteristics (e.g., parent depression, household chaos, single mother) and logistical barriers (e.g., internet and device access) predicted children's remote learning participation. Implications for school administrators and policymakers - with a focus on preparation for future disasters that may once again force school closures - are discussed.
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PURPOSE: STAT2 is both an effector and negative regulator of type I interferon (IFN-I) signalling. We describe the characterization of a novel homozygous missense STAT2 substitution in a patient with a type I interferonopathy. METHODS: Whole-genome sequencing (WGS) was used to identify the genetic basis of disease in a patient with features of enhanced IFN-I signalling. After stable lentiviral reconstitution of STAT2-null human fibrosarcoma U6A cells with STAT2 wild type or p.(A219V), we performed quantitative polymerase chain reaction, western blotting, immunofluorescence, and co-immunoprecipitation to functionally characterize the p.(A219V) variant. RESULTS: WGS identified a rare homozygous single nucleotide transition in STAT2 (c.656C > T), resulting in a p.(A219V) substitution, in a patient displaying developmental delay, intracranial calcification, and up-regulation of interferon-stimulated gene (ISG) expression in blood. In vitro studies revealed that the STAT2 p.(A219V) variant retained the ability to transduce an IFN-I stimulus. Notably, STAT2 p.(A219V) failed to support receptor desensitization, resulting in sustained STAT2 phosphorylation and ISG up-regulation. Mechanistically, STAT2 p.(A219V) showed defective binding to ubiquitin specific protease 18 (USP18), providing a possible explanation for the chronic IFN-I pathway activation seen in the patient. CONCLUSION: Our data indicate an impaired negative regulatory role of STAT2 p.(A219V) in IFN-I signalling and that mutations in STAT2 resulting in a type I interferonopathy state are not limited to the previously reported R148 residue. Indeed, structural modelling highlights at least 3 further residues critical to mediating a STAT2-USP18 interaction, in which mutations might be expected to result in defective negative feedback regulation of IFN-I signalling.
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Interferón Tipo I , Humanos , Anticuerpos/genética , Regulación de la Expresión Génica , Interferón Tipo I/genética , Mutación/genética , Transducción de Señal/fisiología , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT2/genética , Factor de Transcripción STAT2/química , Activación Transcripcional , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , HomocigotoRESUMEN
Bi-allelic variants affecting one of the four genes encoding the AP4 subunits are responsible for the "AP4 deficiency syndrome." Core features include hypotonia that progresses to hypertonia and spastic paraplegia, intellectual disability, postnatal microcephaly, epilepsy, and neuroimaging features. Namely, AP4M1 (SPG50) is involved in autosomal recessive spastic paraplegia 50 (MIM#612936). We report on three patients with core features from three unrelated consanguineous families originating from the Middle East. Exome sequencing identified the same homozygous nonsense variant: NM_004722.4(AP4M1):c.1012C>T p.Arg338* (rs146262009). So far, four patients from three other families carrying this homozygous variant have been reported worldwide. We describe their phenotype and compare it to the phenotype of patients with other variants in AP4M1. We construct a shared single-nucleotide polymorphism (SNP) haplotype around AP4M1 in four families and suggest a probable founder effect of Arg338* AP4M1 variant with a common ancestor most likely of Turkish origin.
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Epilepsia , Discapacidad Intelectual , Paraplejía Espástica Hereditaria , Humanos , Discapacidad Intelectual/genética , Mutación/genética , Efecto Fundador , Paraplejía/genética , Paraplejía Espástica Hereditaria/genética , Epilepsia/genética , Linaje , FenotipoRESUMEN
New onset refractory status epilepticus (NORSE) is a rare and devastating condition occurring in a previously healthy patient. It is called febrile infection-related epilepsy syndrome (FIRES) when preceded by a febrile infection. It often leads to intensive care treatment, including antiseizure drugs in combination with anesthetic agents, and sometimes ketogenic diet. The mortality rate is high, and severe epileptic and neuropsychiatric sequelae are usually observed. Based on the possible role of neuroinflammation, intravenous immunoglobulin, corticosteroids, and immunomodulatory treatment (anti-IL1, IL6) can be added. We describe here a child and a young adult with FIRES, both treated with tocilizumab. We observed a rapid positive response on the status epilepticus and good tolerance, but different neurological outcomes for our two patients. Further prospective studies may be necessary both to confirm the efficacy and the safety of this promising treatment and to optimize the immunomodulatory strategy in FIRES/NORSE.
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Epilepsia Refractaria , Encefalitis , Síndromes Epilépticos , Estado Epiléptico , Humanos , Niño , Adulto Joven , Estudios Prospectivos , Convulsiones , Estado Epiléptico/complicaciones , Estado Epiléptico/tratamiento farmacológico , Epilepsia Refractaria/complicaciones , Epilepsia Refractaria/tratamiento farmacológico , Enfermedad Aguda , Síndromes Epilépticos/complicaciones , Síndromes Epilépticos/tratamiento farmacológicoRESUMEN
Optimal sleep, both in terms of duration and quality, is important for adolescent health. However, young people's sleeping habits have worsened over recent years. Access to and use of interactive electronic devices (e.g., smartphones, tablets, portable gaming devices) and social media have become deep-rooted elements of adolescents' lives and are associated with poor sleep. Additionally, there is evidence of increases in poor mental health and well-being disorders in adolescents; further linked to poor sleep. This review aimed to summarise the longitudinal and experimental evidence of the impact of device use on adolescents' sleep and subsequent mental health. Nine electronic bibliographical databases were searched for this narrative systematic review in October 2022. Of 5779 identified unique records, 28 studies were selected for inclusion. A total of 26 studies examined the direct link between device use and sleep outcomes, and four reported the indirect link between device use and mental health, with sleep as a mediator. The methodological quality of the studies was generally poor. Results demonstrated that adverse implications of device use (i.e., overuse, problematic use, telepressure, and cyber-victimisation) impacted sleep quality and duration; however, relationships with other types of device use were unclear. A small but consistent body of evidence showed sleep mediates the relationship between device use and mental health and well-being in adolescents. Increasing our understanding of the complexities of device use, sleep, and mental health in adolescents are important contributions to the development of future interventions and guidelines to prevent or increase resilience to cyber-bullying and ensure adequate sleep.
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Salud Mental , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Adolescente , Estudios Prospectivos , Sueño , Teléfono InteligenteRESUMEN
AIMS: The study aims to investigate the impact of direct oral anticoagulant (DOAC) management on the incidence of pocket haematoma in patients undergoing pacemaker or implantable cardioverter-defibrillator implantation. METHODS AND RESULTS: All consecutive patients receiving DOAC and undergoing cardiac electronic device implantation were included in a large multicentre prospective observational study (NCT03879473). The primary endpoint was clinically relevant haematoma within 30 days after implantation. Overall, 789 patients were enrolled [median age 80 (IQR 72-85) years old, 36.4% women, median CHA2DS2-VASc score 4 (IQR 0-8)], of which 632 (80.1%) received a pacemaker implantation. Antiplatelet therapy was combined with DOAC in 146 patients (18.5%). Direct oral anticoagulants (DOACs) were interrupted 52 (IQR 37-62) h before the procedure and resumed 31 (IQR 21-47) h later. Ninety-six percent of the patients had at least 12â h DOAC interruption before the procedure, and 78% had at least 12â h DOAC interruption after the procedure. Overall, anticoagulation was interrupted for 72 (IQR 48-96) h. Pre- or post-procedural heparin bridging was used in 8.2% and 3.9%, respectively. Timing of DOAC interruption of resumption was not associated with clinically relevant haematoma. Clinically relevant haematoma occurred in 26 patients (3.3%), and thromboembolic events occurred in 5 patients (0.6%). CONCLUSION: In this large real-life registry where most patients had DOAC interruption, clinically relevant haematoma was rare. Despite DOAC interruption and high CHA2DS2-VASc score, thromboembolic events occurred seldomly, highlighting that bleeding exceeds thromboembolic risk in this peri-procedural period. Future research is needed to identify risk factors for clinically relevant haematoma and meaningfully guide clinicians in optimizing DOAC management.
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Anticoagulantes , Desfibriladores Implantables , Hematoma , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Administración Oral , Anticoagulantes/efectos adversos , Desfibriladores Implantables/efectos adversos , Hematoma/epidemiología , Hematoma/etiología , Hematoma/prevención & control , Marcapaso Artificial/efectos adversos , Estudios Prospectivos , Tromboembolia/etiologíaRESUMEN
The current study provides new evidence on the sustained benefits of preschool attendance on a broader range of skills-both academic and executive functioning (EF)-than many prior studies have examined. Using propensity score methods, we predicted children's (N = 920, M age at 1st = 6.5 years) literacy, language, math, and EF skills in kindergarten and again at first-grade (2020-2021) based on whether they had attended public preschool (school-based pre-k; Head Start) versus no preschool. In our race-ethnically diverse sample of children (48% Hispanic/Latinx; 21% Black; 14% White; 9% Native American; 9% multiracial) from low-income families, preschool attenders showed advantages on English literacy, English language, and math in kindergarten, which mostly persisted into first-grade. Preschool did not boost EF in kindergarten or first-grade.
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Lenguaje , Instituciones Académicas , Niño , Preescolar , Humanos , Lactante , Escolaridad , Alfabetización , Función EjecutivaRESUMEN
BACKGROUND: One in seven UK children have obesity when starting school, with higher prevalence associated with deprivation. Most pre-school children do not meet UK recommendations for physical activity and nutrition. Formal childcare settings provide opportunities to deliver interventions to improve nutritional quality and physical activity to the majority of 3-4-year-olds. The nutrition and physical activity self-assessment for childcare (NAP SACC) intervention has demonstrated effectiveness in the USA with high acceptability in the UK. The study aims to evaluate the effectiveness and cost-effectiveness of the NAP SACC UK intervention to increase physical activity, reduce sedentary time and improve nutritional intake. METHODS: Multi-centre cluster RCT with process and economic evaluation. Participants are children aged 2 years or over, attending UK early years settings (nurseries) for ≥ 12 h/week or ≥ 15 h/week during term time and their parents, and staff at participating nurseries. The 12-month intervention involves nursery managers working with a Partner (public health practitioner) to self-assess policies and practices relating to physical activity and nutrition; nursery staff attending one physical activity and one nutrition training workshop and setting goals to be achieved within 6 months. The Partner provides support and reviews progress. Nursery staff receive a further workshop and new goals are set, with Partner support for a further 6 months. The comparator is usual practice. Up to 56 nurseries will be stratified by area and randomly allocated to intervention or comparator arm with minimisation of differences in level of deprivation. PRIMARY OUTCOMES: accelerometer-assessed mean total activity time on nursery days and average total energy (kcal) intake per eating occasion of lunch and morning/afternoon snacks consumed within nurseries. SECONDARY OUTCOMES: accelerometer-assessed mean daily minutes of moderate-to-vigorous physical activity and sedentary time per nursery day, total physical activity on nursery days compared to non-nursery days, average serving size of lunch and morning/afternoon snacks in nursery per day, average percentage of core and non-core food in lunch and morning/afternoon snacks, zBMI, proportion of children who are overweight/obese and child quality-of-life. A process evaluation will examine fidelity, acceptability, sustainability and context. An economic evaluation will compare costs and consequences from the perspective of the local government, nursery and parents. TRIAL REGISTRATION: ISRCTN33134697, 31/10/2019.
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Cuidado del Niño , Casas Cuna , Humanos , Preescolar , Niño , Lactante , Autoevaluación (Psicología) , Análisis Costo-Beneficio , Promoción de la Salud/métodos , Ejercicio Físico , Obesidad , Reino Unido , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
Objective: Maternal hypertension is considered a risk factor for early neonatal neutropenia. We sought to explore this relationship. Study Design: This retrospective cohort study compared initial neutrophil counts in infants born to mothers with preeclampsia with severe features (PSF) and infants born to normotensive mothers using Negative Binomial Regression (NBR) and logistic regression models. Results: Maternal hypertension negatively affected the early neonatal neutrophil count (adjusted NRB coefficient 0.4 [0.2, 0.6], p < 0.0001) but did not increase the risk of neutropenia (OR 2.07 [0.97, 4.41], p = 0.06). The initial neutrophil count and neutropenia risk were not different between PSF subgroups. Gestational age had the greatest impact on neutropenia risk (OR 0.72 [0.64, 0.81], p < 0.0001). Almost all neutropenia resolved within 48 h. Conclusion: Maternal hypertension negatively affects the early neonatal neutrophil count while not increasing the risk of neonatal neutropenia.
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Hipertensión , Neutropenia , Preeclampsia , Recién Nacido , Lactante , Embarazo , Femenino , Humanos , Estudios Retrospectivos , Recuento de Leucocitos , Neutropenia/complicaciones , Hipertensión/complicacionesRESUMEN
People with severe/profound intellectual disability experience challenges in communicating and require their communication partners to adapt to their means of communication. Augmentative and Alternative Communication (AAC) is recognised as a potential means to meet their communication needs. Interventions need to be aimed at both the individual and their communication partners. We conducted a mixed methods systematic review of the literature to synthesise evidence on communication partners experience of communicating with adults with severe/profound intellectual disability through AAC. Eight publications met the inclusion criteria, they underwent thematic synthesis where four themes emerged. A shared commitment to communication partnership is fundamental for the effective and efficient use of AAC. However, there was a disconnect between communication partners perceptions of their roles and responsibilities. This review prompts further research to explore communication partners perceptions of their roles and responsibilities in the use of AAC with people with severe/profound intellectual disabilities.
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Equipos de Comunicación para Personas con Discapacidad , Trastornos de la Comunicación , Discapacidad Intelectual , Humanos , Adulto , ComunicaciónRESUMEN
Persons with intellectual disabilities require frequent access to acute services. Many also access disability services within the community. Reports and enquiries have highlighted the sub-optimal healthcare provided to this group when accessing healthcare in acute services. Joint working between acute and disability services has been identified as a measure to improve healthcare for this group. A mixed method systematic review was undertaken to explore current evidence of joint working between both service providers. Twelve publications were included, and the data were analysed using thematic analysis. Confusion around responsibility and limited training in acute services prevented joint working from occurring. Information-sharing is pivotal in promoting joint-working, but measures which facilitated it were not always used. Albeit acute services demonstrated a strong commitment to deliver quality care to those with intellectual disabilities. Much of the available research captures the experiences of staff in acute services. There is a paucity of research available exploring experiences of disability service providers.
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BACKGROUND: Higher consumption of coffee and tea has been associated with improved health outcomes in the general population and improved breast cancer (BC) prognosis. This study investigated patterns of coffee and tea consumption and association with patient-reported outcomes (PROs) and clinical outcomes among survivors of BC. METHODS: The authors included survivors of stage I-III BC enrolled in the CANTO cohort (NCT01993498) that provided post-treatment assessment of coffee and tea consumption from years 1 to 4 after diagnosis. Group-based trajectory modeling clustered patients according to daily consumption of coffee and tea. Multivariable mixed models and Cox models examined associations between consumption, PROs and clinical outcomes. RESULTS: Among 3788 patients, the authors identified four stable patterns of consumption: "Low" (25.8%), "Moderate" (37.6%), "High" (25.3%), and "Very high" (11.3%), corresponding to <1, 2, 3, and ≥ 4 cups of coffee and/or tea per day. Patients in the "Very high" group (vs. "Low"), were more likely to be younger, smokers, with higher monthly income and education. PROs and survival outcomes were similar across the four groups. CONCLUSIONS: Over one in three survivors of BC reported high or very high consumption of coffee and/or tea. The authors found no association between higher consumption of coffee and/or tea, worse PROs and clinical outcomes.
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Neoplasias de la Mama , Café , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/epidemiología , Café/efectos adversos , Femenino , Humanos , Estudios Longitudinales , Medición de Resultados Informados por el Paciente , Estudios Prospectivos , Factores de Riesgo , Té/efectos adversosRESUMEN
BACKGROUND: Regular physical activity is associated with improved symptom control in patients with breast cancer but its association with chemotherapy completion or response is unclear. METHODS: Using a prospective design, 1075 breast cancer patients receiving neoadjuvant chemotherapy between March 2012 and February 2017 were studied. Physical activity was assessed using the Global Physical Activity Questionnaire [GPAQ-16], quantified in standardised MET-h/wk. Chemotherapy completion was defined as the proportion of patients completing planned treatment course, requiring dose reduction, or requiring dose delay. Response was evaluated by pathologic complete response (pCR). Associations between physical activity and primary outcomes were assessed using multivariable logistic regression models. RESULTS: There was no differences between any chemotherapy completion outcome on the basis of physical activity classification. The percent of patients not completing planned treatment was 5.7% for â¦0.33 MET-h/wk, compared with 6.8% for 0.34-16.65 MET-h/wk, and 4.6% for ≥16.6 MET-h/wk (p = 0.52). No significant relationships were observed between physical activity dose classification and pCR for the overall cohort or upon stratification by clinical subtype. CONCLUSION: Future studies are required to further investigate the relationship between pre-treatment levels of physical activity and function on treatment completion and response in breast and other cancer populations. CLINICAL TRIAL REGISTRATION: NCT01993498.
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Neoplasias de la Mama , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mama/patología , Neoplasias de la Mama/patología , Ejercicio Físico , Femenino , Humanos , Resultado del TratamientoRESUMEN
OBJECTIVES: Temporary circulatory support (TCS) as a bridge-to-left ventricular assist device (BTL) in cardiogenic shock patients has been increasing, but limited data exists on this BTL strategy. We aimed at analyzing the outcome of BTL patients in a population of cardiogenic shock patients compared with those without TCS at the time of the left ventricular assist device (LVAD) surgery and identify predictors of postoperative mortality in this specific population. DESIGN: A multicenter retrospective observational study conducted in 19 centers from 2006 to 2016. SETTING: Nineteen French centers. PATIENTS: A total of 329 cardiogenic shock patients at the time of LVAD implantation were analyzed. Patients were divided in three groups: those under TCS at the time of LVAD implantation (n = 173), those with TCS removal before LVAD surgery (n = 24), and those who did not undergo a bridging strategy (n = 152). Primary endpoint was 30-day mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the BTL group, 68 (39.3%), 18 (10.4%), and 15 (8.7%) patients were under venoarterial extracorporeal membrane oxygenation, Impella, and IABP support alone, and 72 patients (20.6%) were under multiple TCS support. BTL patients presented similar 30 days survival compared with the TCS removal and non-BTL groups. However, BTL group had a significantly longer ICU duration stay, with two-fold duration of mechanical ventilation time, but the three groups experienced similar postoperative complications. Multivariate analysis identified three independent predictors of mortality in the BTL group: combined surgery with LVAD, body mass index (BMI), and heart failure (HF) duration. BTL strategy was not an independent predictor of mortality in cardiogenic shock patients who underwent LVAD. CONCLUSIONS: BTL strategy is not associated with a lower survival among cardiogenic shock patients with LVAD implantation. Predictors of mortality are combined surgery with LVAD, higher BMI, and HF duration.
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Oxigenación por Membrana Extracorpórea , Insuficiencia Cardíaca , Corazón Auxiliar , Oxigenación por Membrana Extracorpórea/efectos adversos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/cirugía , Corazón Auxiliar/efectos adversos , Humanos , Estudios Retrospectivos , Choque Cardiogénico/etiología , Choque Cardiogénico/cirugía , Resultado del TratamientoRESUMEN
PURPOSE: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. METHODS: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. RESULTS: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. CONCLUSION: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.