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The language network of the human brain has core components in the inferior frontal cortex and superior/middle temporal cortex, with left-hemisphere dominance in most people. Functional specialization and interconnectivity of these neocortical regions is likely to be reflected in their molecular and cellular profiles. Excitatory connections between cortical regions arise and innervate according to layer-specific patterns. Here, we generated a gene expression dataset from human postmortem cortical tissue samples from core language network regions, using spatial transcriptomics to discriminate gene expression across cortical layers. Integration of these data with existing single-cell expression data identified 56 genes that showed differences in laminar expression profiles between the frontal and temporal language cortex together with upregulation in layer II/III and/or layer V/VI excitatory neurons. Based on data from large-scale genome-wide screening in the population, DNA variants within these 56 genes showed set-level associations with interindividual variation in structural connectivity between the left-hemisphere frontal and temporal language cortex, and with the brain-related disorders dyslexia and schizophrenia which often involve affected language. These findings identify region-specific patterns of laminar gene expression as a feature of the brain's language network.
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Lenguaje , Neocórtex , Humanos , Neocórtex/metabolismo , Lóbulo Temporal/metabolismo , Masculino , Femenino , Esquizofrenia/genética , Esquizofrenia/metabolismo , Neuronas/metabolismo , Lóbulo Frontal/metabolismo , Transcriptoma , AdultoRESUMEN
BACKGROUND: The Society of Australia and New Zealand (SOMANZ) published its first sepsis in pregnancy and the postpartum period guideline in 2017 (Aust N Z J Obstet Gynaecol, 57, 2017, 540). In the intervening 6 years, maternal mortality from sepsis has remained static. AIMS: To update clinical practice with a review of the subsequent literature. In particular, to review the definition and screening tools for the diagnosis of sepsis. MATERIALS AND METHODS: A multi-disciplinary group of clinicians with experience in all aspects of the care of pregnant women analysed the clinical evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system following searches of Cochrane, Medline and EMBASE. Where there were conflicting views, the authors reviewed the topic and came to a consensus. All authors reviewed the final position statement. RESULTS: This position statement has abandoned the use of the quick Sequential Organ Failure Assessment score (qSOFA) score to diagnose sepsis due to its poor performance in clinical practice. Whilst New Zealand has a national maternity observation chart, in Australia maternity early warning system charts and vital sign cut-offs differ between states. Rapid recognition, early antimicrobials and involvement of senior staff remain essential factors to improving outcomes. CONCLUSION: Ongoing research is required to discover and validate tools to recognize and diagnose sepsis in pregnancy. Australia should follow New Zealand and have a single national maternity early warning system observation chart.
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BACKGROUND: While the literature has highlighted the immense challenges in caring for family members, it is still unclear what the needs of family carers of persons with intellectual disability and challenging behaviours are and what has worked for them. This study aims to examine 60 parents' and siblings' experiences in managing the challenging behaviours of their adult family member with intellectual disability whilst living at home. METHODS: A qualitative grounded theory approach using semi-structured interviews will be adopted. Purposive sampling will be used to recruit family carers who live with adult persons with intellectual disability and use one community service in Hong Kong. Three special schools for persons with intellectual disability from northern China will be approached. RESULTS: This study will aim to provide an in-depth understanding of the experiences of family carers and compare the different circumstances they face when managing the challenging behaviours of their adult relatives with intellectual disability in their family home. CONCLUSIONS: Although this study targets adults with intellectual disability, the findings will provide a point of reference for adolescents and younger persons who exhibit demanding and challenging behaviours and live with their families. Recommendations can guide the development of appropriate strategies to strengthen services for family carers.
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Cuidadores , Discapacidad Intelectual , Padres , Hermanos , Humanos , Discapacidad Intelectual/psicología , Discapacidad Intelectual/terapia , Hong Kong , China , Adulto , Padres/psicología , Hermanos/psicología , Cuidadores/psicología , Investigación Cualitativa , Masculino , Femenino , Problema de Conducta/psicología , Pueblos del Este de AsiaRESUMEN
We describe our experience with intravenous amoxicillin-clavulanate, which is new to the Canadian market. The majority of patients were successfully de-escalated from piperacillin-tazobactam or a carbapenem for respiratory infections or skin and soft tissue infections. Intravenous amoxicillin-clavulanate provides a good alternative in an era of rising Pseudomonas aeruginosa resistance.
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OBJECTIVES: Data on the use of intravenous (IV) fosfomycin in Canada are limited. Using data captured by the Canadian LEadership on Antimicrobial Real-life usage (CLEAR) registry, we report the use of IV fosfomycin in Canadian patients. METHODS: The CLEAR registry uses the web-based data management program, REDCapTM (https://rcsurvey.radyfhs.umanitoba.ca/surveys/?s=F7JXNDFXEF) to facilitate clinicians' entering of details associated with their clinical experiences using IV fosfomycin. RESULTS: Data were available for 59 patients treated with IV fosfomycin. The most common infections treated were: bacteraemia or sepsis (25.4% of patients), complicated urinary tract infection (20.3%), ventilator-associated bacterial pneumonia (18.6%), and hospital-acquired pneumonia (13.6%). IV fosfomycin was used to treat Gram-negative (88.1%) and Gram-positive (10.2%) infections. The most common pathogens treated were carbapenem-resistant Enterobacterales (44.1%), multidrug-resistant Pseudomonas aeruginosa (18.6%), vancomycin-resistant Enterococcus faecium (5.1%), and methicillin-resistant Staphylococcus aureus (3.4%). IV fosfomycin was primarily used due to resistance to initially prescribed therapies (69.5%), frequently in combination with other agents (86.4%). Microbiological success (eradication/presumed eradication) occurred in 77.4% of patients, and clinical success (clinical cure/improvement) occurred in 62.5%. Overall, 15.3% of patients died because of their infection. Adverse effects were not documented in 73.1% of patients, and no patient discontinued therapy because of an adverse effect. CONCLUSIONS: In Canada, IV fosfomycin is used primarily as directed therapy to treat a variety of severe infections caused by Gram-negative and Gram-positive bacteria. It is primarily used in patients infected with bacteria resistant to other agents and as part of combination therapy. Its use is associated with relatively high microbiological and clinical cure rates, and it has an excellent safety profile.
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Antiinfecciosos , Fosfomicina , Staphylococcus aureus Resistente a Meticilina , Humanos , Fosfomicina/efectos adversos , Antibacterianos/efectos adversos , Liderazgo , CanadáRESUMEN
INTRODUCTION: Three doses of SARS-CoV-2 mRNA vaccines have been recommended for cancer patients to reduce the risk of severe disease. Anti-neoplastic treatment, such as chemotherapy, may affect long-term vaccine immunogenicity. METHOD: Patients with solid or haematological cancer were recruited from 2 hospitals between July 2021 and March 2022. Humoral response was evaluated using GenScript cPASS surrogate virus neutralisation assays. Clinical outcomes were obtained from medical records and national mandatory-reporting databases. RESULTS: A total of 273 patients were recruited, with 40 having haematological malignancies and the rest solid tumours. Among the participants, 204 (74.7%) were receiving active cancer therapy, including 98 (35.9%) undergoing systemic chemotherapy and the rest targeted therapy or immunotherapy. All patients were seronegative at baseline. Seroconversion rates after receiving 1, 2 and 3 doses of SARS-CoV-2 mRNA vaccination were 35.2%, 79.4% and 92.4%, respectively. After 3 doses, patients on active treatment for haematological malignancies had lower antibodies (57.3%±46.2) when compared to patients on immunotherapy (94.1%±9.56, P<0.05) and chemotherapy (92.8%±18.1, P<0.05). SARS-CoV-2 infection was reported in 77 (28.2%) patients, of which 18 were severe. No patient receiving a third dose within 90 days of the second dose experienced severe infection. CONCLUSION: This study demonstrates the benefit of early administration of the third dose among cancer patients.
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COVID-19 , Neoplasias Hematológicas , Neoplasias , Humanos , SARS-CoV-2 , COVID-19/prevención & control , Resultado del Tratamiento , Neoplasias/tratamiento farmacológico , Vacunación , ARN Mensajero , Anticuerpos Antivirales , Inmunogenicidad VacunalRESUMEN
PURPOSE: Competencies for educators of healthcare professionals are important for demonstrating accountability, defining roles and responsibilities, structuring activities for training and development, defining standards, quality assurance, performance reviews, career development, and promoting the professionalisation of teaching. The frameworks and domains of educator competencies have not previously been reviewed or systematically described. Through this integrative review, the authors sought to identify an inclusive structure for competency domains that may be applied to educators. METHODS: Keywords were identified in a pilot search, followed by a multi-database search strategy of records published from 2000 to January 2020 with subsequent backward and forward reference searches. We included all record types that listed or described educator competency domains in medical, nursing and health sciences education. We excluded records that described 'ideal traits' or 'characteristics of good teachers/educators,' presented competencies as part of a larger curricular framework, and teaching assessment tool content. RESULTS: The multi-database search retrieved 2942 initial citations. From a full-text review of 301 records, 67 were identified as describing educator competency domains eligible for analysis. Documents contained a median of six domains (interquartile range = 5-7) and 14.9% incorporated at least one overarching element across their domains. Following an inductive thematic analysis, six distinct domains of educator competence were identified: Teaching and facilitating learning; Designing and planning learning; Assessment of learning; Educational research and scholarship; Educational leadership and management; Educational environment, quality, and safety. The two latter domains contained sub-themes that were able to be further categorised. Documents and frameworks were described for a wide variety of health and allied health disciplines. CONCLUSION: Distinct educator competency domains were identified in this analysis, applicable across a range of healthcare disciplines. Along with the description of design elements, these provide a guide for the development and evaluation of educator competency frameworks.
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Curriculum , Medicina , Humanos , Escolaridad , Educación en Salud , Competencia ClínicaRESUMEN
PURPOSE: Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. METHODS: We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. RESULTS: We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. CONCLUSION: Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.
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Anomalías Múltiples , Enfermedades del Desarrollo Óseo , Discapacidad Intelectual , Proteínas Represoras , Anomalías Dentarias , Anomalías Múltiples/genética , Enfermedades del Desarrollo Óseo/etiología , Enfermedades del Desarrollo Óseo/genética , Deleción Cromosómica , Facies , Humanos , Discapacidad Intelectual/genética , Mutación Missense , Fenotipo , Complejo de la Endopetidasa Proteasomal/genética , Proteínas Represoras/genética , Anomalías Dentarias/diagnóstico , Factores de Transcripción/genéticaRESUMEN
PURPOSE: A case of osteomyelitis caused by multidrug-resistant (MDR) Pseudomonas aeruginosa is reported. SUMMARY: An 84-year-old Caucasian male with an underlying history of type 2 diabetes, peripheral vascular disease, and coronary artery disease had chronic nonhealing wounds on his right foot. Wound care and a course of intravenous (IV) ertapenem with oral ciprofloxacin were ineffective. His initial wound culture grew Staphylococcus aureus, group G streptococcus and P. aeruginosa; the Pseudomonas was susceptible to multiple agents. The patient eventually required midtarsal amputation and angioplasties to his right leg. Twenty days after the operation, 2 openings were discovered at the surgical site, 1 of which was probed to the bone. He was readmitted 5 weeks after the operation. A repeat wound swab grew MDR P. aeruginosa and Finegoldia magna. The Pseudomonas was susceptible to gentamicin and colistin. The patient had revision of the infected amputation site with the goal of salvaging his right lower limb. The patient developed acute renal failure after 26 days of IV gentamicin, IV ceftriaxone, and oral metronidazole. Additional susceptibility testing was performed to identify alternatives. The bacteria were considered susceptible to IV fosfomycin, the last resort, by our microbiology laboratory. This was combined with ceftolozane/tazobactam followed by meropenem to treat the residual infection. After 2 weeks of IV fosfomycin, the patient's wound improved and further amputation was avoided. CONCLUSION: Our case demonstrates that IV fosfomycin may provide an effective salvage therapy when combined with ß-lactams for the treatment of severe diabetic foot infection or osteomyelitis caused by MDR P. aeruginosa.
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Diabetes Mellitus Tipo 2 , Fosfomicina , Osteomielitis , Anciano de 80 o más Años , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Masculino , Osteomielitis/diagnóstico , Osteomielitis/tratamiento farmacológico , Pseudomonas aeruginosa , Terapia RecuperativaRESUMEN
SETBP1 haploinsufficiency disorder (MIM#616078) is caused by haploinsufficiency of SETBP1 on chromosome 18q12.3, but there has not yet been any systematic evaluation of the major features of this monogenic syndrome, assessing penetrance and expressivity. We describe the first comprehensive study to delineate the associated clinical phenotype, with findings from 34 individuals, including 24 novel cases, all of whom have a SETBP1 loss-of-function variant or single (coding) gene deletion, confirmed by molecular diagnostics. The most commonly reported clinical features included mild motor developmental delay, speech impairment, intellectual disability, hypotonia, vision impairment, attention/concentration deficits, and hyperactivity. Although there is a mild overlap in certain facial features, the disorder does not lead to a distinctive recognizable facial gestalt. As well as providing insight into the clinical spectrum of SETBP1 haploinsufficiency disorder, this reports puts forward care recommendations for patient management.
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Trastorno por Déficit de Atención con Hiperactividad/genética , Proteínas Portadoras/genética , Discapacidades del Desarrollo/genética , Haploinsuficiencia , Discapacidad Intelectual/genética , Proteínas Nucleares/genética , Fenotipo , Adolescente , Adulto , Anciano , Trastorno por Déficit de Atención con Hiperactividad/patología , Niño , Preescolar , Discapacidades del Desarrollo/patología , Femenino , Humanos , Lactante , Discapacidad Intelectual/patología , Mutación con Pérdida de Función , Masculino , Persona de Mediana Edad , SíndromeRESUMEN
Expressive communication impairment is associated with haploinsufficiency of SETBP1, as reported in small case series. Heterozygous pathogenic loss-of-function (LoF) variants in SETBP1 have also been identified in independent cohorts ascertained for childhood apraxia of speech (CAS), warranting further investigation of the roles of this gene in speech development. Thirty-one participants (12 males, aged 0; 8-23; 2 years, 28 with pathogenic SETBP1 LoF variants, 3 with 18q12.3 deletions) were assessed for speech, language and literacy abilities. Broader development was examined with standardised motor, social and daily life skills assessments. Gross and fine motor deficits (94%) and intellectual impairments (68%) were common. Protracted and aberrant speech development was consistently seen, regardless of motor or intellectual ability. We expand the linguistic phenotype associated with SETBP1 LoF syndrome (SETBP1 haploinsufficiency disorder), revealing a striking speech presentation that implicates both motor (CAS, dysarthria) and language (phonological errors) systems, with CAS (80%) being the most common diagnosis. In contrast to past reports, the understanding of language was rarely better preserved than language expression (29%). Language was typically low, to moderately impaired, with commensurate expression and comprehension ability. Children were sociable with a strong desire to communicate. Minimally verbal children (32%) augmented speech with sign language, gestures or digital devices. Overall, relative to general development, spoken language and literacy were poorer than social, daily living, motor and adaptive behaviour skills. Our findings show that poor communication is a central feature of SETBP1 haploinsufficiency disorder, confirming this gene as a strong candidate for speech and language disorders.
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Proteínas Portadoras/genética , Desarrollo del Lenguaje , Proteínas Nucleares/genética , Trastornos del Habla/genética , Adolescente , Niño , Femenino , Haploinsuficiencia , Humanos , Masculino , Fenotipo , Trastornos del Habla/patología , Adulto JovenRESUMEN
BACKGROUND: Glomerulonephritis commonly causes kidney failure. Immunosuppressant treatment may be diabetogenic, but data on hyperglycaemia in glomerulonephritis treated with usual clinical care are scant. AIM: To assess the epidemiology, risk factors and outcomes for new-onset diabetes among patients with glomerular disease (NODAG). METHODS: A single-centre retrospective cohort of nondiabetic adults diagnosed with glomerulonephritis between January 2011 and July 2015. Clinical, laboratory and pharmacotherapy data were retrieved from electronic medical records. Using modified American Diabetes Association criteria, the primary outcome of NODAG was present if fasting venous glucose was ≥7 mmol/L for at least two readings, HbA1c was ≥6.5% or if patient required antidiabetic medications. Secondary outcomes were end-stage renal disease, cardiovascular disease and death. RESULTS: NODAG occurred in 48 patients (10.7%); 22 required antidiabetic medication at median 6.2 (interquartile range 1.7, 20.0) months after glomerulonephritis diagnosis. Patients with NODAG had higher prebiopsy fasting glucose, greater proteinuria and lower fasting high-density lipoprotein cholesterol levels. Methylprednisolone and cyclophosphamide were more commonly used among patients with NODAG. In multivariate logistic regression, greater proteinuria (odds ratio 1.08 (95% confidence interval 1.01, 1.16), P = 0.02) and methylprednisolone use (odds ratio 4.02 (95% confidence interval 1.76, 9.18), P = 0.001) were significantly associated with NODAG, independent of the triglyceride/high-density lipoprotein cholesterol ratio as a surrogate measure of insulin resistance. Median follow up was 39.6 (26.9, 57.2) months. Secondary outcomes were not significantly different in patients with and without NODAG. CONCLUSION: Proteinuria and methylprednisolone were associated with incident diabetes among patients with glomerular disease treated with usual care. At-risk patients should be appropriately counselled and monitored for hyperglycaemia.
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Diabetes Mellitus Tipo 2/epidemiología , Glomerulonefritis/complicaciones , Hiperglucemia/epidemiología , Hipoglucemiantes/uso terapéutico , Proteinuria/complicaciones , Adulto , Anciano , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Riñón/patología , Fallo Renal Crónico/fisiopatología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Spinocerebellar ataxia type 14 (SCA14) is a subtype of the autosomal dominant cerebellar ataxias that is characterized by slowly progressive cerebellar dysfunction and neurodegeneration. SCA14 is caused by mutations in the PRKCG gene, encoding protein kinase C gamma (PKCγ). Despite the identification of 40 distinct disease-causing mutations in PRKCG, the pathological mechanisms underlying SCA14 remain poorly understood. Here we report the molecular neuropathology of SCA14 in post-mortem cerebellum and in human patient-derived induced pluripotent stem cells (iPSCs) carrying two distinct SCA14 mutations in the C1 domain of PKCγ, H36R and H101Q. We show that endogenous expression of these mutations results in the cytoplasmic mislocalization and aggregation of PKCγ in both patient iPSCs and cerebellum. PKCγ aggregates were not efficiently targeted for degradation. Moreover, mutant PKCγ was found to be hyper-activated, resulting in increased substrate phosphorylation. Together, our findings demonstrate that a combination of both, loss-of-function and gain-of-function mechanisms are likely to underlie the pathogenesis of SCA14, caused by mutations in the C1 domain of PKCγ. Importantly, SCA14 patient iPSCs were found to accurately recapitulate pathological features observed in post-mortem SCA14 cerebellum, underscoring their potential as relevant disease models and their promise as future drug discovery tools.
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Degeneración Nerviosa/enzimología , Degeneración Nerviosa/etiología , Agregación Patológica de Proteínas/etiología , Proteínas Quinasas/metabolismo , Transporte de Proteínas/genética , Ataxias Espinocerebelosas , Adulto , Anciano , Autopsia , Dominio Catalítico/efectos de los fármacos , Cerebelo/patología , Femenino , Humanos , Células Madre Pluripotentes Inducidas/patología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Mutación/genética , Agregación Patológica de Proteínas/genética , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Ataxias Espinocerebelosas/complicaciones , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patologíaAsunto(s)
Antibacterianos/administración & dosificación , Embalaje de Medicamentos/estadística & datos numéricos , Infusiones Intravenosas , Combinación Piperacilina y Tazobactam/administración & dosificación , Composición de Medicamentos , Humanos , Concentración Osmolar , Servicio de Farmacia en HospitalRESUMEN
The establishment of a reliable model for the study of Purkinje cells in vitro is of particular importance, given their central role in cerebellar function and pathology. Recent advances in induced pluripotent stem cell (iPSC) technology offer the opportunity to generate multiple neuronal subtypes for study in vitro. However, to date, only a handful of studies have generated Purkinje cells from human pluripotent stem cells, with most of these protocols proving challenging to reproduce. Here, we describe a simplified method for the reproducible generation of Purkinje cells from human iPSCs. After 21 days of treatment with factors selected to mimic the self-inductive properties of the isthmic organiser-insulin, fibroblast growth factor 2 (FGF2), and the transforming growth factor ß (TGFß)-receptor blocker SB431542-hiPSCs could be induced to form En1-positive cerebellar progenitors at efficiencies of up to 90%. By day 35 of differentiation, subpopulations of cells representative of the two cerebellar germinal zones, the rhombic lip (Atoh1-positive) and ventricular zone (Ptf1a-positive), could be identified, with the latter giving rise to cells positive for Purkinje cell progenitor-specific markers, including Lhx5, Kirrel2, Olig2 and Skor2. Further maturation was observed following dissociation and co-culture of these cerebellar progenitors with mouse cerebellar cells, with 10% of human cells staining positive for the Purkinje cell marker calbindin by day 70 of differentiation. This protocol, which incorporates modifications designed to enhance cell survival and maturation and improve the ease of handling, should serve to make existing models more accessible, in order to enable future advances in the field.
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Técnicas de Cultivo de Célula/métodos , Células Madre Pluripotentes Inducidas/fisiología , Neurogénesis , Células de Purkinje/fisiología , Anciano , Animales , Técnicas de Cocultivo , Femenino , Humanos , Células Madre Pluripotentes Inducidas/citología , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Neurogénesis/fisiología , Células de Purkinje/citología , Andamios del TejidoRESUMEN
Objective: To review patient characteristics and outcomes after peripheral arterial disease (PAD)-related below-knee amputation (BKA), and identify risk factors predicting subsequent above-knee amputation (AKA). Materials and Methods: A retrospective study of 210 BKAs between May 2008 and December 2015. Results: The mean age of the study population was 66 years. Most of the patients had cardiovascular comorbidities, and 33% had end-stage renal failure (ESRF); 89% were American Society of Anesthesiologists 3 or 4. Previous ipsilateral lower-limb minor amputation was present in 49% and previous contralateral lower-limb major amputation was present in 20% patients. Limb salvage revascularization via angioplasty prior to BKA was performed in 73%, while 27% had extensive tissue loss that was not suitable for limb salvage. Postoperatively, 20% had BKA wound infection, with 3% requiring further surgical debridement, and 9% (19 patients) required subsequent AKA within 1 month. Overall survival analysis at 1-5 years was 75%, 66%, 64%, 59%, and 58%, respectively. Multivariate analysis showed ESRF (Odds Ratio [OR]=3.85; p=0.01) and preoperative non-ambulatory status (OR=5.58; p=0.01) to be independent risk factors in predicting for subsequent AKA. Conclusion: Patients with underlying ESRF or preoperative non-ambulatory status may benefit from direct AKA if major amputation is required.
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The cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to model cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
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SOMANZ (Society of Obstetric Medicine Australia and New Zealand) has written a guideline to provide evidence-based guidance for the investigation and care of women with sepsis in pregnancy or the postpartum period. The guideline is evidence-based and incorporates recent changes in the definition of sepsis. The etiology, investigation and treatment of bacterial, viral and non-infective causes of sepsis are discussed. Obstetric considerations relevant to anaesthetic and intensive care treatment in sepsis are also addressed. A multi-disciplinary group of clinicians with experience in all aspects of the care of pregnant women have contributed to the development of the guidelines. This is an executive summary of the guidelines.
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Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/terapia , Sepsis/diagnóstico , Sepsis/terapia , Anestesia Obstétrica , Cuidados Críticos , Parto Obstétrico , Femenino , Fiebre/terapia , Humanos , Puntuaciones en la Disfunción de Órganos , Embarazo , Complicaciones Infecciosas del Embarazo/etiología , Sepsis/etiología , Choque Séptico/terapia , Factores de TiempoRESUMEN
BACKGROUND: Remote ischemic preconditioning involves providing a brief ischemia-reperfusion event to a tissue to create subsequent protection from a more severe ischemia-reperfusion event to a different tissue/organ. The few pediatric remote ischemic preconditioning studies in the literature show conflicting results. AIM: We conducted a pilot randomized controlled trial to determine the feasibility of conducting a larger trial and to gather provisional data on the effect of early and late remote ischemic preconditioning on outcomes of infants after surgery for congenital heart disease. METHODS: This single-center, double-blind randomized controlled trial of remote ischemic preconditioning vs control (sham-remote ischemic preconditioning) in young infants going for surgery for congenital heart disease at the Stollery Children's Hospital. Remote ischemic preconditioning was performed at 24-48 h preoperatively and immediately prior to cardiopulmonary bypass. Remote ischemic preconditioning stimulus was performed with blood pressure cuffs around the thighs. Primary outcomes were feasibility and peak blood lactate level on day 1 postoperatively. RESULTS: Fifty-two patients were randomized but seven patients became ineligible after randomization leaving 45 patients included in the study. In the included patients, 7 (15%) had protocol deviations (five infants did not have the preoperative intervention and two did not receive the intervention in the operating room). From a comfort point of view, only one subject in the control group and two in the Remote ischemic preconditioning group received sedation during the preoperative intervention. There were no study-related adverse events and no complications to the limbs subjected to preconditioning. There were no significant differences between the Remote ischemic preconditioning group and the control group in the highest blood lactate level on day 1 postoperatively (mean difference, 1.28; 95%CI, -0.22, 2.78; P-value = 0.093). CONCLUSION: In infants who underwent surgery for congenital heart disease, our pilot randomized controlled trial on early and late remote ischemic preconditioning proved to be feasible but did not find any significant difference in acute outcomes. A larger trial may be necessary.