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Evidence supporting recommendations from international guidelines on treatment, diagnosis, and prevention of HAP and VAP in adults
Get PDFClinical practice guidelines (CPGs) are intended to support clinical decisions and should be based on high-quality evidence. The objective of the study was to evaluate the quality of evidence supporting the recommendations issued in CPGs for therapy, diagnosis, and prevention of hospital-acquired and ventilator-associated pneumonia (HAP/VAP). CPGs released by international scientific societies after year 2000, using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology, were analyzed. Number and strength of recommendations and quality of evidence (high, moderate, low, and very low) were extracted and indexed in the aforementioned sections. High-quality evidence was based on randomized control trials (RCT) without important limitations and exceptionally on rigorous observational studies. Eighty recommendations were assessed, with 7 (8.7%), 24 (30.0%), 29 (36.3%), and 20 (25.0%) being supported by high, moderate, low, and very low-quality evidence, respectively. Highest evidence degree was reported for 26 prevention recommendations, with 7 (26.9%) supported by high-quality evidence and no recommendation based on very low-quality evidence. In contrast, among 9 recommendations for diagnosis and 45 for therapy, none was supported by high-quality evidence, in spite of being recommended as strong in 33.3% and 46.7%, respectively. Among HAP/VAP diagnosis recommendations, the majority of evidence was rated as low or very low-quality (55.6% and 22.2%, respectively) whereas among HAP/VAP therapy recommendations, 4/5 were rated as low and very low-quality (40% each). In conclusion, among HAP/VAP international guidelines, most recommendations, particularly in therapy, remain supported by observational studies, case reports, and expert opinion. Well-designed RCTs are urgently needed.info:eu-repo/semantics/publishedVersio
Management of Locally Advanced Esthesioneuroblastoma in a Pregnant Woman
Get PDFEsthesioneuroblastoma (ENB) is a rare malignant tumor that commonly develops in the upper nasal cavity. Standard treatment is not established, especially in locally advanced disease which portends the worse prognosis. Hereby, we report a case of a 27-year-old, 23-week pregnant woman, with a 2-month history of progressively growing right cervical lymphadenopathy, nasal obstruction, anosmia, frequent episodes of epistaxis, and right frontal headache. Imagiological evaluation revealed a lesion with 7×5,2×3,2 cm in the nasal fossae with extension to the ethmoidal complex and right olfactive fend and invasion of the endocranial compartment associated with lymphadenopathy. The biopsy revealed a high-grade EBN. Neoadjuvant chemotherapy with cisplatin and etoposide was administrated during pregnancy and continued after delivery up to 6 cycles of treatment with partial response. Radiotherapy followed, with complete response. This case report is intended to highlight that a high grade of suspicion should be kept in the presence of nonspecific symptoms of nasal obstruction, anosmia, facial pain, and/or headache and focus that chemotherapy is an important component of a combined-treatment modality for locally advanced ENB that can be used during pregnancy in a lifesaving situation.info:eu-repo/semantics/publishedVersio
The Role of AKT3 Copy Number Changes in Brain Abnormalities and Neurodevelopmental Disorders: Four New Cases and Literature Review
Get PDFMicrodeletions at 1q43-q44 have been described as resulting in a clinically recognizable phenotype of intellectual disability (ID), facial dysmorphisms and microcephaly (MIC). In contrast, the reciprocal microduplications of 1q43-q44 region have been less frequently reported and patients showed a variable phenotype, including macrocephaly. Reports of a large number of patients with copy number variations involving this region highlighted the AKT3 gene as a likely key player in head size anomalies. We report four novel patients with copy number variations in the 1q43-q44 region: one with a larger deletion (3.7Mb), two with smaller deletions affecting AKT3 and SDCCAG8 genes (0.16 and 0.18Mb) and one with a quadruplication (1Mb) that affects the entire AKT3 gene. All patients with deletions presented MIC without structural brain abnormalities, whereas the patient with quadruplication had macrocephaly, but his carrier father had normal head circumference. Our report also includes a comparison of phenotypes in cases with 1q43-q44 duplications to assist future genotype-phenotype correlations. Our observations implicate AKT3 as a contributor to ID/development delay (DD) and head size but raise doubts about its straightforward impact on the latter aspect of the phenotype in patients with 1q43-q44 deletion/duplication syndrome.This work has been funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the projects: PIC/IC/83026/2007, PIC/IC/83013/2007 and POCI-01-0145- FEDER-007038. The work has also been funded by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). FL was supported by Foundation for Science and Technology (FCT) through the fellowship SFRH/BD/90167/2012.info:eu-repo/semantics/publishedVersio
Acute Ischemic Stroke in a Child Successfully Treated with Thrombolytic Therapy and Mechanical Thrombectomy
Get PDFAcute ischemic stroke in the pediatric population is rare but carries lasting and often lifelong morbidity. Thrombolysis and mechanical thrombectomy are mainstays of care in adults, yet there is very little evidence for these treatments in children. We present the case of a 4-year-old boy with complex congenital heart disease, admitted 30 min after sudden onset of an aphasia and right hemiplegia, scoring 14 on the Pediatric National Institutes of Health Stroke Scale (PedNIHSS). Non-contrast brain computed tomography (CT) showed no evidence of acute ischemia. CT angiogram demonstrated a thrombus in the M1 segment of the left middle cerebral artery. Intravenous recombinant tissue plasminogen activator (rTPA) was infused 3.5 h after onset of symptoms. An improvement was observed in the hour after rTPA, with a PedNIHSS score of 7. Digital subtraction angiography was performed approximately 9 h from the onset of symptoms, showing a complete left M1 occlusion. The patient underwent successful mechanical thrombectomy and was discharged with a PedNIHSS score of 2. This case emphasizes the importance of early recognition to direct children towards rapid diagnosis and hyperacute treatment.info:eu-repo/semantics/publishedVersio
Pulmonary arterial hypertension registries: past, present and into the future
Get PDFRegistries have greatly contributed to knowledge about PAH epidemiology, risk factors, prognosis and treatment. Future registries face unique challenges but may benefit from integration of multiple data sources and capitalising on “Big Data” opportunitiesConflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc. and Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, and grants from Alberta Lung Association, Canadian Vascular Network, European Respiratory Society and Canadian Thoracic Society, outside the submitted work.
Conflict of interest: A. Reis reports grants, personal fees and non-financial support from Janssen Inc. and Actelion, outside the submitted work.
Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer and Merck, grants from GlaxoSmithKline, grants, and personal fees from United Therapeutics and Gossamer Bio, outside the submitted work.
Conflict of interest: M. Humbert reports personal fees from Actelion and Merck, and grants and personal fees from Bayer, GSK and United Therapeutics, outside the submitted work.info:eu-repo/semantics/publishedVersio
Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients
Get PDFIn order to characterize the genetic architecture of epilepsy in a pediatric population from the Iberian Peninsula (including the Canary Islands), we conducted targeted exome sequencing of 246 patients with infantile-onset seizures with or without neurodevelopmental delay. We detected 107 variants in 48 different genes, which were implicated in neuronal excitability, neurodevelopment, synaptic transmission, and metabolic pathways. In 104 cases (42%) we detected variant(s) that we classified as pathogenic or likely pathogenic. Of the 48 mutated genes, 32 were dominant, 8 recessive and 8 X-linked. Of the patients for whom family studies could be performed and in whom pathogenic variants were identified in dominant or X-linked genes, 82% carried de novo mutations. The involvement of small copy number variations (CNVs) is 9%. The use of progressively updated custom panels with high mean vertical coverage enabled establishment of a definitive diagnosis in a large proportion of cases (42%) and detection of CNVs (even duplications) with high fidelity. In 10.5% of patients we detected associations that are pending confirmation via functional and/or familial studies. Our findings had important consequences for the clinical management of the probands, since a large proportion of the cohort had been clinically misdiagnosed, and their families were subsequently able to avail of genetic counseling. In some cases, a more appropriate treatment was selected for the patient in question, or an inappropriate treatment discontinued. Our findings suggest the existence of modifier genes that may explain the incomplete penetrance of some epilepsy-related genes. We discuss possible reasons for non-diagnosis and future research directions. Further studies will be required to uncover the roles of structural variants, epimutations, and oligogenic inheritance in epilepsy, thereby providing a more complete molecular picture of this disease. In summary, given the broad phenotypic spectrum of most epilepsy-related genes, efficient genomic tools like the targeted exome sequencing panel described here are essential for early diagnosis and treatment, and should be implemented as first-tier diagnostic tools for children with epilepsy without a clear etiologic basis.info:eu-repo/semantics/publishedVersio
Fígado gordo e hepatite autoimune: duas formas de atingimento hepático nas lipodistrofias
Get PDFIntroduction: Lipodystrophies are a heterogeneous group of rare diseases (genetic or acquired) characterized by a partial or generalized deficit of adipose tissue, resulting in less energy storage capacity. They are associated with severe endocrine-metabolic complications with significant morbidity and mortality. In the pathogenesis of the acquired forms, immunological disorders may be involved.
Case 1: A 13-year-old female was diagnosed with acquired generalized lipodystrophy and observed for suspicion of portal hypertension. She presented with generalized absence of adipose tissue, cervical and axillary acanthosis nigricans, and massive hepatosplenomegaly. Laboratory tests revealed AST 116 IU/L, ALT 238 IU/L, GGT 114 IU/L, HOMA-IR 28.2, triglycerides 491 mg/L, and leptin < 0.05 ng/mL. Upper gastrointestinal endoscopy saw no signs of portal hypertension. Hepatic histology showed macrovesicular fatty infiltration (60% of hepatocytes) and advanced fibrosis/cirrhosis. Her clinical condition worsened progressively to diabetes requiring treatment with subcutaneous insulin and hepatopulmonary syndrome.
Case 2: A 15-year-old female, diagnosed with acquired partial lipodystrophy, Parkinson syndrome, autoimmune thyroiditis, and autoimmune thrombocytopenia was observed for hypertransaminasemia since the age of 8 years. She had absence of subcutaneous adipose tissue in the upper and lower limbs and ataxia. Laboratory tests showed AST 461 IU/L, ALT 921 IU/L, GGT 145 IU/L, HOMA-IR 32.6, triglycerides 298 mg/dL, normal leptin levels, platelets 84,000/μL, IgG 1,894 mg/dL, positive anti-LKM and anti-LC-1. Hepatic histology was suggestive of autoimmune hepatitis, without steatosis. She progressed favorably under metformin and immunosuppressive treatment.
Conclusion: Early recognition and adequate characterization of liver disease in lipodystrophies is essential for a correct treatment approach. In acquired generalized lipodystrophy, the severe endocrine-metabolic disorder, which leads to steatohepatitis with cirrhotic progression, may benefit from recombinant leptin treatment.Introdução: As lipodistrofias sao um grupo heterogeneo de doencas raras (formas geneticas e adquiridas) caracterizadas por defice parcial ou generalizado de tecido adiposo, resultando em menor capacidade de armazenamento energetico. Estao associadas a complicacoes endocrino-metabolicas graves com morbilidade e mortalidade significativas. Na patogenese das formas adquiridas poderao estar envolvidos disturbios imunologicos.
Caso 1: Adolescente de 13 anos, sexo feminino, com diagnostico de lipodistrofia generalizada adquirida, observada por suspeita de hipertensao portal. Apresentava ausencia generalizada de tecido adiposo, acantose nigricans cervical e axilar, e hepatoesplenomegalia volumosa. Do estudo destacavam-se: AST 116 UI/L, ALT 238 UI/L, GGT 114 UI/L, HOMA-IR 28.2, triglicerideos 491 mg/L e leptina < 0.05 ng/mL. A endoscopia digestiva alta nao evidenciou sinais de hipertensao portal. Histologia hepatica com esteatose macrovesicular (60% dos hepatocitos) e fibrose avancada/cirrose. A sua condicao clinica evoluiu progressivamente para diabetes com necessidade de tratamento com insulina subcutanea e sindrome hepatopulmonar.
Caso 2: Adolescente de 15 anos, sexo feminino, com diagnostico de lipodistrofia parcial adquirida, sindrome parkinsonico, tiroidite autoimune, e trombocitopenia autoimune, observada por elevacao das transaminases desde os 8 anos. Apresentava ausencia de tecido adiposo subcutaneo nos membros superiores e inferiores, ataxia e tremor das maos, sem sinais de doenca hepatica. Do estudo destacavam-se: AST 461 UI/L, ALT 921 UI/L, GGT 145 UI/L, HOMA-IR 32,6, triglicerideos 298 mg/dL, leptina normal, plaquetas 84,000/μL, IgG 1,894 mg/dL, anticorpos anti-LKM e anti-LC1 positivos. Histologia hepatica sugestiva de hepatite autoimune, sem esteatose. A doente evoluiu favoravelmente com metformina e tratamento imunossupressor.
Discussao: O reconhecimento precoce e a caracterizacao adequada da doenca hepatica nas lipodistrofias sao fundamentais para uma correta abordagem terapeutica. Na lipodistrofia generalizada adquirida, o disturbio endocrino-metabolico grave responsavel por esteatohepatite com evolucao cirrogenea podera beneficiar do tratamento inovador com leptina recombinante.info:eu-repo/semantics/publishedVersio
Changes in End-of-Life Practices in European Intensive Care Units From 1999 to 2016
Get PDFImportance: End-of-life decisions occur daily in intensive care units (ICUs) around the world, and these practices could change over time.
Objective: To determine the changes in end-of-life practices in European ICUs after 16 years.
Design, setting, and participants: Ethicus-2 was a prospective observational study of 22 European ICUs previously included in the Ethicus-1 study (1999-2000). During a self-selected continuous 6-month period at each ICU, consecutive patients who died or had any limitation of life-sustaining therapy from September 2015 until October 2016 were included. Patients were followed up until death or until 2 months after the first treatment limitation decision.
Exposures: Comparison between the 1999-2000 cohort vs 2015-2016 cohort.
Main outcomes and measures: End-of-life outcomes were classified into 5 mutually exclusive categories (withholding of life-prolonging therapy, withdrawing of life-prolonging therapy, active shortening of the dying process, failed cardiopulmonary resuscitation [CPR], brain death). The primary outcome was whether patients received any treatment limitations (withholding or withdrawing of life-prolonging therapy or shortening of the dying process). Outcomes were determined by senior intensivists.
Results: Of 13 625 patients admitted to participating ICUs during the 2015-2016 study period, 1785 (13.1%) died or had limitations of life-prolonging therapies and were included in the study. Compared with the patients included in the 1999-2000 cohort (n = 2807), the patients in 2015-2016 cohort were significantly older (median age, 70 years [interquartile range {IQR}, 59-79] vs 67 years [IQR, 54-75]; P < .001) and the proportion of female patients was similar (39.6% vs 38.7%; P = .58). Significantly more treatment limitations occurred in the 2015-2016 cohort compared with the 1999-2000 cohort (1601 [89.7%] vs 1918 [68.3%]; difference, 21.4% [95% CI, 19.2% to 23.6%]; P < .001), with more withholding of life-prolonging therapy (892 [50.0%] vs 1143 [40.7%]; difference, 9.3% [95% CI, 6.4% to 12.3%]; P < .001), more withdrawing of life-prolonging therapy (692 [38.8%] vs 695 [24.8%]; difference, 14.0% [95% CI, 11.2% to 16.8%]; P < .001), less failed CPR (110 [6.2%] vs 628 [22.4%]; difference, -16.2% [95% CI, -18.1% to -14.3%]; P < .001), less brain death (74 [4.1%] vs 261 [9.3%]; difference, -5.2% [95% CI, -6.6% to -3.8%]; P < .001) and less active shortening of the dying process (17 [1.0%] vs 80 [2.9%]; difference, -1.9% [95% CI, -2.7% to -1.1%]; P < .001).
Conclusions and relevance: Among patients who had treatment limitations or died in 22 European ICUs in 2015-2016, compared with data reported from the same ICUs in 1999-2000, limitations in life-prolonging therapies occurred significantly more frequently and death without limitations in life-prolonging therapies occurred significantly less frequently. These findings suggest a shift in end-of-life practices in European ICUs, but the study is limited in that it excluded patients who survived ICU hospitalization without treatment limitationsinfo:eu-repo/semantics/publishedVersio
Medium-Term Outcomes of Digital Versus Conventional Home-Based Rehabilitation After Total Knee Arthroplasty: Prospective, Parallel-Group Feasibility Study
Get PDFBackground: Physical rehabilitation is recommended after total knee arthroplasty (TKA). With the expected increase in TKA over the next few decades, it is important to find new ways of delivering cost-effective interventions. Technological interventions have been developed with this intent, but only preliminary evidence exists regarding their validity, with short follow-up times.
Objective: This study aimed to present the follow-up results of a feasibility study comparing two different home-based programs after TKA: conventional face-to-face sessions and a digital intervention performed through the use of an artificial intelligence-powered biofeedback system under remote clinical monitoring.
Methods: The digital intervention uses a motion tracker allowing 3D movement quantification, a mobile app and a Web portal. This study presents the results of the previous single-center, prospective, parallel-group, feasibility study including an 8-week active treatment stage and further assessments at 3 and 6 months post-TKA. Primary outcome was the Timed Up and Go score, and secondary outcomes were the Knee Osteoarthritis Outcome Scale (KOOS) score and knee range of motion.
Results: A total of 59 patients completed the study (30 in the digital intervention group and 29 in the conventional rehabilitation group) and follow-up assessments. During the active treatment stage, patients in the digital intervention group demonstrated high engagement and satisfaction levels, with an 82% retention rate. Both groups attained clinically relevant improvements from baseline to 6 months post-TKA. At the end of the 8-week program, clinical outcomes were superior in the digital intervention group. At the 3- and 6-month assessments, the outcomes remained superior for the Timed Up and Go score (P<.001) and all KOOS subscale scores (at 3 months, P<.001 overall; at 6 months, KOOS Symptoms: P=.006, Pain: P=.002, Activities of Daily Living: P=.001, Sports: P=.003, and Quality of Life: P=.001). There was progressive convergence between both groups in terms of the knee range of motion, which remained higher for standing flexion in the digital intervention group than the conventional group at 6 months (P=.01). For the primary outcome, at 6 months, the median difference between groups was 4.87 seconds (95% CI 1.85-7.47), in favor of the digital intervention group.
Conclusions: The present study demonstrates that this novel digital intervention for independent home-based rehabilitation after TKA is feasible, engaging, and capable of maximizing clinical outcomes in comparison to conventional rehabilitation in the short and medium term; in addition, this intervention is far less demanding in terms of human resources.info:eu-repo/semantics/publishedVersio
Genomic imbalances defining novel intellectual disability associated loci
Get PDFBackground: High resolution genome-wide copy number analysis, routinely used in clinical diagnosis for several years, retrieves new and extremely rare copy number variations (CNVs) that provide novel candidate genes contributing to disease etiology. The aim of this work was to identify novel genetic causes of neurodevelopmental disease, inferred from CNVs detected by array comparative hybridization (aCGH), in a cohort of 325 Portuguese patients with intellectual disability (ID).
Results: We have detected CNVs in 30.1% of the patients, of which 5.2% corresponded to novel likely pathogenic CNVs. For these 11 rare CNVs (which encompass novel ID candidate genes), we identified those most likely to be relevant, and established genotype-phenotype correlations based on detailed clinical assessment. In the case of duplications, we performed expression analysis to assess the impact of the rearrangement. Interestingly, these novel candidate genes belong to known ID-related pathways. Within the 8% of patients with CNVs in known pathogenic loci, the majority had a clinical presentation fitting the phenotype(s) described in the literature, with a few interesting exceptions that are discussed.
Conclusions: Identification of such rare CNVs (some of which reported for the first time in ID patients/families) contributes to our understanding of the etiology of ID and for the ever-improving diagnosis of this group of patients.This work has been funded by FEDER funds, through the Competitiveness
Factors Operational Programme (COMPETE), and by National funds, through
the Foundation for Science and Technology (FCT), under the scope of the
projects: PIC/IC/83026/2007, PIC/IC/83013/2007 and POCI-01-0145-FEDER-007038. This work has also been funded by the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational
Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement,
through the European Regional Development Fund (FEDER). FL was supported by Foundation for Science and Technology (FCT) through the fellowship SFRH/BD/90167/2012info:eu-repo/semantics/publishedVersio