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Background and aims: Fast-track care have been proved to reduce the short-term risk of stroke after transient ischemic attack (TIA). We aimed to investigate stroke risk and to characterize short- and long-term stroke predictors in a large cohort of TIA patients undergoing fast-track management. Methods: Prospective study, enrolling consecutive TIA patients admitted to a Northern Italy emergency department from August 2010 to December 2017. All patients underwent fast-track care within 24 h of admission. The primary outcome was defined as the first stroke recurrence at 90 days, 12 and 60 months after TIA. Stroke incidence with 95% confidence interval (CI) at each timepoint was calculated using Poisson regression. Predictors of stroke recurrence were evaluated with Cox regression analysis. The number needed to treat (NNT) of fast-track care in preventing 90-day stroke recurrence in respect to the estimates based on baseline ABCD2 score was also calculated. Results: We enrolled 1,035 patients (54.2% males). Stroke incidence was low throughout the follow-up with rates of 2.2% [95% CI 1.4-3.3%] at 90 days, 2.9% [95% CI 1.9-4.2%] at 12 months and 7.1% [95% CI 5.4-9.0%] at 60 months. Multiple TIA, speech disturbances and presence of ischemic lesion at neuroimaging predicted stroke recurrence at each timepoint. Male sex and increasing age predicted 90-day and 60-month stroke risk, respectively. Hypertension was associated with higher 12-month and 60-month stroke risk. No specific TIA etiology predicted higher stroke risk throughout the follow-up. The NNT for fast-track care in preventing 90-day stroke was 14.5 [95% CI 11.3-20.4] in the overall cohort and 6.8 [95% CI 4.6-13.5] in patients with baseline ABCD2 of 6 to 7. Conclusion: Our findings support the effectiveness of fast-track care in preventing both short- and long-term stroke recurrence after TIA. Particular effort should be made to identify and monitor patients with baseline predictors of higher stroke risk, which may vary according to follow-up duration.
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Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is the standard of care for patients with advanced NSCLC and EGFR-sensitizing mutations. Both in osimertinib pivotal trials and in the post-marketing phase, asymptomatic creatinine phosphokinase elevation and clinically relevant muscle damage have been reported. However, the mechanisms underlying these conditions remain unclear. Herein, we report the first muscle biopsy description of osimertinib-induced myopathy and hypothesize that the mechanisms underpinning muscle toxicity could be driven by hyporegenerative mechanisms and mitochondrial dysfunction with subsequent reduced metabolic endurance, both directly linked to the inhibition of downstream molecular pathways mediated by EGFR in muscle cells.
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PURPOSE: We aim to propose a visual quantitative score for muscle edema in lower limb MRI to contribute to the diagnosis of idiopathic inflammatory myopathy (IIM). MATERIAL AND METHODS: We retrospectively evaluated 85 consecutive patients (mean age 57.4 ± 13.9 years; 56.5% female) with suspected IIM (muscle weakness and/or persistent hyper-CPK-emia with/without myalgia) who underwent MRI of lower limbs using T2-weighted fast recovery-fast spin echo images and fat-sat T2 echo planar images. Muscle inflammation was evaluated bilaterally in 11 muscles of the thigh and eight muscles of the leg. Edema in each muscle was graded according to a four-point Likert-type scale adding up to 114 points ([11 + 8)] × 3 × 2). Diagnostic accuracy of the total edema score was explored by assessing sensitivity and specificity using the area under the ROC curve. Final diagnoses were made by a multidisciplinary Expert Consensus Panel applying the Bohan and Peter diagnostic criteria whenever possible. RESULTS: Of the 85 included patients, 34 (40%) received a final diagnosis of IIM (IIM group) while 51 (60%) received an alternative diagnosis (non-IIM group). A cutoff score ≥ 18 was able to correctly classify patients having an IIM with an area under the curve of 0.85, specificity of 96%, and sensitivity of 52.9%. CONCLUSION: Our study demonstrates that a quantitative MRI score for muscle edema in the lower limbs (thighs and legs) aids in distinguishing IIM from conditions that mimic it.
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Edema , Extremidad Inferior , Imagen por Resonancia Magnética , Miositis , Humanos , Femenino , Masculino , Persona de Mediana Edad , Imagen por Resonancia Magnética/normas , Imagen por Resonancia Magnética/métodos , Miositis/diagnóstico por imagen , Miositis/diagnóstico , Estudios Retrospectivos , Extremidad Inferior/diagnóstico por imagen , Edema/diagnóstico por imagen , Anciano , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Adulto , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
Opinion is divided about the certainty of the evidence base for gender-affirming medical interventions in youth. Proponents claim that these treatments are well supported, while critics claim the poor-quality evidence base warrants extreme caution. Psychotherapy is one of the only available alternatives to the gender-affirming approach. Discussion of the treatment of gender dysphoria in young people is generally framed in terms of two binary approaches: affirmation or conversion. Psychotherapy/exploratory therapy offers a treatment option that lies outside this binary, although it is mistakenly conflated with conversion therapies. Psychotherapy does not impose restrictive gender stereotypes, as is sometimes claimed, but critically examines them. It empowers young people to develop creative solutions to their difficulties and promotes agency and autonomy. Importantly, an exploratory psychotherapeutic process can help to clarify whether gender dysphoria is a carrier for other psychological or social problems that may not be immediately apparent. Psychotherapy can therefore make a significant contribution to the optimal, ethical care of gender-dysphoric young people by ensuring that patients make appropriate, informed decisions about medical interventions which carry risks of harm and have a contested evidence base.
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OBJECTIVE: To systematically review the published cases of bilateral facial palsy (BFP) to gather evidence on the clinical assessment and management of this pathology. METHODS: Following PRISMA statement recommendations, 338 abstracts were screened independently by two authors. Inclusion criteria were research articles of human patients affected by BFP, either central or peripheral; English, Italian, French or Spanish language; availability of the abstract, while exclusion criteria were topics unrelated to FP, and mention of unilateral or congenital FP. Only full-text articles reporting the diagnostic work-up, the management, and the prognosis of the BFP considered for further specific data analysis. RESULTS: A total of 143 articles were included, resulting a total of 326 patients with a mean age of 36 years. The most common type of the paralysis was peripheral (91.7%), and the autoimmune disease was the most frequent aetiology (31.3%). The mean time of onset after first symptoms was 12 days and most patients presented with a grade higher than III. Associated symptoms in idiopathic BFP were mostly non-specific. The most frequently positive laboratory exams were cerebrospinal fluid analysis, autoimmune screening and peripheral blood smear, and the most performed imaging was MRI. Most patients (74%) underwent exclusive medical treatment, while a minority were selected for a surgical or combined approach. Finally, in more than half of cases a complete bilateral recovery (60.3%) was achieved. CONCLUSIONS: BFP is a disabling condition. If a correct diagnosis is formulated, possibilities to recover are elevated and directly correlated to the administration of an adequate treatment.
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Enfermedades del Nervio Facial , Parálisis Facial , Humanos , Adulto , Parálisis Facial/etiología , Parálisis Facial/terapia , Parálisis Facial/diagnóstico , Causalidad , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVE: To investigate neurotoxicity clinical and instrumental features, incidence, risk factors, and early and long-term prognosis in lymphoma patients who received CAR T-cell therapy. METHODS: In this prospective study, consecutive refractory B-cell non-Hodgkin lymphoma patients who received CAR T-cell therapy were included. Patients were comprehensively evaluated (neurological examination, EEG, brain MRI, and neuropsychological test) before and after (two and twelve months) CAR T-cells. From the day of CAR T-cells infusion, patients underwent daily neurological examinations to monitor the development of neurotoxicity. RESULTS: Forty-six patients were included in the study. The median age was 56.5 years, and 13 (28%) were females. Seventeen patients (37%) developed neurotoxicity, characterized by encephalopathy frequently associated with language disturbances (65%) and frontal lobe dysfunction (65%). EEG and brain FDG-PET findings also supported a predominant frontal lobe involvement. The median time at onset and duration were five and eight days, respectively. Baseline EEG abnormalities predicted ICANS development in the multivariable analysis (OR 4.771; CI 1.081-21.048; p = 0.039). Notably, CRS was invariably present before or concomitant with neurotoxicity, and all patients who exhibited severe CRS (grade ≥ 3) developed neurotoxicity. Serum inflammatory markers were significantly higher in patients who developed neurotoxicity. A complete neurological resolution following corticosteroids and anti-cytokines monoclonal antibodies was reached in all patients treated, except for one patient developing a fatal fulminant cerebral edema. All surviving patients completed the 1-year follow-up, and no long-term neurotoxicity was observed. CONCLUSIONS: In the first prospective Italian real-life study, we presented novel clinical and investigative insights into ICANS diagnosis, predictive factors, and prognosis.
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Inmunoterapia Adoptiva , Linfoma , Síndromes de Neurotoxicidad , Linfoma/terapia , Síndromes de Neurotoxicidad/epidemiología , Inmunoterapia Adoptiva/efectos adversos , Estudios Prospectivos , Síndrome de Liberación de Citoquinas , Humanos , Masculino , Femenino , Incidencia , Italia , Biomarcadores , Adulto , Persona de Mediana Edad , AncianoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) represent an effective cancer immunotherapy yet are associated with immune-related adverse events (irAEs). The aim of this study was to characterize irAEs involving the peripheral nervous system (PNS-irAEs) in a real-world cohort of ICI-treated patients. METHODS: Cancer patients treated with ICIs between January 2014 and March 2022 were included. Patients with PNS-irAEs were identified and divided into two groups: (1) cranial/peripheral neuropathies and (2) myasthenia gravis (MG) and/or myositis. Clinical characteristics and outcomes, measured with the modified Rankin Scale (mRS), were compared among the two groups. RESULTS: Among 920 ICI-treated patients, 20 patients (2.17%) developed a PNS-irAEs. The median latency from ICI exposure was 8.8 weeks and the median time from onset to clinical nadir was 3.5 weeks. Eleven patients developed a neuropathy: polyneuropathy (n = 4), cranial neuropathy (n = 3), small-fiber neuropathy (n = 3), brachial plexopathy (n = 1). Nine patients presented MG and/or myositis: concomitant MG and myositis (n = 6), isolated myositis (n = 2), exacerbation of MG (n = 1). Immunosuppressive treatment and/or ICI withdrawal determined a significant clinical improvement, expressed by a mRS reduction, in the neuropathy group (p = 0.004), but not in the MG/myositis group (p = 0.11). Overall, death due to irAEs occurred in four patients (20%), all with MG/myositis. Compared to patients with neuropathies, those with MG/myositis had a shorter latency onset (p = 0.036), developed more frequently concomitant non-neurologic irAEs (p = 0.028) and showed a higher mortality rate (p = 0.026). CONCLUSIONS: In our large cohort of ICI-treated patients, 2.17% developed PNS-irAEs. Compared to ir-neuropathies, ir-MG/myositis tend to occur earlier from ICI exposure and present a worse response to treatment and a higher mortality.
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Miastenia Gravis , Miositis , Neoplasias , Enfermedades del Sistema Nervioso Periférico , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Neoplasias/tratamiento farmacológico , Miastenia Gravis/inducido químicamente , Miastenia Gravis/tratamiento farmacológico , Sistema Nervioso Periférico , Miositis/inducido químicamenteRESUMEN
INTRODUCCIÓN: Durante la pandemia por SARS-CoV-2 se reportaron casos de un síndrome de inflamación multisistémica similar a la enfermedad de Kawasaki con antecedente de infección reciente o contacto con casos de COVID-19, generando una relación temporal con dicha enfermedad (SIM-C). El objetivo de este trabajo fue caracterizar los aspectos clínicos y epidemiológicos de los casos de SIM-C en menores de 18 años. MÉTODOS: Se realizó un estudio transversal, observacional y descriptivo de casos de SIM-C en menores de 18 años asistidos entre marzo de 2020 y junio de 2022 en el sistema público de la provincia de Neuquén. RESULTADOS: Serie de casos: Se incluyó a 9 pacientes con SIM-C: 55,5% de sexo femenino, con una media de edad de 6,1 años. El 77,7% de los casos de COVID-19 fueron confirmados por nexo epidemiológico. Todos los pacientes presentaron fiebre previa a la internación, el 88,8% tuvo manifestaciones mucocutáneas y compromiso abdominal. Otras manifestaciones frecuentes fueron compromiso ocular y edema de manos. El 33,3% de los pacientes requirieron internación en unidades de cuidados intensivos pediátricos. Solo 1 necesitó asistencia respiratoria mecánica por 48 horas por shock. Todos los pacientes fueron tratados con inmunoglobulina intravenosa (IGIV) 2 g/kg, y 3 pacientes recibieron corticoterapia. No hubo fallecimientos ni complicaciones en el seguimiento. DISCUSIÓN: Aunque el pronóstico es favorable, se sugiere realizar estudios que monitoreen los efectos a largo plazo de SIM-C.
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Humanos , Recién Nacido , Lactante , Preescolar , Niño , Pediatría , COVID-19 , Síndrome Mucocutáneo Linfonodular , Epidemiología Descriptiva , Estudios Transversales , Estudio ObservacionalRESUMEN
Over the last two decades the combination of brain slice patch clamp electrophysiology with optogenetic stimulation has proven to be a powerful approach to analyze the architecture of neural circuits and (experience-dependent) synaptic plasticity in such networks. Using this combination of methods, originally termed channelrhodopsin-assisted circuit mapping (CRACM), a multitude of measures of synaptic functioning can be taken. The current review discusses their rationale, current applications in the field, and their associated caveats. Specifically, the review addresses: (1) How to assess the presence of synaptic connections, both in terms of ionotropic versus metabotropic receptor signaling, and in terms of mono- versus polysynaptic connectivity. (2) How to acquire and interpret measures for synaptic strength and function, like AMPAR/NMDAR, AMPAR rectification, paired-pulse ratio (PPR), coefficient of variance and input-specific quantal sizes. We also address how synaptic modulation by G protein-coupled receptors can be studied with pharmacological approaches and advanced technology. (3) Finally, we elaborate on advances on the use of dual color optogenetics in concurrent investigation of multiple synaptic pathways. Overall, with this review we seek to provide practical insights into the methods used to study neural circuits and synapses, by combining optogenetics and patch-clamp electrophysiology.
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Optogenética , Sinapsis , Channelrhodopsins , Electrofisiología/métodos , Optogenética/métodos , Técnicas de Placa-Clamp , Sinapsis/fisiología , Transmisión SinápticaRESUMEN
mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE.
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Trasplante de Hígado , Errores Innatos del Metabolismo , Encefalomiopatías Mitocondriales , ADN Mitocondrial/genética , Humanos , Íleon , Captura por Microdisección con Láser , Rayos Láser , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/terapiaAsunto(s)
Personas Transgénero , Adolescente , Identidad de Género , Humanos , Consentimiento PaternoRESUMEN
Carbapenemase-producing Enterobacterales (CPE) represent a serious threat to public health worldwide. Elderly patients are at increased risk of colonisation/infection with CPE. This study aimed to evaluate the persistence of CPE colonisation and the genotypic characteristics of persistent strains in elderly people discharged from Italian hospitals. A longitudinal study was conducted in two Italian cities (March 2018 to September 2020) enrolling 137 patients aged ≥65 years with CPE intestinal colonisation at hospital discharge. CPE colonisation was evaluated after 4, 8 and 12 months. Competing risk analysis was used to explore the association between baseline characteristics and persistence at 4 months. For all isolates, carbapenemase typing and multilocus sequence typing were performed. Persistent isolates underwent whole-genome sequencing. Of 137 patients, 91% carried carbapenemase-producing Klebsiella pneumoniae (CP-KP) and 8.8% carried carbapenemase-producing Escherichia coli. Although a large number of patients were lost to follow-up owing to death or withdrawal, 28/65 patients (43.1%) remained colonised at Month 4; 16/42 (38.1%) and 5/28 (17.9%) were found colonised up to Months 8 and 12, respectively. Colonisation persistence was more frequent in patients with bacteraemia or complicated urinary tract infection while in hospital and in those staying in long-term care facilities (LTCFs). Clonal characteristics of CP-KP isolates did not appear to influence persistence. Isolates obtained from each persistent carrier were identical or highly related by SNP phylogenetic analysis. Identification of patients at higher risk of persistent intestinal carriage after hospital discharge can prompt control measures to limit the transmission of CPE in the community, especially in LTCF settings.
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Enterobacteriaceae Resistentes a los Carbapenémicos , Infecciones por Enterobacteriaceae , Anciano , Proteínas Bacterianas/genética , Infecciones por Enterobacteriaceae/epidemiología , Escherichia coli , Hospitales , Humanos , Klebsiella pneumoniae , Estudios Longitudinales , Alta del Paciente , Filogenia , beta-Lactamasas/genéticaRESUMEN
This commentary is a critique of a recent systematic review of the evidence for the use of puberty blockers for youth with gender dysphoria (GD) by Rew et al. (2021). In our view, the review suffers from several methodological oversights including the omission of relevant studies and suboptimal analysis of the quality of the included studies. This has resulted in an incomplete and incorrect assessment of the evidence base for the use of puberty blockers. We find that Rew et al.'s conclusions and clinician recommendations are problematic, especially when discussing suicidality. A key message of the review's abstract appears to be that puberty blockers administered in childhood reduce adult suicidality. However, the study used for the basis of this conclusion (Turban et al., 2020) did not make a causal claim between puberty blockers and decreased adult suicidality. Rather, it reported a negative association between using puberty blockers and lifetime suicidal ideation. The study design did not allow for determination of causation. Our commentary concludes by demonstrating how the GD medical literature, as it moves from one publication to the next, can overstate the evidence underpinning clinical practice recommendations for youth with GD.
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Disforia de Género , Personas Transgénero , Adolescente , Adulto , Disforia de Género/tratamiento farmacológico , Identidad de Género , Humanos , Pubertad , Conducta SexualRESUMEN
PURPOSE: To assess efficacy and safety of cone beam computed tomography (CBCT) in the radiofrequency ablation (RFA) of osteoid osteoma (OO) in children and adolescents, and to compare technical success, clinical success, radiation dose and procedure duration time of CBCT guidance to conventional computed tomography (CT) guidance. MATERIALS AND METHODS: Between 2015 and 2019, 53 consecutive percutaneous RFA were performed on pediatric patients with CBCT or conventional CT guidance, respectively, in 24 and 29 children and adolescents with 24-month follow-up. Dose area product (DAP) and dose length product (DLP) were recorded, respectively, for CBCT and conventional CT and converted to effective doses (ED). RESULTS: CBCT and conventional CT groups were similar in terms of patient age and weight, tumor size and tumor location. Technical success was achieved in all cases. Primary clinical success was 91.67% (22/24) for the CBCT group and 89.66% (26/29) for the conventional CT group. Mean DAP was 64.75Gycm2 (range 6.0-266.7). Mean DLP was 972.62mGycm (range 337-2344). ED was significantly lower in the CBCT group compared to the conventional CT group (0.34 mSv vs. 5.53 mSv, p = 0.0119). Procedure duration time was not significantly longer in the CBCT group (102.25 min vs. 92.34 min, p = 0.065). No major complication was registered. Minor complications were observed in 4 patients (2 in CBCT; 2 in conventional CT). CONCLUSIONS: Compared to conventional CT guidance, CBCT guidance for percutaneous OO ablation shows similar technical and clinical success rates, with reduced radiation dose and equivalent procedure duration time. This technique helps sparing dose exposure to pediatric patients.
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Tomografía Computarizada de Haz Cónico/métodos , Osteoma Osteoide/diagnóstico por imagen , Osteoma Osteoide/cirugía , Dosis de Radiación , Ablación por Radiofrecuencia/métodos , Radiografía Intervencional/métodos , Adolescente , Femenino , Humanos , Masculino , Resultado del TratamientoRESUMEN
Chimeric antigen receptor (CAR) T-cell therapy is an emerging highly effective treatment for refractory haematological malignancies. Unfortunately, its therapeutic benefit may be hampered by treatment-related toxicities, including neurotoxicity. Early aggressive treatment is paramount to prevent neurological sequelae, yet it potentially interferes with the anti-cancer action of CAR T-cells. We describe four CAR T-cells infused patients who presented with reiterative writing behaviours, namely paligraphia, as an early manifestation of neurotoxicity, and eventually developed frontal predominant encephalopathy (one mild, three severe). Paligraphia may represent an early, specific, and easily detectable clinical finding of CAR T-cell therapy-related neurotoxicity, potentially informing its management.
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Encefalopatías , Síndromes de Neurotoxicidad , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/terapia , Resultado del TratamientoRESUMEN
OBJECTIVES: This work aimed to report the demographic and clinical characteristics of two new cases with non-paraneoplastic anti-Hu-associated gut motility impairment, and perform a thorough revision covering anti-Hu-associated paraneoplastic (PGID) and non-paraneoplastic (nPGID) gastrointestinal dysmotility. BACKGROUND: Several case series have clearly established a relationship between certain type of cancers, the development of circulating anti-Hu antibodies, and the concomitant usually severe gastrointestinal dysmotility; in contrast, a few studies focused on anti-Hu-associated nPGID. METHODS: We searched for studies regarding anti-Hu-associated gastrointestinal manifestations and extracted data concerning clinical characteristics of patients, including specific demographic, oncological, neurological, gastrointestinal, histological, and treatment response features. RESULTS: Forty-nine articles with a total of 59 cases of anti-Hu-associated gastrointestinal dysmotility were analyzed. The patients' age at symptom onset significantly differed between PGID and nPGID (median 61 vs 31 years, p < 0.001). Most cancers (95%) in PGID were detected within 24 months from the beginning of gastrointestinal symptoms. The impairment of gastrointestinal motility was generalized (i.e., involving the whole gut) in 59.3% of patients, with no significant differences between PGID vs nPGID group. nPGID patients showed a better response to immunomodulatory/immunosuppressive treatment and a longer life expectancy. CONCLUSIONS: Anti-Hu-associated gastrointestinal dysmotility covers a wide clinical spectrum. Patients with otherwise unexplained gastrointestinal dysmotility, especially when associated with other neurological symptoms, should be tested for anti-Hu antibodies regardless age of onset and disease duration. Compared to PGID, nPGID occurs in younger patients with a long duration of disease.