Sentinel lymph node biopsy versus observation in high-risk cutaneous squamous cell carcinoma in immunosuppressed and immunocompetent patients: An inverse probability of treatment weighting study.

BACKGROUND: The survival benefit of sentinel lymph node biopsy (SLNB) in immunocompetent and immunosuppressed patients with high-risk cutaneous squamous cell carcinoma (cSCC) has not been established. OBJECTIVE: To determine whether SLNB improves disease-specific survival (DSS) in high-risk cSCC. Secondary objectives were to analyse disease-free survival, nodal recurrence-free survival and overall survival (OS). METHODS: Multicentre, retrospective, observational cohort study comparing survival outcomes in immunosuppressed and immunocompetent patients treated with SLNB or watchful waiting. Inverse probability of treatment weighting was used to adjust for possible confounding effects. RESULTS: We studied 638 tumours in immunocompetent patients (SLNB n = 42, observation n = 596) and 173 tumours in immunosuppressed patients (SLNB n = 28, observation n = 145). Overall, SLNB was positive in 15.7% of tumours. SLNB was associated with a reduced risk of nodal recurrence (NR) (hazard ratio [HR], 0.05 [95% CI, 0.01-0.43]; p = 0.006), disease specific mortality (HR, 0.17 [95% CI, 0.04-0.72]; p = 0.016) and all-cause mortality (HR, 0.33 [95% CI, 0.15-0.71]; p = 0.004) only in immunocompetent patients. CONCLUSIONS: SLNB was associated with improvements in NR, DSS and OS in immunocompetent but not in immunosuppressed patients with high-risk cSCC.

The contribution of histopathology to the diagnosis of tuberculosis. Lessons from archival biopsy samples.

BACKGROUND: Histopathological analysis of tissue samples is an ancillary complementary diagnostic tool in tuberculosis (TB) with variable sensitivity and specificity according to different clinical settings. We evaluated the spectrum of histological findings, their diagnostic sensitivity, diagnostic utility, and requests over time in a sample of archival biopsies. METHODS: Analysis of biopsies of confirmed TB cases between years 2011-2019 at a reference hospital in Chile. RESULTS: The series included patients with a histological study for TB confirmed by culture (88.9%) or PCR (11.1%). In total, 34 samples were available for analysis, most of them of extrapulmonary origin (82.4%). Biopsies were taken before the start of treatment in 26 cases (76.5%) or after the start-end of treatment for different reasons in 8 cases (23.5%). Restricting the analysis to the group with pretreatment biopsies, the prevalence/diagnostic sensitivity of granulomas was 93.3%, 69.2% for caseous necrosis, 26.9% for granulomas with caseous necrosis without acid-fast bacilli (AFB), and 46.2% for AFB in any histological context. A histological score was constructed to evaluate the homogeneity of lesions, observing that 76.9% had at least four of the six components of the score. The request for biopsies was maintained over time despite the increase in the use of molecular techniques. The presence of AFB contributed to the diagnosis before microbiological results in 23.1% of the cases. CONCLUSIONS: Histological study continues to contribute to the diagnosis of TB, especially in extrapulmonary forms.

Admissions by tuberculosis in a regional reference Center. A complex and worrying scenario.

OBJECTIVES: To characterize clinical aspects, evaluate the diagnostic opportunity, and identify factors associated with mortality in patients hospitalized for tuberculosis (TB). METHODS: Retrospective study of patients admitted for TB to a Regional Hospital in Chile between 2011 and 2019. RESULTS: 142 TB events required hospitalization in this period (38.2% of total cases). All risk groups were identified, with a significant increase in patients with diabetes mellitus. The pulmonary location was the most frequent (71.1%), followed by disseminated forms (16.2%). The sensitivity of microscopy smear in cases of pulmonary TB (isolated or combined) was 78.8% and lower in cases of bronchoalveolar lavage (58.3%). PCR was only occasionally applied (< 10%) with a sensitivity of 100% in sputum samples. Its use increased progressively and reached a positivity of 33% (6 out of 18 cases) in cases with negative sputum staining. The median time between symptom onset and diagnosis was prolonged (9 weeks), and 32.5% of all regional events were diagnosed at the hospital. Dose adjustments (22.1%), corticosteroid use (25%), and treatment interruptions were frequent (11%). Lethality reached 19%, and by multivariate analysis, only shock was associated with a fatal outcome. CONCLUSIONS: In this case series, the diagnosis of TB cases was delayed, scarcely diagnosed by molecular methods, highly concentrated at the hospital level, required admission in a large percentage of cases, and had a high case-fatality rate.

Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping-Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network­targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

A precision functional atlas of personalized network topography and probabilities.

Although the general location of functional neural networks is similar across individuals, there is vast person-to-person topographic variability. To capture this, we implemented precision brain mapping functional magnetic resonance imaging methods to establish an open-source, method-flexible set of precision functional network atlases-the Masonic Institute for the Developing Brain (MIDB) Precision Brain Atlas. This atlas is an evolving resource comprising 53,273 individual-specific network maps, from more than 9,900 individuals, across ages and cohorts, including the Adolescent Brain Cognitive Development study, the Developmental Human Connectome Project and others. We also generated probabilistic network maps across multiple ages and integration zones (using a new overlapping mapping technique, Overlapping MultiNetwork Imaging). Using regions of high network invariance improved the reproducibility of executive function statistical maps in brain-wide associations compared to group average-based parcellations. Finally, we provide a potential use case for probabilistic maps for targeted neuromodulation. The atlas is expandable to alternative datasets with an online interface encouraging the scientific community to explore and contribute to understanding the human brain function more precisely.

The contribution of histopathology to the diagnosis of tuberculosis. Lessons from archival biopsy samples

Background: Histopathological analysis of tissue samples is an ancillary complementary diagnostic tool in tuberculosis (TB) with variable sensitivity and specificity according to different clinical settings. We evaluated the spectrum of histological findings, their diagnostic sensitivity, diagnostic utility, and requests over time in a sample of archival biopsies. Methods: Analysis of biopsies of confirmed TB cases between years 2011-2019 at a reference hospital in Chile. Results: The series included patients with a histological study for TB confirmed by culture (88.9%) or PCR (11.1%). In total, 34 samples were available for analysis, most of them of extrapulmonary origin (82.4%). Biopsies were taken before the start of treatment in 26 cases (76.5%) or after the start-end of treatment for different reasons in 8 cases (23.5%). Restricting the analysis to the group with pretreatment biopsies, the prevalence/diagnostic sensitivity of granulomas was 93.3%, 69.2% for caseous necrosis, 26.9% for granulomas with caseous necrosis without acid-fast bacilli (AFB), and 46.2% for AFB in any histological context. A histological score was constructed to evaluate the homogeneity of lesions, observing that 76.9% had at least four of the six components of the score. The request for biopsies was maintained over time despite the increase in the use of molecular techniques. The presence of AFB contributed to the diagnosis before microbiological results in 23.1% of the cases. Conclusions: Histological study continues to contribute to the diagnosis of TB, especially in extrapulmonary forms.

El análisis histopatológico de muestras de tejidos es una metodología antigua y auxiliar para el diagnóstico de tuberculosis (TB) con sensibilidad y especificidad variable de acuerdo al escenario clínico. Evaluamos el espectro de los hallazgos histológicos, su sensibilidad diagnóstica, su utilidad diagnóstica y cambios de solicitud en el tiempo. Métodos: Análisis de biopsias de casos de TB confirmados entre los años 2011-2019 en un hospital de referencia en Chile. Resultados: La serie incluye pacientes con estudio histológico por TB confirmados por cultivo (88,9%) o PCR (11,1%). En total se contó con 34 muestras para análisis, en su mayoría de origen extrapulmonar (82,4%). Las biopsias fueron tomadas antes del inicio del tratamiento en 26 casos (76,5%) o luego del inicio o al finalizar el tratamiento por diferentes razones en 8 casos (23,5%). Restringiendo el análisis al grupo con biopsias pretratamiento, la prevalencia/sensibilidad diagnóstica de granulomas fue de 93,3%, de necrosis caseosa 69,2%, de granulomas con necrosis caseosa sin bacilos ácido-alcohol resistentes (BAAR) de 26,9% y de BAAR en cualquier contexto histológico de 46,2%. Se construyó un score histológico para ver homogeneidad de lesiones, observando que el 76,9% tenía al menos 4 de los 6 componentes del score. La solicitud de biopsias se mantuvo en el tiempo a pesar del incremento de técnicas moleculares. La presencia de BAAR contribuyó al diagnóstico antes que los resultados microbiológicos en el 23,1% de los casos. Conclusiones: El estudio histológico sigue contribuyendo al diagnóstico, especialmente en las formas extrapulmonares de TB.

Admissions by tuberculosis in a regional reference Center. A complex and worrying scenario / Ingresos por tuberculosis en un hospital regional. Un escenario complejo y preocupante

OBJECTIVES: To characterize clinical aspects, evaluate the diagnostic opportunity, and identify factors associated with mortality in patients hospitalized for tuberculosis (TB). METHODS: Retrospective study of patients admitted for TB to a Regional Hospital in Chile between 2011 and 2019. RESULTS: 142 TB events required hospitalization in this period (38.2% of total cases). All risk groups were identified, with a significant increase in patients with diabetes mellitus. The pulmonary location was the most frequent (71.1%), followed by disseminated forms (16.2%). The sensitivity of microscopy smear in cases of pulmonary TB (isolated or combined) was 78.8% and lower in cases of bronchoalveolar lavage (58.3%). PCR was only occasionally applied (< 10%) with a sensitivity of 100% in sputum samples. Its use increased progressively and reached a positivity of 33% (6 out of 18 cases) in cases with negative sputum staining. The median time between symptom onset and diagnosis was prolonged (9 weeks), and 32.5% of all regional events were diagnosed at the hospital. Dose adjustments (22.1%), corticosteroid use (25%), and treatment interruptions were frequent (11%). Lethality reached 19%, and by multivariate analysis, only shock was associated with a fatal outcome. CONCLUSIONS: In this case series, the diagnosis of TB cases was delayed, scarcely diagnosed by molecular methods, highly concentrated at the hospital level, required admission in a large percentage of cases, and had a high case-fatality rate.

OBJETIVOS: Caracterizar aspectos clínicos, evaluar la oportunidad diagnóstica e identificar factores asociados a mortalidad en pacientes ingresados por tuberculosis (TB). MÉTODOS: Estudio retrospectivo de pacientes ingresados por TB a un Hospital Regional en Chile entre el 2011 y 2019. RESULTADOS: Un total de 142 eventos de TB requirieron hospitalización en el período (38,2% del total). Todos los grupos de riesgo fueron identificados con un aumento significativo de los pacientes con diabetes mellitus. La localización pulmonar fue la más frecuente (71,1%), seguida de la forma diseminada (2 o más sitios; 16,2%). La sensibilidad de la tinción de expectoración en casos de TB pulmonar (aislada o combinada) fue de 78,8% y más baja en casos de lavado broncoalveolar (58,3%). La PCR fue sólo ocasionalmente aplicada (< 10%) con una sensibilidad del 100% en muestras de expectoración. Su uso aumentó progresivamente en el período y el incremento diagnóstico de TB en casos con tinción negativa de expectoración estudiados con PCR fue de 33% (6 de 18 casos). La mediana entre inicio de síntomas y el diagnóstico fue prolongada (9 semanas) y el 32,5% de los eventos regionales fueron diagnosticados en el hospital. Los ajustes de dosis (22,1%), uso de corticoides (25%) e interrupciones del tratamiento fueron hechos frecuentes (11%). La letalidad alcanzó 19% y en el análisis multivariado sólo la aparición de shock se asoció a un desenlace fatal. CONCLUSIONES: En esta serie de casos, el diagnóstico de casos de TB fue tardío, infrecuentemente diagnosticado por métodos moleculares, concentrado en la atención terciaria, requirió hospitalización en un gran porcentaje de casos y tuvo una elevada letalidad.

Enfermedad de Hansen. Una condición emergente en Chile / Hansen disease, an emergent condition in Chile

Resumen La enfermedad de Hansen (EH) es una infección secundaria a Mycobacterium leprae, de curso crónico y que afecta preferentemente la piel y los nervios periféricos. Es una condición emergente en Chile debido a la migración humana. Presentamos un caso que afectó a un trabajador inmigrante desde Haití, que presentó antes de su arribo múltiples lesiones cutáneas en placas, con hipoestesia y madarosis unilateral. El diagnóstico de la forma multibacilar se estableció por los hallazgos clínicos, la presencia de bacilos ácido-alcohol resistentes en una muestra cutánea y la detección de células inflamatorias alrededor de los terminales nerviosos y granulomas en una biopsia de piel, desde donde se amplificaron segmentos específicos de los genes rpoB y hsp65 de M. leprae. El paciente fue tratado con el esquema combinado estándar de la OMS para la forma multibacilar durante un año, con regresión parcial de las lesiones. Durante el seguimiento se detectó por RPC una disminución del número de copias del gen rpoB de M. leprae en muestras nasofaríngeas hasta el sexto mes. El registro de enfermedades de notificación obligatoria demuestra un incremento reciente de casos de EH en Chile, todos relacionados con población migrante. La enfermedad de Hansen es una nueva condición clínica y los clínicos deben estar atentos a esta posibilidad diagnóstica. Las pruebas moleculares pueden ayudar en el diagnóstico y seguimiento.

Hansen's disease (HD) is caused by Mycobacterium leprae. It has a chronic course and preferentially affects the skin and the peripheral nerves. It's an emergent infection in Chile due to migration waves. This case report affecting a migrant worker from Haiti that presented several compatible skin lesions, with hypoesthesia and unilateral madarosis that appeared before arrival. The diagnosis of a multibacillary form was established by clinical findings, presence of fast acid bacilli on a direct skin smear, and inflammatory cell surrounding nerve endings and granulomas on skin biopsy. Besides, specific rpoB and hsp65 gene segments from M. leprae were amplified from skin samples. Patient was treated with the WHO standard combined regimen for multibacillary forms during one year showing partial regression of skin lesions. Nasopharyngeal samples showed the presence of M. leprae rpoB copies detected by PCR decreasing until six months of therapy. Notifiable diseases databases showed a recent increment of cases, all related to migrant population. Hansen's disease is a new condition in Chile and clinicians should be aware of this possibility. Molecular tools may facilitate diagnosis and follow up.