Subcutaneous adipose tissue radiodensity: An emerging risk factor for severe COVID-19.

BACKGROUND: Adipose tissue radiodensity and metabolic activity may influence COVID-19 outcomes. This study evaluated the association between adipose tissue characteristics and clinical outcomes in COVID-19 patients. METHODS: Two retrospective cohorts of hospitalized COVID-19 patients were analyzed. Subcutaneous adipose tissue radiodensity (SATR) and visceral adipose tissue radiodensity were assessed by computed tomography. Fluorine-18-labelled fluorodeoxyglucose PET/computed tomography measured adipose tissue metabolic activity. Associations with mortality, length of stay, ventilation requirement, and complications were examined using regression analyses. RESULTS: High SATR was independently associated with increased mortality risk (OR: 2.70; P = 0.033), longer hospitalization (P < 0.001), higher rates of mechanical ventilation (P = 0.007), and complications: acute kidney injury (P = 0.001), secondary infection (P = 0.007), shock (P = 0.010), and pulmonary embolism (P = 0.011). SATR positively correlated with SAT glucose uptake (ρ = 0.52) and negatively with leptin levels (ρ = -0.48). CONCLUSIONS: Elevated SATR at COVID-19 diagnosis predicts disease severity and worse outcomes. SATR is a potential prognostic biomarker for acute and chronic inflammatory conditions.

PSMA PET/CT in the Brazilian Unified Healthcare System reduces costs with futile salvage therapies in the management of cases of biochemical recurrence of prostate cancer.

Objective: To compare costs between treatment strategies employed prior to and after prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) via the Brazilian Unified Health Care System and their impact on the therapeutic management of biochemical recurrence of prostate cancer. Materials and Methods: The referring physicians were surveyed on their treatment intentions (strategies) at two different time points: prior to and after PSMA PET/CT. Cost comparison results are presented as median (IQR) for each of the two strategies. The shift in therapeutic management after PSMA PET/CT was also analyzed. Results: The study sample included 59 patients (mean age: 65.9 years). The PSMA PET/CT result was considered positive in 38 patients (64.4%) and was found to have an impact on the treatment strategy in for 36 patients (61.0%). Prior to PSMA PET/CT, salvage therapy (i.e., treatment with curative intent) was the intended treatment for most patients, and that was significantly less so after the examination (76.3% vs. 45.8%; p < 0.001). Conversely, a strategy involving systemic (i.e., palliative) therapy became more common after PSMA PET/CT (23.7% vs. 54.2%; p < 0.001). The after-PSMA PET/CT strategy presented higher overall costs than did the before-PSMA PET/CT strategy, in all scenarios evaluated. In all scenarios, nearly half of this cost difference was related to the cost of the PSMA PET/CT itself, the remainder being related to the new treatment choices that stemmed from knowledge of the PSMA PET/CT findings. Conclusion: For patients treated within the Brazilian Unified Health Care System, PSMA PET/CT presented higher costs in comparison with conventional imaging methods. Adding PSMA PET/CT to the workflow had an impact on therapeutic management, mainly representing a shift from futile curative treatments to systemic palliative ones. The amount of funds that could potentially be saved by not providing such futile treatments would suffice to evaluate roughly two patients with PSMA PET/CT scans for each futile treatment strategy avoided.

Objetivo: Comparar custos entre estratégias antes e após o exame de PET/CT-PSMA da perspectiva do Sistema Único de Saúde e seu impacto no manejo terapêutico para pacientes com recidiva bioquímica de câncer de próstata. Materiais e Métodos: Os médicos solicitantes informaram a intenção terapêutica em dois momentos: antes e após o exame. Os resultados de comparação de custo estão apresentados como medianas de custo (p25; p75). A mudança na intenção terapêutica também foi analisada. Resultados: O estudo envolveu 59 pacientes (idade média: 65,9 anos). A PET/CT-PSMA foi considerada positiva em 38 dos 59 pacientes (64.4%). O exame impactou a estratégia de tratamento para 36 pacientes (61%). Antes da obtenção das informações da PET/CT-PSMA, a terapia de resgate (i.e., com intenção curativa) era o tratamento sugerido para a maioria dos pacientes, e após o exame, reduziu significativamente (76,3% vs 45,8%; p < 0,001). Em contrapartida, a terapia sistêmica (i.e., paliativa) aumentou como intenção de tratamento após o exame (23,7% vs 54,2%; p < 0,001). A estratégia "após PET/CT-PSMA" apresentou maiores custos em relação à estratégia "antes da PET/CT-PSMA" nos cenários comparados. Cerca de metade da diferença de custos entre as duas estratégias foi relacionada aos custos do exame propriamente ditos, enquanto a outra metade foi relacionada às novas escolhas de tratamento a partir do exame. Conclusão: Oferecer a PET/CT-PSMA no Sistema Único de Saúde apresentou maiores custos em relação à estratégia com métodos de imagem convencionais e impactou o manejo terapêutico, pelo favorecimento de tratamentos sistêmicos paliativos no lugar de tratamentos curativos fúteis. A quantidade de recursos que poderiam ser poupados ao evitar tratamentos fúteis seria suficiente para avaliar aproximadamente dois pacientes com exames de PET/CT-PSMA para cada estratégia de tratamento fútil evitada.

Lineage-tracing reveals an expanded population of NPY neurons in the inferior colliculus.

Growing evidence suggests that neuropeptide signaling shapes auditory computations. We previously showed that neuropeptide Y (NPY) is expressed in the inferior colliculus (IC) by a population of GABAergic stellate neurons and that NPY regulates the strength of local excitatory circuits in the IC. NPY neurons were initially characterized using the NPY-hrGFP mouse, in which humanized renilla green fluorescent protein (hrGFP) expression indicates NPY expression at the time of assay, i.e., an expression-tracking approach. However, studies in other brain regions have shown that NPY expression can vary based on several factors, suggesting that the NPY-hrGFP mouse might miss NPY neurons not expressing NPY on the experiment date. Here, we hypothesized that neurons with the ability to express NPY represent a larger population of IC GABAergic neurons than previously reported. To test this hypothesis, we used a lineage-tracing approach to irreversibly tag neurons that expressed NPY at any point prior to the experiment date. We then compared the physiological and anatomical features of neurons labeled with this lineage-tracing approach to our prior data set, revealing a larger population of NPY neurons than previously found. In addition, we used optogenetics to test the local connectivity of NPY neurons and found that NPY neurons provide inhibitory synaptic input to other neurons in the ipsilateral IC. Together, our data expand the definition of NPY neurons in the IC, suggest that NPY expression might be dynamically regulated in the IC, and provide functional evidence that NPY neurons form local inhibitory circuits in the IC.NEW & NOTEWORTHY Across brain regions, neuropeptide Y (NPY) expression is dynamic and influenced by extrinsic and intrinsic factors. We previously showed that NPY is expressed by a class of inhibitory neurons in the auditory midbrain. Here, we find that this neuron class also includes neurons that previously expressed NPY, suggesting that NPY expression is dynamically regulated in the auditory midbrain. We also provide functional evidence that NPY neurons contribute to local inhibitory circuits in the auditory midbrain.

Lineage-tracing reveals an expanded population of NPY neurons in the inferior colliculus.

Growing evidence suggests that neuropeptide signaling shapes auditory computations. We previously showed that neuropeptide Y (NPY) is expressed in the inferior colliculus (IC) by a population of GABAergic stellate neurons and that NPY regulates the strength of local excitatory circuits in the IC. NPY neurons were initially characterized using the NPY-hrGFP reporter mouse, in which hrGFP expression indicates NPY expression at the time of assay, i.e., an expression-tracking approach. However, studies in other brain regions have shown that NPY expression can vary based on a range of factors, suggesting that the NPY-hrGFP mouse might miss NPY neurons not expressing NPY proximal to the experiment date. Here, we hypothesized that neurons with the ability to express NPY represent a larger population of IC GABAergic neurons than previously reported. To test this hypothesis, we used a lineage-tracing approach to irreversibly tag neurons that expressed NPY at any point prior to the experiment date. We then compared the physiological and anatomical features of neurons labeled with this lineage-tracing approach to our prior data set, revealing a larger population of NPY neurons than previously found. In addition, we used optogenetics to test the local connectivity of NPY neurons and found that NPY neurons routinely provide inhibitory synaptic input to other neurons in the ipsilateral IC. Together, our data expand the definition of NPY neurons in the IC, suggest that NPY expression might be dynamically regulated in the IC, and provide functional evidence that NPY neurons form local inhibitory circuits in the IC.

Moderate and severe adverse events in pediatrics: characteristics of incidents reported during the COVID-19 pandemic.

OBJECTIVE: To verify the characteristics of safety incident reports resulting in moderate and severe harm to pediatric patients in two hospitals during the COVID-19 pandemic. METHOD: Cross-sectional study conducted in two hospitals in southern Brazil. The sample consisted of 137 notifications from March 2020 to August 2021. The data were collected through the electronic records of the institutions' notification systems and analyzed using descriptive and inferential statistics. RESULTS: The most prevalent incidents were related to clinical processes or procedures (41.6%), affecting slightly more females (49.6%) and infants (39.4%). The majority of incidents (48.2%) occurred in inpatient units. The event sector (p=0.001) and the shift (p=0.011) showed statistically significant associations in both hospitals. CONCLUSION: The characteristics of the notifications are similar between the institutions surveyed, with a low number of moderate and severe incidents.

Moderate and severe adverse events in pediatrics: characteristics of incidents reported during the COVID-19 pandemic / Eventos adversos moderados y graves en pediatría: características de los incidentes reportados durante la pandemia del COVID-19 / Eventos adversos moderados e graves em pediatria: características dos incidentes notificados durante a pandemia COVID-19

ABSTRACT Objective: To verify the characteristics of safety incident reports resulting in moderate and severe harm to pediatric patients in two hospitals during the COVID-19 pandemic. Method: Cross-sectional study conducted in two hospitals in southern Brazil. The sample consisted of 137 notifications from March 2020 to August 2021. The data were collected through the electronic records of the institutions' notification systems and analyzed using descriptive and inferential statistics. Results: The most prevalent incidents were related to clinical processes or procedures (41.6%), affecting slightly more females (49.6%) and infants (39.4%). The majority of incidents (48.2%) occurred in inpatient units. The event sector (p=0.001) and the shift (p=0.011) showed statistically significant associations in both hospitals. Conclusion: The characteristics of the notifications are similar between the institutions surveyed, with a low number of moderate and severe incidents.

RESUMEN Objetivo: Verificar las características de los informes de incidentes de seguridad que resultaron en daños moderados y graves a pacientes pediátricos en dos hospitales durante la pandemia de COVID-19. Método: Estudio transversal realizado en dos hospitales del sur de Brasil. La muestra consistió en 137 notificaciones entre marzo de 2020 y agosto de 2021. Los datos se recogieron a través de los registros electrónicos de los sistemas de notificación de las instituciones y se analizaron mediante estadística descriptiva e inferencial. Resultados: Los incidentes más prevalentes estuvieron relacionados con procesos o procedimientos clínicos (41,6%), afectando ligeramente más a mujeres (49,6%) y lactantes (39,4%). La mayoría de los incidentes (48,2%) se produjeron en unidades de hospitalización. El sector del suceso (p=0,001) y el turno (p=0,011) se asociaron de forma estadísticamente significativa en ambos hospitales. Conclusión: Las características de las notificaciones son similares entre las instituciones encuestadas, con un bajo número de incidentes moderados y graves.

RESUMO Objetivo: Verificar as características das notificações de incidentes de segurança resultantes em dano moderado e grave em pacientes pediátricos de dois hospitais durante a pandemia COVID-19. Método: Estudo transversal, realizado em dois hospitais no sul do Brasil. A amostra foi composta por 137 notificações correspondentes ao período de março de 2020 a agosto de 2021. Os dados foram coletados pelo registro eletrônico dos sistemas de notificação das instituições e analisados por estatística descritiva e inferencial. Resultados: Os incidentes mais prevalentes foram relacionados aos processos ou procedimentos clínicos (41,6%), acometeram discretamente mais o sexo feminino (49,6%) e lactentes (39,4%). A maioria dos incidentes (48,2%) ocorreram em unidades de internação. O setor do evento (p=0,001) e o turno (p=0,011) obtiveram associação estatística significativa nos dois hospitais. Conclusão: As características das notificações são semelhantes entre as instituições pesquisadas, sendo evidenciado baixo número de incidentes moderados e graves.

Panorama dos incidentes de segurança envolvendo pacientes pediátricos em um hospital universitário / Overview of safety incidents involving pediatric patients at a university hospital / Panorama de los incidentes de seguridad de los pacientes pediátricos en un hospital universitario

RESUMO: Objetivo: analisar o perfil e as características dos incidentes de segurança ocorridos entre 2015 e 2019 com pacientes pediátricos notificados no sistema informatizado de um hospital universitário. Método: estudo quantitativo, descritivo, transversal, com 2.558 notificações em instituição do sul do Brasil. Estatística descritiva e teste qui-quadrado foram utilizados para a análise dos dados. Resultados: ocorrência maior de incidentes de segurança relacionada a medicações/fluidos intravenosos (n=643; 25,1%), dieta/alimentação (n=448; 17,5%), processo/procedimento clínico (n=384; 15,0%), dispositivos/equipamentos médicos (n=304; 11,9%), acidentes do paciente (n=273; 10,7%). Unidades de internação e terapia intensiva estão mais relacionadas à ocorrência de incidentes; turno de trabalho não esteve relacionado ao tipo de incidente notificado. Conclusão: o panorama dos incidentes de segurança pode nortear estratégias para a qualificação do cuidado na instituição em estudo e colaborar com outros serviços de saúde na identificação de situações de risco para a criança hospitalizada.

ABSTRACT Objective: To analyze the profile and characteristics of safety incidents that occurred between 2015 and 2019 with pediatric patients reported in the computerized system of a university hospital. Method: quantitative, descriptive, cross-sectional study with 2,558 notifications at an institution in southern Brazil. Descriptive statistics and the chi-square test were used to analyze the data. Results: higher occurrence of safety incidents related to medications/intravenous fluids (n = 643; 25.1%), diet/food (n = 448; 17.5%), clinical process/procedure (n = 384; 15.0%), medical devices/equipment (n = 304; 11.9%), and patient accidents (n = 273; 10.7%). Inpatient and intensive care units are more related to the occurrence of incidents; work shifts were not related to the type of incident reported. Conclusion: The overview of safety incidents can guide strategies for improving care in the institution under study and collaborate with other health services in identifying risk situations for hospitalized children.

RESUMEN: Objetivo: analizar el perfil y las características de los incidentes de seguridad ocurridos entre 2015 y 2019 con pacientes pediátricos notificados en el sistema informatizado de un hospital universitario. Método: estudio cuantitativo, descriptivo, transversal, de 2.558 notificaciones en una institución del sur de Brasil. Para el análisis de los datos se utilizó estadística descriptiva y la prueba de chi-cuadrado. Resultados: mayor incidencia de incidentes de seguridad relacionados con medicamentos/líquidos intravenosos (n=643; 25,1%), dieta/alimentación (n=448; 17,5%), proceso clínico/procedimiento (n=384; 15,0%), dispositivos/equipos médicos (n=304; 11,9%), accidentes de pacientes (n=273; 10,7%). Las unidades de hospitalización y de cuidados intensivos están más relacionadas con la aparición de incidentes; el turno de trabajo no estaba relacionado con el tipo de incidente notificado. Conclusión: el panorama de los incidentes de seguridad puede orientar estrategias para mejorar la atención en la institución estudiada y colaborar con otros servicios de salud en la identificación de situaciones de riesgo para los niños hospitalizados.

Neuropeptide Y Signaling Regulates Recurrent Excitation in the Auditory Midbrain.

Neuropeptides play key roles in shaping the organization and function of neuronal circuits. In the inferior colliculus (IC), which is in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a class of GABAergic neurons that project locally and outside the IC. Most neurons in the IC have local axon collaterals; however, the organization and function of local circuits in the IC remain unknown. We previously found that excitatory neurons in the IC can express the NPY Y1 receptor (Y1R+) and application of the Y1R agonist, [Leu31, Pro34]-NPY (LP-NPY), decreases the excitability of Y1R+ neurons. As NPY signaling regulates recurrent excitation in other brain regions, we hypothesized that Y1R+ neurons form interconnected local circuits in the IC and that NPY decreases the strength of recurrent excitation in these circuits. To test this hypothesis, we used optogenetics to activate Y1R+ neurons in mice of both sexes while recording from other neurons in the ipsilateral IC. We found that nearly 80% of glutamatergic IC neurons express the Y1 receptor, providing extensive opportunities for NPY signaling to regulate local circuits. Additionally, Y1R+ neuron synapses exhibited modest short-term synaptic plasticity, suggesting that local excitatory circuits maintain their influence over computations during sustained stimuli. We further found that application of LP-NPY decreased recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Our findings show that Y1R+ excitatory neurons form interconnected local circuits in the IC, and their influence over local circuits is regulated by NPY signaling.SIGNIFICANCE STATEMENT Local networks play fundamental roles in shaping neuronal computations in the brain. The IC, localized in the auditory midbrain, plays an essential role in sound processing, but the organization of local circuits in the IC is largely unknown. Here, we show that IC neurons that express the Neuropeptide Y1 receptor (Y1R+ neurons) make up most of the excitatory neurons in the IC and form interconnected local circuits. Additionally, we found that NPY, which is a powerful neuromodulator known to shape neuronal activity in other brain regions, decreases the extensive recurrent excitation mediated by Y1R+ neurons in local IC circuits. Thus, our results suggest that local NPY signaling is a key regulator of auditory computations in the IC.

Development of [18F]DASA-10 for enhanced imaging of pyruvate kinase M2.

PURPOSE: The aim of this study was to develop a positron emission tomography (PET) radiotracer for measuring pyruvate kinase M2 (PKM2) with improved physicochemical and pharmacokinetic properties compared to [18F]DASA-23. EXPERIMENTAL DESIGN: First, we synthesized [18F]DASA-10 and tested its uptake and retention compared to [18F]DASA-23 in human and mouse glioma cell lines. We then confirmed the specificity of [18F]DASA-10 by transiently modulating the expression of PKM2 in DU145 and HeLa cells. Next, we determined [18F]DASA-10 pharmacokinetics in healthy nude mice using PET imaging and subsequently assessed the ability of [18F]DASA-10 versus [18F]DASA-23 to enable in vivo detection of intracranial gliomas in syngeneic C6 rat models of glioma. RESULTS: [18F]DASA-10 demonstrated excellent cellular uptake and retention with values significantly higher than [18F]DASA-23 in all cell lines and timepoints investigated. [18F]DASA-10 showed a 73 % and 65 % reduced uptake respectively in DU145 and HeLa cells treated with PKM2 siRNA as compared to control siRNA treated cells. [18F]DASA-10 showed favorable biodistribution and pharmacokinetic properties and a significantly improved tumor-to-brain ratio in rat C6 glioma models relative to [18F]DASA-23 (3.2 ± 0.8 versus 1.6 ± 0.3, p = 0.01). CONCLUSION: [18F]DASA-10 is a new PET radiotracer for molecular imaging of PKM2 with potential to overcome the prior limitations observed with [18F]DASA-23. [18F]DASA-10 shows promise for clinical translation to enable imaging of brain malignancies owing to its low background signal in the healthy brain.

Advancing diagnosis and management of liver disease in adults through exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) is an effective tool for diagnosis in patients who remain undiagnosed despite a comprehensive clinical work-up. While WES is being used increasingly in pediatrics and oncology, it remains underutilized in non-oncological adult medicine, including in patients with liver disease, in part based on the faulty premise that adults are unlikely to harbor rare genetic variants with large effect size. Here, we aim to assess the burden of rare genetic variants underlying liver disease in adults at two major tertiary referral academic medical centers. METHODS: WES analysis paired with comprehensive clinical evaluation was performed in fifty-two adult patients with liver disease of unknown etiology evaluated at two US tertiary academic health care centers. FINDINGS: Exome analysis uncovered a definitive or presumed diagnosis in 33% of patients (17/52) providing insight into their disease pathogenesis, with most of these patients (12/17) not having a known family history of liver disease. Our data shows that over two-thirds of undiagnosed liver disease patients attaining a genetic diagnosis were being evaluated for cholestasis or hepatic steatosis of unknown etiology. INTERPRETATION: This study reveals an underappreciated incidence and spectrum of genetic diseases presenting in adulthood and underscores the clinical value of incorporating exome sequencing in the evaluation and management of adults with liver disease of unknown etiology. FUNDING: S.V. is supported by the NIH/NIDDK (K08 DK113109 and R01 DK131033-01A1) and the Doris Duke Charitable Foundation Grant #2019081. This work was supported in part by NIH-funded Yale Liver Center, P30 DK34989.

Neuropeptide Y signaling regulates recurrent excitation in the auditory midbrain.

Neuropeptides play key roles in shaping the organization and function of neuronal circuits. In the inferior colliculus (IC), which is located in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a large class of GABAergic neurons that project locally as well as outside the IC. The IC integrates information from numerous auditory nuclei making the IC an important hub for sound processing. Most neurons in the IC have local axon collaterals, however the organization and function of local circuits in the IC remains largely unknown. We previously found that neurons in the IC can express the NPY Y1 receptor (Y 1 R + ) and application of the Y 1 R agonist, [Leu 31 , Pro 34 ]-NPY (LP-NPY), decreases the excitability of Y 1 R + neurons. To investigate how Y 1 R + neurons and NPY signaling contribute to local IC networks, we used optogenetics to activate Y 1 R + neurons while recording from other neurons in the ipsilateral IC. Here, we show that 78.4% of glutamatergic neurons in the IC express the Y1 receptor, providing extensive opportunities for NPY signaling to regulate excitation in local IC circuits. Additionally, Y 1 R + neuron synapses exhibit modest short-term synaptic plasticity, suggesting that local excitatory circuits maintain their influence over computations during sustained stimuli. We further found that application of LP-NPY decreases recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Together, our data show that excitatory neurons are highly interconnected in the local IC and their influence over local circuits is tightly regulated by NPY signaling.

Chromatographic method development using multivariate approaches for organic solvents optimized analysis in [18F]fluorocholine.

A fast and simple method using Gas Chromatography combined with Flame Ionization Detection (GC-FID) was developed for the determination of ethanol, acetonitrile, dibromomethane, dimethylaminoethanol, and dimethyl sulfoxide in [18F]fluorocholine. The combination of fractional factorial design, Doehlert design, and Desirability function was used to evaluate the operational parameters and to establish the best working condition. The validation results revealed that the proposed method has good recovery (85.1-104.1%) and repeatability (RSD ≤8.1%). Correlation coefficients (R ≥ 0.983) indicated good linearity over a wide range. The limit of detection (≤2.5 ppm) and the limit of quantification (≤7.5 ppm) were satisfactory. The proposed method is based on minimum manual operation, sample preparation free, direct injection technique, and short chromatographic separation time. This method is useful for routine analysis of organic solvents in [18F]fluorocholine, feasible for the modernization of specific monograph, and was therefore successfully implemented to assess samples manufactured by Nuclear Technology Development Center (CDTN).

Outcomes of immunomodulator and advanced therapies for primary sclerosing cholangitis-associated inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) coexists in up to 80% of patients with primary sclerosing cholangitis (PSC). The aim of this study is to investigate the outcomes of immunomodulator (IMM)/advanced therapies for the treatment of PSC-IBD. METHODS: This was a single-center, retrospective study of patients with PSC from 1 January 2012 to 1 April 2021. Adult patients (age ≥ 18 years) with PSC-IBD were included. Primary outcomes were rates and predictors of IMM/advanced therapies to treat PSC-IBD. Secondary outcomes included rates of cholangitis, PSC-IBD clinical remission, and endoscopic healing. RESULTS: A total of 106 patients with PSC were reviewed and 72 (68%) with confirmed PSC-IBD were included in the study. The median age was 48 years (IQR, 33-59.5) and 69.4% were male. Overall, 28 patients (38.9%) required IMM/advanced therapies to treat PSC-IBD (22 biologic/small molecule therapy and six thiopurine monotherapy). Patients in the IMM/advanced therapies group were more likely to have small bowel involvement (32.1% vs. 4.6%; P = 0.002). In the IMM/advanced therapies group, clinical remission was achieved in 78.6% but endoscopic healing in only 50%. The rate of acute ascending cholangitis was 42.9% in the IMM/advanced therapies group compared with 31.8% in the non-IMM/advanced therapies group (P = 0.34). CONCLUSION: In our cohort, up to a third of patients with PSC-IBD required IMM/advanced therapies with only 50% of these patients achieving endoscopic healing. The use of IMM/advanced therapies was not associated with a higher risk of cholangitis, but larger studies are needed to investigate the risk with different classes of advanced therapies.

Selective visuoconstructional impairment following mild COVID-19 with inflammatory and neuroimaging correlation findings.

People recovered from COVID-19 may still present complications including respiratory and neurological sequelae. In other viral infections, cognitive impairment occurs due to brain damage or dysfunction caused by vascular lesions and inflammatory processes. Persistent cognitive impairment compromises daily activities and psychosocial adaptation. Some level of neurological and psychiatric consequences were expected and described in severe cases of COVID-19. However, it is debatable whether neuropsychiatric complications are related to COVID-19 or to unfoldings from a severe infection. Nevertheless, the majority of cases recorded worldwide were mild to moderate self-limited illness in non-hospitalized people. Thus, it is important to understand what are the implications of mild COVID-19, which is the largest and understudied pool of COVID-19 cases. We aimed to investigate adults at least four months after recovering from mild COVID-19, which were assessed by neuropsychological, ocular and neurological tests, immune markers assay, and by structural MRI and 18FDG-PET neuroimaging to shed light on putative brain changes and clinical correlations. In approximately one-quarter of mild-COVID-19 individuals, we detected a specific visuoconstructive deficit, which was associated with changes in molecular and structural brain imaging, and correlated with upregulation of peripheral immune markers. Our findings provide evidence of neuroinflammatory burden causing cognitive deficit, in an already large and growing fraction of the world population. While living with a multitude of mild COVID-19 cases, action is required for a more comprehensive assessment and follow-up of the cognitive impairment, allowing to better understand symptom persistence and the necessity of rehabilitation of the affected individuals.

Abdominal adiposity as a prognosis biomarker of clinical outcome in metastatic colorectal cancer.

OBJECTIVES: Adipose tissue distribution and radiodensity are associated with prognosis in many types of cancer. However, the roles of adipose tissue distribution and radiodensity in patients with metastatic colorectal cancer (mCRC) remain unclear. The aim of this study was to assess the prognostic effect of adiposity and adipose tissue radiodensities in patients with mCRC. METHODS: Patients with mCRC who received first-line palliative chemotherapy and had a computed tomography (CT) scan at the third lumbar vertebra (L3) level, admitted between January 2010 and December 2018, were sequentially enrolled. Body composition was assessed using CT-derived measurements. Univariate and multivariate logistic regression analyses and Kaplan-Meier curves were used to determine prognostic values. RESULTS: The study included 237 patients. Cox analyses demonstrated that high subcutaneous adipose tissue (SAT) index was associated with a lower risk for death (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.88; Ptrend < 0.025). There was no significant association between visceral adipose tissue (VAT) index tertiles and overall survival. However, high VAT and SAT radiodensities were significantly associated with increased mortality (HR, 1.80; 95% CI, 1.12-2.89; Ptrend < 0.030 and HR, 1.85; 95% CI, 1.19-2.86; Ptrend < 0.021, respectively). CONCLUSIONS: A higher SAT index in patients with mCRC was associated with a favorable overall survival outcome, whereas higher SAT and VAT radiodensities were associated with an increased risk for death, supporting that early nutritional intervention may improve mCRC prognosis.

Construction of a nomogram for predicting COVID-19 in-hospital mortality: A machine learning analysis.

Background and objectives: We aim to verify the use of ML algorithms to predict patient outcome using a relatively small dataset and to create a nomogram to assess in-hospital mortality of patients with COVID-19. Methods: A database of 200 COVID-19 patients admitted to the Clinical Hospital of State University of Campinas (UNICAMP) was used in this analysis. Patient features were divided into three categories: clinical, chest abnormalities, and body composition characteristics acquired by computerized tomography. These features were evaluated independently and combined to predict patient outcomes. To minimize performance fluctuations due to low sample number, reduce possible bias related to outliers, and evaluate the uncertainties generated by the small dataset, we developed a shuffling technique, a modified version of the Monte Carlo Cross Validation, creating several subgroups for training the algorithm and complementary testing subgroups. The following ML algorithms were tested: random forest, boosted decision trees, logistic regression, support vector machines, and neural networks. Performance was evaluated by analyzing Receiver operating characteristic (ROC) curves. The importance of each feature in the determination of the outcome predictability was also studied and a nomogram was created based on the most important features selected by the exclusion test. Results: Among the different sets of features, clinical variables age, lymphocyte number and weight were the most valuable features for prognosis prediction. However, we observed that skeletal muscle radiodensity and presence of pleural effusion were also important for outcome determination. Integrating these independent predictors was successfully developed to accurately predict mortality in COVID-19 in hospital patients. A nomogram based on these five features was created to predict COVID-19 mortality in hospitalized patients. The area under the ROC curve was 0.86 ± 0.04. Conclusion: ML algorithms can be reliable for the prediction of COVID-19-related in-hospital mortality, even when using a relatively small dataset. The success of ML techniques in smaller datasets broadens the applicability of these methods in several problems in the medical area. In addition, feature importance analysis allowed us to determine the most important variables for the prediction tasks resulting in a nomogram with good accuracy and clinical utility in predicting COVID-19 in-hospital mortality.

Neurotransmitter phenotype and axonal projection patterns of VIP-expressing neurons in the inferior colliculus.

Neurons in the inferior colliculus (IC), the midbrain hub of the central auditory pathway, send ascending and descending projections to other auditory brain regions, as well as projections to other sensory and non-sensory brain regions. However, the axonal projection patterns of individual classes of IC neurons remain largely unknown. Vasoactive intestinal polypeptide (VIP) is a neuropeptide expressed by subsets of neurons in many brain regions. We recently identified a class of IC stellate neurons that we called VIP neurons because they are labeled by tdTomato (tdT) expression in VIP-IRES-Cre x Ai14 mice. Here, using fluorescence in situ hybridization, we found that tdT+ neurons in VIP-IRES-Cre x Ai14 mice express Vglut2, a marker of glutamatergic neurons, and VIP, suggesting that VIP neurons use both glutamatergic and VIPergic signaling to influence their postsynaptic targets. Next, using viral transfections with a Cre-dependent eGFP construct, we labeled the axonal projections of VIP neurons. As a group, VIP neurons project intrinsically, within the ipsilateral and contralateral IC, and extrinsically to all the major targets of the IC. Within the auditory system, VIP neurons sent axons and formed axonal boutons in higher centers, including the medial geniculate nucleus and the nucleus of the brachium of the IC. Less dense projections terminated in lower centers, including the nuclei of the lateral lemniscus, superior olivary complex, and dorsal cochlear nucleus. VIP neurons also project to several non-auditory brain regions, including the superior colliculus, periaqueductal gray, and cuneiform nucleus. The diversity of VIP projections compared to the homogeneity of VIP neuron intrinsic properties suggests that VIP neurons play a conserved role at the microcircuit level, likely involving neuromodulation through glutamatergic and VIPergic signaling, but support diverse functions at the systems level through their participation in different projection pathways.

Low skeletal muscle radiodensity and neutrophil-to-lymphocyte ratio as predictors of poor outcome in patients with COVID-19.

Inflammatory states and body composition changes are associated with a poor prognosis in many diseases, but their role in coronavirus disease 2019 (COVID-19) is not fully understood. To assess the impact of low skeletal muscle radiodensity (SMD), high neutrophil-to-lymphocyte ratio (NLR) and a composite score based on both variables, on complications, use of ventilatory support, and survival in patients with COVID-19. Medical records of patients hospitalized between May 1, 2020, and July 31, 2020, with a laboratory diagnosis of COVID-19 who underwent computed tomography (CT) were retrospectively reviewed. CT-derived body composition measurements assessed at the first lumbar vertebra level, and laboratory tests performed at diagnosis, were used to calculate SMD and NLR. Prognostic values were estimated via univariate and multivariate logistic regression analyses and the Kaplan-Meier curve. The study was approved by the local Institutional Review Board (CAAE 36276620.2.0000.5404). A total of 200 patients were included. Among the patients assessed, median age was 59 years, 58% were men and 45% required ICU care. A total of 45 (22.5%) patients died. Multivariate logistic analysis demonstrated that a low SMD (OR 2.94; 95% CI 1.13-7.66, P = 0.027), high NLR (OR 3.96; 95% CI 1.24-12.69, P = 0.021) and both low SMD and high NLR (OR 25.58; 95% CI 2.37-276.71, P = 0.008) combined, were associated with an increased risk of death. Patients who had both low SMD and high NLR required more mechanical ventilation (P < 0.001) and were hospitalized for a longer period (P < 0.001). Low SMD, high NLR and the composite score can predict poor prognosis in patients with COVID-19, and can be used as a tool for early identification of patients at risk. Systemic inflammation and low muscle radiodensity are useful predictors of poor prognosis, and the assessment of these factors in clinical practice should be considered.

Inhibitory NPY Neurons Provide a Large and Heterotopic Commissural Projection in the Inferior Colliculus.

Located in the midbrain, the inferior colliculus (IC) plays an essential role in many auditory computations, including speech processing and sound localization. The right and left sides of the IC are interconnected by a dense fiber tract, the commissure of the IC (CoIC), that provides each IC with one of its largest sources of input (i.e., the contralateral IC). Despite its prominence, the CoIC remains poorly understood. Previous studies using anterograde and retrograde tract-tracing showed that IC commissural projections are predominately homotopic and tonotopic, targeting mirror-image locations in the same frequency region in the contralateral IC. However, it is unknown whether specific classes of neurons, particularly inhibitory neurons which constitute ~10%-40% of the commissural projection, follow this pattern. We, therefore, examined the commissural projections of Neuropeptide Y (NPY) neurons, the first molecularly identifiable class of GABAergic neurons in the IC. Using retrograde tracing with Retrobeads (RB) in NPY-hrGFP mice of both sexes, we found that NPY neurons comprise ~11% of the commissural projection. Moreover, focal injections of Retrobeads showed that NPY neurons in the central nucleus of the IC exhibit a more divergent and heterotopic commissural projection pattern than non-NPY neurons. Thus, commissural NPY neurons are positioned to provide lateral inhibition to the contralateral IC. Through this circuit, sounds that drive activity in limited regions on one side of the IC likely suppress activity across a broader region in the contralateral IC.

Association of Albumin-Corrected Serum Calcium Levels with Colorectal Cancer Survival Outcomes.

In epidemiological studies, higher calcium intake has been associated with decreased colorectal cancer (CRC) incidence. However, whether circulating calcium concentrations are associated with CRC prognosis is largely unknown. In this retrospective cohort analysis, we identified 498 patients diagnosed with stage I-IV CRC between the years of 2000 and 2018 in whom calcium and albumin level measurements within 3 months of diagnosis had been taken. We used the Kaplan-Meier method for survival analysis. We used multivariate Cox proportional hazards regression to identify associations between corrected calcium levels and CRC survival outcomes. Corrected calcium levels in the highest tertile were associated with significantly lower progression-free survival rates (hazard ratio (HR) 1.85; 95% confidence interval (CI) 1.28-2.69; p = 0.001) and overall survival (HR 1.86; 95% CI 1.26-2.74, p = 0.002) in patients with stage IV or recurrent CRC, and significantly lower disease-free survival rates (HR 1.44; 95% confidence interval (CI) 1.02-2.03; p = 0.040) and overall survival rates (HR 1.72; 95% CI 1.18-2.50; p = 0.004) in patients with stage I-III disease. In conclusion, higher corrected calcium levels after the diagnosis of CRC were significantly associated with decreased survival rates. Prospective trials are necessary to confirm this association.