COMT and SCN9A gene variants do not contribute to chronic low back pain in Mexican-Mestizo patients.

BACKGROUND: Chronic low back pain (CLBP) is a complex condition in which genetic factors play a role in its susceptibility. Catechol-O-methyltransferase (COMT) and sodium channel NaV1.7 (SCN9A) genes are implicated in pain perception. The aim is to analyze the association of COMT and SCN9A with CLBP and their interaction, in a Mexican-Mestizo population. METHODS: A case-control study was conducted. Cases corresponded to adults of both sexes with CLBP. Controls were adults with no CLBP. Variants of SCN9A and COMT were genotyped. Allelic and genotypic frequencies and Hardy-Weinberg equilibrium (HWE) were calculated. Association was tested under codominant, dominant, and recessive models. Multifactor dimensionality reduction was developed to detect epistasis. RESULTS: Gene variants were in HWE, and there was no association under different inheritance models in the whole sample. In women, in codominant and dominant models, a trend to a high risk was observed for AA of rs4680 of COMT (OR = 1.7 [0.5-5.3] and 1.6 [0.7-3.4]) and for TT of rs4633 (OR = 1.6 [0.7-3.7] and 1.6 [0.7-3.4]). In men, a trend to low risk was observed for AG genotype of rs4680 in the same models (OR = 0.6 [0.2-1.7] and 0.7 [0.3-1.7]), and for TC genotype of rs4633 in the codominant model (OR = 0.6 [0.2-1.7]). In the interaction analysis, a model of the SCN9A and COMT variants showed a CVC of 10/10; however, the TA was 0.4141. CONCLUSION: COMT and SCN9A variants are not associated with CLBP in the analyzed Mexican-Mestizo population.

Generalized tuberculosis due to Mycobacterium caprae in a red fox phylogenetically related to livestock breakdowns.

BACKGROUND: Tuberculosis (TB) due to Mycobacterium caprae is endemic in goat herds and free-ranging wild boars in Spain, causing infections in other livestock or wild animals to a lesser extent. TB infection in foxes is infrequently reported and they are usually considered spillover hosts of TB. CASE PRESENTATION: A blind, depressed and severely emaciated red fox (Vulpes vulpes) was admitted to a rehabilitation center. After clinical examination it was humanely sacrificed. At necropsy, generalized TB lesions were observed that were subsequently confirmed by histopathology along with a co-infection with canine distemper virus. M. caprae was isolated from mycobacterial culture and spoligotype SB0415 was identified. Whole genome sequencing (WGS) of the isolated M. caprae was carried out and single nucleotide polymorphisms (SNP) were compared with other sequences of M. caprae isolated from livestock and wildlife of the same area throughout the last decade. CONCLUSIONS: This is the first reported case of TB due to M. caprae in a fox in the Iberian Peninsula. WGS and SNP analysis, together with spatial-temporal investigations, associated this case with recent M. caprae outbreaks in cattle and goat herds of the area. The results indicated transmission of M. caprae between livestock and the fox, suggesting that this species may occasionally play a role in the epidemiology of animal TB.

An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients.

To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Within this cohort, the highest diagnostic yield was obtained for patients from Asia (57.5%, mainly from Pakistan). Overall, 701 pathogenic/likely pathogenic unique SNVs and 40 CNVs were identified. In 620 patients, the result of the biochemical tests guided variant classification and reporting. Top five diagnosed diseases were: Gaucher disease, Niemann-Pick disease type A/B, phenylketonuria, mucopolysaccharidosis type I, and Wilson disease. We show that integrated genetic and biochemical testing facilitated the decision on clinical relevance of the variants and led to a high diagnostic yield (37%), which is comparable to exome/genome sequencing. More importantly, up to 43% of these patients (n = 610) could benefit from medical treatments (e.g., enzyme replacement therapy). This multiomic approach constitutes a unique and highly effective tool for the genetic diagnosis of IMDs.

Quistes sinusales en la cirugía de elevación de seno maxilar. Revisión de la literatura / Sinus cysts in maxillary sinus lift surgery. Review of the literature

Introducción: Tras la pérdida de dientes, acontece la reabsorción del hueso alveolar y la neumatización del seno maxilar, lo cual en ocasiones puede dificultar la colocación de implantes. Una de las técnicas para afrontar este problema es la cirugía de elevación del seno, si bien previamente se debe realizar una evaluación exhaustiva ya que el seno podría presentar patologías que puedan provocar complicaciones. Una de las patologías más comunes son los quistes sinusales Objetivo: Valorar la posibilidad de realizar la cirugía de elevación del seno maxilar en presencia de quistes sinusales. Metodología: Se realizó una búsqueda a través de bases de datos científicas, tras someter la bibliografía a criterios de inclusión y exclusión, se referencian 26 artículos. Resultados y discusión: Anteriormente se creía que la presencia de estas lesiones era una contraindicación. Sin embargo, actualmente los autores afirman que se puede realizar elevaciones de seno maxilar aun cuando estos presenten un quiste sinusal. En la actualidad existen tres enfoques principales para tratar los quistes del seno maxilar en pacientes que se someten a una elevación de seno, extirpación antes de la cirugía, durante la cirugía, o sin extirparlos. El factor más importante es elegir el plan quirúrgico correcto. Conclusión: Actualmente la presencia de quistes sinusales es considerada un factor de riesgo para la cirugía de elevación de seno, pero no es una contraindicación. Los tres enfoques de actuación han demostrado dar resultados positivos (AU)

West Nile Virus Lineage 2 Spreads Westwards in Europe and Overwinters in North-Eastern Spain (2017-2020).

West Nile virus lineage 2 (WNV-L2) emerged in Europe in 2004; since then, it has spread across the continent, causing outbreaks in humans and animals. During 2017 and 2020, WNV-L2 was detected and isolated from four northern goshawks in two provinces of Catalonia (north-eastern Spain). In order to characterise the first Spanish WNV-L2 isolates and elucidate the potential overwintering of the virus in this Mediterranean region, complete genome sequencing, phylogenetic analyses, and a study of phenotypic characterisation were performed. Our results showed that these Spanish isolates belonged to the central-southern WNV-L2 clade. In more detail, they were related to the Lombardy cluster that emerged in Italy in 2013 and has been able to spread westwards, causing outbreaks in France (2018) and Spain (2017 and 2020). Phenotypic characterisation performed in vitro showed that these isolates presented characteristics corresponding to strains of moderate to high virulence. All these findings evidence that these WNV-L2 strains have been able to circulate and overwinter in the region, and are pathogenic, at least in northern goshawks, which seem to be very susceptible to WNV infection and may be good indicators of WNV-L2 circulation. Due to the increasing number of human and animal cases in Europe in the last years, this zoonotic flavivirus should be kept under extensive surveillance, following a One-Health approach.

Estimation of lactation curves of Gyr cattle and some associated production parameters in the Colombian low tropic

Background: The Gyr breed is widely used in Colombian low tropic dairy production systems. During the last 10 years, the Asociación Colombiana de Criadores de Ganado Cebú† ASOCEBU, has been leading a dairy milk control program which led to the creation of a dataset that permits to carry out the first analysis of milk yield in Gyr cattle in the country using records from several herds. Objectives: To study milk production dynamics of Gyr cattle in the Colombian low tropic through the estimation of lactation curves and four derived production parameters: total milk yield between 5 and 305 days (TMY305), peak milk yield (PMY), days at peak (DP) and persistency (P). Methods: 13,798 daily milk yield records from 1,510 cows performing in 103 herds were used; the total number of lactations was 2,480. Four models were considered: Wood, Wiltmink, Papajcsik & Bordero, and a second-degree polynomial. Mean square error, mean absolute error, mean square error of prediction, Akaike and Bayesian information criteria were used to select the model better describing each lactation using the majority rule, that is, the model selected by most criteria was the chosen one. The shape of each fitted lactation curve was checked using basic results from calculus which permitted the classification of the estimated curves into two groups: typical and atypical; only typical functions were used to compute the four aforementioned production parameters. Results: The second-order polynomial was the model most frequently selected, while the Papajcsik & Bordero model had the lowest frequency. Average TMY305, PMY, DP and P were 3,489.86 kg, 17.28 kg, 57.17 days, and 0.83, respectively, with coefficients of variation: 0.27, 0.21, 0.41, and 0.16. Conclusions: This study permitted to identify individuals with outstanding phenotypic performance. To the best of our knowledge, this is the first study of this kind involving thousands of lactations from Gyr cows performing in several regions of Colombian low tropic.

Antecedentes: La raza Gyr es ampliamente utilizada en las lecherías de trópico bajo en Colombia. Durante los últimos 10 años, la Asociación Colombiana de Criadores de Ganado Cebú ASOCEBU, ha liderado un programa de control lechero que generó una base de datos que permite llevar a cabo el primer análisis de producción de leche de la raza Gyr en el país, considerando individuos de varias fincas. Objetivos: Caracterizar la dinámica de producción de leche de ganado Gyr en el trópico bajo colombiano mediante la estimación de curvas de lactancia y cuatro parámetros de producción derivados: producción total entre 5 y 305 días (TMY305), pico de lactancia (PMY), días al pico (DP) y persistencia (P) Métodos: Se utilizaron 13.798 registros de producción diaria de leche de 1.510 vacas provenientes de 103 fincas, el total de lactancias fue 2.480. Se consideraron cuatro modelos: Wood, Wiltmink, Papajcsik & Bordero, y un polinomio de segundo grado. Los criterios usados para elegir el modelo que mejor describió cada lactancia fueron: error cuadrático medio, error absoluto medio, error cuadrático medio de predicción, criterio de información de Akaike y criterio de información Bayesiano. Se utilizó el criterio de mayoría, esto es, el modelo seleccionado fue aquel elegido por más criterios. La forma de cada una de las curvas de lactancia estimadas fue chequeada utilizando resultados básicos del cálculo, esto permitió clasificar las curvas estimadas en dos grupos: típicas y atípicas; solamente las curvas típicas fueron empleadas para calcular los cuatro parámetros antes mencionados. Resultados: El polinomio de segundo grado fue el modelo que se seleccionó con mayor frecuencia, mientras que el modelo Papajcsik & Bordero tuvo la menor frecuencia. Los promedios para TMY305, PMY, DP y P fueron 3.489,86 kg, 17,28 kg, 57,17 días, y 0,83, respectivamente, con coeficientes de variación 0,27, 0,21, 0,41 y 0,16 Conclusiones: Este estudio permitió identificar individuos con desempeño fenotípico sobresaliente. De acuerdo al estado del arte, este es el primer estudio de este tipo que considera miles de lactancias de vacas Gyr provenientes de varias regiones del trópico bajo colombiano.

Antecedentes: Gir é uma raça Bos indicus amplamente utilizada em sistemas de produção leiteira no trópico baixo Colombiano. A Asociación Colombiana de Criadores de Ganado CebúASOCEBU, lidera um programa de controle de leite nos últimos 10 anos, o que permitiu à coleta de um conjunto de dados para realizar a primeira análise de produção de leite em bovinos Gir no país com informações de vários rebanhos. Objetivo: Estudar a dinâmica da produção de leite por meio da estimativa das curvas de lactação e quatro parâmetros de produção derivados: produção total de leite entre 5 e 305 dias (TMY305), produção de leite no pico de lactação (PMY), dias em produção de leite no pico de lactação (DP) e persistência (P). Métodos: Foram utilizados 13.798 registros de produção diária de leite de 1.510 vacas de 103 fazendas , totalizando 2.480 lactações. Foram considerados quatro modelos: Wood, Wiltmink, Papajcsik & Bordero e um polinômio de segundo grau. Para selecionar o modelo que melhor descreve cada lactação foram utilizados os seguintes critérios: erro quadrado médio, erro absoluto médio, e erro quadrado médio de predição. O modelo selecionado pela maioria dos parâmetros, de acordo com os critérios de informação de Akaike e Bayesiano, foi o escolhido. A forma de cada curva de lactação ajustada foi verificada utilizando os resultados básicos do cálculo, isso permitiu classificar as curvas estimadas em dois grupos: típico e atípico, e apenas funções típicas foram utilizadas para calcular os quatro parâmetros de produção acima mencionados Resultados: O polinômio de segunda ordem foi o modelo mais frequentemente selecionado, enquanto o modelo Papajcsik & Bordero apresentou a menor frequência. A média de TMY305, PMY, DP e P foram 3.489,86 kg, 17,28 kg, 57,17 d e 0,83, respectivamente, com coeficientes de variação de 0,27, 0,21, 0,41 e 0,16. Conclusões: Este estudo permitiu identificar indivíduos com excelente desempenho fenotípico. De acordo com a literatura atual, este é o primeiro estudo envolvendo milhares de lactações de vacas Gir em várias regiões do trópico baixo colombiano.

Onset of puberty and regularity of oestral cycles in ewe lambs of four breeds under high-altitude conditions in a non-seasonal country.

Twenty-four Colombian Creole, Romney Marsh, Hampshire and Corriedale ewes raised under high-altitude conditions in a non-seasonal country were used to determine and to characterize the onset of puberty and of regularity ovarian function since the age of 3months. They underwent blood collection for determination of progesterone and monthly weight assessment. Oestrus was assessed daily by a teaser ram. In all breeds, age at onset of puberty ranged from 5.4 to 6.9 months and age at onset of regular ovarian function ranged from 7.4 to 8.6 months. Colombian Creole showed a higher body development at onset of puberty: 73.5 ± 8.3% versus 56.2 ± 7.4 in Romney Marsh, 58.8 ± 10.4 in Hampshire, and 57.3 ± 8.0 in Corriedale (p < 0.05), as well as a higher relative daily weight gain (+17%, p < 0.05). A negative correlation between daily weight gain and age at onset of puberty was established. Progesterone at onset of puberty and of regularity did not differ between breeds, but characterization of the luteal phase by the progesterone area under the curve (P4-AUC) revealed at both time points significantly lower values for Creole lambs (p < 0.05). Decreased P4-AUC paralleled a higher proportion of short oestral cycles observed prior to onset of regularity in Creoles, whereas an increased proportion of extra-long cycles were recorded in Romney Marsh (p < 0.05). These results establish first reference data for economically important breeds raised under tropical conditions. In comparison with other breeds, Colombian Creole requires a higher body development to achieve puberty and that an important proportion of short characterizes its prepubertal period cycles.

Systems of Care in Cardiogenic Shock.

Cardiogenic shock presents a significant challenge to the medical community, and there is much debate as to the best classification system and treatment mechanisms. As interventions and technologies improve, systems of care for patients with cardiogenic shock must evolve as well. This review describes the current treatment models for cardiogenic shock, including the "hub-and-spoke" model, and defines specific characteristics of the ideal system of care for this patient population.

A Case of Isolated Left Ventricular Non-Compaction Cardiomyopathy in a HIV Patient Presenting With Acute Heart Failure.

The etiology of cardiomyopathy in a HIV patient is multifactorial. Identifying the etiology of cardiomyopathy in a HIV patient needs extensive evaluation. Common causes include ischemic cardiomyopathy, myocarditis due to viral infections and opportunistic infections, cocaine abuse, alcoholic heart disease, drug toxicity or due to nutritional deficiencies. However, in a number of cases the etiology is unknown. We report a case of 36-year-old African American man with history of HIV who presented with acute heart failure due to left ventricular non-compaction (LVNC). Transthoracic and transesophageal echocardiogram showed significant left ventricular trabeculations and blood flow in deep recesses. Endomyocardial biopsy was suggestive of LVNC. He underwent left ventricular assist device implantation for destination therapy and subsequently cardiac transplantation. The diagnosis of LVNC is often made by echocardiogram. As LVNC could be a normal variant, a comprehensive diagnostic assessment including multimodality imaging, a systematic screening of first degree relatives, and a comprehensive clinical and genetic assessment by a multidisciplinary team may be needed to arrive at the diagnosis. Early diagnosis and timely intervention may reduce the risk of premature death in these young patients.

Molecular detection and clinical characteristics of Bartonella bacilliformis, Leptospira spp., and Rickettsia spp. in the Southeastern Peruvian Amazon basin.

BACKGROUND: Acute febrile illness (AFI) represent a significant health challenge in the Peruvian Amazon basin population due to their diverse etiologies and the unavailability of specific on-site diagnostic methods, resulting in underreporting of cases. In Peru, one of the most endemic regions to dengue and leptospirosis is Madre de Dios, a region also endemic to emergent bacterial etiologic agents of AFI, such as bartonellosis and rickettsiosis, whose prevalence is usually underreported. We aimed to molecularly identify the presence of Leptospira spp., Bartonella bacilliformis, and Rickettsia spp. by Polymerase Chain Reaction in serum samples from patients with AFI from Puerto Maldonado-Madre de Dios in Peru. METHODS: Serum samples from patients with acute febrile illness were analyzed by real-time PCR for detecting the presence of Bartonella bacilliformis, Leptospira spp. and Rickettsia spp. RESULTS: Bartonella bacilliformis was the most prevalent bacteria identified in 21.6% (30/139) of the samples, followed by Leptospira spp. in 11.5% (16/139) and Rickettsia spp. in 6.5% (9/139) of the samples. No co-infections were observed between these bacteria. The most frequent symptoms associated with fever among all groups, were headaches, myalgias, and arthralgias. We found no statistically significant differences in the clinical presentation between patients infected with each bacterium. CONCLUSIONS: In a previous study, we shown the presence of dengue, chikungunya, Zika and oropouche virus. We were able to identify these pathogens in 29.5% of all the samples, with chikungunya and OROV as the most frequently found in 9.4 and 8.6% of all the samples, respectively. In this study we show that B. bacilliformis (21.6%), Leptospira spp. (11.5%) and Rickettsia spp. (6.5%) accounted for the main etiologies of AFI in samples from Puerto Maldonado-Madre de Dios, Perú. Our analysis of their clinical presentation, further shows the importance of implementing more sensitive and specific on-site diagnostic tools in the national surveillance programs.This study confirms that the un-specificity of signs and symptoms is not only associated with arboviral infections, but also with the clinical presentation of endemic bacterial infections.

Linkage disequilibrium levels and allele frequency distribution in Blanco Orejinegro and Romosinuano Creole cattle using medium density SNP chip data.

The linkage disequilibrium (LD) between molecular markers affects the accuracy of genome-wide association studies and genomic selection application. High-density genotyping platforms allow identifying the genotype of thousands of single nucleotide polymorphisms (SNPs) distributed throughout the animal genomes, which increases the resolution of LD evaluations. This study evaluated the distribution of minor allele frequencies (MAF) and the level of LD in the Colombian Creole cattle breeds Blanco Orejinegro (BON) and Romosinuano (ROMO) using a medium density SNP panel (BovineSNP50K_v2). The LD decay in these breeds was lower than those reported for other taurine breeds, achieving optimal LD values (r2 ≥ 0.3) up to a distance of 70 kb in BON and 100 kb in ROMO, which is possibly associated with the conservation status of these cattle populations and their effective population size. The average MAF for both breeds was 0.27 ± 0.14 with a higher SNP proportion having high MAF values (≥ 0.3). The LD levels and distribution of allele frequencies found in this study suggest that it is possible to have adequate coverage throughout the genome of these breeds using the BovineSNP50K_v2, capturing the effect of most QTL related with productive traits, and ensuring an adequate prediction capacity in genomic analysis.

Emerging and reemerging arboviruses: A new threat in Eastern Peru.

BACKGROUND: Arboviral diseases are one of the most common causes of acute febrile illness (AFI) and a significant health problem in South America. In Peru, laboratory etiologic identification of these infections occurs in less than 50% of cases, leading to underdiagnoses of important emerging arboviruses. AIM: To assess the prevalence of the Dengue (DENV), Oropouche (OROV), Chikungunya (CHIKV), Mayaro (MAYV) and Zika (ZIKV) viruses in patients with acute febrile illness from Puerto Maldonado (Peru). METHODOLOGY: Serum samples were obtained from patients with AFI during January 2016 to March 2016. A total of 139 specimens were analyzed for the presence of DENV, OROV, CHIKV, MAYV, and ZIKV using polymerase chain reaction (PCR). RESULTS: CHIKV in 9.4% and OROV in 8.6% were the most prevalent arboviruses, followed by DENV and ZIKV, with a prevalence of 6.5% and 5%, respectively. Among all patients, the most common symptoms accompanying fever were headaches 79.9%, muscle pain 65.5% and joint pain 63.3%. CONCLUSIONS: During this short 3-month period, 4 arboviruses were detected by PCR, CHIKV and OROV being the most common arboviruses in Puerto Maldonado (Peru). Thus, it is crucial to include OROV detection in the national health surveillance. Furthermore, the etiologic clinical diagnosis of arboviral infections is not possible due to the low specificity of symptoms; therefore an increase of cases confirmed by molecular diagnostic methods will enhance arboviral surveillance in Peru.

Ocular Lesions in Congenital Toxoplasmosis in Santa Isabel do Ivaí, Paraná, Brazil.

We verified clinical and psychopedagogic aspects of congenital cases with ocular sequelae, 13 years after toxoplasmosis outbreak in Santa Isabel do Ivaí, and current seroprevalence of this zoonosis in pregnant women. Audiologic and ophthalmologic evaluations were performed in congenital cases, in addition to collection of clinical and psychopedagogic data. In pregnant women, current seroprevalence was observed. Among affected teenagers, 2 of 5 are behind in school grade, and 4 of 5 reported learning difficulties, requiring psychopedagogic monitoring, as well as ocular complaints. We observed predominance of small, scarred, dispersed, type II chorioretinal lesions (hypopigmented halo and hyperpigmented central area), and 1 case of ocular relapse. All patients presented normal audiologic assessment. Among 131 pregnant women, 62 (47.3%) were seronegative and 39 (29.8%) were IgG reactive. Only 1 reported acquiring infection during the outbreak. This is one of the few studies in Brazil showing the outcome of congenital toxoplasmosis, a decade after infection, in one of the world's largest outbreaks.

Diagnostic Strategies for Early Recognition of Cancer Therapeutics-Related Cardiac Dysfunction.

Cardiovascular toxicity in the form of cardiac dysfunction continues to be an obstacle for patients with cancer. Survival and quality of life of cancer survivors are frequently affected by increased incidence of cardiovascular disease. The involvement of the cardiovascular system by primary or secondary malignancies, as well as its dysfunction secondary to the administration of antineoplastics, has led to the development of a new discipline called Cardio-Oncology, an exciting cardiology subspecialty with more questions than answers and as a result an enormous opportunity for research in the field. Multidisciplinary efforts have been focused on the prevention, diagnosis, and treatment of cancer therapeutics-related cardiovascular dysfunction (CTRCD). This review article will focus on the early diagnosis of left ventricular dysfunction associated with chemotherapy. Currently, the identification of cardiac toxicity associated with cancer treatment is the cornerstone for critical decisions regarding anticancer therapy and cardioprotective strategies. Its early detection, especially in subclinical phases, allows immediate intervention to prevent further impairment of the myocardium and other cardiovascular structures. The most significant published studies were selected for this revision, providing an updated document for the health professionals involved in the care of patients with cancer. We examined the current evidence and recommendations for biochemical and noninvasive diagnostic techniques, including their specific role for identification of CTRCD. Traditional and advanced imaging modalities, used alone or in combination with cardiovascular biomarkers, are essential for the recognition of cardiotoxicity during cancer therapy. Evolving basic and clinical research are focused on the development of more sensitive and specific diagnostic tools and for the recognition of cardiac toxicity.

Association of single nucleotide polymorphisms in CAPN1, CAST and MB genes with meat color of Brahman and crossbreed cattle.

The objective of this research was to determine the association of SNPs in the candidate genes Calpain (CAPN1), Calpastatin (CAST) and Myoglobin (MB) with colorimetric parameters (L *, a *, b *, C *, hue) in a F1 population (n = 164) obtained from crossing Bos taurus × Bos indicus and Bos indicus × Bos indicus. SNPs were analyzed using PCR-RFLP and SSCP. Colorimetric measurements were performed in the muscles Longissimus thoracis et lumborum (LTL) and Semitendinosus (ST) at 7, 14 and 21 days postmortem applying the methodology CIE L* a* b*. The CAST gene showed a significant effect on the b* and hue* parameters in both muscles. MB gene showed significant association with all colorimetric parameters in both LTL and ST muscles, except with b* parameter. The CAPN1 gene did not show any significant association. These results suggest an important role of genetics in meat color variation for cattle raised under the tropic conditions.

Cardiac Safety of Paclitaxel Plus Trastuzumab and Pertuzumab in Patients With HER2-Positive Metastatic Breast Cancer.

INTRODUCTION: Myocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer. PATIENTS AND METHODS: Patients with 0-1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m(2)) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle-tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points. RESULTS: Sixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3-38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (±SD) was 19% ± 2% (baseline), 19% ± 2% (month 6), and 19% ± 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline. CONCLUSION: The absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer. IMPLICATIONS FOR PRACTICE: Dual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation.

Role of Coccidioides Antigen Testing in the Cerebrospinal Fluid for the Diagnosis of Coccidioidal Meningitis.

BACKGROUND: Coccidioidal meningitis (CM), a common cause of chronic meningitis in endemic area, is usually diagnosed by detection of anti-Coccidioides antibodies in cerebrospinal fluid (CSF), and findings may be negative in up to one-third of cases. CSF cultures and cytology are infrequently positive. Antigen detection has been used for the diagnosis of other forms of coccidioidomycosis and meningitis caused by other mycoses. The purpose of this study was to assess the diagnostic utility of CSF Coccidioides antigen (CAg) detection for the diagnosis of CM. METHODS: The medical records of patients with clinically suspected meningitis, in whom CSF was tested for Coccidioides antibodies and CAg, were retrospectively reviewed, and CSF CAg testing was prospectively conducted in patients with CM. All specimens were submitted for CAg testing. RESULTS: Thirty-six patients with 42 episode of CM were studied. The sensitivity and specificity of CAg were 93% and 100%, respectively. Cultures of CSF were positive in 7%, antibodies were demonstrated by immunodiffusion in 67% and complement fixation in 70%, and immunoglobulin M and G antibodies were demonstrated by enzyme immunoassay in 8% and 85%, respectively. CONCLUSIONS: Testing CSF for CAg is a useful addition to diagnostic methods in suspected CM and complements testing with CSF antibodies and culture.