Improved breast cancer histological grading using deep learning.

BACKGROUND: The Nottingham histological grade (NHG) is a well-established prognostic factor for breast cancer that is broadly used in clinical decision making. However, ∼50% of patients are classified as grade 2, an intermediate risk group with low clinical value. To improve risk stratification of NHG 2 breast cancer patients, we developed and validated a novel histological grade model (DeepGrade) based on digital whole-slide histopathology images (WSIs) and deep learning. PATIENTS AND METHODS: In this observational retrospective study, routine WSIs stained with haematoxylin and eosin from 1567 patients were utilised for model optimisation and validation. Model generalisability was further evaluated in an external test set with 1262 patients. NHG 2 cases were stratified into two groups, DG2-high and DG2-low, and the prognostic value was assessed. The main outcome was recurrence-free survival. RESULTS: DeepGrade provides independent prognostic information for stratification of NHG 2 cases in the internal test set, where DG2-high showed an increased risk for recurrence (hazard ratio [HR] 2.94, 95% confidence interval [CI] 1.24-6.97, P = 0.015) compared with the DG2-low group after adjusting for established risk factors (independent test data). DG2-low also shared phenotypic similarities with NHG 1, and DG2-high with NHG 3, suggesting that the model identifies morphological patterns in NHG 2 that are associated with more aggressive tumours. The prognostic value of DeepGrade was further assessed in the external test set, confirming an increased risk for recurrence in DG2-high (HR 1.91, 95% CI 1.11-3.29, P = 0.019). CONCLUSIONS: The proposed model-based stratification of patients with NHG 2 tumours is prognostic and adds clinically relevant information over routine histological grading. The methodology offers a cost-effective alternative to molecular profiling to extract information relevant for clinical decisions.

Prevalencia de infecciones osteoarticulares por enterobacterias productoras de ß-lactamasas de espectro extendido / Prevalence of osteoarticular infections by Enterobacteria producing extended-spectrum ß-lactamases

Resumen: Introducción: Las infecciones por enterobacterias productoras de β-lactamasas de espectro extendido (BLEEs) ocasionan una gran carga a los sistemas de salud. Poco se conoce de las infecciones osteoarticulares, por lo que este trabajo estudió la prevalencia de estas infecciones en un hospital de tercer nivel. Material y métodos: Estudio de prevalencia en pacientes de un servicio de traumatología durante 2016, con criterios de infección proporcionados por el CDC de Atlanta, Georgia. Se utilizó el sistema VITEK® 2 AST-N272 (bioMérieux) para la identificación bacteriana a nivel de especie y para las pruebas de susceptibilidad antimicrobiana. Resultados: Se reportaron 7.85% (n = 86) con infecciones osteoarticulares; 22.09% (n = 19) fueron por enterobacterias BLEEs. Con un promedio de 77.1 días de hospitalización (DE 37.7) (46-200 días); el aislamiento del microorganismo se produjo 15 días posteriores al ingreso; 16 (84.2%) pacientes presentaron osteomielitis, tres (15.8%) tuvieron infección protésica de rodilla o cadera. El promedio de días de tratamiento fue de 60 días (21-129 días); 18 pacientes (94.7%) fueron dados de alta con resolución de su cuadro infeccioso; un paciente falleció con infección sobreagregada por neumonía debida a K. pneumoniae resistente a carbapenémicos. Discusión: La prevalencia de infecciones osteoarticulares por enterobacterias BLEEs no se pudo calcular con precisión, pero consideramos que se encuentra dentro de lo esperado, las medidas de control de infecciones requieren tener estándares más elevados y falta desarrollar programas de uso racional de antimicrobianos para controlar la aparición de estas patologías.

Abstract: Introduction: Infections of enterobacteria producing extended-spectrum ß-lactamases place a heavy burden on health systems. Little is known in osteoarticular infections, so this work studied the prevalence of these infections in a third-level hospital. Material and methods: Prevalence study in patients of a Traumatology Service during 2016, with infection criteria provided by the CDC in Atlanta, Georgia. The VITEK® 2 AST-N272 (bioMérieux) system was used for bacterial identification at the species level and for antimicrobial susceptibility tests. Results: 7.85% (n = 86) were reported with osteoarticular infections; 22.09% (n = 19) were by enterobacteria BLEEs. An average of 77.1 days of hospitalization (SD 37.7) (46-200 days); isolation of the microorganism occurred 15 days after entry. Sixteen (84.2%) patients had osteomyelitis, three (15.8%) had a prosthetic knee or hip infection. The average number of treatment days was 60 days (21-129 days). Eighteen patients (94.7%) were discharged with resolution of their infectious picture; one patient died with infection over aggregated pneumonia due to carbapenem-resistant K. pneumoniae. Discussion: The prevalence of osteoarticular infections by enterobacteria BLEEs could not be accurately calculated, but we consider it to be within what is expected, infection control measures require higher standards and there is a lack of development programs to use antimicrobials rationally to control the emergence of these pathologies.

[Prevalence of osteoarticular infections by Enterobacteria producing extended-spectrum -lactamases]. / Prevalencia de infecciones osteoarticulares por enterobacterias productoras de -lactamasas de espectro extendido.

INTRODUCTION: Infections of enterobacteria producing extended-spectrum -lactamases place a heavy burden on health systems. Little is known in osteoarticular infections, so this work studied the prevalence of these infections in a third-level hospital. MATERIAL AND METHODS: Prevalence study in patients of a Traumatology Service during 2016, with infection criteria provided by the CDC in Atlanta, Georgia. The VITEK® 2 AST-N272 (bioMérieux) system was used for bacterial identification at the species level and for antimicrobial susceptibility tests. RESULTS: 7.85% (n = 86) were reported with osteoarticular infections; 22.09% (n = 19) were by enterobacteria BLEEs. An average of 77.1 days of hospitalization (SD 37.7) (46-200 days); isolation of the microorganism occurred 15 days after entry. Sixteen (84.2%) patients had osteomyelitis, three (15.8%) had a prosthetic knee or hip infection. The average number of treatment days was 60 days (21-129 days). Eighteen patients (94.7%) were discharged with resolution of their infectious picture; one patient died with infection over aggregated pneumonia due to carbapenem-resistant K. pneumoniae. DISCUSSION: The prevalence of osteoarticular infections by enterobacteria BLEEs could not be accurately calculated, but we consider it to be within what is expected, infection control measures require higher standards and there is a lack of development programs to use antimicrobials rationally to control the emergence of these pathologies.

INTRODUCCIÓN: Las infecciones por enterobacterias productoras de -lactamasas de espectro extendido (BLEEs) ocasionan una gran carga a los sistemas de salud. Poco se conoce de las infecciones osteoarticulares, por lo que este trabajo estudió la prevalencia de estas infecciones en un hospital de tercer nivel. MATERIAL Y MÉTODOS: Estudio de prevalencia en pacientes de un servicio de traumatología durante 2016, con criterios de infección proporcionados por el CDC de Atlanta, Georgia. Se utilizó el sistema VITEK® 2 AST-N272 (bioMérieux) para la identificación bacteriana a nivel de especie y para las pruebas de susceptibilidad antimicrobiana. RESULTADOS: Se reportaron 7.85% (n = 86) con infecciones osteoarticulares; 22.09% (n = 19) fueron por enterobacterias BLEEs. Con un promedio de 77.1 días de hospitalización (DE 37.7) (46-200 días); el aislamiento del microorganismo se produjo 15 días posteriores al ingreso; 16 (84.2%) pacientes presentaron osteomielitis, tres (15.8%) tuvieron infección protésica de rodilla o cadera. El promedio de días de tratamiento fue de 60 días (21-129 días); 18 pacientes (94.7%) fueron dados de alta con resolución de su cuadro infeccioso; un paciente falleció con infección sobreagregada por neumonía debida a K. pneumoniae resistente a carbapenémicos. DISCUSIÓN: La prevalencia de infecciones osteoarticulares por enterobacterias BLEEs no se pudo calcular con precisión, pero consideramos que se encuentra dentro de lo esperado, las medidas de control de infecciones requieren tener estándares más elevados y falta desarrollar programas de uso racional de antimicrobianos para controlar la aparición de estas patologías.

Herencia autosómica recesiva en paciente no sindrómico con múltiples dientes supernumerarios / Autosomal recessive inheritance in a non-syndromic patient with multiple supernumerary teeth

La hiperdoncia es una condición caracterizada por la presencia de un número de dientes superior al normal en el arco dentario. Su etiología es incierta, aunque factores genéticos y ambientales así como varias teorías han sido propuestas para explicarlo. Describir las características clínicas y radiográficas presentes en un paciente no sindrómico con múltiples supernumerarios, heredados de manera autosómica recesiva. Se presenta el caso de un hombre de 27 años de edad que acudió a consulta para evaluación odontológica. Al examen físico y extrabucal no reveló deformidades, retardo mental ni presencia de ningún síndrome. Al examen intrabucal se evidenció la presencia de irritantes locales y maloclusión dentaria, ocasionada por el aumento del número dientes en los arcos dentarios. Radiográficamente se observaron múltiples imágenes radiopacas compatibles con 9 unidades dentarias incluidas y 2 erupcionadas. Los exámenes de laboratorio no revelaron alteraciones ni relación con algún síndrome. Se solicitaron radiografías panorámicas a los padres, hermanos e hija del paciente, para descartar la presencia de dientes supernumerarios, encontrándose 9 dientes supernumerarios incluidos en un hermano varón, determinándose la trasmisión del rasgo de manera autosómica recesiva. El hallazgo de la trasmisión de manera autosómica recesiva de múltiples supernumerarios en un paciente no sindrómico encontrado en este caso, no es común, lo cual indica que el examen clínico y estudio de cada paciente debe ser llevado a cabo de manera exhaustiva, para determinar este tipo de trastorno o cualquier otro sin evidencias o manifestaciones clínicas.

Hyperdontia is a condition characterized by the presence of a higher number of teeth than normal in the dental arch. Even though genetic and environmental factors as well as a series of theories have been proposed to explain hyperdontia, its etiology is uncertain. To describe clinical and radiographical characteristics found in a non-syndromic patient with multiple supernumerary teeth by autosomal recessive inheritance. A 27-year-old male referred for dental assessment. Physical and extraoral examinations did not reveal deformities, mental retardation or the presence of syndromes. Intraoral examination evidenced the presence of local irritants and dental malocclusion produced by the increased number of teeth in both dental arches. Radiographs revealed multiple radiopaque images compatible with 9 unerupted and 2 erupted teeth. Laboratory tests did not show alterations or a connection to any syndromes. Panoramic radiographs were requested from parents, siblings and daughter of the patient to rule out the presence of supernumerary teeth. Nine supernumerary unerupted teeth were found in one brother, which determined the transmission of characteristics by autosomal recessive inheritance. The incidental finding of the autosomal recessive transmission of multiple supernumerary teeth in a non-syndromic patient observed in this case is not a common result, indicating that clinical examinations and the study of each patient must be carried out thoroughly in order to determine this or any other type of disorders without evidence or clinical manifestations.

Exploring child maltreatment and its relationship to alcohol and cannabis use in selected Latin American and Caribbean countries.

OBJECTIVES: Research from developed countries shows that child maltreatment increases the risk for substance use and problems. However, little evidence on this relationship is available from developing countries, and recognition of this relationship may have important implications for substance demand reduction strategies, including efforts to prevent and treat substance use and related problems. Latin America and the Caribbean is a rich and diverse region of the world with a large range of social and cultural influences. A working group constituted by the Inter-American Drug Abuse Control Commission and the Center for Addiction and Mental Health in June, 2010 identified research on this relationship as a priority area for a multinational research partnership. METHODS: This paper examines the association between self-reported child maltreatment and use in the past 12 months of alcohol and cannabis in 2294 university students in seven participating universities in six participating countries: Colombia, El Salvador, Jamaica, Nicaragua, Panama and Uruguay. The research also considers the possible impact of religiosity and minimal psychological distress as factors contributing to resiliency in these samples. RESULTS: The results showed that experience of maltreatment was associated with increased use of alcohol and cannabis. However, the effects differed depending on the type of maltreatment experienced. Higher levels of religiosity were consistently associated with lower levels of alcohol and cannabis use, but we found no evidence of an impact of minimal psychological distress on these measures. CONCLUSIONS: This preliminary study shows that the experience of maltreatment may increase the risk of alcohol and cannabis use among university students in Latin American and Caribbean countries, but that higher levels of religiosity may reduce that risk. More work to determine the nature and significance of these relationships is needed.

Surgical treatment of arterial ischemia associated with the use of the angioseal vascular closure device.

BACKGROUND: Despite the theoretical effectiveness of the Angio-Seal closure device to control bleeding after arterial puncture it can increase the risk of ischemia. OBJECTIVES: To describe arterial lesions caused by the device, surgical techniques needed to repair those lesions and surgical outcome in patients who underwent surgery for arterial ischemia after heart catheterization. PATIENTS AND METHODS: Seven patients underwent surgery over a period of 12 months at our institution. Five patients underwent emergency surgery and two a delayed procedure. The cause of ischemia was dissection of an atheroma plaque at the puncture site in four cases, dissection of the superficial femoral artery in one case, thrombosis of the common femoral artery in one case, and plication of the posterior arterial wall in one case. Arterial repair in these patients required the insertion of a vascular graft in three cases, endarterectomy plus angioplasty in two cases, endarterectomy plus graft interposition plus thrombectomy of the superficial femoral artery in one case and endarterectomy plus femoropopliteal bypass in one case. RESULTS: Treatment was successful in all patients. Mean follow up was 7.6 months (range 5-11 months). During the study period one patient died due to cardiopathy. No patients had to be re-operated and no limb losses were recorded. All the patients were asymptomatic from a vascular point of view with normal active lives for their age. CONCLUSIONS: Surgical repair is effective, although, generally, it is not restricted to a simple thrombectomy, requiring the use of different arterial repair techniques.

Lower cyclin H and cyclin-dependent kinase-activating kinase activity in cell cycle arrest induced by lack of adhesion to substratum.

Knowledge about adhesion checkpoints is important to counteract dissemination of cells from solid tumors. Lack of anchorage in adherent cells is associated with growth arrest and inhibition of cyclin-dependent kinases (cdks) required to drive cell cycle progression. Because cyclin-cdk complex activation requires CDK-activating kinase comprising cdk7 and cyclin H, we now investigated their relationship to decreased proliferation by lack of cell spreading. This report shows that either UV irradiation on an adhesive substrate or culture on a nonadhesive substrate produced K1735 melanoma growth arrest. Inhibition of proliferation by UV primarily induced the cdk inhibitor p21WAF1 without a significant effect on cyclin H and cdk7. In contrast, lack of adhesion to substratum decreased cyclin H but not cdk7 with accumulation of a slower migrating, presumably unphosphorylated cdk4 isoform. These results were paralleled by decreased cdk7-mediated phosphorylation of GST-cdk2 and lower activation of a baculovirus-derived cdc2-cyclin B kinase complex. This is the first report showing that cyclin H-mediated down-regulation of cdk-activating kinase activity is involved in growth arrest induced by lack of anchorage.

Enhancement of the immune response to poorly immunogenic gangliosides after incorporation into very small size proteoliposomes (VSSP).

Certain gangliosides are tumor-associated antigens that constitute potential targets for cancer immunotherapy. A major drawback in the design of ganglioside-based cancer vaccines, however, is the poor immunogenicity of these glycolipids. Here we report the immunological and physicochemical properties of very small size proteoliposomes (VSSP) obtained by using anionic detergents to incorporate gangliosides into the outer membrane protein complex (OMPC) of N. meningitidis. VSSP of three different gangliosides, GM3, NGcGM3 and GD3, were tested. These gangliosides differ in level of expression in normal tissues and in immunogenicity in different animal species. We show that the immunization with VSSP in an oil adjuvant consistently induced both IgM and IgG anti-ganglioside antibodies. In the mouse, the anti-ganglioside IgG fraction was not restricted to the typical T-independent isotype IgG3. Unexpectedly, significant levels of the T-dependent IgG1, IgG2a and particularly IgG2b were also found. VSSP-mediated enhancement of the immunogenicity was not restricted to the relatively immunogenic ganglioside GD3, satisfactory immune responses against highly tolerated GM3 and NGcGM3 were also obtained. Similar results were achieved in chickens and monkeys. No reactogenicity was observed even when self-gangliosides were used for immunization. VSSP overcame natural tolerance to gangliosides in an adjuvant dependent fashion.

Divergence in proteins, mitochondrial DNA, and reproductive compatibility across the isthmus of Panama.

It is widely believed that gene flow connected many shallow water populations of the Caribbean and eastern Pacific until the Panama seaway closed 3.0 to 3.5 million years ago. Measurements of biochemical and reproductive divergence for seven closely related, transisthmian pairs of snapping shrimps (Alpheus) indicate, however, that isolation was staggered rather than simultaneous. The four least divergent pairs provide the best estimate for rates of molecular divergence and speciation. Ecological, genetic, and geological data suggest that gene flow was disrupted for the remaining three pairs by environmental change several million years before the land barrier was complete.

Carboplatin, methotrexate, vinblastine and epirubicin (Carbo-MVE) for transitional cell bladder carcinoma.

BACKGROUND: MVAC is considered the most effective chemotherapy regimen for transitional cell bladder carcinoma. However, due to its significant toxic effects we substituted carboplatin for cisplatin and epirubicin for adriamycin in an attempt to produce the same response with less toxicity. PATIENTS AND METHODS: Twenty-seven patients with invasive transitional cell bladder carcinoma received Carbo-MVE: carboplatin (300 mgr/m2 d2), methotrexate (30 mgr/m2 d1, 15, 22), vinblastine (3 mgr/m2 d2, 15, 22) and epirubicin (30 mgr/m2 d2) every 4 weeks. RESULTS: There were 2 complete clinical responses (8.4%), 5 partial clinical responses (20.8%), 8 stabilizations (33.3%) and 9 progressions (37.5%). The overall clinical response rate was 29.2% (11%-47.4%, 95% CI), but 2 partial clinical remissions were not pathologically confirmed; were they to be considered as non-responses the response rate would fall even lower (20.8%). Toxicity was moderately severe, with 77.8% developing WHO grade III-IV granulocytopenia, 22.2% grade III-IV thrombocytopenia and 59.3% grade II-III vomiting. There were no toxic deaths nor any renal toxicity. CONCLUSIONS: Our results suggest that Carbo-MVE is less active and at least as hematotoxic as multiagent CDDP-based regimens.

Effects of Rumen-Mate on lactational performance of Holsteins fed a high grain diet.

Three Latin-square trials were conducted to determine the effects of supplementing Rumen-Mate, a commercial buffer containing KCl, NaCl, and Mg and Na carbonates, on lactation performance of Holsteins. Cows were fed a basal ration of 40% corn silage and 60% concentrate in Trials 1 and 2, and 40% corn silage, 55% concentrate, and 5% alfalfa hay in Trial 3 (DM basis). In Trial 1, treatments were: basal diet, or basal diet supplemented with either 1% NaHCO3, or 1, 3, or 4.4% Rumen-Mate. Increasing dietary Rumen-Mate resulted in a linear increase in milk fat production and concentration with no difference between 1% Rumen-Mate and 1% bicarbonate. There was a significant linear decrease in milk protein concentration, but not production, with increasing concentrations of Rumen-Mate. In Trial 2 treatments were: basal diet, or basal diet supplemented with either .8% NaHCO3, 2.6% Rumen-Mate, .5% MgO, .8% NaHCO3 plus .5% MgO, or 1.8% Rumen-Mate plus .8% NaHCO3. Organic matter and CP intakes and milk protein yield and concentration were decreased by Rumen-Mate with a nonsignificant increase in milk fat concentration. Data from Trials 1 and 2 were combined with data from Trial 3, which compared basal diet, 1% bicarbonate, and 3% Rumen-Mate. The combined data showed a larger increase over basal diet in milk fat yield and concentration for 2.6 to 3% Rumen-Mate vs. .8 to 1% bicarbonate. Rumen-Mate did not decrease DM intake or protein yield relative to basal diet but did decrease protein yield 34 g/d compared with that of bicarbonate.

Effects of sodium bicarbonate or sodium sesquicarbonate on lactating Holsteins fed a high grain diet.

Fifteen Holstein cows, 35 to 70 d postpartum, were assigned to five 3 x 3 Latin squares. Treatments were: control (60% concentrate, 40% corn silage, DM basis) or control supplemented with either .71% sodium bicarbonate or .65% sodium sesquicarbonate, DM basis. Orthogonal contrasts compared the effect of both buffered diets versus the control diet, and the effect of sodium bicarbonate supplementation vs. sodium sesquicarbonate supplementation. There were no differences among treatments for milk yield (34.9 kg/d), milk fat yield (.99 kg/d), 3.5% FCM (31.1 kg/d), or milk protein concentration (3.15%). There were no treatment effects on total chewing time. Milk fat concentration tended to be greater for cows fed sodium bicarbonate (2.92%) and sodium sesquicarbonate (2.89%) relative to control (2.82%). Relative to control, sodium bicarbonate and sodium sesquicarbonate supplementation increased DM intake (22.0 and 22.7 vs. 21.4 kg/d), digestible DM intake (16.7 and 16.2 vs. 14.8 kg/d), digestible organic matter intake (16.0 and 15.5 vs. 14.3 kg/d); and apparent digestibility of DM (77.3 and 74.8 vs. 73.3%) and NDF (62.6 and 56.5 vs. 54.7%). Relative to sesquicarbonate, bicarbonate supplementation increased apparent digestibilities of CP (82.3 vs. 78.8%) and NDF, and decreased milk protein yield (1.06 vs. 1.11 kg/d). Sesquicarbonate was as effective as bicarbonate in alleviating milk fat depression and increasing intake of digestible organic matter.

Plasmid profiles of Legionella pneumophila strains isolated in Spain.

An assay for plasmid DNA content was carried out in 100 strains of Legionella pneumophila of distinct serogroups and isolated from various sources (clinical, environment). The strains were isolated from different geographic regions in our country. The presence of plasmids was proved in one of the 11 clinical isolates and in 68 of the 89 isolated of environmental origin studied. In the strains belonging to serogroup 1 and isolated in our region (Cantabria), three plasmid profiles were observed, whereas in strains of the same serogroup from other geographic regions, two profiles were shown which exhibited differences compared to the former ones. Analysis by means of restriction endonucleases suggested that plasmids of similar size in serogroup 1 strains of different source, were related. The results obtained do not appear to reveal any correlation between plasmid profile and source of isolation or serogroup.