A principled framework to assess the information-theoretic fitness of brain functional sub-circuits.

In systems and network neuroscience, many common practices in brain connectomic analysis are often not properly scrutinized. One such practice is mapping a predetermined set of sub-circuits, like functional networks (FNs), onto subjects' functional connectomes (FCs) without adequately assessing the information-theoretic appropriateness of the partition. Another practice that goes unchallenged is thresholding weighted FCs to remove spurious connections without justifying the chosen threshold. This paper leverages recent theoretical advances in Stochastic Block Models (SBMs) to formally define and quantify the information-theoretic fitness (e.g., prominence) of a predetermined set of FNs when mapped to individual FCs under different fMRI task conditions. Our framework allows for evaluating any combination of FC granularity, FN partition, and thresholding strategy, thereby optimizing these choices to preserve important topological features of the human brain connectomes. By applying to the Human Connectome Project with Schaefer parcellations at multiple levels of granularity, the framework showed that the common thresholding value of 0.25 was indeed information-theoretically valid for group-average FCs despite its previous lack of justification. Our results pave the way for the proper use of FNs and thresholding methods and provide insights for future research in individualized parcellations.

Carriers of cystic fibrosis among sperm donors: complete CFTR gene analysis versus CFTR genotyping.

OBJECTIVE: To determine the frequency of cystic fibrosis (CF) carriers among sperm donors in Spain studied through a complete analysis of the CFTR gene and to compare the results with those that would have been obtained by the 4 genotyping panels of the CFTR gene most commonly used as a carrier test in the context of assisted reproduction in our country. DESIGN: Descriptive observational study. SETTING: Private center. PATIENTS: Nine hundred thirty-five sperm donors, from January 2014 to June 2019. INTERVENTION: None. MAIN OUTCOME MEASURE: Presence of pathogenic variants in the CFTR gene. RESULTS: 17% of the donors were carriers of at least 1 pathogenic variant in CFTR, with 39 different pathogenic variants detected. Only 4 of these 39 variants (10.27%) would have been detected by the 4 genotyping tests considered, and 22 variants (56.41%) would not have been detected by any of the genotyping tests. The pathogenic variants of the CFTR gene included in the different genotyping tests analyzed vary widely, and <50% are common to all of them. CONCLUSIONS: Although the was not based in the general population, these results show that the use of genotyping tests is associated with a high reproductive risk, because the rate of detection of CF carriers was lower when these panels were applied, in comparison with the complete study of the CFTR gene. We recommend that complete sequencing of the CFTR gene by next-generation sequencing be performed as a screening method for CF in sperm donors.

Assessing the stability of historical and desiccated snake venoms from a medically important Ecuadorian collection.

Bothrops asper and Bothrops atrox are important venomous snakes from Ecuador responsible for the most of ophidic accidents, which in the past were treated with a national polyvant antivenom. For years, the venom pools were collected and stored at room temperature in a laboratory. Taking into account the controversial ability of desiccated samples to retain their biological effects and enzymatic activities, we investigated the biochemical and toxicological properties of venoms after years of storage. The proteomic profiles of historical venoms analyzed by high-performance liquid chromatography and electrophoresis are very similar. The fresh batches of venom were more lethal than those stored for years, just as the initial and current LD50 values of these samples changed. Significant differences were showed in the myotoxic and hemorrhagic activity of some venom pools, while no significant statistical differences were found for the edema activity. The enzymatic assays revealed a variation in proteolytic activity on azocasein and phospholipase A2 activity, and low differences were reported for thrombin-like serine protease activity. The maintenance of the proteomic profile and certain toxicological activities convert this venom library in a valuable source for research purposes. Nonetheless, the significative reduction of toxicological activities, such as hemorrhagic activity not feasible using these samples for the antivenom production.

Papel del ultrasonido endoscópico en el manejo de las lesiones subepiteliales del tracto digestivo superior / Role of endoscopic ultrasound in the management of subepithelial lesions of the upper digestive tract

INTRODUCCIÓN. Desde la aparición del ultrasonido endoscópico, el campo de la gastroenterología y de manera principal, la endoscopia ha evolucionado, permite la realización de múltiples procedimientos, tanto diagnósticos como terapéuticos, con mínimas complicaciones con baja mortalidad. OBJETIVO. Determinar las caracte-rísticas de las lesiones subepiteliales en el tracto digestivo superior, mediante ul-trasonido endoscópico, sus opciones de diagnóstico y tratamiento. MATERIALES Y MÉTODOS. Estudio retrospectivo, de revisión bibliográfica y análisis sistemático de 95 artículos científicos y selección de muestra de 40 encontradas en las bases de datos Medline y PubMed y cuyas fechas de publicación corresponden a los últimos 10 años; el criterio de búsqueda empleado consistió en términos sobre el diagnósti-co y tratamiento de lesiones subepiteliales, mediante ultrasonido endoscópico. RE-SULTADOS. Se evidenció que las lesiones mayores de 1cm, tuvieron alto riesgo de malignización, la cuarta capa fue el sitio más frecuente de localización de este tipo de lesiones. La histopatología fue el método complementario confirmatorio. CON-CLUSIÓN. El ultrasonido endoscópico fue el método de elección para caracterizar y evaluar las lesiones subepiteliales, sean estas sintomáticas o incidentales, el acceso al mismo fue limitado.

INTRODUCTION. Since the appearance of endoscopic ultrasound, the field of gas-troenterology and, in a main way, endoscopy has evolved, allowing the performance of multiple procedures, both diagnostic and therapeutic, with minimal complications with low mortality. OBJECTIVE. To determine the characteristics of subepithelial le-sions in the upper digestive tract, using endoscopic ultrasound, its diagnostic and treatment options. MATERIALS AND METHODS. Retrospective, literature review and systematic analysis of 95 scientific articles and sample selection of 40 found in the Medline and PubMed databases and whose publication dates correspond to the last 10 years; The search criteria used consisted of terms on the diagnosis and treatment of subepithelial lesions, by endoscopic ultrasound. RESULTS. It was shown that le-sions larger than 1 cm, had a high risk of malignancy, the fourth layer was the most frequent site of location of this type of lesions. Histopathology was the complemen-tary confirmatory method. CONCLUSION. Endoscopic ultrasound was the method of choice to characterize and evaluate subepithelial lesions, whether symptomatic or incidental, access to it was limited.

Enfisema subcutáneo generalizado más neumotórax a tensión posterior a CPRE / Generalized subcutaneous emphysema plus pneumothorax to tension after CPRE

La colangiografía retrograda endoscópica (CPRE) es una técnica invasiva que permite diagnosticar y tratar patologías de vía biliar. La tasa de complicaciones es baja volviendo al procedimiento seguro, no exento de complicaciones como pancreatitis, sangrados, colangitis e incluso perforación (incidencia menor al 1,5%). Se presenta el caso clínico de un paciente de sexo masculino, con dolor en hipocondrio derecho, vómito y fiebre que presenta dilatación del extremo distal del colédoco por causa litiásica evidenciado por colangioresonancia. Se programa para CPR intentándose la canulación sin papilotomía; durante el procedimiento el paciente presenta enfisema subcutáneo y neumotórax a tensión ameritando tratamiento de emergencia. Se decide manejo quirúrgico a las doce horas de la CPRE por la marcada inestabilidad hemodinámica del paciente; en el intraoperatorio y en una endoscopia ulterior no se evidenció una lesión macroscópica que justifiquen la clínica e imágenes radiológicas que presentó el paciente. Se realiza tratamiento quirúrgico de perforación duodenal que obligó una estancia en terapia intensiva durante 11 días. Se complementa con una revisión bibliográfica de las complicaciones post CPRE. (AU)

Endoscopic retrograde cholangiography (ERCP) is an invasive technique that allows diagnosing and treating pathologies of the bile duct. The rate of complications is low returning to the safe procedure, not free of complications such as pancreatitis, bleeding, cholangitis and even perforation (incidence less than 1.5%). We present the clinical case of a male patient, with pain in the right hypochondrium, vomiting and fever that presents dilatation of the distal end of the common bile duct due to lithiasic cause evidenced by cholangioresonance. It is programmed for CPR, trying cannulation without papillotomy; During the procedure, the patient presents subcutaneous emphysema and tension pneumothorax, requiring emergency treatment. Surgical management was decided twelve hours after ERCP due to the marked hemodynamic instability of the patient; In the intraoperative period and in a subsequent endoscopy, there was no evidence of a macroscopic lesion that justified the clinical and radiological images presented by the patient. Surgical treatment of duodenal perforation wasperformed, which forced a stay in intensive therapyfor11 days. It is complemented by a bibliographic review of post-ERCP complications. (AU)

Effectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens.

BACKGROUND AND OBJECTIVE: Significant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens. METHODS: This retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure). RESULTS: A total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI95, 76.8-81.8) and 91.5% (CI95, 89.6-93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations. CONCLUSION: Switching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for the administered drug.

Morphometric and phytochemical characterization of chaura fruits (Gaultheria pumila): a native Chilean berry with commercial potential.

BACKGROUND: For the first time, a morphometric characterization of chaura (Gaultheria pumila) fruits has been conducted between natural populations growing in the Villarrica National Park, Araucania Region, Chile. Chaura is a native Ericaceae from Chile that produces aromatic and tasty fruits which could be of agricultural interest. RESULTS: To influence the decision for a further domestication of G. pumila, both the fruit sizes (indicator of productivity) and the nutritional properties of the fruits have been determined from different subpopulations. Samples were a total of 74 plants and 15 fruits per plant which were randomly harvested following its natural distribution around the Villarrica volcano. Altogether, fresh weight, shape, color, diameter in the pole and the equatorial dimensions were determined as phenotypic traits of the G. pumila fruits. Meanwhile the total soluble solids, anthocyanin and pectin contents were calculated as nutritional traits of the Chaura fruits. Results showed a high phenotypic diversity between the sampled population with three main fruit shapes and three predominant colors. The round shapes were the most abundant, whereas a significant correlation was found among fruit size with weight and color. The highest fresh weight (597.3 mg), pole diameter (7.1 mm) and equatorial diameter (6.5 mm) were estimated in the pink color fruits. CONCLUSIONS: The total amount of anthocyanin was higher in red fruits, while the maximum pectin content was obtained in the round white fruits. Overall results must pave the way for a further domestication and introduction of the Chaura species in the agro-productive system in Chile.

Social adversity experience and blood pressure control following antihypertensive medication use in a community sample of older adults.

BACKGROUND: Psychosocial stress is a risk factor for hypertension and has been shown to affect response to treatment for psychiatric illnesses. PURPOSE: We investigate the relationship between a history of social adversity experience and blood pressure control following antihypertensive medication use. METHODS: A total of 1,186 participants selected from the European Prospective Investigation into Cancer-Norfolk study (531 men and 655 women, aged 42 to 80 years) had attended two health checks at which blood pressure measurements were taken; were taking antihypertensive medication at the second, but not the first health check; and had completed a questionnaire assessment of their social and psychological circumstances which included details of traumatic experiences in childhood and of adverse life events, long-term difficulties, and perceived stress in adulthood. RESULTS: Experience of recent loss events in adulthood was associated with a smaller reduction in systolic blood pressure after starting hypertension treatment (ß = 1.78, 95 % confidence interval 0.15-3.40, per life event), independently of age, sex, preexisting health conditions, cigarette smoking history, alcohol consumption, physical activity, and obesity. CONCLUSION: Results from this study suggest that stress caused by recent losses may be associated with reduced effectiveness of treatment for hypertension. Subject to replication, these findings may help determine the specific physiological mechanisms by which medication treatment effectiveness is affected by stress.

Morphometric and phytochemical characterization of chaura fruits (Gaultheria pumila): a native Chilean berry with commercial potential

BACKGROUND: For the first time, a morphometric characterization of chaura (Gaultheria pumila) fruits has been conducted between natural populations growing in the Villarrica National Park, Araucania Region, Chile. Chaura is a native Ericaceae from Chile that produces aromatic and tasty fruits which could be of agricultural interest. RESULTS: To influence the decision for a further domestication of G. pumila, both the fruit sizes (indicator of productivity) and the nutritional properties of the fruits have been determined from different subpopulations. Samples were a total of 74 plants and 15 fruits per plant which were randomly harvested following its natural distribution around the Villarrica volcano. Altogether, fresh weight, shape, color, diameter in the pole and the equatorial dimensions were determined as phenotypic traits of the G. pumila fruits. Meanwhile the total soluble solids, anthocyanin and pectin contents were calculated as nutritional traits of the Chaura fruits. Results showed a high phenotypic diversity between the sampled population with three main fruit shapes and three predominant colors. The round shapes were the most abundant, whereas a significant correlation was found among fruit size with weight and color. The highest fresh weight (597.3 mg), pole diameter (7.1 mm) and equatorial diameter (6.5 mm) were estimated in the pink color fruits. CONCLUSIONS: The total amount of anthocyanin was higher in red fruits, while the maximum pectin content was obtained in the round white fruits. Overall results must pave the way for a further domestication and introduction of the Chaura species in the agro-productive system in Chile.

Estimating kidney function in the critically ill patients.

Glomerular filtration rate (GFR) is an accepted measure for assessment of kidney function. For the critically ill patient, creatinine clearance is the method of reference for the estimation of the GFR, although this is often not measured but estimated by equations (i.e., Cockroft-Gault or MDRD) not well suited for the critically ill patient. Functional evaluation of the kidney rests in serum creatinine (Crs) that is subjected to multiple external factors, especially relevant overhydration and loss of muscle mass. The laboratory method used introduces variations in Crs, an important fact considering that small increases in Crs have serious repercussion on the prognosis of patients. Efforts directed to stratify the risk of acute kidney injury (AKI) have crystallized in the RIFLE or AKIN systems, based in sequential changes in Crs or urine flow. These systems have provided a common definition of AKI and, due to their sensitivity, have meant a considerable advantage for the clinical practice but, on the other side, have introduced an uncertainty in clinical research because of potentially overestimating AKI incidence. Another significant drawback is the unavoidable period of time needed before a patient is classified, and this is perhaps the problem to be overcome in the near future.

Medicina intensiva: bases fisiopatológicas del tratamiento

Contenido: Fisiopatología general de los estados críticos. Alteraciones agudas del metabolismo de oxígeno en el paciente crítico. Alteraciones agudas del sistema cardiovascular. Alteraciones agudas del sistema respiratorio. Alteraciones agudas del agua y los principales electrolitos. Alteraciones renales. Alteraciones agudas del metabolismo. Alteraciones agudas del sistema nervioso. Alteraciones agudas de la hemostasia. Miscelánea

Comparative pharmacokinetics of a single oral dose of two formulations of amlodipine. A randomized, single-blind, two-period, two-sequence, crossover study.

Amlodipine, a long acting dihydropyridine calcium channel antagonist, is prescribed worldwide for the treatment of angina and hypertension. The objective of this study was to compare the pharmacokinetics and to establish bioequivalence of two formulations of amlodipine. The study was performed at the Clinical Pharmacology Unit, Hospital de Clínicas, Medical School of Buenos Aires University. This randomized, single blind, two-period, two-sequence, comparative crossover study was conducted in 24 Caucasian healthy volunteers. A single oral 10 mg dose of amlodipine besylate (CAS 111470-99-6) test formulation and reference formulation were administered to the volunteers separated by a 3-week washout period in a crossover manner. Blood samples for pharmacokinetic analysis were collected over a period of 144 h after drug administration. Amlodipine was measured in plasma samples using a validated HPLC method with LC-MS-MS detection. A non-compartmental method was used for pharmacokinetic analysis. Bioequivalence between test and reference amlodipine samples were demonstrated as the calculated 90% confidence interval for the corresponding ratios of log transformed pharmacokinetic parameters (AUC(t), AUC(infinity) and C(max)) fell within the 80-125% range, the predetermined criterion for pharmacokinetic equivalence.

Relapse risk after autologous transplantation in patients with newly diagnosed myeloma is not related with infused tumor cell load and the outcome is not improved by CD34+ cell selection: long term follow-up of an EBMT phase III randomized study.

BACKGROUND AND OBJECTIVES: This European Group for Blood and Marrow Transplantation (EBMT) multicentre randomized phase III study was designed to assess the safety and efficacy of CD34+ selection in newly diagnosed myeloma patients undergoing autologous transplantation. DESIGN AND METHODS: One hundred and eleven patients responsive to initial chemotherapy were randomized to receive CD34+ selected (arm A) or unselected PBPC (arm B) after conditioning with high-dose melphalan and TBI. ASO-PCR was used to assess purging efficacy and reinfused tumor load. Tumor load could be assessed in 59 patients. RESULTS: CD34+ selection gave a median tumor cell depletion of 2.2 logs (0.77-5.96). No tumor cells were detected in products infused in 17/26 (A) and 5/33 (B) patients. The five year overall survival (OS), event free survival (EFS) and relapse rate (RR) were 51%, 20% and 80% in arm A and 45%, 18% and 80% in arm B respectively with no significant difference between the two groups. Thirteen patients in arm A and 2 in arm B experienced episodes of serious early infection (p=0.02). There were 3 early transplant related deaths in A but none in B. INTERPRETATION AND CONCLUSIONS: Despite significant tumor cell reduction, CD34+ selection does not reduce RR and increases the risk of severe post-transplant infections. There was also no difference in RR between patients in either arm who received grafts with detectable tumor cells and those receiving grafts with no detectable tumor cells, suggesting that reinfused tumor cells may not be the main cause of relapse after autologous transplant in myeloma.

[Assessment of clinical practice in patients with infectious meningitis]. / Evaluación de la práctica clínica en pacientes diagnosticados de meningitis infecciosa.

OBJECTIVES: Medical practice assessments for a specific patient population can be useful for improving health care quality and decreasing the variations in clinical practice. Our aim was to assess compliance with clinical practice guidelines established for patients with meningitis using previously formulated indicators. METHODS: The indicators of quality were based on clinical practice guidelines and selected through consensus meetings. A data protocol was designed and applied retrospectively to the medical records of all patients with a diagnosis of meningitis between 1987 and 2004 in a 280-bed general hospital. RESULTS: A total of 99 episodes were included. Information on pre-treatment was recorded in 94%, duration of symptoms in 65%, funduscopic examination in 21%, and cerebrospinal fluid (CSF) pressure in 5% of patients. Biochemical and microbiological CSF study was adequate (93%-99%), but blood culture (73%) was not. Cranial CT scan was adequate in 52% of patients, since in many cases it was performed without an indication for this study. Treatment was given according to the local protocol in 53.6% of patients with suspected bacterial meningitis and 79.5% of those with suspected viral meningitis. Three patients died due to meningitis. CONCLUSIONS: The use of funduscopic examination was poor, whereas the use of cranial CT scanning was excessive. Treatment of bacterial meningitis adhered to the established local antibiotic protocol in half the patients. This type of auditing is useful for determining compliance with guidelines and designing strategies to improve health care quality.

Failure of high-dose cyclophosphamide and etoposide combined with double-dose cisplatin and bone marrow support in patients with high-volume metastatic nonseminomatous germ-cell tumours: mature results of a randomised trial.

OBJECTIVES: To assess the impact on survival of high-dose chemotherapy with haematopoietic support in patients with high-volume, metastatic nonseminomatous germ cell tumours. METHODS: One hundred fifteen patients were randomised to receive either four cycles every 21 d of vinblastine (0.2 mg/kg on day 1), etoposide (100 mg/m2/d on days 1 through 5), cisplatin (40 mg/m2/d on days 1 through 5), and bleomycin (30 mg on days 1, 8, and 15) (arm A), or a slightly modified regimen followed by a high-dose chemotherapy including etoposide (350 mg/m2/d on days 1 through 5), cisplatin (40 mg/m2/d on days 1 through 5), and cyclophosphamide (1600 mg/m2/d on days 2 through 5) (arm B). RESULTS: In an intent-to-treat analysis, there were 32 (56%) and 24 (42%) complete responses in arms A and B, respectively (p=0.099). After a median follow-up of 9.7 yr, 31 and 27 patients have continuously shown no evidence of disease in arms A and B, respectively. There was no significant difference between the overall survival curves (p=0.167). According to the International Germ Cell Cancer Collaborative Group prognostic classification, the 5-yr survival rates were 88% and 82% in the intermediate group and 69% and 44% in the poor group (p=0.045) in arms A and B, respectively. CONCLUSIONS: This trial failed to demonstrate an impact on response and survival of high-dose chemotherapy with haematopoietic support in first-line treatment of patients with high-volume, metastatic nonseminomatous germ cell tumours.

Neulasta (pegfilgrastim): a once-per-cycle option for the management of chemotherapy-induced neutropenia.

Neutropenia is a significant hematologic complication induced by cytotoxic chemotherapy. The clinical consequences of chemotherapy-induced neutropenia are often severe and can be potentially life-threatening. Patients who develop febrile neutropenia often need to be hospitalized, reducing their quality of life and increasing costs. Neutropenia can also compromise the ability to deliver chemotherapy at the full dose and on schedule. To help prevent the occurrence of neutropenia, patients with a high risk of developing chemotherapy-related infections may be given prophylactic colony-stimulating factors. Filgrastim is a recombinant human granulocyte colony-stimulating factor that has been widely used (in over 3 million patients) for over 12 years in the management of neutropenia. Pegfilgrastim is an approved, long-acting, next generation of granulocyte colony-stimulating factor that has similar clinical benefits to filgrastim but has novel pharmacokinetic properties. Pegfilgrastim shows at least comparable safety and efficacy to filgrastim, with the added benefit of simplified once-per-chemotherapy-cycle dosing. In addition, two randomized, controlled pivotal trials have shown that a single dose of pegfilgrastim given once per cycle led to a lower observed incidence of febrile neutropenia following myelosuppressive chemotherapy, compared with daily injections of filgrastim. Clinical trials are currently expanding the clinical experience with pegfilgrastim in a variety of solid tumors and hematologic malignancies. In addition to prevention of chemotherapy-induced neutropenia in 21- and 28-day regimens, future studies are examining the suitability of pegfilgrastim in dose-dense therapy and other cancer settings.