Reproducibility and prognostic ability of chronicity parameters in kidney biopsy - Comprehensive evaluation comparing microscopy and artificial intelligence in digital pathology.

INTRODUCTION: Semi-quantitative scoring of various parameters in renal biopsy is accepted as an important tool to assess disease activity and prognostication. There are concerns on the impact of interobserver variability in its prognostic utility, generating a need for computerized quantification. METHODS: We studied 94 patients with renal biopsies, 45 with native diseases and 49 transplant patients with index biopsies for Polyomavirus nephropathy. Chronicity scores were evaluated using two methods. A standard definition diagram was agreed after international consultation and four renal pathologists scored each parameter in a double-blinded manner. Interstitial fibrosis (IF) score was assessed with five different computerized and AI-based algorithms on trichrome and PAS stains. RESULTS: There was strong prognostic correlation with renal function and graft outcome at a median follow-up ranging from 24 to 42 months respectively, independent of moderate concordance for pathologists scores. IF scores with two of the computerized algorithms showed significant correlation with estimated glomerular filtration rate (eGFR) at biopsy but not at the end of follow-up. There was poor concordance for AI based platforms. CONCLUSION: Chronicity scores are robust prognostic tools despite interobserver reproducibility. AI-algorithms have absolute precision but are limited by significant variation when different hardware and software algorithms are used for quantification.

Vancomycin nephrotoxicity: A comprehensive clinico-pathological study.

INTRODUCTION: Vancomycin, a commonly prescribed antibiotic particularly in the setting of multi-drug resistant infections, is limited by its nephrotoxicity. Despite its common occurrence, much remains unknown on the clinicopathologic profile as well as the pathogenesis of vancomycin nephrotoxicity. Clinical studies included patients often with severe comorbidities and concomitant polypharmacy confounding the causal pathogenesis. Animal models cannot recapitulate this complex clinical situation. Kidney biopsy was not commonly performed. METHODS: To address this limitation, we studied 36 patients who had renal biopsies for acute kidney injury (AKI) for suspicion of vancomycin nephrotoxicity. Detailed renal biopsy evaluation, meticulous evaluation of clinical profiles, and up-to-date follow-up allowed for a diagnostic categorization of vancomycin nephrotoxicity (VNT) in 25 patients and absence of vancomycin nephrotoxicity (NO-VNT) in 11 patients. For careful comparison of these two groups, we proceeded to compile a clinicopathologic and morphologic profiles characteristic for each group. RESULTS: Patients with VNT had a characteristic clinical profile including a common clinical background, a high serum trough level of vancomycin, a rapidly developed and severe acute kidney injury, and a recovery of renal function often shortly after discontinuation of vancomycin. This clinical course was correlated with characteristic renal biopsy findings including acute tubulointerstitial nephritis of allergic type, frequent granulomatous inflammation, concomitant and pronounced acute tubular necrosis of nephrotoxic type, and vancomycin casts, in the absence of significant tubular atrophy and interstitial fibrosis. This clinico-pathologic profile was different from that of patients with NO-VNT, highlighting its role in the diagnosis, management and pathogenetic exploration of vancomycin nephrotoxicity. CONCLUSION: Vancomycin nephrotoxicity has a distinctive morphologic and clinical profile, which should facilitate diagnosis, guide treatment and prognostication, and confer pathogenetic insights.

Myoglobin Cast Nephropathy Diagnosed on Renal Biopsy in a Patient Treated for Malarial Infection.

Myoglobin cast nephropathy occurs in cases of acute renal injury in which large amounts of myoglobin accumulate in the renal tubules, presenting as muscle pain, reddish-brown urine, and elevated creatine kinase levels. Our case describes a 60-year-old male who came to the emergency department with fevers, mild abdominal pain, and constitutional symptoms one day after returning to the United States from a trip to Nigeria. Initial workup demonstrated an acute kidney injury and elevated aminotransferase levels and the patient was started onatovaquone-proguanil for possible malaria given a recent diagnosis in Nigeria. Two days later, the patient was found to have rhabdomyolysis, resulting in a renal biopsy that showed myoglobin cast nephropathy. Previous literature has suggested mechanisms for the development of rhabdomyolysis in malarial infection, including inflammatory processes, direct effect of parasite accumulation, and drug-induced toxicity. Our case further implicates antimalarial therapy as a cause of rhabdomyolysis and increases awareness of myoglobin cast nephropathy as a potential complication of malaria.

Hyperoxia Disrupts Lung Lymphatic Homeostasis in Neonatal Mice.

Inflammation causes bronchopulmonary dysplasia (BPD), a common lung disease of preterm infants. One reason this disease lacks specific therapies is the paucity of information on the mechanisms regulating inflammation in developing lungs. We address this gap by characterizing the lymphatic phenotype in an experimental BPD model because lymphatics are major regulators of immune homeostasis. We hypothesized that hyperoxia (HO), a major risk factor for experimental and human BPD, disrupts lymphatic endothelial homeostasis using neonatal mice and human dermal lymphatic endothelial cells (HDLECs). Exposure to 70% O2 for 24-72 h decreased the expression of prospero homeobox 1 (Prox1) and vascular endothelial growth factor c (Vegf-c) and increased the expression of heme oxygenase 1 and NAD(P)H dehydrogenase [quinone]1 in HDLECs, and reduced their tubule formation ability. Next, we determined Prox1 and Vegf-c mRNA levels on postnatal days (P) 7 and 14 in neonatal murine lungs. The mRNA levels of these genes increased from P7 to P14, and 70% O2 exposure for 14 d (HO) attenuated this physiological increase in pro-lymphatic factors. Further, HO exposure decreased VEGFR3+ and podoplanin+ lymphatic vessel density and lymphatic function in neonatal murine lungs. Collectively, our results validate the hypothesis that HO disrupts lymphatic endothelial homeostasis.

Rapid Remission of Secondary Membranous Glomerulonephritis Due to Syphilis: A Case Report.

Membranous glomerulonephritis (MGN) is an antibody-mediated autoimmune disease that targets the glomerular basement membrane-podocyte complex, causing defects in the glomerular filtration barrier and resulting in nephrotic syndrome. Management of patients with MGN now relies on identifying the underlying etiology. A 36-year-old female patient, with a recent history of transient vision loss, presented with 11 days of progressive edema and episodes of vomiting, headache, and stomach pain. Evaluation of progressive proteinuria led to a renal biopsy, which showed normal glomerular histology by light microscopy and a full-house pattern of immune-complex deposits by immunofluorescence microscopy. Electron microscopy showing very occasional subepithelial deposits confirmed the diagnosis of MGN. Testing for anti-PLA2R antibody, a biomarker for primary (idiopathic) MGN, was negative by immunohistochemistry and serology. Extensive clinical evaluation and workup led to a rapid plasma reagin (RPR) test for syphilis, which was positive. Treatment was immediately initiated with furosemide, losartan, and weekly intramuscular benzathine penicillin, and within two weeks, the patient's edema had subsided, and her proteinuria had resolved. The patient remained in clinical remission at 11-month follow-up with good overall health. We emphasize the importance of early diagnosis of syphilis-induced MGN as prompt treatment results in rapid remission of renal disease. In the evaluation of secondary MGN, atypical presentations of syphilis should be considered in the differential diagnosis to ensure the timely initiation of appropriate management.

Papillary Fibroelastoma Incidentally Found on Left Atrial Wall During Minimally Invasive Aortic Valve Replacement.

A 60-year-old man was about to undergo minimally invasive aortic valve replacement when transesophageal echocardiography revealed an intracardiac mass on the left atrial free wall. Multimodal images from 5 months earlier had shown no mass. We converted the procedure to open surgery. The excised mass resembled a cardiac myxoma but was determined to be a papillary fibroelastoma. This case illustrates that papillary fibroelastomas can form and grow rapidly, warranting alertness for their unexpected discovery before and during cardiac surgical procedures.

Extracellular Signal-Regulated Kinase 1 Alone Is Dispensable for Hyperoxia-Mediated Alveolar and Pulmonary Vascular Simplification in Neonatal Mice.

Bronchopulmonary dysplasia (BPD) is a morbid lung disease distinguished by lung alveolar and vascular simplification. Hyperoxia, an important BPD causative factor, increases extracellular signal-regulated kinases (ERK)-1/2 expression, whereas decreased lung endothelial cell ERK2 expression reduces angiogenesis and potentiates hyperoxia-mediated BPD in mice. However, ERK1's role in experimental BPD is unclear. Thus, we hypothesized that hyperoxia-induced experimental BPD would be more severe in global ERK1-knockout (ERK1-/-) mice than their wild-type (ERK1+/+ mice) littermates. We determined the extent of lung development, ERK1/2 expression, inflammation, and oxidative stress in ERK1-/- and ERK1+/+ mice exposed to normoxia (FiO2 21%) or hyperoxia (FiO2 70%). We also quantified the extent of angiogenesis and hydrogen peroxide (H2O2) production in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs) with normal and decreased ERK1 signaling. Compared with ERK1+/+ mice, ERK1-/- mice displayed increased pulmonary ERK2 activation upon hyperoxia exposure. However, the extent of hyperoxia-induced inflammation, oxidative stress, and interrupted lung development was similar in ERK1-/- and ERK1+/+ mice. ERK1 knockdown in HPMECs increased ERK2 activation at baseline, but did not affect in vitro angiogenesis and hyperoxia-induced H2O2 production. Thus, we conclude ERK1 is dispensable for hyperoxia-induced experimental BPD due to compensatory ERK2 activation.

Endothelial Adenosine Monophosphate-Activated Protein Kinase-Alpha1 Deficiency Potentiates Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension.

Bronchopulmonary dysplasia and pulmonary hypertension, or BPD-PH, are serious chronic lung disorders of prematurity, without curative therapies. Hyperoxia, a known causative factor of BPD-PH, activates adenosine monophosphate-activated protein kinase (AMPK) α1 in neonatal murine lungs; however, whether this phenomenon potentiates or mitigates lung injury is unclear. Thus, we hypothesized that (1) endothelial AMPKα1 is necessary to protect neonatal mice against hyperoxia-induced BPD-PH, and (2) AMPKα1 knockdown decreases angiogenesis in hyperoxia-exposed neonatal human pulmonary microvascular endothelial cells (HPMECs). We performed lung morphometric and echocardiographic studies on postnatal day (P) 28 on endothelial AMPKα1-sufficient and -deficient mice exposed to 21% O2 (normoxia) or 70% O2 (hyperoxia) from P1-P14. We also performed tubule formation assays on control- or AMPKα1-siRNA transfected HPMECs, exposed to 21% O2 or 70% O2 for 48 h. Hyperoxia-mediated alveolar and pulmonary vascular simplification, pulmonary vascular remodeling, and PH were significantly amplified in endothelial AMPKα1-deficient mice. AMPKα1 siRNA knocked down AMPKα1 expression in HPMECs, and decreased their ability to form tubules in normoxia and hyperoxia. Furthermore, AMPKα1 knockdown decreased proliferating cell nuclear antigen expression in hyperoxic conditions. Our results indicate that AMPKα1 is required to reduce hyperoxia-induced BPD-PH burden in neonatal mice, and promotes angiogenesis in HPMECs to limit lung injury.

Adrenomedullin Deficiency Potentiates Lipopolysaccharide-Induced Experimental Bronchopulmonary Dysplasia in Neonatal Mice.

Lung inflammation interrupts alveolarization and causes bronchopulmonary dysplasia (BPD). Besides mechanical ventilation and hyperoxia, sepsis contributes to BPD pathogenesis. Adrenomedullin (Adm) is a multifunctional peptide that exerts anti-inflammatory effects in the lungs of adult rodents. Whether Adm mitigates sepsis-induced neonatal lung injury is unknown. The lung phenotype of mice exposed to early postnatal lipopolysaccharide (LPS) was recently shown to be similar to that in human BPD. This model was used to test the hypothesis that Adm-deficient neonatal mice will display increased LPS-induced lung injury than their wild-type (WT) littermates. Adm-deficient mice or their WT littermates were intraperitoneally administered 6 mg/kg of LPS or vehicle daily on postnatal days (PNDs) 3 to 5. The lungs were harvested at several time points to quantify inflammation, alveolarization, and vascularization. The extent of LPS-induced lung inflammation in Adm-deficient mice was 1.6-fold to 10-fold higher than their WT littermates. Strikingly, Adm deficiency induced STAT1 activation and potentiated STAT3 activation in LPS-exposed lungs. The severity of LPS-induced interruption of lung development was also greater in Adm-deficient mice at PND7. At PND14, LPS-exposed WT littermates displayed substantial improvement in lung development, whereas LPS-exposed Adm-deficient mice continued to have decreased lung development. These data indicate that Adm is necessary to decrease lung inflammation and injury and promote repair of the injured lungs in LPS-exposed neonatal mice.

Vancomycin-Associated Tubular Casts and Vancomycin Nephrotoxicity.

INTRODUCTION: Vancomycin nephrotoxicity is frequent and may be due to drug-induced acute tubular necrosis (ATN) or tubulointerstitial nephritis (TIN). Vancomycin-associated tubular cast (VTC) was recently described and may represent a novel cause of vancomycin nephrotoxicity. However, much is still unknown about VTC. MATERIALS AND METHODS: Thirty-seven kidney biopsy specimens from patients who were treated with vancomycin and developed acute kidney injury (AKI) were found among a total of 4673 biopsy samples between 2010 and 2019. These biopsy specimens were subjected to light microscopy, immunofluorescence, electron microscopy, and immunolocalization for vancomycin, uromodulin, myoglobin, tubular segment-specific markers, and examined for VTCs. The findings were correlated with the clinical course. RESULTS: VTCs displayed precipitated vancomycin casts in a background of uromodulin; the casts were limited to the distal tubules, and always associated with a background of more diffuse renal injury (ATN or TIN). The diagnosis of vancomycin nephrotoxicity was made in in 28 of 37 patients. VTC was noted in 25 of 28 biopsy samples from patients diagnosed with vancomycin nephrotoxicity and in one of nine biopsy samples from patients without this diagnosis. Vancomycin nephrotoxicity was diagnosed in 25 of 26 patients whose biopsy specimens showed VTC, but in only 3 of 11 patients without VTC in the biopsy samples. CONCLUSIONS: VTC displays a characteristic morphologic profile amenable to ready recognition in biopsy specimens. It results from coprecipitation of vancomycin and uromodulin. It facilitates the biopsy diagnosis of vancomycin nephrotoxicity. It may have a nephrotoxic effect superimposing on and independent from the ATN or interstitial nephritis in the pathogenesis of vancomycin nephrotoxicity.

A Japanese-American female with rapidly progressive interstitial lung disease associated with clinically amyopathic dermatomyositis.

Patients with clinically amyopathic dermatomyositis (CADM) have a risk of developing rapidly progressive interstitial lung disease (ILD). CADM-ILD is associated with the anti-MDA-5 antibody. In the USA, however, patients with CADM have these antibodies less frequently than those in Japan. In addition, those with this disorder are less often complicated with rapidly progressive ILD than those in Japan. We present a case of a 42-year-old Japanese-American female with a 3-month history of a rash on her hands and face with joint pain. Based on the negative results from lupus tests, her primary care provider and a rheumatologist treated her with steroids, hydroxychloroquine, and methotrexate. During treatment, the patient started noticing shortness of breath because of pneumonia, which was revealed by a CT scan. The woman was finally diagnosed with acute respiratory failure due to CADM with ILD. She underwent a double lung transplant as well as treatment with multiple immunosuppressive agents and repeated plasma exchange but died 15 days after transplantation. Her clinical course is similar to that of Japanese patients with CADM-ILD. Outside Japan, primary care providers, rheumatologists, and dermatologists, as well as pulmonary physicians, may be less familiar with this disorder than those in Japan. Since CADM-ILD progresses very quickly and could be fatal, these doctors should be aware of this disease to treat such patients as soon as possible, particularly when seeing a patient of Japanese descent.

Prevalence, Characteristics, and Outcomes of Incidental IgA Glomerular Deposits in Donor Kidneys.

INTRODUCTION: Incidental IgA deposits in donor kidneys have unknown sequelae and may predate clinical kidney disease if primed by adverse immunologic or hemodynamic stimuli or may remain dormant. METHODS: The presence of incidental IgA in post-implantation (T0) biopsies from living (LDK) and deceased donor (DDK) kidneys, and its relationship to post-transplant patient and graft outcomes was investigated in an ethnically diverse US population at a large transplant center. RESULTS: Mesangial IgA was present in 20.4% of 802 T0 biopsies; 13.2% and 24.5% of LDK and DDK, respectively. Donors with incidental IgA deposits were more likely to have hypertension and be of Hispanic or Asian origin. Intensity of IgA staining was 1+ (57.3%), 2+ (26.8%), or 3+ (15.8%) of the T0 IgA+ biopsies. Mesangial pathology correlated with higher-intensity IgA staining with less clearance on follow-up (53.8%) versus 79.2% without mesangial pathology. IgA cleared in 91%, 63%, and 40% of follow-up biopsies with 1+, 2+, and 3+ IgA staining, respectively. Early post-transplant rejection and rejection-related graft loss occurred more frequently in IgA+ kidney recipients; however, 5-year kidney function and graft survival were comparable to kidneys without IgA. CONCLUSION: This first and largest report of incidental IgA in T0 biopsies of LDK and DDK in a US ethnically diverse population demonstrated no adverse association between the presence of IgA in donor kidneys and graft or patient survival. Whether IgA in donor kidneys represents latent IgA nephropathy (IgAN) is uncertain; nevertheless, living donors who demonstrate IgA on T0 biopsy deserve careful follow-up.

Interactive and independent effects of early lipopolysaccharide and hyperoxia exposure on developing murine lungs.

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a chronic infantile lung disease that lacks curative therapies. Infants with BPD-associated PH are often exposed to hyperoxia and additional insults such as sepsis that contribute to disease pathogenesis. Animal models that simulate these scenarios are necessary to develop effective therapies; therefore, we investigated whether lipopolysaccharide (LPS) and hyperoxia exposure during saccular lung development cooperatively induce experimental BPD-PH in mice. C57BL/6J mice were exposed to normoxia or 70% O2 (hyperoxia) during postnatal days (PNDs) 1-5 and intraperitoneally injected with varying LPS doses or a vehicle on PNDs 3-5. On PND 14, we performed morphometry, echocardiography, and gene and protein expression studies to determine the effects of hyperoxia and LPS on lung development, vascular remodeling and function, inflammation, oxidative stress, cell proliferation, and apoptosis. LPS and hyperoxia independently and cooperatively affected lung development, inflammation, and apoptosis. Growth rate and antioxidant enzyme expression were predominantly affected by LPS and hyperoxia, respectively, while cell proliferation and vascular remodeling and function were mainly affected by combined exposure to LPS and hyperoxia. Mice treated with lower LPS doses developed adaptive responses and hyperoxia exposure did not worsen their BPD phenotype, whereas those mice treated with higher LPS doses displayed the most severe BPD phenotype when exposed to hyperoxia and were the only group that developed PH. Collectively, our data suggest that an additional insult such as LPS may be necessary for models utilizing short-term exposure to moderate hyperoxia to recapitulate human BPD-PH.

A novel BMPR2 mutation with widely disparate heritable pulmonary arterial hypertension clinical phenotype.

Mutations in the gene encoding bone morphogenetic protein receptor type II (BMPR2) have been associated with heritable pulmonary arterial hypertension (HPAH), whereas mutations in the gene encoding eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) are associated with heritable pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (HPVOD/PCH). We describe two unrelated patients found to carry the same hitherto unreported pathogenic BMPR2 mutation; one of whom presented with typical pulmonary arterial hypertension, whereas the second patient presented with aggressive disease and characteristic clinical features of PVOD/PCH. These two clinically divergent cases representative of the same novel pathogenic mutation exemplify the variable phenotype of HPAH and the variable involvement of venules and capillaries in the pathology of the pulmonary vascular bed in pulmonary arterial hypertension.

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice.

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a significant lung morbidity of infants, and disrupted lung angiogenesis is a hallmark of this disease. We observed that extracellular signal-regulated kinases (ERK) 1/2 support angiogenesis in vitro, and hyperoxia activates ERK1/2 in fetal human pulmonary microvascular endothelial cells (HPMECs) and in neonatal murine lungs; however, their role in experimental BPD and PH is unknown. Therefore, we hypothesized that Tie2 Cre-mediated deficiency of ERK2 in the endothelial cells of neonatal murine lungs would potentiate hyperoxia-induced BPD and PH. We initially determined the role of ERK2 in in vitro angiogenesis using fetal HPMECs. To disrupt endothelial ERK2 signaling in the lungs, we decreased ERK2 expression by breeding ERK2flox/flox mice with Tie-Cre mice. One-day-old endothelial ERK2-sufficient (eERK2+/+) or -deficient (eERK2+/-) mice were exposed to normoxia or hyperoxia (FiO2 70%) for 14 d. We then performed lung morphometry, gene and protein expression studies, and echocardiography to determine the extent of inflammation, oxidative stress, and development of lungs and PH. The knockdown of ERK2 in HPMECs decreased in vitro angiogenesis. Hyperoxia increased lung inflammation and oxidative stress, decreased lung angiogenesis and alveolarization, and induced PH in neonatal mice; however, these effects were augmented in the presence of Tie2-Cre mediated endothelial ERK2 deficiency. Therefore, we conclude that endothelial ERK2 signaling is necessary to mitigate hyperoxia-induced experimental BPD and PH in neonatal mice. Our results indicate that endothelial ERK2 is a potential therapeutic target for the management of BPD and PH in infants.

Adrenomedullin Is Necessary to Resolve Hyperoxia-Induced Experimental Bronchopulmonary Dysplasia and Pulmonary Hypertension in Mice.

Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is an infantile lung disease characterized by aberrant angiogenesis and impaired resolution of lung injury. Adrenomedullin (AM) signals through calcitonin receptor-like receptor and receptor activity-modifying protein 2 and modulates lung injury initiation. However, its role in lung injury resolution and the mechanisms by which it regulates angiogenesis remain unclear. Consequently, we hypothesized that AM resolves hyperoxia-induced BPD and PH via endothelial nitric oxide synthase (NOS3). AM-sufficient (ADM+/+) or -deficient (ADM+/-) mice were exposed to normoxia or hyperoxia through postnatal days (PNDs) 1 to 14, and the hyperoxia-exposed mice were allowed to recover in normoxia for an additional 56 days. Lung injury and development and PH were quantified at different time points. Human pulmonary microvascular endothelial cells were also used to examine the effects of AM signaling on the NOS3 pathway and angiogenesis. Lung blood vessels and NOS3 expression decreased and the extent of hyperoxia-induced BPD and PH increased in ADM+/- mice compared with ADM+/+ mice. Hyperoxia-induced apoptosis and PH resolved by PND14 and PND70, respectively, in ADM+/+ mice but not in ADM+/- mice. Knockdown of ADM, calcitonin receptor-like receptor, and receptor activity-modifying protein 2 in vitro decreased NOS3 expression, nitric oxide generation, and angiogenesis. Furthermore, NOS3 knockdown abrogated the angiogenic effects of AM. Collectively, these results indicate that AM resolves hyperoxic lung injury via NOS3.

Factores que limitan la descentralización del Sistema Nacional de Salud del Paraguay / Factors that limit the decentralization of the National health system of Paraguay

Introducción: La descentralización ha sido una política de Estado en Paraguay desde la promulgación de la Constitución Nacional en 1992 y la ley del Sistema Nacional de Salud en 1996. Aunque el marco legal es favorable el proceso es incipiente y está estancado. Objetivos: describir la importancia de ciertos factores políticos, jurídicos, institucionales, financieros y técnicos como limitantes de la descentralización sanitaria en Paraguay. Materiales y Métodos: se aplicó una encuesta a 511 informantes claves seleccionados por conveniencia para valorar sus percepciones sobre 8 factores identificados mediante entrevistas. Respondieron utilizando una escala ordinal de 1 a 4 referidos a que tan críticos son para ellos estos factores limitantes. Se calculó una resultante para cada factor y se categorizó como mínimo, incipiente, moderado y máximo. Previamente se realizaron entrevistas en profundidad exploratorias para identificar estos factores. Resultados: sobre la percepción de los encuestados señalan que el marco legal inadecuado es un determinante moderado (3 de la escala) con 81,0% mientras que los demás son valorados como máximos (4 de la escala): reticencia a delegar autoridad 81,7%; capacidad técnica limitada 84,7%; acceso limitado a tecnologías 85,4%; capacidad de gestión limitada 86,6%; afinidad política 87,9%; burocracia excesiva 90,9% y presupuesto insuficiente 92,7%. Conclusión: el hecho que la descentralización sanitaria haya avanzado poco se debe a un conjunto de factores, algunos más críticos que otros, que deberían ser considerados en las políticas sectoriales.

Introduction: Decentralization has been a state policy in Paraguay since the promulgation of both the National Constitution in 1992 and the law of the National Health System in 1996. Although the legal framework is favorable, the process is incipient and it's stagnating. Objective: describe the importance of certain political, legal, institutional, financial and technical factors as limitations of the health decentralization in Paraguay. Material and Methods: a poll was applied to 511 key informants selected for convenience to value their perceptions about 8 identified factors through interviews. They answered using an ordinal scale from 1 to 4 referring to how critical these limiting factors are to them. Was calculated a resultant for every factor and was categorized as minimum, incipient, moderate, and maximum. First, exploratory interviews were conducted to identify these factors. Results: about perceptions of the surveyed demonstrate that inadequate legal framework is a moderate determinant (3 from the scale) with 81.0% while others are evaluated as maximums (4 from the scale); reluctance to delegate authority 81.7%; limited technical capacity 84.7%; limited access to technology 85.4%; limited management capacity 86.6%; political affinity 87.9%; excessive bureaucracy 90.9% and insufficient budget 92.7%. Conclusion: the fact that health decentralization has advance poorly is due to a set of factors, some more critical than others, that should be considered in sectoral policies.

Micropapillary adenocarcinoma of lung: Morphological criteria and diagnostic reproducibility among pulmonary pathologists.

CONTEXT: Invasive micropapillary adenocarcinoma (MPC) is an aggressive variant of lung adenocarcinoma, frequently manifesting with advanced stage lymph node metastasis and decreased survival. OBJECTIVE: Identification of this morphology is important, as it is strongly correlated with poor prognosis regardless of the amount of MPC component. To date, no study has investigated the morphological criteria used to objectively diagnose it. DESIGN: Herein, we selected 30 cases of potential MPC of lung, and distributed 2 digital images per case among 15 pulmonary pathology experts. Reviewers were requested to diagnostically interpret, assign the percentage of MPC component, and record the morphological features they identified. The noted features included: columnar cells, elongated slender cell nests, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial signet ring-like forms, intracytoplasmic vacuolization, multiple nests in the same alveolar space, back-to-back lacunar spaces, epithelial nest anastomosis, marked pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, small/medium/large tumor nest size, fibrovascular cores, and spread through air-spaces (STAS). RESULTS: Cluster analysis revealed three subgroups with the following diagnoses: "MPC", "combined papillary and MPC", and "others". The subgroups correlated with the reported median percentage of MPC. Intracytoplasmic vacuolization, epithelial nest anastomosis/confluence, multiple nests in the same alveolar space, and small/medium tumor nest size were the most common criteria identified in the cases diagnosed as MPC. Peripherally oriented nuclei and epithelial signet ring-like forms were frequently identified in both the "MPC" and "combined papillary and MPC" groups. CONCLUSIONS: Our study provides objective diagnostic criteria to diagnose MPC of lung.