Implementation of the delayed antibiotic prescribing strategy. Prospective observation study in primary care.

OBJECTIVE: We aimed to compare the actual consumption of antibiotics among patients issued delayed antibiotic prescribing with the consumption observed in a non-systematic review of studies on delayed prescribing. METHODS: Observational study carried out in three primary care centres from September 2018 until March 2020. We tracked the electronic records of the 82 patients with episodes of acute bronchitis and 44 acute pharyngitis who were given a patient-led delayed prescription to determine whether the prescription was filled and when this medication was obtained. RESULTS: The prescriptions were never filled in 50 cases (39.7%), but five patients took another antibiotic within the first two weeks. Out of 76 patients who did take the delayed prescription, only 12 obtained the medication based on the instructions given by the doctors (15.8%). CONCLUSIONS: The strategy of delayed antibiotic prescribing resulted in a reduction in antibiotic use, but this reduction was lower than in randomised clinical trials, being comparable to the results obtained with other observational studies on delayed antibiotic prescribing. In addition, only a few patients adhered to the doctors' instructions.

Effects of Hesperidin Consumption on the Cardiovascular System in Pre- and Stage 1 Hypertensive Subjects: Targeted and Non-Targeted Metabolomic Approaches (CITRUS Study).

SCOPE: The aim of the present work is to determine new biomarkers of the biological effects of hesperidin in orange juice (OJ) applying a non-targeted metabolomics approach validated by targeted metabolomics analyses of compliance biomarkers. METHODS AND RESULTS: Plasma/serum and urine targeted (HPLC-MS/MS) and untargeted (1 H-NMR) metabolomics signatures are explored in a subsample with pre- and stage-1 hypertension subjects of the CITRUS study (N = 159). Volunteers received 500 mL day-1 of control drink, OJ, or hesperidin-enriched OJ (EOJ) for 12-weeks. A 6-h postprandrial study is performed at baseline. Targeted analyses reveals plasma and urine hesperetin 7-O-ß-d-glucuronide as the only metabolite differing between OJ and EOJ groups after 12-weeks consumption, and in urine is correlated with a decreased systolic blood pressure level. The non-targeted approach shows that after single dose and 12-weeks consumption of OJ and EOJ change several metabolites related with an anti-inflammatory and antioxidant actions, lower blood pressure levels and uremic toxins. CONCLUSIONS: Hesperetin 7-O-ß-d-glucuronide can be a candidate marker for distinguishing between the consumption of different hesperidin doses at 12-weeks consumption as well as a potential agent mediating blood pressure reduction. Moreover, changes in different endogenous metabolites can explain the mechanisms of action and the biological effects of hesperidin consumption.

[Prevalence of microbiologically-confirmed influenza in patients with influenza-like illness in primary care and clinical and epidemiological characteristics]. / Prevalencia de gripe confirmada microbiológicamente en pacientes con síntomas gripales en atención primaria y características clínico-epidemiológicas.

OBJECTIVE: We evaluated the prevalence of microbiologically-confirmed influenza infection among patients with influenza-like symptoms and compared the clinical and epidemiological characteristics of patients with and without influenza infection. METHODS: Retrospective study of a cohort of patients with influenza-like symptoms from 2016 to 2018 who participated in a clinical trial in thirteen urban primary centres in Catalonia. Different epidemiological data were collected. Patients rated the different symptoms and signs on a Likert scale (absent, little problem, moderate problem and severe problem) and self-reported the measure of health status with the EuroQol visual analogue scale. A nasopharyngeal swab was taken for microbiological isolation of influenza and other microorganisms. RESULTS: A total of 427 patients were included. Microbiologically confirmed influenza was found in 240 patients (56.2%). The percentage of patients with moderate-to-severe cough, muscle aches, tiredness and dizziness was greater among patients with microbiologically confirmed influenza. The self-reported health status was significantly lower among patients with true flu infection (mean of 36.3 ± 18.2 vs 41.7 ± 17.8 in patients without influenza; p<0.001). CONCLUSIONS: Clinical findings are not particularly useful for confirming or excluding the diagnosis of influenza when intensity is not considered. However, the presence of moderate-to-severe cough, myalgias, tiredness and dizziness along with a poor health status is more common in patients with confirmed flu infection.

[Utilisation of first-line antibiotics six years after a multifaceted intervention]. / Uso de antibióticos de primera línea 6 años después de una intervención multifacética.

OBJECTIVE: No study has evaluated the impact of a multifaceted intervention on the quality of the antibiotics prescribed more than 5 years later. METHODS: A total of 210 general practitioners (GP) from eight different regions of Spain were asked to participate in two registrations of respiratory tract infections (RTI) in 2008, before, and in 2009, just after a multifaceted intervention including prescriber feedback, clinical guidelines, training sessions focused on appropriate antibiotic prescribing, workshop on rapid tests and provision of these tests in the GP consultation. They were all again invited to participate in a similar registration in 2015. A new group of clinicians from the same areas who had never participated in antimicrobial stewardship courses were also invited to participate and acted as controls. RESULTS: The 121 GPs who continued the study (57.6%) and the 117 control GPs registered 22,407 RTIs. The antibiotic most commonly prescribed was amoxicillin and clavulanic acid, prescribed in 1,801 cases (8.1% of the total), followed by amoxicillin (1,372 prescriptions, 6.2%), being lower among GPs just after the intervention. The third leading antibiotic among GPs just after the intervention was penicillin V (127 cases, 3.3%) whereas macrolides ranked third in the other three groups of GPs. CONCLUSIONS: The use of first-line antibiotic for RTIs wanes over time after an intervention, but their utilisation is still significantly greater among intervened clinicians six years later compared to GPs who have never been exposed to any antimicrobial stewardship programmes.

Misconceptions of Spanish general practitioners' attitudes toward the management of urinary tract infections and asymptomatic bacteriuria: an internet-based questionnaire study.

OBJECTIVE: The diagnosis and management of urinary tract infections (UTI) vary widely across countries and practices. The objective of this study was to gain insight into general practitioners' (GP) perceptions on the current management of UTIs and asymptomatic bacteriuria in Spain. METHODS: Cross-sectional, internet-based questionnaire study answered from July to September 2013. GPs affiliated with the largest Spanish scientific society in primary care (Sociedad Española de Medicina Familiar y Comunitaria) were invited to participate in the study. They were asked about the tests ordered in both uncomplicated and complicated UTIs and about the management in three clinical scenarios, depicting a 50-year woman with: 1. An uncomplicated UTI, 2. A complicated UTI, and 3. An asymptomatic bacteriuria. RESULTS: The questionnaire was completed by 1,239 GPs (6.7%). Urine cultures were reportedly requested by 26.3% of the GPs in uncomplicated UTIs and by 71.8% of the cases corresponding to the complicated UTIs whereas it was declared that dipsticks were the preferred tests in only uncomplicated UTIs (38.2%). A total of 22% and 13.2% of the GPs stated that they would withhold antibiotic therapy in patients with low-count and high-count asymptomatic bacteriuria, respectively. CONCLUSIONS: GPs have important misconceptions as to the indications for ordering urine cultures and in interpreting the definitions of common UTIs and treating UTIs and asymptomatic bacteriuria. The unnecessary use of antibiotics in patients with asymptomatic bacteriuria is considerable in Spain.

Usefulness of a patient symptom diary card in the monitoring of exacerbations of chronic bronchitis and chronic obstructive pulmonary disease.

OBJECTIVE: To assess the usefulness of a patient diary card of symptoms for monitoring the evolution of an exacerbation of chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD) in primary care. METHOD: Multicentre, observational study. Patients with an exacerbation filled out a diary every day before bedtime during 10 days. The diary score ranged from 0 (best) to 28 (worst). A visit was performed at day 15 to collect the patient diaries. RESULTS: Of the 1101 patients studied 921 returned the diaries (83.7%). Clinical failure was found in 236 patients (25.6%). The mean global score on day 1 was 21.5 ± 3.8. Patients considered as cured at day 10 presented a lower score at day 1 (21.1 ± 3.9) vs. those who failed (22.6 ± 4.2; p < 0.001). When no reduction was observed in the score from days 1 to 3, the percentage of failures was 36.1%, being only 11.6% with a reduction of 5 points or more (p < 0.001). The strongest correlation with failure was observed with general status, breathing, symptom scale and the need for extra inhaler doses. CONCLUSION: A symptom diary card seems to be a valuable tool to monitor the evolution of an acute exacerbation of CB/COPD in primary care.

[Compliance rate of antibiotic therapy in patients with acute pharyngitis is very low, mainly when thrice-daily antibiotics are given]. / El cumplimiento del tratamiento antibiótico en la faringitis aguda es muy bajo, principalmente con antibióticos que se toman tres veces al día.

OBJECTIVE: To assess drug-compliance observed among patients with suspected streptococcal pharyngitis treated with twice-daily antibiotic regimens (b.i.d.) and others with thrice-daily regimens (t.i.d.). METHODS: A prospective study in the primary care setting was designed in which patients with pharyngitis and three or more Centor criteria, non-allergic to beta-lactam agents, treated with several b.i.d and t.i.d antibiotic regimens based on doctor's choice, were recruited. Patient compliance was assessed with electronic monitoring. RESULTS: A total of 113 patients were enrolled (64 in the t.i.d. group and 49 in the b.i.d. group). Mean openings ranged from 70.3 to 83.3% of the total amount of pills. All the parameters analysed indicated significantly worse compliance with the t.i.d. regimens. Eleven patients allocated to the t.i.d. group took at least 80% of the pills (17.2%), this being significantly lower than those who received b.i.d. antibiotics (59.2%; p < 0.001). The percentage of patients who opened the Medication Event Monitoring System (MEMS) container the satisfactory number of times a day was systematically lower among t.i.d. regimens, this being statistically significant from day three (p < 0.05). Patients assigned to t.i.d. regimens more frequently forgot the afternoon dose. CONCLUSION: Compliance rate was very low, mainly when patients are given t.i.d antibiotic regimens. This may lead to storage of antibiotics and subsequent self-medication. New strategies addressed to improve drug-compliance with antibiotics among outpatients are therefore necessary.

[Gastrointestinal stromal tumors: prognostic value of DNA analysis with flow cytometry and of classical clinicopathologic parameters]. / Tumores mesenquimales del tubo digestivo: valor pronóstico del análisis del ADN por citometría de flujo y de los parámetros clinicopatológicos clásicos.

BACKGROUND: Biological behavior of gastrointestinal stromal tumours (GIST) is still difficult to predict. The aim of this study was to analyze the prognostic valve of DNA study by flow cytometry in addition to the classical clinicopathologic parameters. PATIENTS AND METHODS: 82 GIST were investigated to assess by multivariable analysis the prognostic significance of classical morphologic and clinical features and DNA flow-cytometric analysis. RESULTS: Features significantly correlated with bad prognosis were: pain, recurrences, metastasis, small intestine tumours, invasion of adjacent tissues, size > 6 cm, infiltrative pattern, high cellularity, high-grade of atypia, mitosis count > 2/50 high powered field, necrosis, DNA aneuploid-hyperploid or near-diploid, S and SG2M-phase of aneuploid/s population/s > 11% and average S-phase > 11%. Multivariable analysis showed that mitotic activity was the only independent variable indicating poor prognosis. CONCLUSIONS: In this series of GIST mitosis count was the only independent prognostic factor, being more important than flow-cytometric variables like DNA ploidy and cellular cycle values.

Image analysis of dermal collagen changes during skin aging.

OBJECTIVE: To determine progressive quantitative, directional and textural changes in dermal collagen as a function of age and sex and to estimate their evolutive trend with appropriate regression models. STUDY DESIGN: Ninety-six samples of abdominal skin from autopsy cases were analyzed. The ages ranged from 3.5 months to 86 years. Picro-Sirius-stained slides were examined by polarizing microscopy, and spatial density, directional features and texture of collagen were measured by computerized image analysis. Nonlinear regression models were built to estimate evolutive changes with respect to age. The relationship between spatial orientation of collagen bundles and age was best modeled by linear regression. RESULTS: The evolutive patterns of dermal thickness and spatial density of collagen bundles correspond to a second-order polynomial model with a progressive increase from childhood to middle age and a relatively sharp decrease after the seventh decade. The evolution of textural pattern of dermal collagen, defined by gradient analysis, depicts a sort of inverted U. Its complexity is maximum in the first year of life, decreases until the period 25-50 years and increases progressively after the sixth decade. The horizontal orientation of collagen bundles with intermingled fascicles oriented in other directions, shown by young individuals, is progressively simplified with aging. In elderly subjects, collagen bundles have a horizontal orientation. No significant sex-related differences were found. CONCLUSION: Dermal collagen changes related to aging are apparently independent of sex, at least in abdominal skin, and show characteristic curvilinear evolutive trends defined by decreased dermal thickness in the elderly, decrease in the spatial density of collagen bundles and increase in textural heterogeneity of the dermis. Progressive simplification in the orientation of collagen bundles leading to a predominant horizontal disposition followed a linear trend. These changes could contribute to providing a substantial morphologic basis to age-associated biomechanical alterations in the skin.

Characteristics of perisinusoidal collagenization in liver cirrhosis: computer-assisted quantitative analysis.

OBJECTIVE: To determine the respective roles of septal fibrosis, necroinflammatory activity, iron deposition, steatosis, and patterns of nodular and septal remodeling in the collagenization of the perisinusoidal space in livers from patients undergoing transplantation for alcoholic or posthepatitis C cirrhosis and to ascertain whether perisinusoidal collagenization has clinical implications added to those of septal fibrosis. STUDY DESIGN: Sixty-six hepatectomy specimens from patients undergoing liver transplantation for cirrhosis were analyzed. Thirty-two alcoholic and 34 posthepatitis C cirrhoses were included. Picro Sirius-stained slides were examined with polarized light and the amount of perisinusoidal collagenization measured by computerized image analysis. Size distributions of septa and nodules were assessed by mathematical morphology methods. RESULTS: The septal and perisinusoidal fibrosis indices and Knodell and Pugh-Child scores showed significant differences between alcoholic and posthepatitis cirrhoses. Correlation between septal fibrosis and perisinusoidal collagenization was weak, though significant. Both variables correlated significantly with the clinical score. The correlation was negative between septal fibrosis or perisinusoidal collagenization and the Knodell score. CONCLUSION: Perisinusoidal collagenization was not a feature of all cases of cirrhosis, although it was more prominent in alcoholics. For the whole series, it significantly correlated with the clinical score, which increased significantly when high perisinusoidal collagenization was added to high septal fibrosis. No absolute dependence was found between perisinusoidal collagenization and septal fibrosis; percentage of slender fibrous septa and amount of iron deposition were other factors entered in the regression equation.

Differential diagnosis of malignant and reactive cells from serous effusions: image and texture analysis study.

The interrelationship of textural primitives which define morphological texture can be estimated by quite different descriptors; the discriminant value of which varies considerably. In the present study three different approaches to the texture analysis of nuclear chromatin were assayed to correctly allocate 332 cells from a pool obtained from serous effusions (six malignant mesotheliomas, six reactive mesothelial proliferations and five pleural metastases of lung adenocarcinoma). In all cases, initial cytological diagnosis posed considerable problems and final diagnosis was established by histologic examination of surgical specimens. The three approaches were based on binarization of the image obtained by edge detection, gradient analysis and pattern spectrum by morphological opening-closing, respectively. Characteristics afforded by each method were: (a) spatial distribution of heterochromatin, besides geometric features, (b) features related to transitions and contrast between dark and light chromatin primitives, and (c) granulometric characteristics of the theoretically biphasic heterochromatin-euchromatin image defined by mathematical morphology. The three methods were applied to the raw grey-tone image and did not require interactive handling. Although each of the three approaches yielded relatively satisfactory results, with percentages of well-classified cells in the test set ranging from 61.45 to 67.47, the best results (78.31% of well-classified cells) were obtained taking into consideration the three types of variables (area, 2nd opening, 5th closing, and S.D. of the amplitude image). A point to be stressed is the considerably high proportion of correctly-allocated reactive mesothelial cells (82.0%) in a field where subjective assessment commonly yields rather poor results. Nevertheless, classification yielded 14.8% and 3.3% false positives as adenocarcinomatous and malignant mesothelioma cells, respectively. In the theorectical situation devised in the study, results on a cell-by-cell basis encouraging and suggest that a textural approach might be useful in a dedicated expert system or on a more real case-by-case basis.

Nuclear texture in poorly differentiated small round cell tumors. Image analysis study of fine needle aspiration material.

Gradient analysis and pattern spectrum decomposition based on mathematical morphology concepts were used to explore nuclear texture patterns in a pool of 108 cells obtained by fine needle aspiration of five undifferentiated small round cell tumors of childhood, including one case each of Wilms' tumor, neuroblastoma, lymphoblastic lymphoma, Ewing's sarcoma and rhabdomyosarcoma. The aim of the study was to determine the presumptive value of nuclear pattern to correctly allocate each isolated cell to each of the five patients. The cells were examples of five histogenetically different tumors, all undifferentiated and with a close microscopic resemblance to one another. High gradient structures (heterochromatin-euchromatin and nuclear membrane edges) were estimated by a difference-of-boxes filter, and pattern spectrum decomposition was obtained by successive openings and closings performed on the input gray tone image. One important feature of these procedures was that no prior selection by thresholding of the structures to be studied was required, thus obviating subjective bias. Percentages of correctly allocated cells by canonical analysis ranged from 70.0% (rhabdomyosarcoma) to 92.9% (Ewing's sarcoma). Although the five cases could be distinguished using seven texture variables, this does not imply generalization of the results for the differential diagnosis of these tumors. Nonetheless, the possibility that undifferentiated small round cells present distinctive nuclear patterns when studied by sensitive image analysis techniques is suggested by our results.

Image analysis of hemosiderin-laden macrophages in bronchoalveolar lavage fluid.

The aim of this study was to assess quantitatively the relationship between the number of iron-laden macrophages, extent of hemosiderin content and amount of dark-stained hemosiderin clumps in bronchoalveolar lavage (BAL) fluids. The series included specimens from 20 subjects whose BAL had yielded iron-laden macrophages. Six had developed hemoptysis 3-15 days prior to BAL. Quantitative studies were performed on smears stained by the ferrocyanide reaction, using true color image analysis for image segmentation. A top-hat function based on mathematical morphologic concepts was used for extraction of dark clumps of hemosiderin. The results demonstrated the presence of iron-laden macrophages three days after hemoptysis. There was a moderate correlation between the percentage of macrophages and amount of hemosiderin content, but the extent of dark-stained clumps did not increase in parallel to the increase in hemosiderin content and probably represented an advanced stage in the phagocytic processing of hemosiderin formed from engulfed red blood cells. The main difference between subjects with and without previous hemoptysis was higher values for dark clumps of hemosiderin in the former.

Textural analysis of lymphoid cells in serous effusions. A mathematical morphologic approach.

Nuclear texture of reactive and well-differentiated neoplastic lymphocytes from serous effusions was studied by an approach based on principles of mathematical morphology. Density features were obtained before and after gray level nuclear image transformation by morphologic closing (dilation followed by erosion) and application of a top-hat function, which detects light or dense spots with a determined width and contrast. Five cases of benign reactive lymphocytic serous effusions and 11 cases of effusions in well-differentiated lymphocytic lymphomas were analyzed retrospectively. Each lymphoid cell was characterized by 24 densitometric features. Rank-order transformation was used for linear discriminant analysis given non-normal distributions of variables. In a first model formed by pooling all cells, discriminant function distinguished between 110 reactive and 216 malignant lymphocytes in the learning set and between 111 reactive and 226 malignant lymphocytes in the test set with better than 81% accuracy in both. In a second model, correct classification of cases as reactive or malignant was achieved in 5/5 reactive and 11/11 malignant lymphoid effusions. The results indicate that mathematical morphologic transformations of the gray level image may be an effective adjunct to other textural descriptors of cellular atypia, especially in the differential diagnosis of lymphoid serous effusions.

Fine needle aspiration diagnosis of renal oncocytoma. A mathematical morphologic approach.

Differentiation between renal oncocytomas and well-differentiated oxyphilic cell renal carcinomas from fine needle aspiration cytology smears may present considerable difficulties. To better define diagnostic criteria, we used high-resolution architectural characteristics of nucleus and cytoplasm based on mathematical morphologic concepts. Particulate structural elements were selected for their size and optical density by the so-called top-hat function. Spatial density, size distribution and a function of distance between particles were computed. We quantitated cellular samples from fine needle aspirates obtained from 10 renal oncocytomas and 5 well-differentiated oxyphilic cell renal carcinomas. In two of the former, cytologic diagnosis was doubtful. Subsequent removal of the tumor and its histologic examination established the final diagnosis in all cases. Stepwise discriminant analysis correctly classified all cases as oncocytomas or renal carcinomas, although the results need to be considered with caution due to the necessarily limited number of observations. Multivariate graphic representation by star glyphs clearly depicted the differences between oncocytoma and oxyphilic cell renal carcinomas and the abnormal characteristics of two oncocytoma cases misclassified initially.

Mathematical morphologic analysis of aging-related epidermal changes.

Fractographic techniques based on mathematical morphology were used to study aging-related epidermal changes in abdominal skin samples obtained from 96 autopsy cases. Three linear roughness indices were evaluated for the rete peg profile and the shrinkage effect on the basal layer and interface between the granular and horny layers. Elderly subjects had a 36.3% decrease in rete peg-related roughness index when compared with younger subjects. This roughness index has been corrected, with shrinkage due to skin elasticity taken into account. For females, fitting of a logistic decay function yielded a curve with right and left asymptotes and a steeper descent between 40 and 60 years. Half value time--i.e., the time when half rete peg profile flattening occurred--was 46.8 years. In contrast, males showed almost monotonical decay. Epidermal thickness measured between rete pegs showed the same exponential decline for both sexes, with values from 22.6 to 11.4 microns. Skin shrinkage in elderly subjects decreased 22% in superficial layers and only 6% in the lower epidermis. In both cases shrinkage had a linear relation with age, and no sex differences were found.

Mathematical morphologic analysis of the aortic medial structure. Biomechanical implications.

The architecture of the aortic tunica media was studied in 55 autopsy specimens (26 normotensive and 29 hypertensive patients). The purpose of the study was to elucidate whether, as commonly stated, homogeneous disposition of concentric lamellar units could be substantiated or whether an architectural gradient reflecting the decreasing biomechanical gradient in the circumferential stress, concentrated towards the inner wall, was present. The elastin lamellae thickness, interlamellar distance, fibrosis index and fragmentation index were quantitated by mathematical morphology methods. The results did not support classic histologic descriptions but showed that lamellar units were significantly thicker in the inner than in the outer zones of the media--i.e., a morphologic gradient was present. The differences between inner and outer zones were more marked in hypertensive patients than in controls. The fibrosis index increased with age, especially in hypertensive patients. The fragmentation index in hypertensive patients was significantly higher than in controls and more marked in abdominal than in thoracic aorta. This weakening in the biomechanical resistance of elastin fibers could be one of the factors explaining the predominance of aneurysms in the abdominal aorta.

Mathematical morphologic analysis of liver cirrhosis. Correlation with etiology, clinical score and hepatocellular carcinoma.

Remodeling of the cirrhotic liver was studied retrospectively by mathematical morphologic methods in 75 autopsy cases (40 alcoholic, 17 hepatitis B virus (HBV)-related and 18 cryptogenetic cirrhosis), including 28 hepatocellular carcinomas. The aim was to obtain objective measurements of cirrhotic patterns that could be correlated with liver function evaluated by the Pugh-Child score, establish the relationship among different morphogenetic features and evaluate the implications of an objective classification of cases by numerical taxonomy in terms of their etiology, liver function and malignant transformation. The results indicate that the Pugh-Child score was closely related to the global amount of fibrosis or to the percentage of regenerative nodules < 0.8 mm in diameter. In contrast, the higher the percentage of lobular-sized regenerative nodules (0.8-1.6 mm), the better the functional score, suggesting that they are probably residual lobules, albeit completely surrounded by fibrous tissue, rather than true regenerative pseudolobules. The four groups of cases obtained by numerical taxonomy (cluster analysis) showed different distributions for alcoholic and HBV-related cirrhosis. The pattern of the latter was practically analogous to that in classically labeled cryptogenetic cirrhosis, suggesting its viral etiology. Taxonomic classification had functional implications. The Pugh-Child score showed a definite relationship with the different clusters obtained. The incidence of malignant transformation gradually decreased from group G1 to G4, with a steeper descent between G2 and G3. These results might contribute to a more dynamic concept of morphologic changes in liver biopsies from patients with cirrhosis.