Endophthalmitis: Microbiology and Organism Identification Using Current and Emerging Techniques.

Endophthalmitis is an ophthalmological emergency requiring timely and appropriate diagnosis and treatment. Microbiological methods of microscopy (Gram's staining) and culture are the current gold standard for organism identification. However, a significant proportion of endophthalmitis remains culture-negative-perhaps the inflammation is non-infectious in origin, results from a novel organism are unidentifiable or because the causative organism is non-culturable often due to pre-treatment with antibiotics. This review outlines the microbiological profile of endophthalmitis, current clinically used methods for organism identification, and the newer molecular techniques of polymerase chain reaction (PCR) and next-generation sequencing (NGS) technology as diagnostic tools for endophthalmitis. They offer the potential to improve organism identification rates and clinical outcomes in infectious diseases, representing an exciting future direction for organism identification in endophthalmitis. Based on the largest ophthalmic hospital in Australia, we highlight the key practical challenges faced by Australian diagnostic laboratories for their use in a clinical setting.

Phosphine-catalyzed regio- and stereo-selective hydroboration of ynamides to (Z)-ß-borylenamides.

We report a tri-n-butyl phosphine catalyzed regio- and stereo-selective hydroboration of ynamides to yield (Z)-ß-borylenamides in good yields. Surprisingly, a formal cis addition to the triple bond was observed as confirmed by NMR and X-ray crystallography. 31P NMR studies suggest that a zwitterionic vinylphosphonium intermediate is key in the mechanism. The resulting products were further transformed to ß-CF3 enamides via stereoretentive trifluoromethylation.

Surgical Techniques for Tonsillectomy and Perioperative Respiratory Complications in Children.

OBJECTIVES: The aim of this study was to determine the incidence of perioperative respiratory complications in children following tonsillectomy with cold and hot dissection surgical techniques. STUDY DESIGN: The study was a retrospective cohort study. SETTING: Retrospective chart review was performed for all children presenting for a tonsillectomy at Texas Children's Hospital from November 2015 to December 2017. METHODS: Pre- and intraoperative patient factors, including surgical technique with cold or hot dissection (electrocautery or radiofrequency ablation), and perioperative anesthetic factors were collected to determine the incidence of perioperative respiratory complications. RESULTS: A total of 2437 patients underwent a tonsillectomy at Texas Children's Hospital from November 2015 to December 2017. The incidence of perioperative respiratory complications was 20.0% (n = 487). Sickle cell disease, cardiac disease, reactive airway disease, pulmonary disease, age >2 and <3 years, and obesity, defined as a body mass index >95th percentile for age, were significant for overall perioperative respiratory complications. There was no difference in the incidence of perioperative respiratory complications in children undergoing tonsillectomy by cold or hot dissection. CONCLUSION: Perioperative respiratory complications following tonsillectomy are more affected by patient factors than surgical technique.

Prevalence and Age of Onset of Regression in Children with Autism Spectrum Disorder: A Systematic Review and Meta-analytical Update.

A systematic review published in 2013 reported 32% of children on the autism spectrum experience skill loss, known as autistic regression. However, the frequency varied depending on definition and measures used to capture skills. Retrospective parent report and prospective observation indicate loss of language and/or social skills, with motor skills typically unaffected. Our aim was to update the prevalence and age of onset of autistic regression through a meta-analysis of the literature to understand if there have been changes to the reported onset and prevalence since 2010. A systematic literature search was conducted using Medline, Embase, PsycINFO, and the Cochrane Library databases and included studies published from 2010 onward. Risk of bias assessment was performed on included studies. A random effects model was used to calculate the pooled prevalence and age of onset of autistic regression. Ninety-seven studies were included in the systematic review, of which 75 studies involving 33,014 participants had sufficient data for meta-analytic syntheses. The pooled proportion of autistic regression was 30% (95% confidence interval [CI]: 27-32%) but heterogeneity was high (I2 = 96.91) and did not reduce with sensitivity or subgroup analyses based on study design or clinical differences, respectively. Prevalence varied according to risk of bias (low: 27%) and definition of regression (language: 20%, language/social: 40%, mixed: 30%, and unspecified: 27%). Weighted average age of onset was 19.8 months. Findings from this meta-analysis highlight the importance of developing a standardized definition of autistic regression, and tools to measure this at multiple time points during early childhood development. LAY SUMMARY: About a third of children with Autism Spectrum Disorder experience loss of skills, which is also known as autistic regression. This paper provides an update of the rate of autistic regression in children and the age when they first experience loss of skills, based on current studies. The findings from this review contribute to our understanding of the onset patterns of autistic regression. Unfortunately, studies are not sufficiently similar, making it difficult to provide clear answers on the exact timing or type of regression seen in different children.

Accumulation of integrase strand transfer inhibitor resistance mutations confers high-level resistance to dolutegravir in non-B subtype HIV-1 strains from patients failing raltegravir in Uganda.

BACKGROUND: Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, especially with previous raltegravir exposure, is poorly understood due to infrequent reporting of INSTI failures and testing for INSTI drug resistance mutations (DRMs). METHODS: A total of 51 non-subtype B HIV-1 infected patients failing third-line (raltegravir-based) therapy in Uganda were initially selected for the study. DRMs were detected using Sanger and deep sequencing. HIV integrase genes of 13 patients were cloned and replication capacities (RCs) and phenotypic susceptibilities to dolutegravir, raltegravir and elvitegravir were determined with TZM-bl cells. Spearman's correlation coefficient was used to determine cross-resistance between INSTIs. RESULTS: INSTI DRMs were detected in 47% of patients. HIV integrase-recombinant virus carrying one primary INSTI DRM (N155H or Y143R/S) was susceptible to dolutegravir but highly resistant to raltegravir and elvitegravir (>50-fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to raltegravir, elvitegravir and even dolutegravir. The former multi-DRM virus had WT RC whereas the latter had lower RCs than WT. CONCLUSIONS: In HIV-1 subtype A- and D-infected patients failing raltegravir and harbouring INSTI DRMs, there is high-level resistance to elvitegravir and raltegravir. More routine monitoring of INSTI treatment may be advised in LMICs, considering that multiple INSTI DRMs may have accumulated during prolonged exposure to raltegravir during virological failure, leading to high-level INSTI resistance, including dolutegravir resistance.

Corrigendum: Potentials of Cellular Reprogramming as a Novel Strategy for Neuroregeneration.

[This corrects the article DOI: 10.3389/fncel.2018.00460.].

Potentials of Cellular Reprogramming as a Novel Strategy for Neuroregeneration.

Cellular reprogramming technology holds great potential for tissue repair and regeneration to replace cells that are lost due to diseases or injuries. In addition to the landmark discovery of induced pluripotent stem cells, advances in cellular reprogramming allow the direct lineage conversion of one somatic cell type to another using defined transcription factors. This direct reprogramming technology represents a rapid way to generate target cells in the laboratory, which can be used for transplantation and studies of biology and diseases. More importantly, recent work has demonstrated the exciting application of direct reprogramming to stimulate regeneration in vivo, providing an alternative approach to transplantation of donor cells. Here, we provide an overview of the underlying concept of using cellular reprogramming to convert cell fates and discuss the current advances in cellular reprogramming both in vitro and in vivo, with particular focuses on the neural and retinal systems. We also discuss the potential of in vivo reprogramming in regenerative medicine, the challenges and potential solutions to translate this technology to the clinic.

Managed Care Peer-Led Teaching: An Innovative Learning Approach Outside the College of Pharmacy Core Curriculum.

BACKGROUND: Managed care pharmacy is a growing field, but there are still limited educational opportunities available in pharmacy school core curricula. Students often seek self-directed learning opportunities to further explore the field. OBJECTIVES: To (a) evaluate practicality and effectiveness of a student-designed managed care pharmacy elective and (b) determine emerging best practices for design and sustainability of peer-led, self-directed courses. METHODS: A managed care elective course was designed as a student, peer-led course during the 2012-2013 school year at the University of Minnesota College of Pharmacy. As the course evolved, coordinators evaluated the effectiveness and sustainability of a student-led elective. The course required students to select a managed care topic of interest and deliver a discussion-based presentation. Teleconferencing was used to maximize participation and flexibility of pharmacist delegates from local managed care organizations who provided industry insight and expert mentorship. Data sources were gathered via course evaluation surveys, peer evaluations of presentations, and postgraduation surveys. Data were used to guide course improvement, gain insight into motivation for student participation, and evaluate the effect on career choices. RESULTS: During the fall and spring semesters of 2014-2015, 45 students participated and completed surveys: 28 in the fall and 17 in the spring. Seventy percent of enrollees took the course because of interest in managed care; 12% took the course because of referrals from past students; and 12% enrolled to explore topics outside of the pharmacy core curriculum. After completion of the course, 50% of students felt "somewhat comfortable" in discussing managed care topics, and 31% felt "very comfortable." None of the 17 students from the spring semester class answered "not comfortable" or "somewhat not comfortable." Suggestions for improvement from the fall semester class led to smaller class size, a roundtable setting, and new meeting times. In a survey of 6 graduates, 1 student pursued a fellowship; 2 students obtained managed care residencies; and 1 student worked as a managed care pharmacist. CONCLUSIONS: Data collected from students enrolled in the managed care elective indicated increased exposure and enhanced knowledge on topics discussed. Data also indicated value and support for the addition of peerled courses to the College of Pharmacy's curriculum. Graduates who took the course have pursued managed care careers and confirmed the benefits of peer-led learning. DISCLOSURES: No outside funding supported this study. The authors have nothing to disclose. Study concept and design were contributed by Tang, Smith, Tse, Tan, and Pittenger. Lau took the lead in data collection, along with Tang and Smith. Data interpretation was performed primarily by Lau, along with Tang, Smith, and Pittenger. The manuscript was written by all the authors and revised primarily by Tang, along with Smith, Lau, Pittenger, and Tan. This research was presented as a poster at the Academy of Managed Care Pharmacy Nexus 2015; October 26-29, 2015; Orlando, Florida.

Seroprevalence of Q Fever in Patients Undergoing Heart Valve Replacement Surgery.

BACKGROUND AND AIM OF THE STUDY: Q fever, caused by the rickettsia Coxiella burnetii, is a worldwide zoonotic disease with both acute and chronic manifestations. Endocarditis is the principal chronic manifestation. Q fever can easily be mistaken for degenerative valve disease due to its indolent presentation, the fastidious nature of the organism (routine cultures are negative), and the absence of a typical echocardiographic and macroscopic appearance for endocarditis. Prosthetic valve failure, with associated morbidity and mortality, have been described following unrecognized infections. METHODS: Previous studies have documented the value of screening strategies in areas of high prevalence. Hence, a pilot study was conducted in a low-prevalence setting, in which 139 patients at two tertiary cardiac centers attending for elective valve replacement for degenerative valvular disease underwent testing for chronic Q fever infection by serological and molecular methods on blood and valve tissue. RESULTS: Five patients (3.7%) had serological evidence of past exposure to Q fever (consistent with rates in the literature). None had evidence of chronic Q fever endocarditis. The cost of adopting a universal screening strategy is around £40,000 per case (if serology is used to screen patients prior to surgery). CONCLUSIONS: Alternative and more cost-effective methods for identifying clinically quiet cases of chronic Q fever endocarditis are required.

Building intentions with the Theory of Planned Behaviour: the mediating role of knowledge and expectations in implementing new pharmaceutical services in Malaysia

Background: Pharmacy value added services (PVAS) was introduced as a matter of public health policy by Malaysia’s Ministry of Health to improve health outcomes through public healthcare services. For example, drive through pharmacy services is a major policy implementation of the Ministry. However, adoption rates are low and therefore hampering the achievement of national health policy goals. Objective: Our objective is to explore the key determinants and mediators of successful implementation of new public pharmaceutical services by investigating the cognitive perspectives of patients’ intentions to adopt with the Theory of Planned Behavior as the theoretical framework. Methods: A two phase mixed methodology involving first a qualitative exploration and the second a quantitative phase was conducted in public health facilities in Negeri Sembilan, Malaysia. Multiple regression and mediation analysis were performed. Results: Subjective norms, perceived behavioural control, knowledge and expectations are found to be significant predictors of intentions to adopt PVAS. Knowledge and expectations are found to exert significant indirect effects on intentions. Conclusion: Overall, we suggest that patient knowledge be enhanced through appropriate channels and expectations of service quality be met to increase intentions (AU)

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Building intentions with the Theory of Planned Behaviour: the mediating role of knowledge and expectations in implementing new pharmaceutical services in Malaysia.

BACKGROUND: Pharmacy value added services (PVAS) was introduced as a matter of public health policy by Malaysia's Ministry of Health to improve health outcomes through public healthcare services. For example, drive through pharmacy services is a major policy implementation of the Ministry. However, adoption rates are low and therefore hampering the achievement of national health policy goals. OBJECTIVE: Our objective is to explore the key determinants and mediators of successful implementation of new public pharmaceutical services by investigating the cognitive perspectives of patients' intentions to adopt with the Theory of Planned Behavior as the theoretical framework. METHODS: A two phase mixed methodology involving first a qualitative exploration and the second a quantitative phase was conducted in public health facilities in Negeri Sembilan, Malaysia. Multiple regression and mediation analysis were performed. RESULTS: Subjective norms, perceived behavioural control, knowledge and expectations are found to be significant predictors of intentions to adopt PVAS. Knowledge and expectations are found to exert significant indirect effects on intentions. CONCLUSION: Overall, we suggest that patient knowledge be enhanced through appropriate channels and expectations of service quality be met to increase intentions.

Building intentions with the theory of planned behaviour: a qualitative assessment of salient beliefs about pharmacy value added services in Malaysia.

OBJECTIVE: To improve pharmaceutical care delivery in Malaysia, the Ministry of Health (MOH) had introduced the concept of value added services (VAS). Despite its reported convenience and advantages, VAS utilization rate is low in the country. The study aims to explore patients' understanding, beliefs and expectations towards VAS in Malaysia using the theory of planned behaviour (TPB) as the theoretical model. METHODS: A qualitative methodology was used whereby face-to-face interviews were conducted with 12 patients who collected partial medicine supplies from government pharmacies. Participants were recruited using purposive and snowball sampling method in the state of Negeri Sembilan, Malaysia. Interviews were audio-recorded. Verbatim transcription and thematic content analysis were performed on the data. RESULTS: Thematic content analysis yielded five major themes: (i) attitudes towards using VAS, (ii) subjective norms, (iii) perceived behavioural control, (iv) lack of knowledge and understanding of VAS and (v) expectations towards VAS. CONCLUSION: The interviews explored and informed new information about salient beliefs towards pharmacy VAS. The findings suggest that VAS is still in its infancy and a more robust and effective advertising and marketing campaign is needed to boost the adoption rate. Behavioural attitudes, subjective norms and perceived control elements were discussed and serve as important variables of interest in future study. Expectations towards VAS serve as an important guideline to further improve patient-oriented services.

Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function.

Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed. We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours. Here we show that targeting RSPO3 in PTPRK-RSPO3-fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.

Differentiating Aging Among Adults With Down Syndrome and Comorbid Dementia or Psychopathology.

Differences were examined between three groups of adults with Down syndrome in their behavioral presentation, social life/activities, health, and support needs. We compared those with comorbid dementia, with comorbid psychopathology, and with no comorbid conditions. Adults with comorbid dementia were more likely to be older, have lower functional abilities, have worse health and more health conditions, and need more support in self-care. Adults with comorbid psychopathology were more likely to exhibit more behavior problems and to be living at home with their families. Adults with no comorbidities were most likely to be involved in community employment. Differences in behavioral presentation can help facilitate clinical diagnoses in aging in Down syndrome, and implications for differential diagnosis and service supports are discussed.

Discovery of Novel Blood-Brain Barrier Targets to Enhance Brain Uptake of Therapeutic Antibodies.

The blood-brain barrier (BBB) poses a major challenge for developing effective antibody therapies for neurological diseases. Using transcriptomic and proteomic profiling, we searched for proteins in mouse brain endothelial cells (BECs) that could potentially be exploited to transport antibodies across the BBB. Due to their limited protein abundance, neither antibodies against literature-identified targets nor BBB-enriched proteins identified by microarray facilitated significant antibody brain uptake. Using proteomic analysis of isolated mouse BECs, we identified multiple highly expressed proteins, including basigin, Glut1, and CD98hc. Antibodies to each of these targets were significantly enriched in the brain after administration in vivo. In particular, antibodies against CD98hc showed robust accumulation in brain after systemic dosing, and a significant pharmacodynamic response as measured by brain Aß reduction. The discovery of CD98hc as a robust receptor-mediated transcytosis pathway for antibody delivery to the brain expands the current approaches available for enhancing brain uptake of therapeutic antibodies.

Mono-, di- and trimethylated homologues of isoprenoid tetraether lipid cores in archaea and environmental samples: mass spectrometric identification and significance.

Higher homologues of widely reported C(86) isoprenoid diglycerol tetraether lipid cores, containing 0-6 cyclopentyl rings, have been identified in (hyper)thermophilic archaea, representing up to 21% of total tetraether lipids in the cells. Liquid chromatography-tandem mass spectrometry confirms that the additional carbon atoms in the C(87-88) homologues are located in the etherified chains. Structures identified include dialkyl and monoalkyl ('H-shaped') tetraethers containing C(40-42) or C(81-82) hydrocarbons, respectively, many representing novel compounds. Gas chromatography-mass spectrometric analysis of hydrocarbons released from the lipid cores by ether cleavage suggests that the C(40) chains are biphytanes and the C(41) chains 13-methylbiphytanes. Multiple isomers, having different chain combinations, were recognised among the dialkyl lipids. Methylated tetraethers are produced by Methanothermobacter thermautotrophicus in varying proportions depending on growth conditions, suggesting that methylation may be an adaptive mechanism to regulate cellular function. The detection of methylated lipids in Pyrobaculum sp. AQ1.S2 and Sulfolobus acidocaldarius represents the first reported occurrences in Crenarchaeota. Soils and aquatic sediments from geographically distinct mesotemperate environments that were screened for homologues contained monomethylated tetraethers, with di- and trimethylated structures being detected occasionally. The structural diversity and range of occurrences of the C(87-89) tetraethers highlight their potential as complementary biomarkers for archaea in natural environments.

Development, test-retest reliability and validity of the Pharmacy Value-Added Services Questionnaire (PVASQ).

OBJECTIVE: (i) To develop the Pharmacy Value-Added Services Questionnaire (PVASQ) using emerging themes generated from interviews. (ii) To establish reliability and validity of questionnaire instrument. METHODS: Using an extended Theory of Planned Behavior as the theoretical model, face-to-face interviews generated salient beliefs of pharmacy value-added services. The PVASQ was constructed initially in English incorporating important themes and later translated into the Malay language with forward and backward translation. Intention (INT) to adopt pharmacy value-added services is predicted by attitudes (ATT), subjective norms (SN), perceived behavioral control (PBC), knowledge and expectations. Using a 7-point Likert-type scale and a dichotomous scale, test-retest reliability (N=25) was assessed by administrating the questionnaire instrument twice at an interval of one week apart. Internal consistency was measured by Cronbach's alpha and construct validity between two administrations was assessed using the kappa statistic and the intraclass correlation coefficient (ICC). Confirmatory Factor Analysis, CFA (N=410) was conducted to assess construct validity of the PVASQ. RESULTS: The kappa coefficients indicate a moderate to almost perfect strength of agreement between test and retest. The ICC for all scales tested for intra-rater (test-retest) reliability was good. The overall Cronbach' s alpha (N=25) is 0.912 and 0.908 for the two time points. The result of CFA (N=410) showed most items loaded strongly and correctly into corresponding factors. Only one item was eliminated. CONCLUSIONS: This study is the first to develop and establish the reliability and validity of the Pharmacy Value-Added Services Questionnaire instrument using the Theory of Planned Behavior as the theoretical model. The translated Malay language version of PVASQ is reliable and valid to predict Malaysian patients' intention to adopt pharmacy value-added services to collect partial medicine supply.

Development, test-retest reliability and validity of the Pharmacy Value-Added Services Questionnaire (PVASQ) / Desarrollo, confiabilidad test-retest y validez del pharmacy value-added services questionnaire (PVASQ)

Objective: (i) To develop the Pharmacy Value-Added Services Questionnaire (PVASQ) using emerging themes generated from interviews. (ii) To establish reliability and validity of questionnaire instrument. Methods: Using an extended Theory of Planned Behavior as the theoretical model, face-to-face interviews generated salient beliefs of pharmacy value-added services. The PVASQ was constructed initially in English incorporating important themes and later translated into the Malay language with forward and backward translation. Intention (INT) to adopt pharmacy value-added services is predicted by attitudes (ATT), subjective norms (SN), perceived behavioral control (PBC), knowledge and expectations. Using a 7-point Likert-type scale and a dichotomous scale, test-retest reliability (N=25) was assessed by administrating the questionnaire instrument twice at an interval of one week apart. Internal consistency was measured by Cronbach’s alpha and construct validity between two administrations was assessed using the kappa statistic and the intraclass correlation coefficient (ICC). Confirmatory Factor Analysis, CFA (N=410) was conducted to assess construct validity of the PVASQ. Results: The kappa coefficients indicate a moderate to almost perfect strength of agreement between test and retest. The ICC for all scales tested for intra-rater (testretest) reliability was good. The overall Cronbach’ s alpha (N=25) is 0.912 and 0.908 for the two time points. The result of CFA (N=410) showed most items loaded strongly and correctly into corresponding factors. Only one item was eliminated. Conclusions: This study is the first to develop and establish the reliability and validity of the Pharmacy Value- Added Services Questionnaire instrument using the Theory of Planned Behavior as the theoretical model. The translated Malay language version of PVASQ is reliable and valid to predict Malaysian patients’ intention to adopt pharmacy value-added services to collect partial medicine supply (AU)

Objetivo: (i) Desarrollar el Pharmacy Value-Added Services Questionnaire (PVASQ) utilizando temas salidos de entrevistas, (ii) establecer la fiabilidad y validez del cuestionario. Métodos: Utilizando la Teoría del Comportamiento Planeado aumentada como modelo teórico, unas entrevistas presenciales extrajeron los creencias sobre los servicios farmacéuticos de valor añadido. Se construyó el PVASQ inicialmente en Ingles incorporando temas importantes y más tarde se tradujo al malayo, con traducción y retro-traducción. La Intención (INT) de adoptar servicio farmacéuticos de valor añadido se predice por las Actitudes (ATT), Normal Subjetiva (SN), Control Comportamental Percibido (PBC), Conocimiento y Expectativas. Usando una escala de Likert de 7 puntos y una escala dicotómica se evaluó la fiabilidad test-retest (N=25) administrando el cuestionario dos veces en el intervalo de una semana. La consistencia interna se midió con el alfa de Cronbach y la validez de constructo entre dos administradores se evaluó con el estadístico kappa y el coeficiente intra-clase (ICC). Se realizó un análisis factorial confirmatorio (CFA) (N=410) para evaluar la validad de constructo del PVASQ. Resultados: Los coeficientes kappa indicaron una fuerza de acuerdo moderada a casi perfecta en el test-retest. Los ICC para todas las escalas probaron que la fiabilidad intra-evaluador (test-retest) era buena. El alfa de Cronbach global (N=25) es de 0,912 y 0,908 para cada tiempo medido. Los resultados del CFA (N=410) mostraron que la mayoría de los ítems cargaban fuerte y correctamente en sus correspondientes factores. Sólo se eliminó un ítem. Conclusiones: Este estudio es el primero para desarrollar y establecer la fiabilidad y validez del Pharmacy Value Added Services Questionnaire utilizando la Teoría del Comportamiento Plneado como modelo teórico. La versión traducida al malayo del PVASQ es fiable y válida para predecir las intenciones de los pacientes para adoptar servicios farmacéuticos de valor añadido al recoger su provisión de medicamentos (AU)