Dual effect of Algerian propolis on lung cancer: antitumor and chemopreventive effects involving antioxidant activity

Abstract The purpose of our study was to divulge the antiproliferative effect of an ethanolic extract of Algerian propolis (EEP) in the human lung adenocarcinoma cell line (A549) and reveal the chemopreventive role against benzo(a)pyrene-induced lung carcinogenesis in albino Wistar rats. Cytotoxicity of EEP was evaluated using the MTT assay and cell adhesion in A549 cells. Moreover, rats were given 25 mg/kg of propolis for 5 days before induction of experimental lung cancer by a single intraperitoneal dose of 200 mg/kg benzo(a)pyrene. Body weight, lung weight, lipid peroxidation, marker enzymes, and enzymatic and non-enzymatic antioxidants were estimated. The EEP demonstrated an inhibitory effect on proliferation of A549 at 24 and 72 hours in a dose-dependent manner and blocked adhesion of the cells by fibrinogen. Moreover, EEP reduced the oxidative stress generated by benzo(a)pyrene. The pre-treatment showed that enzymatic and non-enzymatic antioxidants increased and lipid peroxidation decreased. A histological analysis further supported these findings and showed a decrease in the number of side effects. These results are particularly important for both clinical applications of propolis and the possibility for its use as a potential chemotherapeutic agent.

Carcinogénesis experimental con 7, 12-dimetilbenzantraceno (DMBA) y su inhibición con aceite de oliva virgen extra y dieta con aceitunas maduras (variedad Picual) / Experimental carcinogenesis with 7, 12-dimethylbenz(a)anthrazene (DMBA) and its inhibition with extra virgin olive oil and a diet of mature olives (Picual variety)

El DMBA es un carcinógeno químico que induce carcinomas a las pocas semanas de su aplicación. En 44 hámsteres machos distribuidos en 4 grupos —DMBA disuelto en aceite de parafina (DMBA-Ap), DMBA disuelto en aceite de oliva (DMBA-Ao), aceite de parafina y aceite de oliva— se aplicó diariamente, en las bolsas bucales, aceite de parafina o aceite de oliva virgen extra en las 2 primeras semanas, alternativamente, durante la aplicación bisemanal de DMBA al 0,5% disuelto en aceite de parafina o de oliva durante 5semanas, y diariamente, hasta la vigésima semana. Los animales de los grupos DMBA-Ao y aceite de oliva, recibieron una dieta adicional con aceitunas maduras variedad Picual. El efecto carcinógeno DMBA-Ap (35carcinomas) es el 100%, y el efecto inhibidor, 0. La combinación de aceite de oliva como disolvente del DMBA y la dieta ad líbitum con aceituna Picual tiene un efecto inhibidor del 80% —solo 3 carcinomas intraepiteliales y 4 carcinomas verrugosos—, y no se desarrollaron carcinomas invasores (AU)

DMBA is a carcinogen that induces carcinomas within a few weeks of application. Forty-four male hamsters were divided into four groups: DMBA dissolved in paraffin oil (DMBA-Po), DMBA dissolved in olive oil (DMBA-Oo), paraffin oil and olive oil. Their mouths were swabbed daily with paraffin oil or extra virgin olive oil alternatively for the first two weeks, during the biweekly application of DMBA at 0.5% diluted in paraffin oil or olive oil for five weeks and daily until the twentieth week. The animals in the DMBA-Oo and olive oil groups received an additional diet of mature Picual olives. The DMBA-Po carcinogen effect (35 carcinomas) is 100% and the inhibitory effect 0. The combination of olive oil as DMBA solvent and the ad libitum diet with Picual olive has an inhibitory effect of 80%, with only three intraepithelial carcinomas and four verrucous carcinomas occurring and no invasive carcinomas (AU)

Posicionamiento y actitudes de manejo sobre la profilaxis antifúngica en el paciente hematológico (proyecto PROMIC) / Consensus opinion on antifungal prophylaxis in haematologic patients: Results of the PROMIC project

Introducción. La enfermedad fúngica invasora (EFI) es una importante causa de morbimortalidad en pacientes hematológicos. La profilaxis antifúngica (PAF) está indicada en muchos episodios de este grupo de pacientes. El objetivo de este trabajo fue alcanzar un consenso sobre el abordaje profiláctico de las EFI en el paciente hematológico con el fin de optimizar su manejo. Métodos. Un comité de expertos en hematología y enfermedades infecciosas planteó un cuestionario de 79 ítems con aspectos controvertidos sobre la profilaxis antifúngica en el paciente hematológico. El cuestionario fue evaluado en dos rondas por un panel de expertos siguiendo una metodología Delphi modificada. Resultados. El cuestionario fue respondido por 44 expertos en hematología y enfermedades infecciosas. Tras dos rondas de evaluación se consensuaron 48 ítems en el acuerdo (60,7%) y 19 en el desacuerdo (24%) por lo que hubo consenso en 67 de los 79 ítems planteados (84,8%). Se consensuaron los perfiles de pacientes candidatos a profilaxis y se dilucidaron cuestiones relacionadas con indicaciones, mecanismos de acción, espectro de actividad, toxicidad e interacciones de los antifúngicos. Se analizó particularmente la utilidad de micafungina como profilaxis de EFI. Se consensuó que micafungina es un antifúngico a considerar en este contexto. Puede presentar ventajas sobre otros antifúngicos por su seguridad y menor potencial de interacciones. Conclusiones. Se encontró un alto nivel de consenso en el manejo de la profilaxis de la EFI en el paciente hematológico. Este consenso ofrece indicaciones prácticas sobre su manejo óptimo y puede ayudar a determinar el perfil de los pacientes idóneos a recibir este tipo de intervención (AU)

Introduction. Invasive fungal disease (IFD) is an important cause of morbidity and mortality in haematological patients. Antifungal prophylaxis (AFP) is indicated for a number of clinical scenarios in this group of patients. The aim of this study was to reach a consensus on IFD prophylaxis in haematological patients in order to optimize their management. Methods. A committee of experts in haematology and infectious diseases compiled a survey of 79 items with controversial aspects about antifungal prophylaxis in haematological patients. The survey was evaluated in two rounds by a panel of experts following a modified Delphi methodology. Results. Forty-four experts in haematology and infectious diseases answered the survey. After two evaluation rounds, consensus was reached in 67 of the 79 items (84.8%), specifically 48 items were consensually agreed on (60.7%) and 19 were disagreed on (24.0%). Consensus was reached on prophylaxis candidates profiles and questions related to indications, mechanisms of action, spectrum of activity, toxicity and interactions of antifungal were elucidated. The usefulness of micafungin in IFD prophylaxis was particularly analysed. The consensus reached was that micafungin is an antifungal to be considered in this context as its safety profile and lower interaction potential may be advantageous. Conclusions. A broad consensus was found in the management of IFD prophylaxis in the haematological patient. This consensus provides practical indications about its optimal management and can help determine the profile of patients eligible for this type of intervention (AU)

Efeito quimiopreventivo da ß-ionona nas fases de iniciação e seleção/promoção da hepatocarcinogênese associada ao desenvolvimento de esteatose hepática não alcoólica em ratos Wistar / Chemopreventive effect of ß-ionone in the phases of initiation and selection/promotion of hepatocarcinogenesis associated with the development of non-alcoholic steatosis in Wistar rats

O câncer é um dos principais problemas de saúde pública no mundo. Dentre as neoplasias primárias que acometem o fígado, o carcinoma hepatocelular (HCC) é a mais frequente. Diversos fatores de risco predispõem ao HCC, entre eles a doença hepática gordurosa não-alcoólica (NAFLD). Segundo estudos prévios do grupo, a ß-ionona (BI), presente em uvas e aromatizantes de vinho, apresenta potencial quimiopreventivo da hepatocarcinogênese. Além disso, a ßI parece atuar na redução da colesterolemia podendo, assim, influenciar a NAFLD. Desta forma pretendeu-se, neste projeto, avaliar o desenvolvimento da NAFLD e sua influência nas etapas de iniciação e seleção/promoção da hepatocarcinogênese em ratos Wistar submetidos ao modelo do hepatócito resistente (RH), além da atividade quimiopreventiva da ßI, nessas condições experimentais em ratos. Para isso, os animais foram alocados em 6 grupos experimentais: RH iniciação (n=11), NAFLD iniciação (n=15), BI iniciação (n=15), RH seleção/promoção (n=11), NAFLD seleção promoção (n=15) e BI seleção/promoção (n=15). Na fase de iniciação os animais do grupo NAFLD receberam, diariamente, emulsão hipercalórica até a sexta semana do experimento um dia antes da administração de DEN. Já na fase de seleção/promoção os animais do grupo NAFLD receberam a emulsão hipercalórica, a partir de um dia após a DEN. Os animais dos grupos RH da iniciação e da seleção/promoção servem como controles e receberam, diariamente, 1mL/100g peso corpóreo de água até a sexta semana do experimento e um dia após a DEN, respectivamente. Na fase de iniciação, após 13 semanas os animais do grupo NAFLD não demonstraram sinais de esteatose, apresentaram maiores níveis séricos de triacilglicerol, colesterol total e LDL comparados ao grupo RH (P<0,05). O grupo NAFLD apresentou maior porcentagem de nódulos macroscópicos, bem como maior número e porcentagem de área hepática de lesões pré neoplásicas persistentes (pLPN) comparado ao grupo RH (P<0,05). Já o grupo BI apresentou menor número de pLPN e maior número de lesões em remodelação e uma maior porcentagem de área hepática de rLPN (p<0,05). Em relação a proliferação celular, o grupo NAFLD apresentou maior número de células em sourrounding, pLPN e rLPN comparada ao grupo RH e o grupo BI menor número em pLPN comparada a NAFLD. Já na fase de seleção/promoção foi possível observar o grupo NAFLD tem maiores valores de focos de inflamação, hepatócitos balonizados e grau de esteatose hepática em relação ao grupo BI, assim como maiores níveis séricos de triacilgliceróis, colesterol total e LDL (p<0,05). O grupo NAFLD apresentou maior porcentagem de nódulos macroscópicos <1, maior número, menor tamanho médio de pLPN comparados ao grupo RH (p<0,05). O grupo BI apresentou menor número e menor porcentagem de área em pLPN e maior porcentagem de área em rLPN (p<0,05). Em relação a proliferação celular, o grupo NAFLD apresentou maior número de células em sourrounding, pLPN e rLPN comparada ao grupo RH (p<0,05). Na expressão gênica, o grupo BI apresentou maior expressão de HMGCR em relação grupo NAFLD (p<0,05), O grupo NAFLD apresentou maior expressão de INSIG1 em relação ao grupo RH (p<0,05) e tendência na expressão de INSIG 2

Cancer is a major public health problems in the world. Among the primary neoplasm affecting the liver, hepatocellular carcinoma (HCC) is the most frequent. Several risk factors predispose to HCC, including the non-alcoholic fatty liver disease (NAFLD). According to previous studies of the group, ß-ionone (BI), present in grapes and flavors of wine, it presents potential chemopreventive of hepatocarcinogenesis. Furthermore, ßI appears to act in reducing blood cholesterol and may thus influence NAFLD. In this way it was intended in this project, evaluate the development of NAFLD and its influence on the steps of initiation and selection/promotion of hepatocarcinogenesis in Wistar rats resistant hepatocyte model (HR), and the chemopreventive activity of ßI, these experimental conditions in rats. For this, the animals were divided into 6 groups: RH initiation (n = 11), NAFLD initiation (n = 15), BI initiation (n = 15), HR selection / promotion (n = 11), NAFLD selection promotion ( n = 15) and BI selection / promotion (n = 15). In the inception phase of the NAFLD group animals received daily calorie emulsion until the sixth week of the experiment one day prior to DEN administration. In the selection / promotion stage NAFLD group of animals received hypercaloric emulsion, from one day after the DEN. The animals of groups HR and selection of initiation / promotion serve as controls and received daily 1mL / 100g body weight of water until the sixth week of the experiment, and one day after DEN respectively. In the initiation phase, after 13 weeks the animals of group NAFLD showed no signs steatosis, had higher serum levels of triglyceride, total cholesterol and LDL compared to the HR group (P <0.05). The NAFLD showed higher prevalence of macroscopic nodules as well as higher number and percentage of liver area of persistent pre-neoplastic lesions (pLPN) compared to the HR group (P <0.05). But the BI group had fewer pLPN and higher number of lesions in remodeling and a higher percentage of liver area rLPN (p <0.05). In relation to cell proliferation, the NAFLD group had a higher number of cells in sourrounding, pLPN and rLPN compared to the RH group and the lowest number in pLPN BI group compared to NAFLD. In the selection / promotion layer was observed NAFLD group has the highest values of inflammation foci, balonizados hepatocytes and hepatic steatosis grade in relation to BI group as well as higher serum levels of triglyceride, total cholesterol and LDL (p <0 , 05). The NAFLD showed higher prevalence of macroscopic nodules <1, more, smaller average size pLPN compared to the HR group (p <0.05). The BI group had fewer and smaller percentage area in pLPN and higher percentage of area rLPN (p <0.05). In relation to cell proliferation, the NAFLD group had a higher number of cells in sourrounding, pLPN and rLPN compared to the HR group (p <0.05). In gene expression, the BI group showed higher expression of HMGCR regarding NAFLD group (p <0.05), the NAFLD group had higher expression of INSIG1 against the RH group (p <0.05) and a tendency in the expression of INSIG 2

Evaluation of a Urine Pooling Strategy for the Rapid and Cost-Efficient Prevalence Classification of Schistosomiasis.

BACKGROUND: A key epidemiologic feature of schistosomiasis is its focal distribution, which has important implications for the spatial targeting of preventive chemotherapy programs. We evaluated the diagnostic accuracy of a urine pooling strategy using a point-of-care circulating cathodic antigen (POC-CCA) cassette test for detection of Schistosoma mansoni, and employed simulation modeling to test the classification accuracy and efficiency of this strategy in determining where preventive chemotherapy is needed in low-endemicity settings. METHODOLOGY: We performed a cross-sectional study involving 114 children aged 6-15 years in six neighborhoods in Azaguié Ahoua, south Côte d'Ivoire to characterize the sensitivity and specificity of the POC-CCA cassette test with urine samples that were tested individually and in pools of 4, 8, and 12. We used a Bayesian latent class model to estimate test characteristics for individual POC-CCA and quadruplicate Kato-Katz thick smears on stool samples. We then developed a microsimulation model and used lot quality assurance sampling to test the performance, number of tests, and total cost per school for each pooled testing strategy to predict the binary need for school-based preventive chemotherapy using a 10% prevalence threshold for treatment. PRINCIPAL FINDINGS: The sensitivity of the urine pooling strategy for S. mansoni diagnosis using pool sizes of 4, 8, and 12 was 85.9%, 79.5%, and 65.4%, respectively, when POC-CCA trace results were considered positive, and 61.5%, 47.4%, and 30.8% when POC-CCA trace results were considered negative. The modeled specificity ranged from 94.0-97.7% for the urine pooling strategies (when POC-CCA trace results were considered negative). The urine pooling strategy, regardless of the pool size, gave comparable and often superior classification performance to stool microscopy for the same number of tests. The urine pooling strategy with a pool size of 4 reduced the number of tests and total cost compared to classical stool microscopy. CONCLUSIONS/SIGNIFICANCE: This study introduces a method for rapid and efficient S. mansoni prevalence estimation through examining pooled urine samples with POC-CCA as an alternative to widely used stool microscopy.

Despistaje de tuberculosis latente en el paciente con psoriasis moderada grave candidato a terapia sistémica y/o biológica / Screening for Latent Tuberculosis in the Patient With Moderate to Severe Psoriasis Who Is a Candidate for Systemic and/or Biologic Therapy

Los pacientes con psoriasis moderada-grave que van a iniciar tratamiento con agentes biológicos deben ser monitorizados para la detección de infección tuberculosa latente antes, durante y después del tratamiento. En el último informe publicado de BIOBADADERM la prevalencia de infección latente por M.tuberculosis (ILMT) alcanzaba el 20,5% de los pacientes psoriásicos tratados con agentes biológicos en nuestro país. En la actualidad no existe un método diagnóstico gold standard que permita una aplicación sistemática y consensuada, con variaciones en los diferentes países según el grado de endemicidad y vacunación con BCG. La prueba de tuberculina (PT) continúa siendo el método de elección para el diagnóstico de infección, pero presenta importantes limitaciones en su sensibilidad (principalmente en pacientes inmunodeprimidos). Esta situación, junto a su falta de especificidad conocida, errores en su administración, la subjetividad en la interpretación de los resultados, la necesidad de una segunda visita para la lectura y la ausencia de privacidad hacen de ella una prueba limitada, cuyas principales ventajas resultarían su bajo coste y fácil realización. Por eso la mayoría de los estudios de coste beneficio se inclinan por el método IGRA para el diagnóstico de la ILMT, ya que minimiza los falsos positivos (especialmente en población vacunada), eliminando costes extra y efectos secundarios de la quimioprofilaxis antituberculosa. Valoramos la aplicabilidad en pacientes psoriásicos candidatos a terapia biológica y discutimos la necesidad de su realización previamente a terapia sistémica convencional, puesto que la mayoría de las guías actuales no consideran imprescindible su realización

Screening to detect latent tuberculosis infection (LTBI) is essential before patients with moderate to severe psoriasis start treatment with biologics and vigilance will continue to be needed during and after such treatment. The most recently analyzed statistics from the BIOBADADERM registry show a 20.5% prevalence of LTBI in psoriasis patients treated with biologics in Spain. Various screening protocols are in effect in different countries according to their levels of endemic TB and bacillus Calmette-Guérin (BCG) vaccination, and there is no consensus on a gold-standard approach to the diagnosis of LTBI. Tuberculin skin testing (TST) continues to be the diagnostic method of choice in spite of its limited sensitivity, mainly in immunocompromised patients. Additional problems include the TST’s well-established lack of specificity, errors in application, subjectivity in the interpretation of results (which must be read during a second visit), and lack of privacy; the main advantages of this test are its low cost and ease of application. Most cost-benefit studies are therefore inclined to favor using interferon- release assays to detect LTBI because they minimize false positives (especially in BCG-vaccinated individuals), thereby eliminating the extra costs and side effects of unnecessary chemoprophylaxis. We review the methods used for LTBI screening in psoriasis patients who are candidates for biologic therapy. Additionally, given the fact that most guidelines do not currently consider it necessary to screen patients about to start conventional systemic therapy, we discuss the reasons underlying the need for such screening

Constatación del papel de la búsqueda de contactos y estrategias de prevención en a interrupción de la transmisión de la Lepra - quimio profilaxis: llamamiento para pedir una mayor investigación / No disponible

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Clinical guide SEOM on venous thromboembolism in cancer patients

Venous thromboembolism (VTE) is a common event in cancer patients and one of the major causes of cancer-associated mortality and a leading cause of morbidity. In recent years, the incidence rates of VTE have notably increased; however, VTE is still commonly underestimated by oncologists. VTE is considered an adverse prognostic factor in cancer patients in all settings. In 2011 the Spanish Society of Medical Oncology (SEOM) first published a clinical guideline of prophylaxis and treatment of VTE in cancer patients. In an effort to incorporate evidence obtained since the original publication, SEOM presents an update of the guideline for thrombosis and cancer in order to improve the prevention and management of VTE (AU)

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Cribado tuberculínico: prevención de la tuberculosis / Tuberculin screening: tuberculosis prevention

El cribado tuberculínico se utiliza para identificar, evaluar y poder tratar a las personas que tienen mayor riesgo de padecer una infección tuberculosa latente o de desarrollar la enfermedad tuberculosa una vez infectados por el M. tuberculosis. Se revisan los criterios, las indicaciones y la metodología del cribado tuberculínico para la detección de la infección tuberculosa y otras medidas disponibles en Atención Primaria para la prevención de la tuberculosis en la infancia y adolescencia, incluyendo el estudio de contactos de personas con infección tuberculosa y el tratamiento de la exposición a la tuberculosis y de la tuberculosis latente(AU)

Tuberculin skin testing is used to identify, evaluate, and treat people who are at higher risk for latent tuberculosis infection or for developing tuberculosis disease after the infection by M. tuberculosis. We review the criteria, indications and methodology of tuberculin skin testing for the detection of tuberculosis infection and other measures available in primary care for the prevention of tuberculosis in childhood and adolescence, including the study of contacts of people with tuberculosis infection and the treatment of exposure to tuberculosis and of latent tuberculosis infection(AU)

Antibióticos y resistencia antibiótica en la quimioprofilaxis de la enfermedad meningocócica / Antibiotics and antibiotic resistance in chemoprophylaxis of meningococcal disease

La profilaxis antibiótica debe considerarse en personas con contacto con algún caso de enfermedad meningocócica o en poblaciones con altos porcentajes de portadores de N. meningitidis. El uso de antibióticos produce una reducción significativa del riesgo de enfermedad entre los contactos; así, la rifampicina, la ciprofloxacina y la ceftriaxona se consideran como las mejores opciones para la quimioprofilaxis, sin embargo su empleo está asociado con el aumento de resistencia antibiótica. Actualmente, la tendencia a la aparición de meningococos resistentes a la rifampicina después de la profilaxis es un aspecto reconocido, aunque parece que no es un fenómeno ampliamente extendido. La aparición de resistencia de alto nivel a la rifampicina está provocada por mutaciones en el gen rpoB, aunque se puede asociar a mutaciones del locus mtr implicadas en mecanismos de expulsión y bombeo. Sin embargo, los cambios en el gen rpoB dan lugar a cepas poco adaptadas a la supervivencia y este costo biológico podría explicar la ausencia de diseminación clonal de los aislamientos con resistencia adquirida a la rifampicina. La resistencia o sensibilidad disminuida a la ciprofloxacina se relaciona con mutaciones en la región determinante de resistencia a quinolonas (QRDR) del gen gyrA, además existen datos que apoyan la existencia de mecanismos de expulsión. Hasta el momento, la resistencia o la sensibilidad reducida a las quinolonas ha avanzado lentamente. No se han comunicado problemas de resistencia a la ceftriaxona, siendo la opción más segura para su uso en quimioprofilaxis.La espiramicina no es una opción adecuada aunque sigue siendo recomendada por la OMS.

Prevención, cribado y seguimiento de las neoplasias colorrectales / Prevention, screening and follow-up of colorectal tumors

Una de las principales novedades presentadas en la Digestive Disease Week (DDW) de 2006 fue la presentación de las guías clínicas de seguimiento de los adenomas colorrectales. Esta nueva guía persigue un doble objetivo: la identificación de los factores de riesgo de recurrencia y diferenciar a 2 grupos de pacientes, los de bajo y los de alto riesgo de recurrencia. Esta división ha de permitir optimizar un recurso escaso, la colonoscopia, evitando colonoscopias innecesarias, y destinar este recurso escaso al cribado. Se dedicó especial atención, además, a recalcar la importancia crítica de una excelente colonoscopia inicial en toda pauta de seguimiento de pacientes con adenoma colorrectal, no únicamente en relación con el requerimiento de una excelente preparación sino también con la importancia del tiempo de duración de la exploración durante la retirada del endoscopio. Finalmente, se presentaron diferentes estudios de seguridad y eficacia de fármacos con potencial efecto quimiopreventivo en el desarrollo de adenomas (AU)

One of the main novelties of Digestive Diseases Week (DDW) of 2006 was the presentation of the clinical guidelines for surveillance of colorectal adenomas. The objective of these guidelines is two-fold: to identify risk factors for recurrence and to differentiate two groups of patients, those with low risk and those with high risk of recurrence. This division should allow a scarce resource – colonoscopy – to be optimized, avoiding unnecessary colonoscopies and allowing this technique to be reserved for screening. The crucial importance of an excellent initial colonoscopy in the follow-up of patients with colorectal adenoma was also highlighted, not only in relation to the requirement of optimal preparation but also the importance of the time and duration of the procedure during endoscope withdrawal. Finally, several studies on the safety and efficacy of drugs with a potential chemopreventive effect in the development of adenomas were presented (AU)

Optimizing a District of Columbia Strategic National Stockpile dispensing center.

On October 4, 2003, the District of Columbia Department of Health (DOH) held a Strategic National Stockpile (SNS) exercise designed to test its plan for operating mass dispensing centers during a bioterrorist attack or other emergency. The main goals of the exercise were to maximize the throughput of the dispensing plan and improve dispensing procedures. These goals are important for quantifying the resources (eg, numbers and types of staff) necessary to respond to different types and sizes of events, as well as for minimizing the potential for errors or confusion in dispensing medications. We set up the dispensing center according to the District's SNS plan and recruited volunteers to role-play potentially exposed residents. During the exercise, we collected detailed data on the service times for each step in the dispensing process. We also collected observations from exercise participants and observers. We found that the DOH dispensing center could achieve a throughput of 2.5 persons per minute. Using computer modeling, we recommended changes to the dispensing plan that would enable it to achieve a higher throughput of four to five persons per minute. Other recommendations addressed improvements to dispensing plans and procedures.