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Live chicken egg embryos offer new opportunities for evaluation and continuous monitoring of tumour growth for in vivo studies compared to traditional rodent models. Here, we report the first use of surface enhanced Raman scattering (SERS) mapping and surface enhanced spatially offset Raman scattering (SESORS) for the detection and localisation of targeted gold nanoparticles in live chicken egg embryos bearing a glioblastoma tumour.

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Oro , Nanopartículas del Metal , Espectrometría Raman , Animales , Espectrometría Raman/métodos , Oro/química , Embrión de Pollo , Nanopartículas del Metal/química , Glioblastoma/patología , Glioblastoma/diagnóstico por imagen , Humanos , Propiedades de Superficie , Modelos Animales de Enfermedad , Línea Celular Tumoral

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AIM: To evaluate the utilization and prescribing patterns of antidiabetic drugs (ADDs) for patients with type 2 diabetes mellitus (T2DM) at treatment initiation and first intensification. METHODS: A retrospective cohort study was performed using linked routinely collected data of patients with T2DM who received ADDs between January 2010 and December 2020 in Scotland. The prescribing patterns were quantified using frequency/percentages, absolute/relative change, and trend tests. RESULTS: Overall, 145 909 new ADD users were identified, with approximately 91% (N = 132 382) of patients receiving a single ADD at first treatment initiation. Metformin was the most often prescribed monotherapy (N = 118 737, 89.69%). A total of 50 731 patients (39.40%) who were started on metformin (N = 46 730/118 737, 39.36%) or sulphonylurea (SU; N = 4001/10 029, 39.89%) monotherapy had their treatment intensified with one or more additional ADD. Most initial-metformin (45 963/46 730; 98.36%) and initial-SU users (3894/4001; 97.33%) who added further drugs were intensified with single ADDs. SUs (22 197/45 963; 48.29%) were the most common first-intensifying monotherapy after initial metformin use, but these were replaced by sodium-glucose cotransporter-2 (SGLT2) inhibitors in 2019 (SGLT2 inhibitors: 2039/6065, 33.62% vs. SUs: 1924/6065, 31.72%). Metformin was the most frequently added monotherapy to initial SU use (2924/3894, 75.09%). Although the majority of patients received a single ADD, the use of combination therapy significantly increased over time. Nevertheless, there was a significant increasing trend towards prescribing the newer ADD classes (SGLT2 inhibitors, dipeptidyl peptidase-4 inhibitors) as monotherapy or in combination compared with the older ones (SUs, insulin, thiazolidinediones) at both drug initiation and first intensification. CONCLUSIONS: An overall increasing trend in prescribing the newer ADD classes compared to older ADDs was observed. However, metformin remained the most commonly prescribed first-line ADD, while SGLT2 inhibitors replaced SUs as the most common add-on therapy to initial metformin use in 2019.

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Diabetes Mellitus Tipo 2 , Hipoglucemiantes , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Hipoglucemiantes/uso terapéutico , Estudios Retrospectivos , Escocia/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Metformina/uso terapéutico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Pautas de la Práctica en Medicina/tendencias , Compuestos de Sulfonilurea/uso terapéutico , Quimioterapia Combinada , Estudios de Cohortes , Utilización de Medicamentos/estadística & datos numéricos , Utilización de Medicamentos/tendencias , Adulto

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PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria for lower-grade gliomas (LGGs) define tumor progression as ≥25% change in the T2/FLAIR signal area based on an operator's discretion of the perpendicular diameter of the largest tumor cross-section. Potential sources of error include acquisition inconsistency of 2D slices, operator selection variabilities in both representative tumor cross-section and measurement line locations, and the inability to quantify infiltrative tumor margins and satellite lesions. Our goal was to assess the accuracy and reproducibility of RANO in LG. MATERIALS AND METHODS: A total of 651 FLAIR MRIs from 63 participants with LGGs were retrospectively analyzed by three blinded attending physicians and three blinded resident trainees using RANO criteria, 2D visual assessment, and computer-assisted 3D volumetric assessment. RESULTS: RANO product measurements had poor-to-moderate inter-operator reproducibility (r2 = 0.28-0.82; coefficient of variance (CV) = 44-110%; mean percent difference (diff) = 0.4-46.8%) and moderate-to-excellent intra-operator reproducibility (r2 = 0.71-0.88; CV = 31-58%; diff = 0.3-23.9%). When compared to 2D visual ground truth, the accuracy of RANO compared to previous and baseline scans was 66.7% and 65.1%, with an area under the ROC curve (AUC) of 0.67 and 0.66, respectively. When comparing to volumetric ground truth, the accuracy of RANO compared to previous and baseline scans was 21.0% and 56.5%, with an AUC of 0.39 and 0.55, respectively. The median time delay at diagnosis was greater for false negative cases than for false positive cases for the RANO assessment compared to previous (2.05 > 0.50 years, p = 0.003) and baseline scans (1.08 > 0.50 years, p = 0.02). CONCLUSION: RANO-based assessment of LGGs has moderate reproducibility and poor accuracy when compared to either visual or volumetric ground truths.

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BACKGROUND: There is a lack of consensus on prescribing alternatives to initial metformin therapy and intensification therapy for type 2 diabetes mellitus (T2DM) management. This review aimed to identify/quantify factors associated with prescribing of specific antidiabetic drug classes for T2DM. METHODS: Five databases (Medline/PubMed, Embase, Scopus, Web of Science) were searched using the synonyms of each concept (patients with T2DM, antidiabetic drugs and factors influencing prescribing) in both free text and Medical Subject Heading (MeSH) forms. Quantitative observational studies evaluating factors associated with antidiabetic prescribing of metformin, sulfonylurea, thiazolidinedione, Dipeptidyl-peptidase 4 inhibitors (DPP4-I), sodium glucose transporter 2 inhibitors (SGLT2-I), Glucagon-Like peptide receptor agonist (GLP1-RA) and insulin in outpatient settings and published from January 2009 to January 2021 were included. Quality assessment was performed using a Newcastle-Ottawa scale. The validation was done for 20% of identified studies. The pooled estimate was measured using a three-level random-effect meta-analysis model based on odds ratio [95% confidence interval]. Age, sex, body mass index (BMI), glycaemic control (HbA1c) and kidney-related problems were quantified. RESULTS: Of 2331 identified studies, 40 met the selection criteria. Of which, 36 and 31 studies included sex and age, respectively, while 20 studies examined baseline BMI, HbA1c and kidney-related problems. The majority of studies (77.5%, 31/40) were rated as good and despite that the overall heterogeneity for each studied factor was more than 75%, it is mostly related to within-study variance. Older age was significantly associated with higher sulfonylurea prescription (1.51 [1.29-1.76]), yet lower prescribing of metformin (0.70 [0.60-0.82]), SGLT2-I (0.57 [0.42-0.79]) and GLP1-RA (0.52 [0.40-0.69]); while higher baseline BMI showed opposite significant results (sulfonylurea: 0.76 [0.62-0.93], metformin: 1.22 [1.08-1.37], SGLT2-I: 1.88 [1.33-2.68], and GLP1-RA: 2.35 [1.54-3.59]). Both higher baseline HbA1c and having kidney-related problems were significantly associated with lower metformin prescription (0.74 [0.57-0.97], 0.39 [0.25-0.61]), but more insulin prescriptions (2.41 [1.87-3.10], 1.52 [1.10-2.10]). Also, DPP4-I prescriptions were higher for patients with kidney-related problems (1.37 [1.06-1.79]) yet lower among patients with higher HbA1c (0.82 [0.68-0.99]). Sex was significantly associated with GLP1-RA and thiazolidinedione prescribing (F:M; 1.38 [1.19-1.60] and 0.91 [0.84-0.98]). CONCLUSION: Several factors were identified as potential determinants of antidiabetic drug prescribing. The magnitude and significance of each factor differed by antidiabetic class. Patient's age and baseline BMI had the most significant association with the choice of four out of the seven studied antidiabetic drugs followed by the baseline HbA1c and kidney-related problems which had an impact on three studied antidiabetic drugs, whereas sex had the least impact on prescribing decision as it was associated with GLP1-RA and thiazolidinedione only.

Asunto(s)

Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Metformina , Tiazolidinedionas , Humanos , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Transportador 2 de Sodio-Glucosa/uso terapéutico , Hemoglobina Glucada , Dipeptidil Peptidasa 4/uso terapéutico , Metformina/uso terapéutico , Compuestos de Sulfonilurea/uso terapéutico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Insulina/uso terapéutico , Tiazolidinedionas/uso terapéutico

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INTRODUCTION: Worldwide statistics highlight that around 40% of breast cancer cases occur in patients aged 65 years and above, with expectations that this will increase as the population gets older. Cancer management in elderly patients is still unclear and depends primarily on individual oncologist decisions. The literature suggests that elderly breast cancer patients receive less intensive chemotherapy than younger patients, which is mainly attributed to a lack of effective individualized assessment or age bias. The current study explored the impact of elderly patient involvement in the decision-making process of breast cancer management and less intensive treatment allocation in Kuwait. METHODS: In an observational exploratory populationbased study, 60 newly diagnosed breast cancer patients aged 60 years and above and candidates for chemotherapy were included. Patients were grouped based on the treating oncologists' decision to receive either intensive first-line chemotherapy (standard treatment) or less intensive/ other than first-line chemotherapy (non-standard treatment) according to standardized international guidelines recommendations. Patients' attitudes toward the recommended treatment (accept/ reject) were documented through a short semi-structured interview. The prevalence of patients' interference with the treatment was reported, and individual causes were investigated. RESULTS: Data showed that 58.8% and 41.2% of elderly patients were allocated for intensive and less intensive treatment, respectively. Overall, 15% of patients interfered with the treatment plan against their oncologists' recommendations even though they were allocated for less intensive treatment. Among those, 6.7% of patients rejected the recommended treatment, 3.3% delayed initiating treatment, and 5% received <3 cycles of chemotherapy but refused to continue cytotoxic treatment. None of the patients requested intensive treatment. This interference was mainly directed by cytotoxic treatment toxicity concerns and targeted treatment preference. CONCLUSION: In clinical practice, oncologists allocate selected breast cancer patients aged 60 years and above for less intensive cytotoxic treatment to enhance their tolerance; however, this was not always associated with patients' acceptance and compliance. Lack of awareness of targeted treatment indications and utilization directed 15% of patients to reject, delay, or refuse to continue the recommended cytotoxic treatment against their oncologists' recommendations.

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Antineoplásicos , Neoplasias de la Mama , Anciano , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/diagnóstico , Kuwait , Participación del Paciente , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante

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BACKGROUND: This study aimed to assess the predictive power of three different Sepsis Scoring Systems (SSSs), namely maternity Systematic Inflammatory Response Syndrome (mSIRS), quick Sepsis-related Organ Failure Assessment (qSOFA) and Modified Early Warning System (MEWS) in identifying sepsis by comparing them with positive culture. This study also sought to evaluate compliance with using the Sepsis Six Care Bundle (SSCB) operated in an individual health board. METHODS: A retrospective cohort study was conducted in 3 maternity hospitals of a single Scottish health board that admitted 2690 pregnancies in a 12 weeks period in 2016. Data for study was obtained from medical notes, handheld and electronic health records for women who were prescribed antibiotics with a confirmed or suspected diagnosis of sepsis. Data on clinical parameters was used to classify women according to mSIRS, qSOFA and MEWS as having sepsis or not and this was compared to results of positive culture to obtain sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under Receiver Operating Characteristic curve (AUROC) along with their 95% confidence intervals. Data was also obtained on SSCB compliance. RESULTS: A total of 89 women were diagnosed with sepsis, of which 14 had missing data, leaving 75 for final analysis. Sensitivity, specificity, PPV, NPV and AUROC of mSIRS and MEWS were almost similar with AUROC of both being around 50%. Only 33 (37.1%) had identifiable sepsis six sticker displayed on medical notes and only 2 (2.2%) had all elements of SSCB delivered within the recommended one-hour post-diagnosis period. Blood culture and full blood count with other lab tests had been performed for most women (97%) followed by intravenous antibiotics and fluids (93.9%). CONCLUSIONS: mSIRS and MEWS were quite similar in detecting sepsis when compared to positive culture, with their ability to detect sepsis being close to chance. This underlines the need for creating a valid SSS with high sensitivity and specificity for clinical use in obstetric settings. Clinical use of SSCB was limited despite it being a health board policy, although there is considerable possibility of improvement following detailed audits and removal of barriers for implementing SSCB.

Asunto(s)

Maternidades/estadística & datos numéricos , Sepsis/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Área Bajo la Curva , Estudios de Cohortes , Puntuación de Alerta Temprana , Femenino , Mortalidad Hospitalaria , Humanos , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Paquetes de Atención al Paciente , Embarazo , Pronóstico , Curva ROC , Estudios Retrospectivos , Escocia , Adulto Joven

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Antimicrobial resistance (AMR) is a global public health threat associated with increased mortality, morbidity and costs. Inappropriate antimicrobial prescribing, particularly of broad-spectrums antimicrobials (BSAs), is considered a major factor behind growing AMR. The aim of this study was to explore physician perception and views about BSAs and factors that impact upon their BSAs prescribing decisions. Qualitative semistructured telephone interviews over an eleven-week period were conducted with physicians in a single tertiary care hospital in Riyadh, Saudi Arabia. Purposeful and snowball sampling techniques were adopted as sampling strategy. All interviews were audio recorded, transcribed verbatim, uploaded to NVivo® software and analysed following thematic analysis approach. Four major themes emerged: views on BSAs, factors influencing BSA prescribing and antimicrobial stewardship: practices and barriers and recommendations to improve appropriate BSA prescribing. Recommendations for the future include improving clinical knowledge, feedback on prescribing, multidisciplinary team decision-making and local guideline implementation. Identification of views and determinants of BSA prescribing can guide the design of a multifaceted intervention to support physicians and policymakers to improve antimicrobial prescribing practices.

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OBJECTIVES: Most patients receive systemic anticancer therapy (SACT) as day cases and toxicities, if they occur, are likely to appear first in primary care. Pharmaceutical care can be delivered by community pharmacists, but little is known about the epidemiology of SACT toxicities in the community and potential interventions to address these which raise the following questions: what are the typologies of SACT-associated toxicities experienced by community-based patients and what are the associated pharmaceutical care issues (PCIs)? The aim of this study was to identify toxicities and pharmaceutical care issues of patients prescribed SACT for lung cancer and understand the potential for community pharmacists to deliver aspects of cancer care including toxicity management. METHODS: Retrospective analysis of clinical records of patients prescribed oral and parenteral SACT in 2013-14, to describe patient characteristics; SACT toxicity; PCIs and episodes of unscheduled care. KEY FINDINGS: Twelve categories of toxicity and 13 categories of PCIs were identified from 50 patients. More PCIs were observed with oral SACT/oral-parenteral combinations than with parenteral regimens. The PCIs which could be managed by community pharmacists were mucositis; skin toxicity; gastrointestinal toxicity; reinforcing patient education and identification/prevention of drug interactions. CONCLUSIONS: Community pharmacists are ideally placed to provide pharmaceutical care to patients with lung cancer prescribed SACT. Cancer specialists in secondary care can signpost patients to community pharmacists for early management of low-grade SACT toxicity.

Asunto(s)

Servicios Comunitarios de Farmacia , Neoplasias Pulmonares , Servicios Farmacéuticos , Enfermedades de la Piel , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Farmacéuticos , Estudios Retrospectivos

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Infection with Leishmania infantum causes the disease visceral leishmaniasis (VL), which is a serious clinical and veterinary problem. The drugs used to treat canine leishmaniasis (CanL) do not cause complete parasite clearance; they can be toxic, and emerging drug resistance in parasite populations limits their clinical utility. Therefore, in this study we have evaluated the toxicity and efficacy of joint treatment with a 1:1 mixture of sodium stibogluconate-NIV (SSG-NIV, 10 mg Sbv/day) and paromomycin-NIV (PMM-NIV, 10 mg PMM/kg/day), given intravenously daily for seven days from day 270 post-infection, to nine-month-old female beagle dogs (n = 6) experimentally infected with Leishmania infantum. Treatment significantly improved the clinical symptoms of VL infection in all the treated dogs, reduced parasite burdens in lymph nodes and bone marrow, and all symptomatic treated dogs, were asymptomatic at 90 days post-treatment. Treatment was associated with a progressive and significant decrease in specific IgG anti-Leishmania antibodies using parasite soluble antigen (p < 0.01) or rK39 (p < 0.01) as the target antigen. In addition, all dogs were classified as parasite negative based on Leishmania nested PCR and quantitative real time PCR tests and as well as an inability to culture of promastigote parasites from lymph nodes and bone marrow tissue samples taken at day 90 post-treatment. However, treatment did not cure the dogs as parasites were detected at 10 months post-treatment, indicating that a different dosing regimen is required to cause long term cure or prevent relapse.

Asunto(s)

Gluconato de Sodio Antimonio/uso terapéutico , Antiprotozoarios/uso terapéutico , Leishmania donovani/efectos de los fármacos , Leishmania infantum/efectos de los fármacos , Paromomicina/uso terapéutico , Administración Intravenosa , Análisis de Varianza , Animales , Gluconato de Sodio Antimonio/administración & dosificación , Gluconato de Sodio Antimonio/farmacología , Antiprotozoarios/administración & dosificación , Antiprotozoarios/farmacología , Recuento de Células Sanguíneas , Análisis Químico de la Sangre , Médula Ósea/parasitología , Cricetinae , Reservorios de Enfermedades , Perros , Femenino , Leishmania donovani/inmunología , Leishmania donovani/aislamiento & purificación , Leishmania infantum/inmunología , Leishmania infantum/aislamiento & purificación , Hígado/parasitología , Ganglios Linfáticos/parasitología , Masculino , Mesocricetus , Ratones , Ratones Endogámicos BALB C , Paromomicina/administración & dosificación , Paromomicina/farmacología , Piel/parasitología , Bazo/parasitología

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(1) Background: Sepsis is the leading cause of maternal death in 11-15% of women worldwide. This emphasises the importance of administrating timely and appropriate antibiotic therapy to women with sepsis. We aimed to evaluate the appropriateness of antimicrobial prescribing in women diagnosed with peripartum sepsis. (2) Method: A prospective observational cohort study in a single Scottish health region with 12,233 annual live births. Data were collected on women diagnosed with sepsis in the peripartum period using physical and electronic medical records, drug Kardex® (medication administration) and ward handover records. (3) Results: A sepsis diagnosis was concluded in 89 of the 2690 pregnancy cases reviewed, with a median hospital stay of four days. Good overall adherence to the local guidelines for the empiric antimicrobial treatment of sepsis was observed. Group B Streptococcus was associated with 20.8% of maternal sepsis cases, whilst in 60% of clinical specimens tested no causative pathogen was isolated. (4) Conclusion: The lack of specific and sensitive clinical markers for sepsis, coupled with their inconsistent clinical application to inform diagnosis, hindered effective antimicrobial stewardship. This was further exacerbated by the lack of positive culture isolates from clinical specimens, which meant that patients were often continued on broader-spectrum empiric treatment.

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BACKGROUND: Antimicrobial resistance (AMR) is presently considered an emergent major global public health concern and excessive and/or inappropriate use of broad-spectrum antimicrobials contribute to the development of AMR. OBJECTIVE: To evaluate the appropriateness of carbapenems and piperacillin-tazobactam use in a tertiary care hospital. METHODS: A retrospective, observational, cross-sectional, drug-utilization study was conducted. The study included all adult hospitalized patients who had received at least one dose of the antimicrobials during their admission for the period between 1 January 2016 and 31 December 2017. The appropriateness of antimicrobial therapy was evaluated according to the Infectious Diseases Society of America (IDSA) guidelines with the consideration of the institutional antibiogram. RESULTS: Overall, 2731 patients received 5005 courses with one of the antimicrobials, for a total of 5045.9 defined daily doses (DDD) of imipenem-cilastatin, 6492.3 of meropenem and 15,595 of piperacillin-tazobactam (4.93, 6.34 and 15.24 DDD/100 bed days, respectively). The mean age of the patients who received either antimicrobial was 55.5 ± 20.3 years, with a 14-day average length of hospital stay. About half (52%) of the prescriptions were written for patients treated in the medical ward. Pneumonia (26.6%) and sepsis (24.9%) were the most common indication for the initiation of antimicrobial therapy. Of the assessed prescriptions, only 2787 (56.5%) were prescribed appropriately, with 2142 (43.5%) deemed inappropriate. The three most common reasons for inappropriate prescription were: the spectrum of activity was too broad (44.6%), followed by antimicrobial use without culture request (32.4%), and failure of suitable antimicrobial de-escalation (19.9%). CONCLUSIONS: The study indicates that the overall rate of inappropriateness was high, emphasizing the need to develop initiatives to effectively improve broad-spectrum antimicrobial prescribing.

RESUMEN

Background: In 2014, the Sepsis Six Care Bundle (SSCB) was introduced into a Scottish health region to improve patient outcomes. Poor compliance was demonstrated with the SSCB across different specialities. This study explored determinants of non-compliance with the SSCB in maternity wards. Methods: In-depth interviews were conducted with midwives in a single Scottish health region. Convenience sampling was used to recruit interviewees. The interviews were digitally recorded, transcribed verbatim, entered into NVivo software, and analysed using thematic analysis. Results: Thirteen face-to-face interviews were completed and lasted an average of 33 min. Three main barriers were identified to SSCB implementation; the difficulty of diagnosing sepsis, the suitability of the SSCB in a maternity setting as part of the pre-conditions phase, and the lack of staff training as part of the pre-implementation phase. Conclusion: The findings emphasize the importance of adapting improvement initiatives with sufficient preparation of staff in the rationale use to the context of care bundles.

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Amid the coronavirus disease (COVID-19) crisis, we have witnessed true physicianship as our frontline doctors apply clinical problem-solving to an illness without a textbook algorithm. Yet, for over a century, medical education in the United States has plowed ahead with a system that prioritizes content delivery over problem-solving. As resident trainees, we are acutely aware that memorizing content is not enough. We need a preclinical system designed to steer early learners from "know" to "know how." Education leaders have long advocated for such changes to the medical school structure. For what may be the first time, we have a real chance to effect change. In response to the COVID-19 pandemic, medical educators have scrambled to conform curricula to social distancing mandates. The resulting online infrastructures are a rare chance for risk-averse medical institutions to modernize how we train our future physicians-starting by eliminating the traditional classroom lecture. Institutions should capitalize on new digital infrastructures and curricular flexibility to facilitate the eventual rollout of flipped classrooms-a system designed to cultivate not only knowledge acquisition but problem-solving skills and creativity. These skills are more vital than ever for modern physicians.

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Cachexia is a multifactorial wasting syndrome associated with high morbidity and mortality in patients with cancer. Diagnosis can be difficult and, in the clinical situation, usually relies upon reported weight loss. The 'omics' technologies allow us the opportunity to study the end points of many biological processes. Among these, blood-based metabolomics is a promising method to investigate the pathophysiology of human cancer cachexia and identify candidate biomarkers. In this study, we performed liquid chromatography mass spectrometry (LC/MS)-based metabolomics to investigate the metabolic profile of cancer-associated weight loss. Non-selected patients undergoing surgery with curative intent for upper gastrointestinal cancer were recruited. Fasting plasma samples were taken at induction of anaesthesia. LC/MS analysis showed that 6 metabolites were highly discriminative of weight loss. Specifically, a combination profile of LysoPC 18.2, L-Proline, Hexadecanoic acid, Octadecanoic acid, Phenylalanine and LysoPC 16:1 showed close correlation for eight weight-losing samples (≥5% weight loss) and nine weight-stable samples (<5%weight loss) between predicted and actual weight change (r = 0.976, p = 0.0014). Overall, 40 metabolites were associated with ≥5% weight loss. This study provides biological validation of the consensus definition of cancer cachexia (Fearon et al.) and provides feasible candidate markers for further investigation in early diagnosis and the assessment of therapeutic intervention.

RESUMEN

A three-year-old girl was found altered with an unknown timeline. Gas chromatography mass spectrometry was positive for hydromorphone, dihydrocodeine, and hydrocodone. Initial computed tomography and magnetic resonance imaging suggested a malignant cerebellar edema not confined to a vascular distribution. She received fentanyl boluses on hospital days 0 and 1 before receiving a continuous infusion on day 1. On day 3, she had an episode of acute hypertension and bradycardia. Emergent computed tomography showed an evolving hydrocephalus and similar diffuse edema throughout both cerebellar hemispheres. External ventricular drain was placed to relieve the increased intracranial pressure. Following drain placement and fentanyl discontinuation, the patient recovered, though not without fine- and gross-motor deficits at the four-month follow-up. Our case adds to a handful of case reports of opioid toxicity in pediatric patients that present as toxic leukoencephalopathy. Though the mechanism is poorly understood, it has been suggested to be a consequence of the neurotoxic effects of the drug, which has particular affinity for µ opioid receptors-the primary opioid receptor found in the cerebellum. Clinicians would do well to recognize that this syndrome is primarily caused by direct toxicity rather than ischemia. This case adds insight by suggesting that lipophilic opioid analgesics may worsen this neurotoxicity. When intervening with mechanical ventilation, clinicians should consider avoiding lipophilic opioid drugs for analgesia until the pathogenesis of cerebellar edema is better understood.

Asunto(s)

Analgésicos Opioides/envenenamiento , Edema Encefálico/inducido químicamente , Cerebelo , Fentanilo/envenenamiento , Preescolar , Sobredosis de Droga , Femenino , Humanos , Leucoencefalopatías/inducido químicamente , Resultado del Tratamiento

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Oral Thin Film (OTF) is a newly emerging drug delivery system which has many benefits for patients. Although there has been some formulation of OTF products, these have mainly been as confectionary or dental health products. The most significant benefit of this dosage format will only be realised once more pharmaceutical products become available. Within this paper, OTF strips containing Diclofenac Sodium were prepared using the solvent casting method and then characterised to ensure the method could conform to acceptable levels of uniformity, the mean (SD) diclofenac sodium content was 25.43 (1.39) mg, range 22.84-27.44 mg. Bioburden was tested against coliforms, yeasts and moulds and all results were confirmed to be <10 CFU/g, also similar dissolution profile when compared to a commercial product to ensure biowaiver. An acceptable level of uniformity of mass was produced. K-F titration was employed to reduce the water content of the strips and it was found to be acceptable, this represented a level of water which would not be viable for microbial growth. The technique employed here in the production of OTF resulted in high quality products and amenability to being up scaled. Furthermore, the characterisation method was also sufficient to assess the quality of the products and may be used for future analysis of OTF pharmaceuticals.

Asunto(s)

Diclofenaco/química , Sistemas de Liberación de Medicamentos/métodos , Administración Oral , Diclofenaco/administración & dosificación , Diclofenaco/análisis , Diclofenaco/farmacología , Contaminación de Medicamentos/estadística & datos numéricos , Liberación de Fármacos

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A selective aziridinium ring-opening was used to etherify an α-aryl-ß-amino alcohol with stereochemical retention. This transformation was achieved in a biphasic system to address phenoxide solubility and the formation of a sulfonate ester impurity. The protecting group strategy was directed by a stability study of the activated α-aryl-ß-amino alcohol in this system. Process analytical techniques were used to establish reaction understanding, and mixing on large scale was modeled in silico. The process provided a selective and efficient method of preparing the nonsteroidal, inhaled selective glucocorticoid receptor modulator AZD7594.

Asunto(s)

Amino Alcoholes/química , Aziridinas/química , Dioxinas/síntesis química , Ésteres/síntesis química , Furanos/síntesis química , Indazoles/síntesis química , Dioxinas/química , Dioxinas/farmacología , Ésteres/química , Ésteres/farmacología , Furanos/química , Furanos/farmacología , Indazoles/química , Indazoles/farmacología , Estructura Molecular , Receptores de Glucocorticoides/metabolismo , Estereoisomerismo

RESUMEN

RNA interference is an effective and naturally occurring post-transcriptional gene regulatory mechanism. This mechanism involves the degradation of a target messenger RNA (mRNA) through the introduction of short interfering RNA (siRNA) that is complementary to the target mRNA. The application of siRNA-based therapeutics is limited by the development of an effective delivery system, as naked siRNA is unstable and cannot penetrate the cell membrane. In this study, we investigated the use of cationic niosomes (CN) prepared by microfluidic mixing for siRNA delivery. In an in vitro model, these vesicles were able to deliver anti-luciferase siRNA and effectively suppress luciferase expression in B16-F10 mouse melanoma cells. More importantly, in an in vivo mouse model, intratumoral administration of CN-carrying anti-luciferase siRNA led to significant suppression of luciferase expression compared with naked siRNA. Thus, we have established a novel and effective system for the delivery of siRNA both in vitro and in vivo, which shows high potential for future application of gene therapeutics.

Asunto(s)

Técnicas de Silenciamiento del Gen/métodos , Liposomas/química , Nanocápsulas/química , ARN Interferente Pequeño/administración & dosificación , Tensoactivos/química , Animales , Línea Celular Tumoral , Supervivencia Celular , Femenino , Silenciador del Gen , Técnicas de Transferencia de Gen , Luciferasas/genética , Luciferasas/metabolismo , Melanoma Experimental , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Prueba de Estudio Conceptual , ARN Interferente Pequeño/metabolismo

RESUMEN

Background: Concern about increasing carbapenem and piperacillin/tazobactam use led the Scottish Antimicrobial Prescribing Group (SAPG) to develop national guidance on optimal use of these agents, and to implement a quality improvement programme to assess the impact of guidance on practice. Objectives: To evaluate how SAPG guidance had been implemented by health boards, assess how this translated into clinical practice, and investigate clinicians' views and behaviours about prescribing carbapenems and alternative agents. Methods: Local implementation of SAPG guidance was assessed using an online survey. A bespoke point prevalence survey was used to evaluate prescribing. Clinicians' experience of using carbapenems and alternatives was examined through semi-structured interviews. National prescribing data were analysed to assess the impact of the programme. Results: There were greater local restrictions for carbapenems than for piperacillin/tazobactam. Laboratory result suppression was inconsistent between boards and carbapenem-sparing antibiotics were not widely available. Compliance with local guidelines was good for meropenem but lower for piperacillin/tazobactam. Indication for use was well documented but review/stop dates were poorly documented for both antibiotics. Decisions to prescribe a carbapenem were influenced by local guidelines and specialist advice. Many clinicians lacked confidence to de-escalate treatment. Use of both antibiotics decreased during the course of the programme. Conclusions: A multifaceted quality improvement programme was used to gather intelligence, promote behaviour change, and focus interventions on the use of carbapenems and piperacillin/tazobactam. Use of these antimicrobials decreased during the programme-a trend not seen elsewhere in Europe. The programme could be generalized to other antimicrobials.

Asunto(s)

Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Carbapenémicos/uso terapéutico , Utilización de Medicamentos/normas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Política de Salud , Investigación sobre Servicios de Salud , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mejoramiento de la Calidad , Escocia , Encuestas y Cuestionarios , Adulto Joven

RESUMEN

Metabolomic profiling of nine trained ultramarathon runners completing an 80.5 km self-paced treadmill-based time trial was carried out. Plasma samples were obtained from venous whole blood, collected at rest and on completion of the distance (post-80.5 km). The samples were analyzed by using high-resolution mass spectrometry in combination with both hydrophilic interaction (HILIC) and reversed phase (RP) chromatography. The extracted putatively identified features were modeled using Simca P 14.1 software (Umetrics, Umea, Sweden). A large number of amino acids decreased post-80.5 km and fatty acid metabolism was affected with an increase in the formation of medium-chain unsaturated and partially oxidized fatty acids and conjugates of fatty acids with carnitines. A possible explanation for the complex pattern of medium-chain and oxidized fatty acids formed is that the prolonged exercise provoked the proliferation of peroxisomes. The peroxisomes may provide a readily utilizable form of energy through formation of acetyl carnitine and other acyl carnitines for export to mitochondria in the muscles; and secondly may serve to regulate the levels of oxidized metabolites of long-chain fatty acids. This is the first study to provide evidence of the metabolic profile in response to prolonged ultramarathon running using an untargeted approach. The findings provide an insight to the effects of ultramarathon running on the metabolic specificities and alterations that may demonstrate cardio-protective effects.