ARGNet: using deep neural networks for robust identification and classification of antibiotic resistance genes from sequences.

BACKGROUND: Emergence of antibiotic resistance in bacteria is an important threat to global health. Antibiotic resistance genes (ARGs) are some of the key components to define bacterial resistance and their spread in different environments. Identification of ARGs, particularly from high-throughput sequencing data of the specimens, is the state-of-the-art method for comprehensively monitoring their spread and evolution. Current computational methods to identify ARGs mainly rely on alignment-based sequence similarities with known ARGs. Such approaches are limited by choice of reference databases and may potentially miss novel ARGs. The similarity thresholds are usually simple and could not accommodate variations across different gene families and regions. It is also difficult to scale up when sequence data are increasing. RESULTS: In this study, we developed ARGNet, a deep neural network that incorporates an unsupervised learning autoencoder model to identify ARGs and a multiclass classification convolutional neural network to classify ARGs that do not depend on sequence alignment. This approach enables a more efficient discovery of both known and novel ARGs. ARGNet accepts both amino acid and nucleotide sequences of variable lengths, from partial (30-50 aa; 100-150 nt) sequences to full-length protein or genes, allowing its application in both target sequencing and metagenomic sequencing. Our performance evaluation showed that ARGNet outperformed other deep learning models including DeepARG and HMD-ARG in most of the application scenarios especially quasi-negative test and the analysis of prediction consistency with phylogenetic tree. ARGNet has a reduced inference runtime by up to 57% relative to DeepARG. CONCLUSIONS: ARGNet is flexible, efficient, and accurate at predicting a broad range of ARGs from the sequencing data. ARGNet is freely available at https://github.com/id-bioinfo/ARGNet , with an online service provided at https://ARGNet.hku.hk . Video Abstract.

Preclinical Application of CEST MRI to Detect Early and Regional Tumor Response to Local Brain Tumor Treatment.

Treating glioblastoma and monitoring treatment response non-invasively remain challenging. Here, we developed a robust approach using a drug-loaded liposomal hydrogel that is mechanically compatible with the brain, and, simultaneously, we successfully monitored early tumor response using Chemical Exchange Saturation Transfer (CEST) MRI. This CEST-detectable liposomal hydrogel was optimized based on a sustainable drug release and a soft hydrogel for the brain tumor, which is unfavorable for tumor cell proliferation. After injecting the hydrogel next to the tumor, three distinctive CEST contrasts enabled the monitoring of tumor response and drug release longitudinally at 3T. As a result, a continuous tumor volume decrease was observed in the treatment group along with a significant decrease in CEST contrasts relating to the tumor response at 3.5 ppm (Amide Proton Transfer; APT) and at -3.5 ppm (relayed Nuclear Overhauser Effect; rNOE) when compared to the control group (p < 0.05). Interestingly, the molecular change at 3.5 ppm on day 3 (p < 0.05) was found to be prior to the significant decrease in tumor volume on day 5. An APT signal also showed a strong correlation with the number of proliferating cells in the tumors. This demonstrated that APT detected a distinctive decrease in mobile proteins and peptides in tumors before the change in tumor morphology. Moreover, the APT signal showed a regional response to the treatment, associated with proliferating and apoptotic cells, which allowed an in-depth evaluation and prediction of the tumor treatment response. This newly developed liposomal hydrogel allows image-guided brain tumor treatment to address clinical needs using CEST MRI.

Tolerating clear fluids diet on postoperative day 0 predicts early recovery of gastrointestinal function after laparoscopic colectomy.

INTRODUCTION: A high proportion of colorectal surgery patients within an enhanced recovery pathway (ERP) do not experience complications but remain hospitalized mainly waiting for gastrointestinal (GI) recovery. Accurate identification of these patients may allow discharge prior to the return of GI function. Therefore, the objective of this study is to determine if tolerating clear fluid (CF) on postoperative day (POD) 0 was associated with uncomplicated return of GI function after laparoscopic colorectal surgery. METHODS: Pooled data from three prospective studies from a single specialist colorectal referral center were analyzed (2013-2019). The present study included adult patients that underwent elective laparoscopic colectomy without stoma. Postoperative GI symptoms were collected daily in all three datasets. The main exposure variable, whether CF diet was tolerated on POD0, was defined as patients drinking at least 300 mL of CF without any nausea, anti-emetics, or vomiting (CF+ vs CF-). The main outcome measure was time to GI-3 (tolerating solid diet and passage of gas or stools). RESULTS: A total of 221 patients were included in this study, including 69% CF+ and 31% CF-. The groups were similar in age, gender, and comorbidities, but the CF- patients were more likely to have surgery for inflammatory bowel disease. CF+ patients had faster time to GI-3 (mean 1.6d (SD 0.7) vs. 2.3d (SD 1.5), p < 0.001). The CF+ group also experienced fewer complications (19% vs. 35%, p = 0.009), shorter mean LOS (mean 3.6d (SD 2.9) vs. 6.2d (SD 9.4), p = 0.002), and were more likely to be discharged by the target LOS (66% vs. 50%, p = 0.024). CONCLUSION: Toleration of CF on POD0 was associated with faster return of GI function, fewer complications, and shorter LOS. This may be used as a criteria for potential discharge prior to full return of GI function after laparoscopic colectomy within an ERP.

Cultural consideration for cognitive-behavioural therapy for sexual minority young people in Chinese societies: Perspectives from practitioners and target users.

Although cognitive-behavioural therapy has demonstrated effectiveness in improving mental health outcomes for sexual minority young people (SMYP), existing interventions are primarily designed and evaluated in Western contexts, and their acceptability and responsiveness to culturally relevant issues in the Chinese contexts is uncertain. This study aimed to address this gap by exploring how a manualised community-based cognitive-behavioural intervention (AFFIRM) could be culturally reconsidered for SMYP in Taiwan and Hong Kong and suggest recommendations for future adaptation. Following an empirical, community-based participatory approach, qualitative data were collected between August and September 2018 through five focus groups with 15 SMYP and 18 frontline practitioners in Taiwan and Hong Kong. Thematic analysis revealed that at the surface structural level, translation and examples, and promotion strategies can be fine-tuned to better fit the Chinese context. On the deep structural level, self-differentiation and a pragmatic plan to come out to parents were identified as two concerns of cultural importance for Chinese SMYP. This study exemplifies an empirical, collaborative approach to identifying areas of cultural adaptation for mental health intervention for SMYP in the Chinese cultural milieu. The rationale and strategy for adapting existing intervention protocols to accommodate divergent cultural values are described.

Developing a Tool for Prospective Assessment of Treatment Appropriateness in Urinary Tract Infections.

Background: Antimicrobial resistance is an increasingly serious threat to global public health. Antimicrobial stewardship programs need to identify inappropriate antibiotic use patterns and offer practical recommendations to prescribers and institutions. Urinary tract infection (UTI) is a common syndrome for which a standardized tool would be useful when treatment appropriateness is assessed. To date, few UTI treatment assessment tools have been published, and the available tools do not support appropriateness assessment against published guidelines, or consistent adjudication from one auditor to another. Objective: To develop a tool for auditing UTI antibiotic therapy that assesses treatment appropriateness based on guideline concordance, and with high inter-rater reliability. Methods: An audit tool was developed iteratively by the local antimicrobial stewardship team. Two auditors used the tool to adjudicate treatment appropriateness in a sample of UTI cases against local treatment guidelines. Inter-rater agreement was estimated with Cohen's kappa statistic. Results: The final design of the tool had individual sections for evaluating five aspects of treatment appropriateness, depending on the stage at which a patient was in his or her course of antibiotic therapy: diagnosis, empiric therapy, culture-directed therapy, route of antimicrobial administration, and duration of therapy. A total of 50 cases were assessed; among these, the two auditors agreed on 45 cases (90% agreement). The estimated kappa was 0.8. Conclusion: A unique tool with substantial inter-rater agreement was developed for assessing appropriateness of antimicrobial therapy in UTI. The process and design features that were outlined can be adapted by other antimicrobial stewardship programs to monitor antimicrobial use and improve quality of care.

Efficacy of affirmative cognitive behavioural group therapy for sexual and gender minority adolescents and young adults in community settings in Ontario, Canada.

OBJECTIVE: This study tested the efficacy of AFFIRM, a brief affirmative cognitive-behavioural group intervention tailored to reduce psychosocial distress and improve coping among sexual and gender minority adolescents and young adults (SGMY). METHOD: SGMY (n = 138; M age = 22.44) were allocated to immediate 8-week AFFIRM intervention delivered at 12 community-based organisations or an 8-week waitlisted control. At baseline, post-intervention or post-waitlist, participants completed self-reported assessments of depression, hope, coping, and stress appraisal. Implementation outcomes of feasibility and acceptability were also assessed. RESULTS: Compared to waitlist, SGMY in the intervention condition significantly reduced their depressive symptoms (b = - 5.79, p = .001) as well as increased reports of hope (agency: b = 0.84, p = .001; pathway: b = 0.79, p = .001), and coping by emotional support (b = 0.59, p < .001), instrumental support (b = 0.67, p < .001), positive framing (b = 0.59, p < .001), humour (b = 0.36, p = .014), planning (b = 0.49, p < .001) as well as reflective coping (b = 0.27, p = .009). Intervention participants were also less likely to perceive stress as a threat (b = - 0.43, p = .001), and more likely to perceive stress as challenge (b = 0.67, p < .001) and have the resources to deal with that stress (b = 0.38, p = .016) in comparison to waitlisted control participants. All outcomes had medium to large effect sizes. AFFIRM participants reported low attrition (8.5%) and high levels of engagement and acceptability (e.g. 99% agreed intervention was relevant to their lives). Over 63% of the community organizations that participated in the training hosted AFFIRM at least once during the study. CONCLUSIONS: Results demonstrate efficacy for the community-based implementation of an affirmative clinical intervention designed for SGMY to address depression and foster coping with universal and minority stressors.

AFFIRM Online: Utilising an Affirmative Cognitive-Behavioural Digital Intervention to Improve Mental Health, Access, and Engagement among LGBTQA+ Youth and Young Adults.

Digital mental health interventions may enable access to care for LGBTQA+ youth and young adults that face significant threats to their wellbeing. This study describes the preliminary efficacy of AFFIRM Online, an eight-session manualised affirmative cognitive behavioural group intervention delivered synchronously. Participants (Mage = 21.17; SD = 4.52) had a range of sexual (e.g., queer, lesbian, pansexual) and gender (e.g., non-binary, transgender, cisgender woman) identities. Compared to a waitlist control (n = 50), AFFIRM Online participants (n = 46) experienced significantly reduced depression (b = -5.30, p = 0.005, d = 0.60) and improved appraisal of stress as a challenge (b = 0.51, p = 0.005, d = 0.60) and having the resources to meet those challenges (b = 0.27, p = 0.059, d = 0.39) as well active coping (b = 0.36, p = 0.012, d = 0.54), emotional support (b = 0.38, p = 0.017, d = 0.51), instrumental support (b = 0.58, p < 0.001, d = 0.77), positive framing (b = 0.34, p = 0.046, d = 0.42), and planning (b = 0.41, p = 0.024, d = 0.49). Participants reported high acceptability. This study highlights the potential of digital interventions to impact LGBTQA+ youth mental health and explores the feasibility of digital mental health to support access and engagement of youth with a range of identities and needs (e.g., pandemic, lack of transportation, rural locations). Findings have implications for the design and delivery of digital interventions for marginalised youth and young adults.

Frequencies and patterns of adverse childhood events in LGBTQ+ youth.

BACKGROUND: Trauma, specifically adverse childhood experiences (ACEs), predicts significant health and mental health disparities, yet there is a paucity of research with LGBTQ + youth. OBJECTIVE: This study explored ACE prevalence in a large sample of LGBTQ+ youth; examined ACE patterns within and across subgroups; and compared results with the general population. PARTICIPANTS AND SETTING: Participant (n = 3,508) ages ranged between 14-18 (x̄ = 16.02) and represented a range of sexual orientations: pansexual (33.9 %), bisexual (26.6 %), and queer (16.2 %), and gender identities: female (39.9 %), non-conforming (38 %), male (14.9 %), and transgender (16.6 %). METHODS: An online cross-sectional survey was conducted with LGBTQ+ youth ages 14-18 that self-identified as LGBTQ+ and resided in the US or Canada. Descriptive statistics generated the prevalence of ACEs, and ANOVAs and post-hoc tests were run for comparisons. RESULTS: Participants reported multiple ACEs (M = 3.14, SD = 2.44) with emotional neglect (58 %), emotional abuse (56 %), and living with a family member with mental illness (51 %) as the most prevalent. Notably, 43 % of participants experienced 4+ ACEs, considered to be a high level of trauma exposure. Compared to national samples, LGBTQ + youth demonstrated unique patterns of ACEs and were higher in 9 of 10 categories. Significantly high (all p < .001) ACEs were found in pansexual (t = 7.67), transgender and gender non-conforming (t = 5.19), American-Indian (t = 6.42), Latinx (t = 2.83) and rural youth (F = 12.12) while those with highly educated parents (F = 83.30, p < .001), lived with a parent (t = 6.02), and in Canada (t = 6.14) reported fewer ACEs. CONCLUSION: LGBTQ+ youth experience significant childhood trauma with potential impact on their mental health. This study identifies implications for trauma-informed practice and research.

A case report on lipofuscin deposition in a graft biopsy two years after kidney transplantation: an insignificant bystander or a pathogenic benefactor?

BACKGROUND: Lipofuscin deposition is a characteristic manifestation of aging. There is very limited literature in humans and in animals describing these deposits in native kidneys. Overall, it is thought to be non-pathogenic and successful transplants from a donor with lipofuscin deposits have been reported. We present the case of a patient who underwent a kidney transplant and a for-cause biopsy post-transplantation incidentally revealed lipofuscin deposition. CASE PRESENTATION: A 48-year old gentleman with a past medical history of diabetes, hypertension, coronary artery disease, and ischemic and then hemorrhagic cardiovascular accident underwent a successful kidney transplant. His donor was an expanded criteria donor with no major past medical history. Post-transplant course was complicated by delayed graft function requiring one dialysis treatment for hyperkalemia. After that he had an uneventful course and achieved a baseline creatinine of 1.2 mg/dL, with no proteinuria. On a routine 19-month follow-up he was noted to have proteinuria and an antibody against the major-histocompatibility-complex class I-related chain A. A graft biopsy revealed acute antibody-mediated rejection and impressive lipofuscin deposition. He was subsequently treated with an antibody-mediated rejection protocol that included high dose steroids, Rituximab, plasmapheresis, and intravenous immunoglobulin, but responded poorly to this regimen. A 6-month follow up biopsy continued to show lipofuscin deposition, with similar microvascular injury scores and 12-months later his creatinine remained stable but his proteinuria worsened. Patient was struggling with recurrent infectious episodes requiring hospitalizations and thus no further diagnostic or therapeutic treatments were pursued. CONCLUSIONS: Lipofuscin deposition has been reported in solid organ transplants but the significance and cause are not well understood. Several physiologic and some pathologic causes to these deposits have been reported including age, diabetes, medications and a genetic syndrome. We propose that immunologic causes such as rejection in the presence of other risk factors could potentiate the oxidative stress leading to excessive lipofuscin deposition in kidney transplants. In the case of our patient, we conclude that these deposits were likely recipient-derived, and postulate that the cumulative burden of inflammation from rejection, and underlying medical conditions led to increased lipofuscin deposition. We speculate them to be an innocent bystander.

MRI Performance in Detecting pCR After Neoadjuvant Chemotherapy by Molecular Subtype of Breast Cancer.

BACKGROUND: MRI performance in detecting pathologic complete response (pCR) post-neoadjuvant chemotherapy (NAC) in breast cancer has been previously explored. However, since tumor response varies by molecular subtype, it is plausible that imaging performance also varies. Therefore, we performed a literature review on subtype-specific MRI performance in detecting pCR post-NAC. METHODS: Two reviewers searched Cochrane, PubMed, and EMBASE for articles published between 2013 and 2018 that examined MRI performance in detecting pCR post-NAC. After filtering, ten primary research articles were included. Statistical metrics, such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were extracted per study for triple negative, HR+/HER2-, and HER2+ patients. RESULTS: Ten studies involving 2310 patients were included. In triple negative breast cancer, MRI showed NPV (58-100%) and PPV (72.7-94.7%) across 446 patients and sensitivity (45.5-100%) and specificity (49-94.4%) in 375 patients. In HR+/HER2- breast cancer patients, MRI showed NPV (29.4-100%) and PPV (21.4-95.1%) across 851 patients and sensitivity (43-100%) and specificity (45-93%) across 780 patients. In HER2+-enriched subtype, MRI showed NPV (62-94.6%) and PPV (34.9-72%) in 243 patients and sensitivity (36.2-83%) and specificity (47-90%) in 255 patients. CONCLUSION: MRI accuracy in detecting pCR post-NAC by subtype is not as consistent, nor as high, as individual studies suggest. Larger studies using standardized pCR definition with appropriate timing of surgery and MRI need to be conducted. This study has shown that MRI is in fact not an accurate prediction of pCR, and thus, clinicians may need to rely on other approaches such as biopsies of the tumor bed.

Digitally Barcoding Mycobacterium tuberculosis Reveals In Vivo Infection Dynamics in the Macaque Model of Tuberculosis.

Infection with Mycobacterium tuberculosis causes a spectrum of outcomes; the majority of individuals contain but do not eliminate the infection, while a small subset present with primary active tuberculosis (TB) disease. This variability in infection outcomes is recapitulated at the granuloma level within each host, such that some sites of infection can be fully cleared while others progress. Understanding the spectrum of TB outcomes requires new tools to deconstruct the mechanisms underlying differences in granuloma fate. Here, we use novel genome-encoded barcodes to uniquely tag individual M. tuberculosis bacilli, enabling us to quantitatively track the trajectory of each infecting bacterium in a macaque model of TB. We also introduce a robust bioinformatics pipeline capable of identifying and counting barcode sequences within complex mixtures and at various read depths. By coupling this tagging strategy with serial positron emission tomography coregistered with computed tomography (PET/CT) imaging of lung pathology in macaques, we define a lesional map of M. tuberculosis infection dynamics. We find that there is no significant infection bottleneck, but there are significant constraints on productive bacterial trafficking out of primary granulomas. Our findings validate our barcoding approach and demonstrate its utility in probing lesion-specific biology and dissemination. This novel technology has the potential to greatly enhance our understanding of local dynamics in tuberculosis.IMPORTANCE Classically, M. tuberculosis infection was thought to result in either latent infection or active disease. More recently, the field has recognized that there is a spectrum of M. tuberculosis infection clinical outcomes. Within a single host, this spectrum is recapitulated at the granuloma level, where there can simultaneously be lesional sterilization and poorly contained disease. To better understand the lesional biology of TB infection, we digitally barcoded M. tuberculosis to quantitatively track the fate of each infecting bacterium. By combining this technology with serial PET-CT imaging, we can dynamically track both bacterial populations and granuloma trajectories. We demonstrate that there is little constraint on the bacterial population at the time of infection. However, the granuloma imposes a strong bottleneck on dissemination, and the subset of granulomas at risk of dissemination can be distinguished by physical features.

Population-based evaluation of the effectiveness of two regimens for emergency contraception.

OBJECTIVE: To estimate and compare the effectiveness of the levonorgestrel and Yuzpe regimens for hormonal emergency contraception in routine clinical practice. METHODS: A retrospective population-based study included women who accessed emergency contraceptives for immediate use prescribed by community pharmacists in British Columbia, Canada, between December 2000 and December 2002. Linked administrative healthcare data were used to discern the timings of menses, unprotected intercourse, and any pregnancy-related health services. A panel of experts evaluated the compatibility of observed pregnancies with the timing of events. The two regimens were compared with statistical adjustments for potential confounding. RESULTS: Among 7493 women in the cohort, 4470 (59.7%) received levonorgestrel and 3023 (40.3%) the Yuzpe regimen. There were 99 (2.2%) compatible pregnancies in the levonorgestrel group and 94 (3.1%) in the Yuzpe group (P=0.017). The estimated odds ratio for levonorgestrel compared with the Yuzpe regimen after adjusting for potential confounders was 0.64 (95% confidence interval 0.47-0.87). Against an expected pregnancy rate of approximately 5%, the relative and absolute risk reductions were 56.0% and 2.8%, respectively, for levonorgestrel and 36.7% and 1.8% for the Yuzpe regimen. CONCLUSION: The levonorgestrel regimen is more effective than the Yuzpe regimen in routine use. The data suggest that both regimens are less effective than has been observed in randomized trials.

Assessment of clinical pharmacy interventions in the intensive care unit.

BACKGROUND: Clinical pharmacy services have been shown to reduce adverse drug events and health care costs. However, few studies have assessed their effect on patient outcomes in the intensive care unit (ICU). OBJECTIVE: To describe characteristics of ICU patients with documented pharmacist interventions and to evaluate the relationships between patients' complexity level and pharmacists' interventions and between pharmacists' interventions and mortality rate. METHODS: Inpatient records of admissions between January 1, 2004, and March 31, 2007, were analyzed to identify the presence of clinical pharmacy notes (CPNs). The characteristics of patients with and without CPNs were compared using descriptive statistics. For primary analysis of the association between patient complexity level and presence of CPNs, logistic regression modelling was performed to adjust for potential confounding. Logistic regression was also used to explore the possible association between CPNs and mortality. Finally, mortality analysis was carried out for patients with and without CPNs, with matching by complexity level. RESULTS: The main study cohort comprised 1561 patients: 333 (21.3%) with CPNs and 1228 (78.7%) with no CPNs. A greater proportion of those with a CPN had the highest complexity level: 295 (88.6%) of those with CPNs versus 660 (53.7%) of those with no CPNs. After adjustment for age and sex, the odds ratio for having a CPN among patients with complexity level 4 (relative to patients with lower complexity levels) was 8.20 (95% confidence interval 5.44-12.38). Mortality rates were not significantly different between the 2 groups: 26.7% (89/333) among patients with CPNs and 27.9% (343/1228) among those without CPNs (p = 0.66). After adjustment for age, sex, complexity level, and length of stay in the ICU, the presence of a CPN was not significantly associated with mortality. Mortality rates in the matched cohort (n = 1078) were also similar between patients with and without CPNs (89/333 [26.7%] and 226/745 [30.3%], respectively; p = 0.23), and the presence of a CPN was not significantly associated with mortality after adjustments for potential confounding factors. CONCLUSION: Documenting clinical pharmacy activities is essential for assessing pharmacists' impact on patient outcomes. These data suggest that ICU pharmacists prioritize clinical activities to care for the sickest patients.

CONTEXTE: Il a été montré que les services de pharmacie clinique réduisaient les événements indésirables liés aux médicaments et les coûts de soins de santé. En revanche, peu d'études ont évalué leurs effets sur les résultats thérapeutiques chez les patients des unités de soins intensifs (USI). OBJECTIF: Décrire les caractéristiques des patients des USI pour lesquels les pharmaciens avaient consignés des interventions et évaluer les liens entre le niveau de complexité de l'état des patients et les interventions des pharmaciens et entre les interventions des pharmaciens et le taux de mortalité. MÉTHODES: Les dossiers des patients hospitalisés entre le 1er janvier 2004 et le 31 mars 2007 ont été analysés à la recherche de notes de pharmaciens cliniciens (NPC). Les caractéristiques des patients dont le dossier comportait des NPC et de ceux dont le dossier n'en comportait pas ont été comparées au moyen de statistiques descriptives. L'analyse primaire de l'association entre le niveau de complexité de l'état des patients et la présence de NPC a été réalisée au moyen d'un modèle de régression logistique pour compenser les facteurs de confusion potentiels. Ce modèle a aussi été utilisé pour évaluer l'association possible entre les NPC et la mortalité. En dernier lieu, une analyse de mortalité a comparé les patients dont le dossier comportait des NPC à ceux dont le dossier n'en comportait pas, avec un appariement du niveau de complexité. RÉSULTATS: La principale cohorte de l'étude comptait 1561 patients : 333 (21,3 %) dont le dossier comportait des NPC et 1228 (78,7 %) dont le dossier n'en comportait pas. Une plus grande proportion des patients dont le dossier comportait des NPC présentaient le plus haut niveau de complexité : 295 (88,6 %) de ceux avec des NPC contre 660 (53,7 %) de ceux sans NPC. Après ajustement pour l'âge et le sexe, le risque relatif approché de NPC chez les patients présentant un niveau de complexité 4 (par rapport aux patients présentant un niveau de complexité moindre) était de 8,20 (intervalle de confiance à 95 % : 5,44 ­ 12,38). Les taux de mortalité n'étaient pas significativement différents entre les deux groupes : 26,7 % (89/333) chez les patients avec NPC et 27,9 % (343/1228) chez les patients sans NPC (p = 0,66). Après ajustement pour l'âge, le sexe, le niveau de complexité et la durée du séjour à l'USI, la présence d'une NPC au dossier n'était pas associée de façon significative à la mortalité. Les taux de mortalité au sein de la cohorte appariée (n = 1078) étaient également similaires entre les patients avec NPC et ceux sans NPC : respectivement 89/333 (26,7 %) et 226/745 (30,3 %) (p = 0,23); la présence d'une NPC n'a pas été associée de façon significative à la mortalité après ajustements pour les facteurs de confusion potentiels. CONCLUSION: La consignation des activités de pharmacie clinique est essentielle à l'évaluation de l'influence des pharmaciens sur les résultats cliniques pour les patients. Ces données suggèrent que les pharmaciens des USI accordent la priorité aux activités cliniques destinées aux soins des patients les plus malades. [Traduction par l'éditeur].

Measuring and reporting of the treatment effect of hormonal emergency contraceptives.

STUDY OBJECTIVES: To derive summary estimates of observed pregnancy rates in women who used the Yuzpe or levonorgestrel emergency contraceptive regimen and identify the various ways in which data related to regimen effectiveness were reported, to discuss the limitations of the effectiveness estimates as they are currently reported, and to propose alternative reporting methods that are less susceptible to misinterpretation. DESIGN: Analysis of pooled data from 34 experimental or observational studies that had an explicit method of follow-up to systematically evaluate pregnancy outcome after a single course of emergency contraception treatment within a given menstrual cycle. PATIENTS: Women who took either the Yuzpe or levonorgestrel emergency contraceptive regimen to prevent pregnancy. MEASUREMENTS AND MAIN RESULTS: We searched the MEDLINE and EMBASE databases for clinical studies that systematically evaluated pregnancy outcomes of women who used the Yuzpe or levonorgestrel regimen for emergency contraception. The effectiveness of these regimens is typically reported in relative terms as the reduction of pregnancy risk from a theoretical baseline risk. We reported the effectiveness using absolute risk reductions and numbers needed to treat. We pooled relevant data by using the ß-binomial method to derive observed pregnancy rates. The pooled observed pregnancy rates for studies of the Yuzpe and levonorgestrel regimens were 2.0% (95% confidence interval [CI] 1.5-2.5%) and 1.7% (95% CI 1.2-2.2%), respectively. Against expected pregnancy rates of 4-8%, relative emergency contraceptive effectiveness ranges were 50.0-75.0% and 57.5-78.8% for the Yuzpe and levonorgestrel regimens, respectively. Absolute risk reductions were 2.0-6.0% and 2.3-6.3%, respectively. This means that 17-50 women would need to have received the Yuzpe regimen and 16-43 women the levonorgestrel regimen to prevent one pregnancy. CONCLUSION: Emergency contraception effectiveness data are susceptible to misinterpretation when data are reported in relative terms without the expected pregnancy rate (i.e., the baseline risk). We recommend that the effect of emergency contraceptives be expressed in absolute terms and accompanied by the expected pregnancy rate used in its estimation.

Mechanisms of action of hormonal emergency contraceptives.

Hormonal emergency contraceptives have been used to prevent unwanted pregnancy for more than 3 decades. The mechanisms of action of the regimen containing a combination of estrogen and progestin, known as the Yuzpe regimen, and those of the levonorgestrel regimen continue to be controversial, especially over the possibility that these regimens might act by interfering with implantation of the fertilized ovum. We performed a search of the PubMed (1949-July 2009) and EMBASE (1980-July 2009) databases to identify literature on the mechanisms of action of these contraceptive regimens, and data were extracted from pertinent English-language studies. We classified studies according to the approach taken by the investigators to study the actions of emergency contraceptives on pregnancy: an indirect method that uses statistical models to determine whether emergency contraceptives would be as effective as reported if they act only by disrupting ovulation; direct observation of the effects of emergency contraceptives on surrogate outcomes, including ovulation, sperm activity, hormonal levels, and endometrial receptivity to implantation; and analysis of directly observed pregnancy outcomes against statistical data. Acceptability of emergency contraceptives by women and clinicians may depend on personal opinions about when life or pregnancy begins. The evidence strongly supports disruption of ovulation as a mechanism of action. The data suggest that emergency contraceptives are unlikely to act by interfering with implantation, although the possibility has not been completely excluded. The data also suggest that emergency contraceptives are ineffective after ovulation. Women and clinicians who consider implantation or later events to be the beginning of pregnancy should be aware that emergency contraceptives are likely nonabortive by this definition of pregnancy.

Prevalence of use and the risk of adverse effects associated with complementary and alternative medicine in a cohort of patients receiving warfarin.

BACKGROUND: The use of complementary and alternative medicine (CAM), including orally administered herbals, botanicals, vitamins, and supplements, may pose a risk to patients on warfarin therapy. OBJECTIVE: To estimate the prevalence of CAM use among patients taking warfarin and evaluate the impact of CAM exposure on the risk of warfarin-related adverse effects. METHODS: A survey was administered to hospital inpatients and clinic outpatients on drug exposure (including CAM) over the previous month, self-reported bleeding events, use of alcohol and vitamin K-rich foods, and medical conditions. Prescription medication use was verified, and laboratory records were checked for out-of-range international normalized ratios (INRs) (defined as INR >4 or <2). The use of CAM, including products with reported or theoretical interactions with warfarin, was compared between patients with and without self-reported bleeding or out-of-range INR. RESULTS: Among the 314 patients who completed the survey, 44.3% reported using CAM at least weekly. Potentially interacting CAM was used by 34.1% of all patients, or 18.2% if vitamin E was excluded as an interacting CAM. Vitamin E was used by 24.2% of all patients and 71.0% of those who used potentially interacting CAM. There was no significant difference in CAM use or consumption of vitamin K-rich foods between patients with and without INRs greater than 4 or for patients with and without INRs less than 2. CONCLUSIONS: The use of potentially interacting CAM in this cohort was higher than the use previously reported among patients on warfarin therapy. However, exposure to CAM was not associated with an increase in the risk of self-reported bleeding or out-of-range INR.

Acute clenbuterol overdose resulting in supraventricular tachycardia and atrial fibrillation.

OBJECTIVE: We are presenting a case illustrating the complex metabolic and rhythm disturbances associated with acute clenbuterol intoxication. BACKGROUND: Clenbuterol is a long-acting beta2-adrenergic agonist primarily used in veterinary medicine in the United States. It has become a common drug of abuse by body builders because of its reported anabolic and lipolytic properties. In this case report, a body builder using veterinary clenbuterol developed significant electrolyte and cardiac manifestations. CASE REPORT: A 31-year-old man presented to the emergency department approximately 30 minutes after ingesting 1.5 ml (a tenfold dosing error) of Ventipulmin syrup (72.5 mcg/ml clenbuterol HCl). The product was brought to the emergency department (ED) by the patient. He reported no current use of anabolic steroids. He presented in an anxious state with complaints of palpitations and shortness of breath. Vital signs upon examination were as follows: BP, 122/77 mmHg (16.3/10.3 kPa); HR 254 bpm; RR, 22 bpm; Temperature, 97.1 degrees F (36 degrees C); and oxygen saturation, 100% on ambient air. His electrocardiogram (ECG) demonstrated supraventricular tachycardia with a ventricular rate of 254 bpm. Esmolol was recommended for rate control after the unsuccessful use of adenosine and diltiazem. Laboratory studies showed potassium, 2.1 mmol/L; magnesium, 1.3 mg/dL (0.54 mmol/L); phosphorus, 1.0 mg/dL (0.32 mmol/L); serum glucose, 209 mg/dL (11.6 mmol/L); creatinine, 0.8 mg/dL (70.7 micromol/L); AST, 20 U/L; ALT, 55 U/L; hemoglobin, 12.6 g/dL (126 g/L); CPK total, 87 U/L; and troponin I, 0.23 mug/L. The patient's urine was negative for any drugs of abuse. Clenbuterol levels were not obtained. A second ECG, 16 hours post ingestion, reflected atrial fibrillation with a ventricular rate of 125 to 147 bpm. On hospital day 3, he was electively cardioverted to sinus rhythm; heart rate and rhythm returned to normal, and he was discharged with oral metoprolol. DISCUSSION: Clenbuterol is approved for use in countries outside the U.S. as a bronchodilator for the treatment of acute asthma exacerbations in humans. Although clenbuterol is not a steroid hormone, it possesses anabolic properties that increase muscle mass. Its longer duration of action compared to other beta2-agonists (such as albuterol) make it a desired agent for body-building because of its high and prolonged serum level. The mechanism for the short and long-term cardiovascular complications of clenbuterol is complex. The anabolic effects of clenbuterol are associated with its beta2-adrenoreceptor agonist activity on striated skeletal muscles. In addition, clenbuterol promotes lipolysis through adipocyte beta3-adrenoreceptors. CONCLUSION: Considering the significant number of body-building enthusiasts, physicians will continue to encounter clenbuterol abuse in their clinical practices.

Switching from abciximab to eptifibatide for percutaneous coronary interventions: a local analysis (SWAP study).

BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPI) are recommended as adjunctive therapy with percutaneous coronary interventions (PCI). Before October 2000, abciximab (AB) was the only GPI available at the authors' institution. Eptifibatide (EP) was added to the formulary in October 2000 and became the preferred agent primarily due to lower cost. OBJECTIVES: To describe the impact of switching from AB to EP in the cardiac catheterization laboratory and compare clinical and practice-related outcomes of these agents following PCI. METHODS: Retrospective chart review was performed on patients who received PCI for all indications except as primary therapy for ST-segment elevation myocardial infarction. The AB group consisted of all consecutive patients within the six months preceding formulary addition of EP in October 2000. A matching number of consecutive patients following this date were included in the EP group. RESULTS: A total of 160 patients were included (80 per group). Use of adjunctive GPI increased from 11% to 25% of PCI within three months of adding EP to the formulary (P<0.001). The composite of in-hospital death, myocardial infarction, recurrent ischemia and repeat revascularization occurred in 12.5% of EP- and 2.5% of AB-treated patients (P<0.025). Minor bleeding was more common in the EP group than in the AB group at 8.8% and 2.5%, respectively (not significant). Premature GPI discontinuation was significantly more common in the EP group (46.3% versus 7.5%, P<0.001). The mean +/- SD length of stay post-PCI was 44.4+/-51.2 h for EP and 25.1+/-12.3 h for AB (P<0.0001). CONCLUSIONS: Adjunctive GPI usage more than doubled following the introduction of EP to the formulary. The present results suggest that EP may be associated with inferior clinical outcomes compared with AB for PCI patients.