Economic and health impact modelling of a whole genome sequencing-led intervention strategy for bacterial healthcare-associated infections for England and for the USA.

Bacterial healthcare-associated infections (HAIs) are a substantial source of global morbidity and mortality. The estimated cost associated with HAIs ranges from $35 to $45 billion in the USA alone. The costs and accessibility of whole genome sequencing (WGS) of bacteria and the lack of sufficiently accurate, high-resolution, scalable and accessible analysis for strain identification are being addressed. Thus, it is timely to determine the economic viability and impact of routine diagnostic bacterial genomics. The aim of this study was to model the economic impact of a WGS surveillance system that proactively detects and directs interventions for nosocomial infections and outbreaks compared to the current standard of care, without WGS. Using a synthesis of published models, inputs from national statistics, and peer-reviewed articles, the economic impacts of conducting a WGS-led surveillance system addressing the 11 most common nosocomial pathogen groups in England and the USA were modelled. This was followed by a series of sensitivity analyses. England was used to establish the baseline model because of the greater availability of underpinning data, and this was then modified using USA-specific parameters where available. The model for the NHS in England shows bacterial HAIs currently cost the NHS around £3 billion. WGS-based surveillance delivery is predicted to cost £61.1 million associated with the prevention of 74 408 HAIs and 1257 deaths. The net cost saving was £478.3 million, of which £65.8 million were from directly incurred savings (antibiotics, consumables, etc.) and £412.5 million from opportunity cost savings due to re-allocation of hospital beds and healthcare professionals. The USA model indicates that the bacterial HAI care baseline costs are around $18.3 billion. WGS surveillance costs $169.2 million, and resulted in a net saving of ca.$3.2 billion, while preventing 169 260 HAIs and 4862 deaths. From a 'return on investment' perspective, the model predicts a return to the hospitals of £7.83 per £1 invested in diagnostic WGS in the UK, and US$18.74 per $1 in the USA. Sensitivity analyses show that substantial savings are retained when inputs to the model are varied within a wide range of upper and lower limits. Modelling a proactive WGS system addressing HAI pathogens shows significant improvement in morbidity and mortality while simultaneously achieving substantial savings to healthcare facilities that more than offset the cost of implementing diagnostic genomics surveillance.

Continuous infusion of ceftolozane-tazobactam resulted in high cerebrospinal fluid concentrations of ceftolozane in a patient with multidrug-resistant Pseudomonas aeruginosa meningitis.

Multidrug-resistant Pseudomonas aeruginosa has limited treatment options. Treatment of healthcare-associated meningitis requires agents active against the organism in vitro and able to penetrate the cerebrospinal fluid adequately. Ceftolozane-tazobactam has been recently approved to treat various Gram-negative organisms, including Pseudomonas aeruginosa; however, ceftolozane's penetration into human cerebrospinal fluid is unknown. Here, we present a case of a patient with multidrug-resistant Pseudomonas aeruginosa meningitis treated with a continuous infusion of ceftolozane-tazobactam. Samples of both serum and cerebrospinal fluid were analyzed for ceftolozane concentration on continuous infusion. Cerebrospinal fluid concentrations of ceftolozane were 83% of that in serum. Treatment with ceftolozane-tazobactam, along with combinations of other antibiotics, resulted in clearance of organism from the patient's cerebrospinal fluid and marked decrease in inflammatory cells. Studies are warranted to determine the efficacy of ceftolozane-tazobactam for patients with healthcare-associated meningitis.

Impact of pharmacists on outcomes for patients with psychiatric or neurologic disorders.

INTRODUCTION: Psychiatric and neurologic illnesses are highly prevalent and are often suboptimally treated. A 2015 review highlighted the value of psychiatric pharmacists in improving medication-related outcomes. There is a need to describe areas of expansion and strengthened evidence regarding pharmacist practice and patient care impact in psychiatric and neurologic settings since 2015. METHODS: A systematic search of literature published from January 2014 to June 2019 was conducted. Publications describing patient-level outcome results associated with pharmacist provision of care in a psychiatric/neurologic setting and/or in relation to central nervous system (CNS) medications were included. RESULTS: A total of 64 publications were included. There was significant heterogeneity of published study methods and data, prohibiting meta-analysis. Pharmacists practicing across a wide variety of health care settings with focus on CNS medication management significantly improved patient-level outcomes, such as medication adherence, disease control, and avoidance of hospitalization. The most common practice approach associated with significant improvement in patient-level outcomes was incorporation of psychiatric pharmacist input into the interprofessional health care team. DISCUSSION: Pharmacists who focus on psychiatric and neurologic disease improve outcomes for patients with these conditions. This is important in the current health care environment as most patients with psychiatric or neurologic conditions continue to have unmet needs. Additional studies designed to measure pharmacists' impact on patient-level outcomes are encouraged to strengthen these findings.

The skeletal phenotype of achondrogenesis type 1A is caused exclusively by cartilage defects.

Inactivating mutations in the ubiquitously expressed membrane trafficking component GMAP-210 (encoded by Trip11) cause achondrogenesis type 1A (ACG1A). ACG1A is surprisingly tissue specific, mainly affecting cartilage development. Bone development is also abnormal, but as chondrogenesis and osteogenesis are closely coupled, this could be a secondary consequence of the cartilage defect. A possible explanation for the tissue specificity of ACG1A is that cartilage and bone are highly secretory tissues with a high use of the membrane trafficking machinery. The perinatal lethality of ACG1A prevents investigating this hypothesis. We therefore generated mice with conditional Trip11 knockout alleles and inactivated Trip11 in chondrocytes, osteoblasts, osteoclasts and pancreas acinar cells, all highly secretory cell types. We discovered that the ACG1A skeletal phenotype is solely due to absence of GMAP-210 in chondrocytes. Mice lacking GMAP-210 in osteoblasts, osteoclasts and acinar cells were normal. When we inactivated Trip11 in primary chondrocyte cultures, GMAP-210 deficiency affected trafficking of a subset of chondrocyte-expressed proteins rather than globally impairing membrane trafficking. Thus, GMAP-210 is essential for trafficking specific cargoes in chondrocytes but is dispensable in other highly secretory cells.

A Retrospective Cohort Study of Acute Kidney Injury Risk Associated with Antipsychotics.

BACKGROUND: A recent large database analysis raised concerns of potential acute kidney injury (AKI) risk associated with antipsychotics. However, whether individual atypical and typical antipsychotics are associated with differential AKI risks has not been investigated. OBJECTIVE: The current study compared the risks of AKI and known causes of AKI associated with a broad range of atypical and typical antipsychotics. METHOD: This retrospective cohort analysis used January 2007-June 2013 US nationwide Humana claims data to define episodes of antipsychotic drug therapy for patients with schizophrenia and bipolar disorder. Study drugs were aripiprazole, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone. Study outcomes were hospitalizations with AKI, and known causes of AKI, i.e., hypotension, acute urinary retention, neuroleptic malignant syndrome/rhabdomyolysis, and pneumonia. AKI was the primary outcome of the study. Cox regressions using haloperidol as the baseline comparator were used to estimate the impact of alternative antipsychotics on the risks of study adverse events following the initiation of treatment. The Cox models controlled for treatment history, comorbidities, and concomitant drug use in the prior 6 months. They also controlled for patient demographics and dose of current treatment. RESULTS: The overall incidence of AKI was 25.0 per 1000 person-years. According to our multivariate regression results, the risk of AKI was significantly increased in patients taking olanzapine [hazard ratio (HR) 1.344, 95% confidence interval (CI) 1.057-1.708], quetiapine (HR 1.350, 95% CI 1.082-1.685), and ziprasidone (HR 1.338, 95% CI 1.035-1.729) relative to haloperidol. Aripiprazole (HR 1.152, 95% CI 0.908-1.462) and risperidone (HR 1.147, 95% CI 0.923-1.426) had insignificantly higher risks of AKI compared with haloperidol, whereas fluphenazine (HR 0.729, 95% CI 0.483-1.102) had an insignificantly lower risk of AKI. When compared between drug classes, atypical antipsychotics had a significantly higher risk of AKI (HR 1.313, 95% CI 1.083-1.591) than typical antipsychotics. CONCLUSIONS: Antipsychotics are associated with differential AKI risks, with several atypical antipsychotics having higher risks than haloperidol. However, the overall incidence of AKI was moderate, and AKI risk should only raise concern for clinicians with elderly patients or patients who are vulnerable to kidney disease.

Do Cardiac Rehabilitation Programs Offer Cardiopulmonary Resuscitation Training in Australia and New Zealand?

BACKGROUND: Cardiac rehabilitation may provide an ideal environment to train high-risk cardiac patients and their families in cardiopulmonary resuscitation (CPR). However, whether this training is currently offered is unknown. The aims of this study were to: 1) describe the prevalence of CPR training in cardiac rehabilitation programs in Australia and New Zealand (NZ); and 2) examine perceived barriers and attitudes of cardiac rehabilitation coordinators towards providing CPR training. METHODS: We conducted a cross-sectional online survey of Australian and NZ cardiac rehabilitation coordinators. RESULTS: We received 253 completed surveys (46.7% response rate) (Australia n=208, NZ n=45). Cardiopulmonary resuscitation training was included in 23.9% of Australian programs and 56.6% in NZ. Common barriers to CPR training included lack of resources (49.7%) and a lack of awareness to provide CPR training for this high-risk group (33.7%). The majority of coordinators believed that lay people should be trained in CPR (96.3%) and were comfortable with recommending CPR training to this high-risk group (89.4%). CONCLUSIONS: While cardiac rehabilitation coordinators have positive attitudes towards CPR training, it is not currently part of most programs - particularly in Australia. Organisations formulating cardiac rehabilitation recommendations and guidelines should give consideration to include the provision of CPR training.

Seizure associated with clozapine: incidence, etiology, and management.

Seizures are a known adverse effect of clozapine therapy. The literature varies on incidence rates of seizures, secondary to varying time frames in which each seizure occurred. Tonic-clonic seizures comprise the majority of seizures experienced secondary to clozapine use, but it is imperative to recognize the potential variety of seizure presentation. The exact etiology of clozapine-induced seizure is unknown. Conflicting reports regarding total oral dose, serum concentration, dose titration, and concomitant medications make it difficult to identify a single cause contributing to seizure risk. Following seizure occurrence, it may be in the best interests of the patient to continue clozapine treatment. In this clinical situation, the use of an antiepileptic drug (AED) for seizure prophylaxis may be required. The AED of choice appears to be valproate, but several successful case reports also support the use of lamotrigine, gabapentin and topiramate. Well-designed clinical trials regarding clozapine seizure prophylaxis are lacking. Given clozapine's strong evidence for efficacy in the treatment of schizophrenia and schizoaffective disorder, every attempt to manage side effects, including seizure, should be implemented to allow for therapeutic continuation.

Serotonin syndrome: is it a reason to avoid the use of tramadol with antidepressants?

BACKGROUND: There is a warning associated with all serotonergic antidepressants and its concomitant use with tramadol due to the concern for a drug-drug interaction resulting in serotonin syndrome (SS). The prescribing of antidepressants with tramadol may be unnecessarily restricted due to fear of causing this syndrome. OBJECTIVES: There are 3 objectives of this review. To (1) review case reports of SS associated with the combination of tramadol and antidepressant drugs in recommended doses, (2) describe the mechanisms of the drug interaction, and (3) identify the potential risk factors for SS. METHODS: Case reports of SS associated with tramadol and antidepressants were identified via Cochrane Library, PubMed, and Ovid (through October 2012) using search terms SS, tramadol, antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, milnacipran, trazodone, vilazodone, and bupropion. Cases involving monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were excluded. RESULTS: Nine articles were identified describing 10 cases of suspected SS associated with therapeutic doses of tramadol combined with an antidepressant. Mechanisms of the drug-drug interactions involve pharmacodynamic, pharmacokinetic, and possible pharmacogenetic factors. CONCLUSIONS: Review of the available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the potential for SS but does not constitute a contraindication to their use. Tramadol is only contraindicated in combination with MAOIs but not other antidepressants in common use today. These case reports do suggest several factors associated with a greater risk of SS, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors. Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a new serotonergic agent or when doses are increased.

Liver injury associated with antidepressants.

Antidepressants are commonly prescribed and used in the management of depression, anxiety disorders, and other psychiatric illnesses. Antidepressants used in therapeutic dosing ranges are associated with causing several adverse drug reactions including hepatotoxicity. Paroxetine, fluoxetine, fluvoxamine, citalopram, mirtazapine and venlafaxine are associated with reversible liver injury upon discontinuation of the agent. Patient cases of hepatotoxicity involving the use of nefazodone, trazodone, duloxetine, bupropion, and sertraline are linked to causing death in its users. Due to the idiosyncratic nature of hepatotoxicity, monitoring of liver function tests and immediate discontinuation upon abnormal lab findings or signs and symptoms of liver dysfunction are crucial since most cases of hepatic damage are reversible when detected early. Onset of antidepressant-associated hepatotoxicity varies from 5 days to 3 years. Antidepressant-induced liver injury can occur in the absence of identifiable, underlying risk factors such as cirrhosis and hepatitis infection; only a few cases of hepatic injury involve patients with chronic hepatitis infection. Some of these cases involve possible drug interactions between antidepressants and concomitant agents that increase the risk for liver injury. Understanding druginduced liver injury associated with antidepressants and the importance of safety monitoring is essential to optimize outcomes for antidepressant treatment.

Screening for multiple phosphodiesterase type 5 inhibitor drugs in dietary supplement materials by flow injection mass spectrometry and their quantification by liquid chromatography tandem mass spectrometry.

A flow injection tandem mass spectrometry method (FI-MS/MS) has been developed to detect enzyme phosphodiesterase type 5 inhibitors, including tadalafil, sildenafil, and vardenafil. Multiple reaction monitoring (MRM) was used to detect the drugs and product ion ratios were used for identification. FI-MS/MS was used for semi-quantification and liquid chromatography tandem mass spectrometry (LC-MS/MS) was used for further confirmation and quantification. One of 13 samples has been found to be adulterated with prescription levels of tadalafil and also low level of sildenafil. The method can be used for screening large numbers of herbal products for adulteration since it takes less than 1 min without chromatographic separation on a column.

Fast screening of lovastatin in red yeast rice products by flow injection tandem mass spectrometry.

Drug adulteration in dietary supplement materials is a world-wide problem and poses a regulatory challenge. Red yeast rice is a product used by consumers to lower blood levels of cholesterol. While most current methods to analyze red yeast rice are based on HPLC separation with a photo-diode array detector and/or a mass spectrometry detector, which takes 20-40min analysis time per sample, we developed a method to do fast screening of the active compound lovastatin by direct infusion into a mass spectrometer. This method takes under 1min per analysis on the instrument. By using multiple reaction monitoring with five product ions, all the ion ratios of the analyte in the samples are compared with those from the standards for qualitative analysis. The results from this method were compared to the result from the liquid chromatography tandem mass spectrometry, which uses retention time and one ion ratio as the confirmation criteria. No false positives or false negatives were found among the 12 samples tested. The method also seems to be effective in measuring the lovastatin in red yeast rice semi-quantitatively. This kind of method could be adapted to the screening of other dietary supplement products.

Retrospective chart review to assess the relationship between depression and sustained virological response from interferon treatment for hepatitis C virus.

BACKGROUND: Hepatitis C virus (HCV) is an infection that, if left untreated, may lead to liver complications and death. Current treatment requires peginterferon alfa (IFN) and ribavirin. Interferon can cause depression and irritability. The treatment goal is sustained virological response (SVR) and the impact of depression on SVR is currently inconclusive. OBJECTIVE: The objective of this study was to compare SVR in patients with and without comorbid depression between different viral genotypes to determine if depressive symptoms impact SVR. METHODS: In this retrospective chart review of HCV-treated patients, the Patient Health Questionnaire-9 (PHQ-9) scale for depression score was recorded to identify patients with depression versus patients without depression. Depression status was compared between SVR and non-SVR groups, as measured at 24 weeks posttreatment completion. Fisher exact or X(2) tests were used to evaluate differences between patients achieving SVR and those that did not. Known predictors of poor response were controlled with possible covariates in a multivariable analysis. RESULTS: A total of 101 patients were enrolled in the study; 74 completed treatment and were included in the analysis. Sixty-five percent (17/26) of patients with depression achieved SVR and 54% (26/48) of patients without depression had SVR. SVR was achieved in 58.1% (43/74) of patients, and genotypes 1, 4 or 6 comprised 58.1% (43/74) of patients. We found 64.9% (48/74) had no depression, 20.3% (15/74) had baseline depression prior to IFN treatment, and 14.8% (11/74) had IFN-treatment-associated depression. The majority of patients were men (59.5%), more than 35 years old (91.9%), and Hispanic (55.4%). When these factors were controlled for, there was no statistical significant relationship between depression and SVR (P = 0.2784). CONCLUSION: In these preliminary results, depression status did not impact SVR in this small, selected population of HCV-infected patients. A larger sample size is needed to achieve sufficient power in this population.

Completion of chronic hepatitis C virus treatment in interferon-induced major depressive disorder with psychotic features.

Interferon (IFN)-associated psychiatric disorders can be managed without interruption to hepatitis C virus (HCV) treatment. The limited number of cases in the literature reporting psychotic depression as an adverse drug reaction to IFN resulted in discontinuation of HCV therapy. The author reports a case of a 49 year-old man with chronic HCV genotype 1a treated with pegylated interferon-alpha and ribavirin developing major depressive disorder with psychotic features. The patient was successfully treated with both an antidepressant and antipsychotic for this suspected IFN-associated adverse drug effect while continuing 12 months of uninterrupted HCV treatment and subsequently achieving sustained hepatitis C virological response. Although IFN can cause distressing psychiatric disturbances, appropriate treatment with psychotropic agents and careful monitoring allows patients to be maintained on a full course of HCV treatment.

Completion of Chronic Hepatitis C Virus Treatment in Interferon-Induced Major Depressive Disorder with Psychotic Features

Interferon (IFN)-associated psychiatric disorders can be managed without interruption to hepatitis C virus (HCV) treatment. The limited number of cases in the literature reporting psychotic depression as an adverse drug reaction to IFN resulted in discontinuation of HCV therapy. The author reports a case of a 49 year-old man with chronic HCV genotype 1a treated with pegylated interferon-alpha and ribavirin developing major depressive disorder with psychotic features. The patient was successfully treated with both an antidepressant and antipsychotic for this suspected IFN-associated adverse drug effect while continuing 12 months of uninterrupted HCV treatment and subsequently achieving sustained hepatitis C virological response. Although IFN can cause distressing psychiatric disturbances, appropriate treatment with psychotropic agents and careful monitoring allows patients to be maintained on a full course of HCV treatment.

Desire for information and involvement in treatment decisions: elderly cancer patients' preferences and their physicians' perceptions.

PURPOSE: Shared decision making is a tenet of contemporary medicine and oncology practice. How involved elderly patients want to be in making treatment decisions and how physicians perceive patient preferences for such involvement are uncertain. PATIENTS AND METHODS: In structured interviews about multiple facets of chemotherapy treatment decision making, we asked patients age 70 years and older with a recent diagnosis of metastatic colorectal cancer (CRC) about their preferences for prognostic information and for involvement in treatment decision making. We also asked treating oncologists (n = 19) to describe their perceptions of patient preferences. Information and decision-making preferences were evaluated in relation to sociodemographic and clinical characteristics. RESULTS: Seventy-three patients age 70 to 89 years completed the study interview within 16 weeks of metastatic CRC diagnosis. Most patients (n = 70; 96%) had decided to receive chemotherapy and 61 had initiated treatment. Relatively few (n = 32; 44%) wanted information about expected survival when they made a treatment decision. Preference for prognostic information was more common among men than women (56% v 29%; P < .05). About half of the patients (n = 38; 52%) preferred a passive role in the treatment decision-making process. Physician perceptions were concordant with patient preferences for information in 44% of patient-physician pairs and for decision control in 41% of patient-physician pairs. CONCLUSION: For older patients with advanced CRC, preferences for prognostic information and for an active role in treatment decision making are not easily predictable. Physicians' perceptions are often inconsistent with patients' stated preferences. Explicit discussion of preferred decision-making styles may improve patient-physician encounters.

Telbivudine: a novel nucleoside analog for chronic hepatitis B.

OBJECTIVE: To review available literature on the pharmacology, pharmacokinetics, dosing and administration, efficacy, and safety of the antiviral nucleoside analog telbivudine. DATA SOURCES: Information was obtained from searching MEDLINE (1966-December 2005), International Pharmaceutical Abstracts (1970-December 2005), and the Cochrane Database of Systematic Reviews (4th quarter 2005) using the search words telbivudine, L-dT, L-deoxythymidine, L-nucleosides, and nucleosides. Abstracts from the Annual Meeting of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver were also searched, including bibliographies from the identified articles. STUDY SELECTION AND DATA EXTRACTION: Data from double-blind, placebo-controlled clinical trials and unpublished information were extracted. DATA SYNTHESIS: Telbivudine is a novel, orally administered nucleoside analog under development for use in the treatment of chronic hepatitis B. In contrast to other nucleoside analogs, telbivudine has not been associated with inhibition of mammalian DNA polymerase with mitochondrial toxicity. Telbivudine demonstrated potent activity against hepatitis B with significantly higher rate of response and superior viral suppression compared with lamivudine, the standard treatment. Telbivudine has been generally well tolerated, with low adverse effect profile, and at its effective dose, no dose-limiting toxicity has been observed. CONCLUSIONS: Telbivudine is a novel oral nucleoside analog effective in the treatment of chronic hepatitis B infection.

Iron nutritional status of adolescent girls from rural area and urban slum.

Iron nutritional status of adolescent girls belonging to an urban slum and rural areas was assessed by measuring serum ferritin levels. Overall anemia was observed in 25% of the girls irrespective of their urban rural residence. A higher percentage of rural girls (37.5%) especially below the age of 12 years showed evidence of anemia. Thereafter, the prevalence was similar in both urban and rural girls who had not attained menarche. With increasing age, urban girls who had attained menarche showed an increase in the prevalence of anemia. The prevalence of iron deficiency (serum ferritin < 12 micrograms/dl) showed a progressive increase from 60% at < 12 to 28% at > 14 yrs especially in the girls not attained menarche in the girls not attained menarche in the rural area. Overall iron deficiency was of much higher order in the rural girls irrespective of the menarcheal status. Distribution of iron/folate tablets to cover girl population may go a long way to correct the anemia and iron deficiency in the vulnerable groups.