Therapeutics and Clinical Risk Management

Published by Dove Medical Press
Online ISSN: 1178-203X
Print ISSN: 1176-6336
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An inflammation of the cutis and subcutis of the external auditory canal is a primary symptom in cases of acute otitis externa. It is usually treated locally, since this type of therapy ensures a high concentration of the drug and interacts at the site of inflammation with no systemic effects. This systematic review compares the efficacy of treatment using a ciprofloxacin 0.2% solution with other therapeutic options. After compiling a catalog of search terms, medical databases were searched systematically for randomized, controlled studies. This search initially yielded a total of 38 studies which were then evaluated by three independent reviewers. The number of studies was subsequently reduced to 14: six studies using a ciprofloxacin 0.2% solution, and eight studies using both 0.2% and 0.3% solutions. The studies included in the review demonstrate the statistical equivalence between the ciprofloxacin solution (0.2%) and the reference products PNH (a combination of polymyxin B, neomycin sulfate and hydrocortisone), auriculum powder, and a ciprofloxacin foam with respect to the cure rate. The research groups consistently observed high in vitro activity of ciprofloxacin against Pseudomonas aeruginosa. This systematic review confirms the hypothesis of ciprofloxacin's noninferiority in the treatment of otitis externa, in terms of the cure rate and microbiological eradication.
 
DDi potential in combination use of DHP-CCBs and statins 
Coadministration of 1,4-dihydropyridine calcium channel blockers (DHP-CCBs) with statins (or 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) is common for patients with hypercholesterolemia and hypertension. To reduce the risk of myopathy, in 2011, the US Food and Drug Administration (FDA) Drug Safety Communication set a new dose limitation for simvastatin, for patients taking simvastatin concomitantly with amlodipine. However, there is no such dose limitation for atorvastatin for patients receiving amlodipine. The combination pill formulation of amlodipine/atorvastatin is available on the market. There been no systematic review of the pharmacokinetic drug-drug interaction (DDI) profile of DHP-CCBs with statins, the underlying mechanisms for DDIs of different degree, or the corresponding management of clinical risk. The relevant literature was identified by performing a PubMed search, covering the period from January 1987 to September 2013. Studies in the field of drug metabolism and pharmacokinetics that described DDIs between DHP-CCB and statin or that directly compared the degree of DDIs associated with cytochrome P450 (CYP)3A4-metabolized statins or DHP-CCBs were included. The full text of each article was critically reviewed, and data interpretation was performed. There were three circumstances related to pharmacokinetic DDIs in the combined use of DHP-CCB and statin: 1) statin is comedicated as the precipitant drug (pravastatin-nimodipine and lovastatin-nicardipine); 2) statin is comedicated as the object drug (isradipine-lovastatin, lacidipine-simvastatin, amlodipine-simvastatin, benidipine-simvastatin, azelnidipine- simvastatin, lercanidipine-simvastatin, and amlodipine-atorvastatin); and 3) mutual interactions (lercanidipine-fluvastatin). Simvastatin has an extensive first-pass effect in the intestinal wall, whereas atorvastatin has a smaller intestinal first-pass effect. The interaction with simvastatin seems mainly driven by CYP3A4 inhibition at the intestinal level, whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition. The interaction of CYP3A4 inhibitor with simvastatin has been more pronounced compared with atorvastatin. From the current data, atorvastatin seems to be a safer CYP3A4-statin for comedication with DHP-CCB. There is no convincing evidence that amlodipine is an unusual DHP-CCB, either as a precipitant drug or as an object drug, from the perspective of CYP3A4-mediated drug metabolism. Amlodipine may have interactions with CYP3A5 in addition to CYP3A4, which may explain its particular characteristics in comparison with other DHP-CCBs. The degree of DDIs between the DHP-CCB and statin and the clinical outcome depends on many factors, such as the kind of statin, physicochemical proprieties of the DHP-CCB, the dose of either the precipitant drug or the object drug, the sex of the patient (eg, isradipine-lovastatin), route of drug administration (eg, oral versus intravenous nicardipine-lovastatin), the administration schedule (eg, nonconcurrent dosing method versus concurrent dosing method), and the pharmacogenetic status (eg, CYP3A5-nonexpressers versus CYP3A5-expressers). Clinical professionals should enhance risk management regarding the combination use of two classes of drugs by increasing their awareness of the potential changes in therapeutic efficacy and adverse drug reactions, by rationally prescribing alternatives, by paying attention to dose adjustment and the administration schedule, and by review of the appropriateness of physician orders. Further study is needed - the DDIs between DHP-CCBs and statins have not all been studied in humans, from either a pharmacokinetic or a clinical perspective; also, the strength of the different pharmacokinetic interactions of DHP-CCBs with statins should be addressed by systematic investigations.
 
schematic diagram of the role of hepcidin affecting the movement of iron.* Note: *Developed from Gantz et al 7 and Gantz et al. 6 Abbreviations: DMT i, divalent metal transporter i; Gi, gastrointestinal; RBCs, red blood cells; Fe, iron.  
Comparative intravenous drip infusion regimens 11–14,29 
Comparative intravenous bolus injection regimens 11–14 
Comparative high-dose infusion regimens 11–14 
The clinical need to be able to administer high doses of intravenous iron conveniently in a single rapid infusion has been addressed by the recent introduction of ferric carboxymaltose and subsequently iron isomaltoside 1000. Neither requires a test dose. Ferric carboxymaltose can be administered at 15 mg/kg body weight to a maximum dose of 1000 mg, whereas iron isomaltoside 1000 can be administered at 20 mg/kg body weight. The ability to give high doses of iron is important in the context of managing iron deficiency anemia in a number of clinical conditions where demands for iron are high (including chronic blood loss associated with inflammatory bowel disease, menorrhagia, and chronic kidney disease). It is also an important component in the strategy as an alternative to a blood transfusion. Affordability is a key issue for health services. This study was a comparative analysis of the costs of administering the newly available intravenous iron formulations against standard practice (blood transfusion, intravenous iron sucrose) by considering the cost of this treatment option plus nursing costs associated with administration, equipment for administration, and patient transportation in the secondary care (hospital) setting across three dosage levels (600 mg, 1000 mg, and 1600 mg). The analysis indicates that the use of iron isomaltoside 1000 results in a net saving when compared with iron sucrose, blood, and ferric carboxymaltose. At 600 mg and 1000 mg doses, it is cheaper than low-molecular-weight iron dextran but more expensive at a dose of 1600 mg. However, it takes six hours to administer low-molecular-weight iron dextran at this dose level, which is inconvenient and reduces patient throughput (productivity).
 
Human papillomaviruses (HPVs) are one of the most common sexually transmitted infections and remains a public health problem worldwide. There is strong evidence that HPV causes cervical, vulva and vaginal cancers, genital warts and recurrent respiratory papillomatosis. The current treatments for HPV-induced infections are ineffective and recurrence is common-place. Therefore, to reduce the burden of HPV-induced infections, several studies have investigated the effi cacy of different prophylactic vaccines in clinical human trials directed against HPV types 6, 11, 16, or 18. Notably, these HPV types contribute to a signifi cant proportion of disease worldwide. This review will focus on the published results of Merck & Co's prophylactic quadrivalent recombinant vaccine targeting HPV types 6, 11, 16, and 18 (referred to as Gardasil((R))). Data from the Phase III trial demonstrated that Gardasil was 100% effi cacious in preventing precancerous lesions of the cervix, vulva, and vagina and effective against genital warts. Due to the success of these human clinical trials, the FDA approved the registration of Gardasil on the 8 June 2006. In addition, since Gardasil has been effi cacious for 5 years post vaccination, the longest evaluation of an HPV vaccine, it is expected to reduce the incidence of these type specifi c HPV-induced diseases in the future.
 
Previous studies have suggested associations between MDM2 (mouse double minute 2 homolog) polymorphisms and cancer risk. The aim of this study was to evaluate the relationship between the MDM2 rs 2279744 polymorphism and the susceptibility of breast cancer. We searched PubMed, Web of Knowledge, Embase, and the Chinese National Knowledge Infrastructure (CNKI) database for case-control studies published up to October 2013 that investigated MDM2 rs 2279744 polymorphism and breast cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of these associations. A total of 19 studies were identified for the meta-analysis, including 9,788 cases and 11,195 controls. The variant heterozygote (TG) was associated with breast cancer risk in the overall population (TG vs TT: OR =1.10, 95% CI =1.04-1.17, P=0.001, P=0.23 for heterogeneity test). In the subgroup analyses by ethnicity, a significantly increased risk was observed among Asians (G vs T: OR =1.12, 95% CI =1.02-1.23, P=0.02, P het=0.04; GG vs TT: OR =1.29, 95% CI =1.06-1.56, P=0.01, P het=0.04; TG vs TT: OR =1.36, 95% CI =1.15-1.60, P=0.0004, P het=0.45; dominant model TG+GG vs TT: OR =1.21, 95% CI =1.03-1.41, P=0.02, P het=0.07). However, among Caucasians, rs 2279744 was associated with breast cancer risk in only one genotype (TG vs TT: OR =1.09, 95% CI =1.00-1.18, P=0.04, P het=0.37). No publication bias was found in the present study. This meta-analysis provides evidence for the association between the MDM2 rs 2279744 polymorphism and breast cancer susceptibility. The results suggest that the MDM2 rs 2279744 polymorphism plays an important role in breast cancer, especially in Asians.
 
Triple mechanism of action of BIBF-1120: it inhibits all three VEGFR subtypes, PDGFR-α and PDGFR-β and FGFR types 1, 2, and 3. Other targets of this drug are the FLT-3 (inhibition of acute myelogenous leukemia cell proliferation), and members of the Src-family (Src, Lyn, and Lck). Abbreviations: FGF, fibroblast growth factor; FGFR, FGF receptor; FLT-3, fms-like tyrosine kinase 3; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.  
Demographic distribution of population from a Phase II randomized double-blind study with BIBF 1120 as monotherapy in advanced non-small cell lung cancer. Abbreviations: ECOG, Eastern Cooperative Oncology Group score; LN, lymph node.  
Demographic distribution by overall clinical response status from Phase II randomized double-blind study with BIBF 1120 as monotherapy in advanced non-small cell lung cancer. Abbreviation: ECOG, Eastern Cooperative Oncology Group score.  
Lung cancer is the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the metastatic disease, the standard therapy is a platinum-based combination chemotherapy; however, in spite of available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process which comprises a complex, complementary, and overlapping network. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes: monoclonal antibodies against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), small molecule inhibitors of VEGF tyrosine kinase activity, VEGF Trap, and a new class named "vascular disrupting agents," tested in ongoing clinical trials which will further define their role in the management of NSCLC. BIBF 1120 is an investigational orally administered receptor tyrosine kinase inhibitor that has shown antiangiogenic and antineoplastic activity, inhibiting VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor tyrosine kinases, preventing tumor growth and interfering with the angiogenesis-signaling cascade and overcoming drug resistances.
 
Physician's overall ratings for the response of inflammatory acne
Counts of lesions (mean percentage reduction).
The purpose of this study was to investigate the efficacy of phototherapy with a newly-developed 1450-nm diode laser in patients with mild to moderate acne. An open study was performed in acne patients who were treated up to five times with a two week interval. Acne lesions were reduced by 63%. Only one patient discontinued treatment due to vesicle formation as an adverse effect. Phototherapy using this diode laser source was effective and well tolerated in acne patients, suggesting that this phototherapy may be a new modality for the treatment of acne.
 
Diagnostic criteria for two definitions of metabolic syndrome 
Clinical and laboratory characteristics of subjects 
The purpose of this study was to estimate the presence of metabolic syndrome (MS) in a group of children and adolescents with a body mass index (BMI) above the 85th percentile for their age and sex in Qazvin Province, Iran; to evaluate the relationship between obesity and metabolic abnormalities; and to compare two proposed definitions of MS. The study was conducted on 100 healthy subjects aged between 6 and 16 years (average age, 10.52 ± 2.51 years) with a high BMI for their age and sex. Fifty- eight percent of subjects were female. Physical examination including evaluation of weight, height, BMI, and blood pressure measurement was performed ("overweight" was defined as a BMI between the 85th and 95th percentiles for children of the same age and sex; "obese" was defined as a BMI over the 95th percentile for children of the same age and sex). Blood levels of glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid were measured after a 12-hour overnight fast. The authors used and compared two definitions of MS: the National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III) criteria and a modified definition by Weiss et al. Variables were compared using the Student's t-test and chi-square and Mann-Whitney U tests, and agreement between the two definitions was analyzed using kappa values. The subjects had a mean BMI of 26.02 ± 4.38 and 80% had obesity. Insulin resistance was found in 81% of the study population. MS was present in ten (50%) of the overweight and 53 (66.2%) of the obese subjects using the NCEP ATP III criteria. MS was present in five (25%) of the overweight and 34 (42.5%) of the obese subjects using the definition by Weiss et al. The overall kappa value for the two definitions of MS was 0.533. There were no statistically significant differences between the two definitions of MS in participants. The prevalence of MS in children and adolescents depends on the criteria chosen and their respective cutoff points. The NCEP ATP III criteria, the parameters of which include higher cutoff values for high-density lipoprotein cholesterol and triglycerides, detected the higher prevalence and therefore the NCEP ATP III criteria are able to diagnose a larger number of children and adolescents at metabolic risk.
 
Group definitions and malignancy exclusion criteria, i3 InVision Data Mart Multiplan analysis 
of cumulative reporting rates for suspected reactions coded to malignancies by primary site in the intramuscular IFNβ-1a global safety database with GLOBOCAN 2008 incidence rates for more developed regions a 
in MS patients after IM IFNβ-1a use (n = 12,894) compared with non-MS population controls (n = 25,786), i3 InVision Data Mart Multiplan 
Intramuscular interferon beta-1a (IFNβ-1a), a multiple sclerosis (MS) therapy that has been commercially available for over a decade, provides a unique opportunity to retrospectively assess postmarketing data for evidence of malignancy risk, compared with relatively limited data available for more recently approved therapies. Postmarketing and claims data were analyzed to determine the risk of malignancy in MS patients treated with intramuscular IFNβ-1a. The cumulative reporting rates of suspected adverse drug reactions coded to malignancy in the intramuscular IFNβ-1a global safety database were compared with malignancy incidence rates in the World Health Organization GLOBOCAN database. In addition, using data from a large US claims database, the cumulative prevalence of malignancy in MS patients treated with intramuscular IFNβ-1a was compared with non-MS population controls, MS patients without intramuscular IFNβ-1a use, and untreated MS patients. Mean follow-up was approximately 3 years for all groups, ie, 3.1 years for the intramuscular IFNβ-1a group (range 0.02-6.0 years), 2.6 years for non-MS population controls (range 0-6.0 years), 2.6 years for the intramuscular IFNβ-1a nonuse group (range 0.01-6.0 years), and 2.4 years for the untreated MS group (range 0.01-6.0 years). An estimated 402,250 patients received intramuscular IFNβ-1a during the postmarketing period. Cumulative reporting rates of malignancy in this population were consistent with GLOBOCAN incidence rates observed within the general population. The claims database included 12,894 MS patients who received intramuscular IFNβ-1a. No significant difference in malignancy prevalence was observed in intramuscular IFNβ-1a users compared with other groups. Results from this evaluation provide no evidence of an increased risk of malignancy with intramuscular IFNβ-1a use.
 
Characteristics of patients admitted after the Bam earthquake in iran
Prevalence of specific injuries
Natural disasters, especially earthquakes, result in many health problems all over the world, of which urological injuries should not be underestimated. Car accidents and falling from a height are the most common causes of genitourinary system injury. The lack of specific data in the literature regarding the outcome of earthquake-related genitourinary system trauma prompted us to undertake this study. We retrospectively evaluated the genitourinary system injury in patients who had survived the Bam earthquake. In this study, all patients admitted to two main back-up hospitals of Kerman were included. Of 256 patients who had been referred to Kerman hospitals, 28 cases were found to have urologic damage on physical examination, intravenous pyelography, abdominopelvic X-ray, and ultrasonography. Of 28 patients with urologic damage, 22 (78.5%) were male and six (21.5%) were female. Their age ranged from 18 to 65 years. The injures included urethral disruption in 21 cases (75.5%), vesicovaginal fistula in four cases (14%), kidney rupture in two cases (7%) and bladder neck disruption accompanied with total right ureteral disruption and vesicovaginal fistula in a female patient (3.5%). We have evaluated the incidence of genitourinary injuries after an earthquake disaster for the first time. The most and least common urologic injury in our patients was urethral disruption and ureteral injury, respectively.
 
In order to examine the efficacy and side effects of the monoclonal antibody anti-CD20 (rituximab) on autoimmune blistering skin diseases, we performed a comprehensive survey of 71 consecutive patients from initial use up to 2007, using the PubMed database. A heterogeneous group of patients, including 51 patients with pemphigus vulgaris, one with pemphigus vegetans, nine with pemphigus foliaceus, five with paraneoplastic pemphigus, four with epidermolysis bullosa acquisita, and one with both bullous pemphigoid and graft vs host disease was included in this survey. Overall the monoclonal antibody seems to be effective in that 69% of patients showed complete response, 25% of patients showed partial response, whereas 6% of patients showed progressive disease. Six deaths occurred in association with the treatment, with four of these deaths in patients with paraneoplastic pemphigus, a disease characteristically resistant to conventional medication and with a high mortality rate. Of note, 11 patients who received combined rituximab and intravenous immune globulin treatments had the best outcome: complete response without any serious side effects. Therefore further investigation on rituximab with controlled clinical trial is a worthy pursuit.
 
UK vaccination program for the influenza A H1N1p virus 
Demographic and clinical characteristics of respondents by combinations and types of influenza vaccines received at baseline 
number (%) of respondents with local side effects of discomfort and/or pain and their duration after baseline influenza vaccination 
number (%) of respondents recording action taken due to a side effect following baseline vaccination, with type of side effect requiring hospital use 
There has been worldwide interest in the safety of the pandemic influenza A (H1N1p) vaccines, although limited data are available from the vaccine recipients' perspective. This evaluation was designed to collect data from people who had received an influenza vaccination during the 2009-2010 season using a web-based data collection tool supplemented by telephone reporting (PROBE). People scheduled to receive the influenza A (H1N1p) or seasonal influenza vaccines were recruited through media advertising and campaigns throughout the West of Scotland. Vaccine recipients participated in the evaluation by answering demographic and side effect questions using PROBE methodology on the day of the immunization, after 3 days, 8 days, 6 weeks, 12 weeks, and 26 weeks. A total of 1103 vaccine recipients including 134 young children (0-4 years) participated in the evaluation; 694 (63%) received H1N1p vaccine only, 135 (12%) seasonal vaccine only, 224 (20%) both H1N1p and seasonal vaccines, and 50 (5%) received H1N1p or seasonal vaccine with a non-influenza vaccine (eg, travel or pneumococcal). Overall, 42% of recipients reported experiencing a side effect after their baseline vaccination; the most commonly reported were general and arm side effects (>20%). Injection site discomfort/pain and flu-like symptoms were reported by 57% and 24% of recipients, respectively. A significantly higher proportion of the 960 H1N1p vaccine recipients experienced a side effect (44% vs 27%, P < 0.001) or injection site discomfort/pain (61% vs 26%, P < 0.001) than those receiving seasonal influenza vaccines. Female sex and H1N1p vaccination were associated with a significantly higher risk of injection site discomfort/pain, whereas the 70+ age group was associated with a significantly lower risk. H1N1p vaccine was well tolerated by children under 5 years with side effects reported at a similar frequency to that found in the total population. Safety and tolerability data from influenza vaccine recipients including young children (via parents/carers) can be effectively collected using an online questionnaire with a telephone option (PROBE). The influenza A (H1N1p) vaccine was well tolerated, but was associated with more local short-term reactions than the seasonal influenza vaccine.
 
Influenza A H1N1 and H3N2 are two influenza waves that have been identified in past years. Data from 77 inpatients from three tertiary hospitals were included and statistical analysis was performed in three different clusters. Thirty-four patients (44.2%) had respiratory distress upon admission, 31.2% had a smoking history or were active smokers, 37.7% manifested disease symptoms, and 7.8% were obese (body mass index >41). The mean age of patients was 51.1 years. Cough was the most common symptom observed in 77.9% of the patients, accompanied by sputum production (51.9%) and fatigue (42.9%). Hemoptysis and vomiting were rarely recorded in the patients (9.1% and 16.9%, respectively). Oseltamivir administration varied between 0 and 10 days, giving a mean value of 2.2 days. In particular, 19 patients received no drug, 31 patients received drug for only for 1 day, 19 patients for 5 days, and 8 patients from 2 to 10 days. Clusters of symptoms can be used to identify different types of influenza and disease severity. Patients with vaccination had pneumonia, whereas patients without vaccination had influenza A. Patients more than 54.5 years old had H3N2 and patients less than 54.5 years had H1N1. White blood cell count values increased from normal to elevated in H3N2 patients but still remained abnormal in lower tract infection and H1N1 patients.
 
The pathogenesis of psoriasis is unknown, although it is generally accepted that this chronic inflammatory skin disorder is a complex autoimmune condition similar to other T-cell mediated disorders. Psoriasis imposes a heavy burden on the lifestyle of those affected due to the psychological, arthritic, and cutaneous morbidities; thus significant research has focused on the genetic and immunologic features of psoriasis in anticipation of more targeted, efficacious, and safe therapies. Recently, CD4(+) T helper (Th) 17 cells and interleukins (IL)-12 and -23 have been important in the pathogenesis of T-cell mediated disorders such as psoriasis and has influenced the development of medications that specifically target these key immunological players. Ustekinumab is a monoclonal antibody belonging to a newly developed class of biological, anti-cytokine medications that notably targets the p40 subunit of both IL-12 and -23, both naturally occurring proteins that are important in regulating the immune system and are understood to play a role in immune-mediated inflammatory disorders. Ustekinumab's safety and efficacy has been evaluated for the treatment of moderate-to-severe plaque psoriasis in 3 phase III clinical trials, 2 placebo-controlled (PHOENIX 1 and 2), and 1 comparator-controlled (ACCEPT) study which proved advantageous in patients who were treatment-naive, previously failed other immunosuppressive medications including cyclosporine or methotrexate, were unresponsive to phototherapy, or were unable to use or tolerate other therapies. Ustekinumab has also been investigated for other indications such as psoriatic arthritis, Crohn's disease, and relapsing/remitting multiple sclerosis. We present a concise review evaluating the evidence that supports the use of ustekinumab in the treatment of plaque psoriasis and other conditions.
 
Quantification of proteinuria is usually predicated upon 24-hour urine collection. Multiple factors influence urine collection and the rate of protein and creatinine excretion. Urine collection is often incomplete, and therefore creatinine and protein excretion rates are underestimated. A random urine protein-creatinine (P-C) ratio has been shown over the years to be a reliable alternative to the 24-hour collection for detection and follow up of proteinuria. However, urine protein excretion may be influenced by physical activity. We studied 48 patients with proteinuria and varying levels of physical activity to determine the correlation between the measures of urine protein excretion. The correlation coefficient (r) between 24-hour urine total protein and random urine P-C ratio was 0.75 (P < 0.01) in the overall study population, but varied according to the level of proteinuria and physical activity in a stratified analysis: r = 0.99 (P < 0.001) and r = 0.95 (P < 0.01) in bedridden patients; r = 0.44 (P = not significant [NS]) and r = 0.54 (P = NS) in semiactive patients; and r = 0.44 (P = NS) and r = 0.58 (P < 0.05) in active patients with nephrotic- (>3500 mg/day) and non-nephrotic (<3500 mg/day) range proteinuria, respectively. The correlation appeared to be stronger between random urine and 24-hour urine P-C ratio for the overall study population (r = 0.84; P < 0.001), and when stratified according to the level of proteinuria and physical activity: r = 0.99 (P < 0.001) and r = 0.92 (P < 0.01) in bedridden patients; r = 0.61 (P = NS) and r = 0.54 (P = NS) in semiactive patients; and r = 0.64 (P < 0.02) and r = 0.52 (P < 0.05) in active patients with nephrotic and non-nephrotic range proteinuria, respectively. We conclude that the random urine P-C ratio is a reliable and practical way of estimating and following proteinuria, but its precision and accuracy may be affected by the level of patient physical activity.
 
Results RCTs of cannabinoids in treatment of pain syndromes ()
This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol((R))) and nabilone (Cesamet((R))) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex((R)), a cannabis derived oromucosal spray containing equal proportions of THC (partial CB(1) receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB(1) receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.
 
Coinfection with hepatitis C virus (HCV) and HIV is an increasingly recognized clinical dilemma, particularly since the advent of highly active antiretroviral therapy. Several studies of this population have demonstrated both more rapid progression of liver disease and poorer overall prognosis compared to HCV monoinfected patients. Consensus guidelines, based primarily on the results of 4 major randomized trials, recommend treatment with peginterferon and ribavirin for 48 weeks in coinfected patients. However, this current standard of care is associated with lower response rates to therapy than those seen in monoinfected patients. Important predictors of response include HCV genotype, pretreatment HCV RNA level, and presence of rapid virologic response (RVR) and early virologic response (EVR). Use of weight-based ribavirin dosing appears to be safe and enhances the likelihood of sustained virologic response (SVR). Adverse effects most commonly encountered are anemia and weight loss. Mitochondrial toxicity can occur in the setting of concomitant nucleoside reverse transcriptase inhibitor use, especially didanosine, abacavir, and zidovudine, and these should be discontinued before initiation of ribavirin therapy. Discontinuation of therapy should be considered in patients failing to demonstrate EVR, though ongoing trials are investigating a potential role for maintenance therapy in these patients. Peginterferon combined with weight-based ribavirin is appropriate and safe for treatment of HCV in HIV - HCV coinfected patients. This review summarizes the data supporting these recommendations.
 
Radiation treatment has been associated with radiation induced cardiotoxicity, especially with older, long-outdated, techniques. Such complications include pericarditis, myocardial fibrosis, valvular injury, ischemic heart disease, and myocardial infarction. To assess the effect of outdated breast radiation therapy (RT) - using a diagnostic CT scanner in the absence of a CT simulator - on cardiac function in women with stage II left breast cancer. Sixty-two women under 65 with stage II left breast cancer who received post-operative RT using a diagnostic computed tomography scanner were studied between 1997 and 2001. Participants underwent a clinical interview, ECG, and echocardiography before and 6 months and 5 years after RT. There was no serious cardiotoxicity at 6 months and 5 years after radiotherapy. A 23% increase in hypertensive patients, and a slight decrease (2.3%) in ejection fraction was observed after 5 years, with 3 patients (5%) developing abnormalities. Two patients presented abnormal electrocardiographic findings within 6 months of RT. Our study showed that RT for left breast cancer was not associated with significant alteration in heart morbidity or mortality within 5 years of treatment, despite the lack of a simulator.
 
Mechanism-based inhibition of cytochrome P450 (CYP) 3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Such inhibition of CYP3A4 can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The inactivation of CYP3A4 by drugs has important clinical significance as it metabolizes approximately 60% of therapeutic drugs, and its inhibition frequently causes unfavorable drug-drug interactions and toxicity. The clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs, and patients. Clinical professionals should adopt proper approaches when using drugs that are mechanism-based CYP3A4 inhibitors. These include early identification of drugs behaving as CYP3A4 inactivators, rational use of such drugs (eg, safe drug combination regimen, dose adjustment, or discontinuation of therapy when toxic drug interactions occur), therapeutic drug monitoring, and predicting the risks for potential drug-drug interactions. A good understanding of CYP3A4 inactivation and proper clinical management are needed by clinical professionals when these drugs are used.
 
Pan-reduction of intrapidermal nerve fiber (IENF) density in the skin of the forearm, proximal leg, and distal leg with PGP 9.5 (Protein Gene Product) used as a fluorescent marker for IENF.
Baseline and post-etanercept quantitative autonomic function tests demonstrating severe reduction in vagal sympathetic tone. Note the improvement in deep breathing and Valsalva responses after etanercept treatment.
Laser Doppler perfusion response to heating for baseline and post-etanercept treatment. The grey area is normal. a month and a half, we conclude his continued improvement in autonomic function is from the etanercept.
Orthostasis due to autonomic neuropathy can cause severe debilitation and prove refractory to treatment. This report describes a case of severe sympathetic and parasympathetic autonomic dysfunction as a consequence of acetylcholine receptor antibodies and Sjogren's syndrome. Symptomatic management, plasma fluid expanders, and IVIG therapy failed to offer a salutary response to the condition. Etanercept therapy provided improvement of the orthostasis and autonomic function measured as high and low frequency respiratory effects on heart rate variability as well as enhancement of skin blood flow using Laser Doppler. It would be of considerable interest to determine the effectiveness of etanercept in other autoimmune neuropathies.
 
Differences in enteral nutrition (en) and parenteral nutrition (Pn) use by disease/conditon 
The aim of the study reported here was to assess the use of parenteral nutrition (PN) and enteral nutrition (EN), and the prevalence of PN and EN formulas, in the People's Republic of China. Fifty-nine hospitals in the People's Republic of China participated in a nutrition survey. The resulting information on nutritional support was analyzed. We received 379,584 nutritional-support prescriptions over 40 days in 2013. PN provided approximately 63.2% and EN provided approximately 36.8% of nitrogen intake. PN provided 63.5% and EN provided 36.5% of lipid intake. There were obvious differences in nitrogen and lipid intake between PN and EN in different regions, departments, and diseases. The percentage of nourishment provided by PN in different regions was highest in Chengdu, followed by the Beijing, Guangzhou, and Hangzhou areas. The percentage of nourishment provided by PN in different departments was highest in general surgery, followed by gastroenterology and the intensive care unit. The percentage of nourishment provided by PN in different diseases/conditions was highest in acute pancreatitis, followed by cancer, and burns. The main source of nitrogen in PN was balanced amino-acid preparations, and in EN, it was protein. The main source of lipids in PN was long- and medium-chain triglyceride lipid emulsion injection. Despite recent improvements in the application of nutritional support in the People's Republic of China, a much higher percentage of nitrogen and lipids is delivered through PN than through EN. Furthermore, there are marked regional, departmental, and disease-based differences in the selection of PN versus EN. The rationale for use of nutritional support needs to be improved.
 
Characteristics of currently available drugs for malaria prevention
Characteristics of future prophylaxis drugs
Possible phase III-equivalent study designs 
Malaria is of continuing concern in nonimmune traveling populations. Traditionally, antimalarial drugs have been developed as agents for dual indications (treatment and prophylaxis). However, since 2000, when the 5th Amendment to the Declaration of Helsinki (DH2000) was adopted, development of new malaria prophylaxis drugs in this manner has ceased. As a consequence, there may not be any new drugs licensed for this indication in the foreseeable future. Major pharmaceutical companies have interpreted DH2000 to mean that the traditional development paradigm may be considered unethical because of doubt over the likelihood of benefit to endemic populations participating in clinical studies, the use of placebo, and the sustainability of post-trial access to study medications. In this article, we explore the basis of these concerns and suggest that the traditional development paradigm remains ethical under certain circumstances. We also consider alternative approaches that may be more attractive to sponsors as they either do not use placebo, or utilize populations in endemic countries who may unambiguously benefit. These approaches represent the way forward in the future, but are at present unproven in clinical practice, and face numerous regulatory, logistical and technical challenges. Consequently, in the short term, we argue that the traditional clinical development paradigm remains the most feasible approach and is ethical and consistent with the spirit of DH2000 under the appropriate circumstances.
 
general instability.  
One-way analysis of variance (ANOVA) test: instability values referring to Romberg test results 
In the elderly population, problems with walking and balance are very common. These problems seriously affect the quality of life of the elderly. When gait and balance problems are caused by neurological disease, these problems can be more serious and difficult to handle. The aim of this pilot study was to verify the effect of a noninvasive radioelectric conveyor asymmetric brain stimulation protocol, named neuropostural optimization (NPO), to improve balance in neurological elderly. Twelve patients suffering from various neurological diseases participated in this study. They were assessed with the Romberg test, which was performed on a computerized stabilometric platform before, immediately following, and 72 hours after NPO was used to improve balance. The results showed that a stabilization of balance was recorded in all subjects a few minutes after administration of NPO. This stabilization increased 72 hours after treatment. The results show that NPO could be a valuable therapeutic approach to improve sensory-motor strategies and neurological control of balance in elderly patients suffering from various neurological diseases.
 
Schematic representation of mechanisms of drug-induced hyperprolactinemia.
Hyperprolactinemia is a common endocrinological disorder that may be caused by several physiological and pathological conditions. Several drugs may determine a significant increase in prolactin serum concentration that is frequently associated with symptoms. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. Risperidone is one of the atypical neuroleptics most likely to induce hyperprolactinemia, while other atypical drugs are unfrequenlty and only transiently associated with increase of prolactin levels. Women are more sensitive than men to the hyperprolactinemic effect of antipsychotics. Classical and risperidone-induced hyperprolactinemia may be revert when a gradual antipsychotic drug discontinuation is combined with olanzapine or clozapine initiation. Antidepressant drugs with serotoninergic activity, including selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAO-I) and some tricyclics, can cause hyperprolactinemia. A long list of other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Finally, hyperprolactinemia has also been documented during conditioning and after autologous blood stem-cell transplantation and during chemotherapy, even though disturbances of prolactin seem to occur less frequently than impairments of the hypothalamus-pituitary-gonad/thyroid axis after intensive treatment and blood marrow transplantation.
 
The nontherapeutic use of prescription medicines by individuals involved in sport is increasing. Anabolic-androgenic steroids (AAS) are the most widely abused drug. Much of our knowledge of the psychological and physiological effects of human growth hormone (hGH) and insulin has been learned from deficiency states. As a consequence of the Internet revolution, previously unobtainable and expensive designer drugs, particularly recombinant human growth hormone (rhGH) and insulin, have become freely available at ridiculously discounted prices from countries such as China and are being abused. These drugs have various physiological and psychological effects and medical personnel must become aware that such prescription medicine abuse appears to be used not only for performance and cosmetic reasons, but as a consequence of psychological pre-morbidity.
 
Abacavir has been at the center of research and clinical interest in the last two years. The frequency of the associated abacavir hypersensitivity syndrome has decreased substantially since the introduction of routine testing for the HLA-B*5701 allele; the activity of the drug in HIV-infected persons with HIV RNA values more than 100,000 copies/mL has been questioned; the possible increased risk of myocardial infarction after recent exposure to abacavir has been debated; and the drug has been moved from the "recommended" category to the "alternative" category in several guidelines. Still, the drug remains a useful agent in combination with other drugs, including lamivudine, for the treatment of HIV infection. This review will focus on the pharmacokinetics, activity, side effects, and resistance profile of both abacavir and lamivudine, including a thorough review of all of the recent studies relevant to both drugs.
 
Abatacept (CTLA4-Ig) is a new agent which targets T-cell activation, an event which is thought to be critical to the onset and maintenance of rheumatoid arthritis (RA). Abatacept now has substantial evidence from phase III trials for efficacy in patients with RA who have failed to respond to disease-modifying antirheumatic drugs (DMARDs) and antitumor necrosis factor-alpha (TNF-alpha) biologic agents. Safety profile is favorable in combination with DMARDs. The mechanism of action and available evidence of its efficacy and safety are reviewed in this article.
 
Summary of Phase iii trials of subcutaneous abatacept in rheumatoid arthritis 
Biologic therapies in rheumatoid arthritis are now part of standard practice for disease that proves difficult to control with conventional disease-modifying anti-rheumatic drugs. While anti-tumor necrosis factor therapies have been commonly used, other targeted biologic therapies with different mechanisms of action are becoming increasingly available. Abatacept is a recombinant fusion protein that inhibits the T-cell costimulatory molecules required for T-cell activation. Intravenous abatacept has good clinical efficacy with an acceptably low toxicity profile in rheumatoid arthritis, but the subcutaneous mode of delivery has only recently become available. In this article, we examine key efficacy and safety data for subcutaneous abatacept in rheumatoid arthritis, incorporating evidence from five large Phase III studies that included people with an inadequate response to methotrexate and an inadequate response to biologic disease-modifying anti-rheumatic drugs. The results demonstrate that subcutaneous abatacept has efficacy and safety comparable with that of intravenous abatacept and adalimumab. In addition, inhibition of radiographic progression at year 1 in relatively early rheumatoid arthritis is consistent with that of adalimumab. Subcutaneous abatacept is well tolerated, with very low rates of discontinuation in both short-term and long-term follow-up.
 
Hysterosalpingogram. Notes: Hysterosalpingogram showing tubal occlusion on the right side with correct location of the device (right arrow) and a patent tube on the left side. The left device is abnormally positioned (left arrow). 
Flow diagram for study selection. Abbreviation: MaUDe, Manufacturer and User Facility Device experience.
To report a case of Essure microinsert abdominal migration and literature review. A 41-year-old woman was counseled to undergo Essure sterilization. The procedure was hampered by the presence of endometrial cavity adhesions, obscuring left tubal ostium. By using microscissors the adhesions were progressively lysed. Since the procedure had become very painful, the patient required general anesthesia. Once adhesion lysis was completed, the tubal ostium was well visible. Both devices were then easily introduced into the fallopian tubes. At the end of the procedure, five coils were visible on the right side and five coils on the left side, as recommended. The 3-month hysterosalpingogram follow-up suspected abdominal migration of the left device. Laparoscopy confirmed the device displacement in the left lower abdominal quadrant. Both fallopian tubes and the uterus appeared normal. No signs of perforation were detected. The device was embedded into the omentum, but it was easily removed. Bilateral tubal sterilization was performed by bipolar coagulation. There are only 13 cases, including the present, of Essure abdominal migration in the literature. In most cases, abdominal displacement of the microinsert is asymptomatic and does not induce tissue damage. However, in some cases, it may cause a severe adverse event, requiring major surgery. Therefore, removal of the migrated device should be performed as soon as possible. Moreover, during presterilization counseling, the patient should also be correctly informed about the risk of this rare but relevant complication, as well as about the surgical interventions that could be required to solve it.
 
Antimicrobial agents that are not effective against resistant organisms
Complicated intra-abdominal and skin and skin structure infections are widely varied in presentation. These infections very often lead to an increase in length of hospital stay, with a resulting increase in costs and mortality. In addition, these infections may be caused by a wide variety of bacteria and are often polymicrobial with the possibility of the presence of antimicrobial-resistant strains, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum β-lactamase strains (Escherichia coli, Klebsiella pneumoniae), and K. pneumoniae carbapenemase-producing strains. In combination with patients' immunosuppression or comorbidities, the treatment and management options for initial therapy success are few. Tigecycline, a new glycylcyline antimicrobial from the tetracycline drug class, represents a viable option for the successful treatment of these infections. It has been shown to have activity against a wide variety of bacteria, including the antimicrobial-resistant strains. As with all tetracycline drugs, it is not recommended for pregnant or nursing women. The potential side effects are those typical of tetracycline drugs: nausea, vomiting, and headaches. Drug-drug interactions are not expected, and renal function monitoring is not necessary.
 
Logistic regression analysis results: multivariate analysis 
The seven-year experience of elective abdominal aortic aneurysm (AAA) repair of a vascular surgical unit in a teaching hospital was reviewed to determine the factors associated with in-hospital mortality. All patients who underwent elective open repair of an AAA between July 1, 1991, and June 30, 1998, were identified using International Classification of Diseases Ninth Revision (ICD-9) codes. Twenty-four variables were selected for investigation by reviewing the published literature and by discussion with local vascular surgeons. Data were obtained by retrospective medical record review. Variables were first analysed by univariate analysis, and those with a p-value up to 0.25 were included in multivariate analysis. Of the 219 patients reviewed, 8 (3.7%, 95% confidence interval, 1.6%, 7.1%) died during the admission. The mean age of patients was 69.9 years, and 81% of them were male. Univariate analysis found that female sex, renal artery involvement in the aneurysm, and aortic cross-clamp duration of 90 min or greater were significantly associated with mortality. Multivariate analysis found that female sex, use of a bifurcated graft, and performance of an additional procedure at the time of operation were the only variables independently associated with mortality. Use of a bifurcated graft was a significant prognostic variable on logistic regression analysis confirming that the technical difficulty of the operation and the morphology of the aneurysm are important factors in determining mortality. Why women may be at higher risk for death is unclear. This study also highlights that caution is required when interpreting raw audit data.
 
In vitro susceptibilities of select aerobic and anaerobic organisms to tigecycline a 
Tigecycline, a glycylcycline related to the tetracycline class of antibiotics, represents a new option for the treatment of complicated intra-abdominal and complicated skin and skin structure infections. It displays favorable activity in vitro against the most common causative Gram-positive, Gram-negative and anaerobic pathogens. In addition, tigecycline demonstrates activity against drug-resistant pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and organisms (such as Escherichia coli and Klebsiella pneumoniae) producing extended-spectrum beta-lactamases. Tigecycline lacks activity in vitro against Pseudomonas and Proteus spp. In randomized clinical trials, tigecycline administered intravenously twice daily has demonstrated efficacy similar to comparators for a variety of complicated skin and skin structure and complicated intra-abdominal infections. The potential for significant drug interactions with tigecycline appears to be minimal. Dosing adjustment is needed for patients with severe hepatic impairment. The predominant side effect associated with its use to date has been gastrointestinal intolerance (nausea and vomiting).
 
Postoperative brain computed tomography scan 6 weeks after abscess drainage and antibiotic therapy confirms obvious shrinkage of cavities and exvacuum ventriculomegaly.
Sagital view, T2-weighted lumbar magnetic resonance image, 2 days after urgent operation is suggestive of cord edema and severe arachnoiditis.
Dermal sinuses have been associated with a wide spectrum of clinical manifestations ranging from asymptomatic to drainage of purulent material from the sinus tract, inclusion tumors, meningitis, and spinal abscess. To date, there has been no documented report of brain abscess as a complication of spinal dermal sinus. Here, we report an 8-month-old girl who was presented initially with a brain abscess at early infancy but lumbar dermal sinus and associated spinal abscess were discovered afterwards. The probable mechanisms of this rare association have been discussed.
 
Summary of association studies regarding the polymorphisms at Asp299Gly and Thr399Ile
Toll-like receptor 4 (TLR4) is the transuding subunit of lipopolysaccharide receptor and an important intracellular signal pathway of the innate immune response. Published data about the relationship between TLR4 mutations and atopy/asthma are not consistent. This study was performed to detect two commonly reported Asp299Gly and Thr399Ile polymorphisms in TLR4 gene in Singaporean Chinese and their possible association with atopy-related phenotypes. A total of 117 unrelated Singapore residents were randomly selected for this study. Among them, atopy was evident in 66 subjects while 61 had allergic rhinitis. Twenty-one patients had concomitant asthma and 17 were atopic. In all subjects, neither the Asp299Gly nor Thr399Ile polymorphism was found by DNA sequencing. This discrepant result could be due to the ethnic variation of allelic distribution in TLR4 gene. Although it is still debatable whether there is any role of TLR4 polymorphisms on atopy-related phenotypes, one needs to develop an appropriate model to investigate the interactions between genetic variations and environmental factors that contribute to the complex traits in allergic diseases.
 
Adverse event profi le summarized from multiple ran- domized controlled trials (derived from Wilt et al 2002) 
response and adverse event rates in men on various doses of tamsulosin oral-controlled absorption system or placebo (derived from data of Chapple et al 2005a) 
The efficacy of tamsulosin at the cost of a relatively benign side effect profile has been attributed to receptor selectivity directed at the alpha(1a) and alpha(1d) adrenergic receptor subtypes. The oral-controlled absorption system (OCAS((R))) represents a drug delivery refinement that incorporates a matrix of gel-forming and gel-enhancing agents to promote a constant drug release independent of environmental food or fluid. There are clinical data to support the concept that drug peaks are lessened and that drug release continues throughout the alimentary tract due to the OCAS formulation. Furthermore this equates with less adverse effects on physiologic parameters. To date however improvements in cardiovascular symptoms such as dizziness, headache and syncope have not been demonstrated in healthy men. Ejaculatory dysfunction appears less problematic with the OCAS preparation. Tamsulosin OCAS may be of greatest benefit to men with cardiovascular co-morbidities taking anti-hypertensive medications that might predispose them to symptomatic hypotensive episodes. It will be necessary to evaluate this group of men more closely in further trials to determine what they stand to gain from changing medications, and then relate this to drug costs to draw a final conclusion as to the place of tamsulosin OCAS in contemporary urological practice.
 
This paper overviews the controversies surrounding the abuse of prescription analgesic OxyContin((R)) (oxycodone hydrochloride; Purdue Pharma, Stamford, CT, USA). It discusses solutions to this medication-related issue, which has been touted as reaching epidemic proportions. Relevant literature from 1990 to 2004 was identified through a MEDLINE search, and a thorough internet-based search was conducted to obtain the latest updates and government reports. OxyContin became popular as a street drug through its ability to induce a quick heroin-like euphoria. The media hype surrounding OxyContin abuse and the "black box" warning on its label may have added to the abuse and diversion. The US Food and Drug Administration took steps by writing letters to Purdue Pharma, the manufacturers of OxyContin. Purdue Pharma developed a database to identify OxyContin abusers throughout the nation and also launched campaigns to educate patients through the internet. Further suggestions to managing the abuse of OxyContin include: community pharmacists' assessment of behavioral risk factors that could lead to patient medication abuse; medication abuse risk management courses for physicians; development of a national database linking all pharmacies specifically designed to identify abusers; and tamper-resistant prescription pads for controlled substances, which seems the most plausible and immediate solution to this problem.
 
DVT prophylaxis outcomes (p<0.01). Abbreviations: DVT, deep vein thrombosis; GFR, glomerular filtration rate. 
Patient characteristics 
Modality of DVT prophylaxis 
Time to a stable therapeutic INR during warfarin initiation (p=0.03). Abbreviations: INR, international normalized ratio. 
Assess the impact of using academic detailing-assisted guideline roll-out on warfarin initiation, reversal of warfarin overanticoagulation, and uptake of deep vein thrombosis (DVT) prophylaxis across 4 metropolitan teaching hospitals. Baseline data were collected for 3 months prior to intervention. Prescribers were then informed about the guidelines, including feedback of current hospital performance and the basis for the guidelines. Post-intervention data were collected for 3 months after guideline implementation. Uptake of DVT prophylaxis in medical patients increased from 52.8% to 67.0% (p=0.004). No impact on operative surgical patients was seen, possibly due to the high pre-existing rate of uptake (86.1% vs 84.1%, p=0.7). DVT prophylaxis rates in non-operative surgical patients were similar to medical patients, with similar, but non-significant improvements. The time to reach a stable therapeutic international normalized ratio (INR) after warfarin initiation was reduced (p=0.03) as were the number of INR's >4 in the first week of therapy (p=0.03). There were significant improvements in appropriate vitamin K use for warfarin overanticoagulation in patients with an INR above 6 (48% vs 74%, p=0.007), timely follow-up tests (49% vs 62%, p=0.009), and the proportion of next INR's being less than 4 (49% vs 61%, p=0.04). The use of academic detailing to facilitate guideline roll-out had a positive impact on nearly all areas studied. The academic detailing process within the hospital setting was received enthusiastically by prescribers.
 
Medication errors may occur during prescribing, transcribing, prescription auditing, preparing, dispensing, administration, and monitoring. Medication administration errors (MAEs) are those that actually reach patients and remain a threat to patient safety. The Joint Commission International (JCI) advocates medication error prevention, but experience in reducing MAEs during the period of before and after JCI accreditation has not been reported. An intervention study, aimed at reducing MAEs in hospitalized patients, was performed in the Second Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China, during the journey to JCI accreditation and in the post-JCI accreditation era (first half-year of 2011 to first half-year of 2014). Comprehensive interventions included organizational, information technology, educational, and process optimization-based measures. Data mining was performed on MAEs derived from a compulsory electronic reporting system. The number of MAEs continuously decreased from 143 (first half-year of 2012) to 64 (first half-year of 2014), with a decrease in occurrence rate by 60.9% (0.338% versus 0.132%, P<0.05). The number of MAEs related to high-alert medications decreased from 32 (the second half-year of 2011) to 16 (the first half-year of 2014), with a decrease in occurrence rate by 57.9% (0.0787% versus 0.0331%, P<0.05). Omission was the top type of MAE during the first half-year of 2011 to the first half-year of 2014, with a decrease by 50% (40 cases versus 20 cases). Intravenous administration error was the top type of error regarding administration route, but it continuously decreased from 64 (first half-year of 2012) to 27 (first half-year of 2014). More experienced registered nurses made fewer medication errors. The number of MAEs in surgical wards was twice that in medicinal wards. Compared with non-intensive care units, the intensive care units exhibited higher occurrence rates of MAEs (1.81% versus 0.24%, P<0.001). A 3-and-a-half-year intervention program on MAEs was confirmed to be effective. MAEs made by nursing staff can be reduced, but cannot be eliminated. The depth, breadth, and efficiency of multidiscipline collaboration among physicians, pharmacists, nurses, information engineers, and hospital administrators are pivotal to safety in medication administration. JCI accreditation may help health systems enhance the awareness and ability to prevent MAEs and achieve successful quality improvements.
 
Patients receiving activated protein C, in-hospital mortality, and major bleeding event by year. Note: *Data for 2009 is through the month of June.  
Univariate analysis of major bleeding events 
Univariate analysis of baseline data and outcomes of patients with or without in hospital mortality 
Early clinical trials of recombinant human activated protein C (rhAPC) for severe sepsis excluded patients at high risk of bleeding. Recent literature suggests bleeding rates are higher in clinical practice and may be associated with worsened outcomes. Our objective was to evaluate baseline demographics; incidence, and risk factors for major bleeding; and mortality of patients receiving rhAPC for severe sepsis at our institution. A retrospective study was performed for all patients receiving rhAPC for treatment of severe sepsis at a tertiary academic medical center from January 2002 to June 2009. Demographic information, clinical variables, intensive care unit, and hospital outcomes were recorded. Of the 156 patients that received rhAPC, 54 (34.6%) did not meet institutional criteria for safe use at baseline due to bleeding precaution or contraindication. Twenty-three (14.7%) patients experienced a major bleeding event. Multivariate analysis demonstrated baseline International Normalized Ratio ≥2.5 (odds ratio [OR] 3.68, 95% confidence interval [CI]: 1.28-10.56; P = 0.03) and platelet count ≤100 × 10(3)/mm(3) (OR 2.86, 95% CI: 1.07-7.67; P = 0.01) as significant predictors of a major bleed. Overall hospital mortality was 57.7%. Multivariate analysis demonstrated the presence of ≥3 organ dysfunctions (OR 2.46, 95% CI: 1.19-5.09; P < 0.05) and medical intensive care unit admission (OR 1.99, 95% CI: 1.00-3.98; P = 0.05) were independent variables associated with hospital mortality. Patients receiving rhAPC at our institution had higher APACHE II scores, mortality, and major bleeding events than published postmarketing studies. Risk factors for major bleeding other than package-labeling contraindications and bleeding precautions were identified in our patient population.
 
Acamprosate, or N-acetyl homotaurine, is an N-methyl-D-aspartate receptor modulator approved by the Food and Drug Administration (FDA) as a pharmacological treatment for alcohol dependence. The exact mechanism of action of acamprosate is still under investigation, but the drug appears to work by promoting a balance between the excitatory and inhibitory neurotransmitters, glutamate and gamma-aminobutyric acid, respectively, and it may help individuals with alcohol dependence by reducing withdrawal-associated distress. Acamprosate has low bioavailability, but also has an excellent tolerability and safety profile. In comparison with naltrexone and disulfiram, which are the other FDA-approved treatments for alcohol dependence, acamprosate is unique in that it is not metabolized by the liver and is also not impacted by alcohol use, so can be administered to patients with hepatitis or liver disease (a common comorbid condition among individuals with alcohol dependence) and to patients who continue drinking alcohol. Acamprosate has demonstrated its efficacy in more than 25 placebo-controlled, double-blind trials for individuals with alcohol dependence, and has generally been found to be more efficacious than placebo in significantly reducing the risk of returning to any drinking and increasing the cumulative duration of abstinence. However, acamprosate appears to be no more efficacious than placebo in reducing heavy drinking days. Numerous trials have found that acamprosate is not significantly more efficacious than naltrexone or disulfiram, and the efficacy of acamprosate does not appear to be improved by combining acamprosate with other active medications (eg, naltrexone) or with psychosocial treatment (eg, cognitive-behavioral therapy). In this review, we present the data on acamprosate, including its pharmacology, efficacy, safety, and tolerability in the treatment of alcohol dependence.
 
illustration of the synchronous mode of vibration transmission in wholebody vibration exercise. Both legs extend and stretch at the same time, and a purely linear acceleration is directed to the trunk.
effects of aT on muscle strength (A), cross-sectional area (B), fat deposition (C) in the femoral muscle (quadriceps), intrahepatocellular lipids measured by magnetic resonance spectroscopy (D), intrahepatocellular lipids measured by Fibroscan 502 (E), and liver stiffness (F) in obese patients with nonalcoholic fatty liver disease. Notes: *P,0.05, significant difference versus baseline and week 12. † P 0.05, † † P,0.01, significant difference between groups (normal group versus AT group pre and post). The lower edge, midline, and upper edge of each box represent the 25th percentile, median, and 75th percentile scores, respectively. The line from each box extends to the minimum and maximum score. Abbreviations: aT, acceleration training; iMCl, intramyocellular lipids; eMCl, extramyocellular lipids; ihl, intrahepatic lipids.
intervention adherence outcomes for blood biochemistry in obese patients with nonalcoholic fatty liver disease
Changes in sF-36 scores prior to and after acceleration training in obese patients with nonalcoholic fatty liver disease. Notes: *P,0.05, significant difference between baseline and week 12. Abbreviations: BP, bodily pain; gh, general health perception; sF-36, short Form health survey; eR, emotional role; Mh, mental health; PF, physical functioning; PR, physical role; sF, social functioning; VT, vitality.
Figure S1 The acceleration training program conducted in this study. 
While aerobic training is generally recommended as therapeutic exercise in guidelines, the effectiveness of resistance training has recently been reported in the management of nonalcoholic fatty liver disease (NAFLD). Acceleration training (AT) is a new training method that provides a physical stimulation effect on skeletal muscles by increasing gravitational acceleration with vibration. AT has recently been indicated as a component of medicine. In this study, we evaluated the effectiveness of AT in the management of NAFLD in obese subjects. A total of 18 obese patients with NAFLD who had no improvement in liver function test abnormalities and/or steatosis grade after 12 weeks of lifestyle counseling were enrolled in an AT program. These patients attended a 20-minute session of AT twice a week for 12 consecutive weeks. During the AT program, the NAFLD patients showed a modest increase in the strength (+12.6%) and cross-sectional area (+3.1%) of the quadriceps, coupled with a significant reduction in intramyocellular lipids (-26.4%). Notably, they showed a modest reduction in body weight (-1.9%), abdominal visceral fat area (-3.4%), and hepatic fat content (-8.7%), coupled with a significant reduction in levels of aminotransferase (-15.7%), γ-glutamyltransferase (-14.4%), leptin (-9.7%), interleukin-6 (-26.8%), and tumor necrosis factor-α (-17.9%), and a significant increase of adiponectin (+8.7%). On a health-related quality of life survey, the patients showed an improvement in physical functioning (+17.3%), physical role (+9.7%), general health (+22.1), and social functioning (+6.0%). AT reduced hepatic and intramyocellular fat contents and ameliorated liver function test abnormalities in obese patients with NAFLD, which was coupled with improved physical function and body adiposity. AT is clinically beneficial for the management of NAFLD.
 
Characteristics of study population
History of chemoprophylaxis in study population
International travelers from non-endemic areas are at high risk of contracting malaria due to their lack of immunity. Prevention is therefore of outmost importance and is achieved through effective and safe chemoprophylaxis, which reduces the risk of fatal disease. Among the various antimalarial drugs available, the synergistic combination of atovaquone and proguanil (A/P) (Malarone((R)); Glaxo-SmithKline) has proven a valuable option in terms of effective protection against chloroquine and multi-drug resistant falciparum malaria, safety, tolerability, and ease of use, thus favoring compliance. The purpose of the present study was to assess acceptability and ease of use of A/P chemoprophylaxis in a population of employees of the oil industry bound to malarious areas. Particular attention was paid to treatment adherence. A survey was conducted on a sample of 700 employees on A/P chemoprophylaxis. Demographic data and specific information on A/P treatment were collected by means of a 16-item questionnaire administered immediately before departure. All questionnaires returned were then entered into a database and statistically analyzed. Both habitual and first-time travelers showed good adherence to A/P chemoprophylactic regimen. In general, only few adverse side-effects were reported, none of which were serious. Travelers with previous experience of other antimalarials stated A/P prophylaxis had proven advantageous due to fewer adverse reactions, better condition of administration, and better sense of protection compared with other available treatments.
 
Contraindications to the levonorgestrel-releasing intrauterine system according to organizational recommendations
Levonorgestrel-releasing intrauterine system (LNG-IUS, Mirena®).3
The levonorgestrel-releasing intrauterine system (LNG-IUS) is a safe, effective and acceptable form of contraception used by over 150 million women worldwide. It also has a variety of noncontraceptive benefits including treatment for menorrhagia, endometriosis, and endometrial hyperplasia. The LNG-IUS has also been used in combination with estrogen for hormone replacement therapy and as an alternative to hysterectomy. Overall, the system is very well tolerated and patient satisfaction is quite high when proper education regarding possible side effects is provided. However, despite all of the obvious benefits of the LNG-IUS, utilization rates remain quite low in the developed countries, especially in the United States. This is thought to be largely secondary to the persistent negative impressions from the Dalkon Shield intrauterine experience in the 1970s. This history continues to negatively influence the opinions of both patients and health care providers with regards to intrauterine devices. Providers should resolve to educate themselves and their patients on the current indications and uses for this device, as it, and intrauterine contraception in general, remains a largely underutilized approach to a variety of women's health issues.
 
Effect of vildagliptin on α-cell function in hyperglycemia (A) and hypoglycemia (B). Notes: *P = 0.019; **P = 0.039. Adapted with permission from Ahrén B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab. 2004;89(5):2078-2084.24 ©2009, The Endocrine Society. Abbreviation: AUC, area under the curve. 
instant effect of vildagliptin 100 mg/day versus placebo on glucose fluctuations. Note: *P , 0.05 or better than placebo. Plasma GLP-1(A), GIP(B) during the meal tolerance test after ingestion of vildagliptin and placebo. Data are the mean± SE. Adapted with permission from Balas B, Baig MR, Watson C, et al. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007;92(4):1249-1255. 52 © 2007, The Endocrine Society. Abbreviations: GLP-1, glucagon-like peptide-1; GIP, gastric inhibitory polypeptide. 
Vildagliptin is a selective and potent dipeptidyl peptidase-4 inhibitor that improves glycemic control by inhibiting the degradation of both endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. This article is a comprehensive review of the safety and efficacy of vildagliptin in patients with type 2 diabetes. Clinical evidence has proven that it effectively decreases hemoglobin A1c with a low risk of hypoglycemia and is weight neutral. The addition of vildagliptin to metformin improves glucose control and significantly reduces gastrointestinal adverse events, particularly in patients inadequately controlled with metformin monotherapy. Its long-term advantages include preservation of β-cell function, reduction in total cholesterol, decrease in fasting lipolysis in adipose tissue, and triglyceride storage in non-fat tissues. Vildagliptin is well tolerated with a low incidence of AEs, and it does not increase the risk of cardiovascular/cerebrovascular (CCV) events. It can be taken before or after meals, and has little drug interaction, thus it will be well accepted.
 
Sustained virological response by HIV status and genotype. Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus. 
Language barrier, race, immigration status, mental health illness, substance abuse and socioeconomic status are often not considered when evaluating hepatitis C virus (HCV) sustained virological response (SVR) in human immunodeficiency virus (HIV) infection. The influence of these factors on HCV work-up, treatment initiation and SVR were assessed in an HIV-HCV coinfected population and compared to patients with HCV mono-infection. The setting was a publicly funded, urban-based, multidisciplinary viral hepatitis clinic. A clinical database was utilized to identify HIV and HCV consults between June 2000 and June 2007. Measures of access to HCV care (ie, liver biopsy and HCV antiviral initiation) and SVR as a function of the above variables were evaluated and compared between patients with HIV-HCV and HCV. HIV-HCV co-infected (n = 106) and HCV mono-infected (n = 802) patients were evaluated. HIV-HCV patients were more often white (94% versus 84%) and male (87% versus 69%). Bridging fibrosis or cirrhosis on biopsy was more frequent in HIV-HCV (37% versus 22%; P = 0.03). HIV infection itself did not influence access to biopsy (50% versus 52%) or treatment initiation (39% versus 38%). Race, language barrier, immigration status, injection drug history and socioeconomic status did not influence access to biopsy or treatment. SVR was 54% in HCV and 30% in HIV-HCV (P = 0.003). Genotype and HIV were the only evaluated variables to predict SVR. Within the context of a socialized, multidisciplinary clinic, HIV-HCV co-infected patients received similar access to HCV work-up and care as HCV mono-infected patients. SVR is diminished in HIV-HCV co-infection independent of language barrier, race, immigration status, or socioeconomic status.
 
A flowchart for management of ingestion or aspiration can aid clinicians to make instant decisions in the event of this emergency.
Abbreviation: CXR, chest radiograph; GIT, gastrointestinal tract.
Prefabricated bands prior to placement in the mouth being secured with an adequate length of floss as a precaution.
A removable quadhelix on a patient’s model just prior to placement that has been tethered with a length of floss to preclude any emergency.
Among the myriad emergencies that could arise in the dental clinical setting there are a few that occur occasionally despite being entirely preventable. Ingestion or aspiration of dental materials, appliances, or instruments comprises this category. Regardless of incidence, foreign body ingestion or aspiration episodes are recognized as potential complications in the specialty of orthodontics. Despite their infrequent occurrence, the morbidity from a single incident and the amount of specialty medical care that may be needed to manage such incidents is too high to ignore. There is also the associated risk of malpractice litigation given the fact that these incidents are preventable. At present, no clear guidelines exist regarding prevention of this emergency in practice. This article attempts to review relevant literature and aims to formulate certain recommendations based on best available evidence to minimize the incidence of such events, while also suggesting guidelines toward making their management more effective. A flow chart outlining management options and strategies to aid the clinician in the event of such an emergency is also presented.
 
Accidental ingestion of medium-to-large instruments is relatively uncommon during dental treatment but can be potentially dangerous. A case of BiTine ring ingestion is presented with a note on inefficient ring separation forceps. A 28-year-old male patient accidentally ingested the BiTine ring (2 cm diameter, 0.5 cm outward projections) while it was being applied to a distoproximal cavity in tooth # 19. The ring placement forceps were excessively flexible; bending of the beaks towards the ring combined with a poor no-slippage mechanism led to sudden disengagement of the ring and accelerated movement towards the pharynx. We followed the patient with bulk forming agents and radiographs. Fortunately the ring passed out without any complications. Checking equipment and methods is as important as taking precautions against any preventable medical emergency. It is the responsibility of the clinician to check, verify and then use any instrument/equipment.
 
Ling-ling Zhu,1 Quan Zhou21Geriatric VIP Ward, Division of Nursing, 2Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of ChinaWe read with great interest the study by Fadare et al,1 who assessed the prescribing pattern for elderly Nigerian outpatients and concluded that polypharmacy and the prescription of potentially inappropriate medications are major therapeutic issues in Nigeria, and there is a need for prescriber training and retraining with emphasis on the geriatric population. We completely agree with Fadare et al’s1 point of view that a low proportion of patients with potentially inappropriate medications highlights the importance of information technology in medication management. We discuss and share our perspectives in the following paragraphs.View original paper by Fadare and colleagues.
 
To explore the relationship between actual and expected general medical practitioner (GP) practice prescribing rates for statins, angiotensin converting enzyme (ACE) inhibitors, and beta-blockers. There is a growing body of literature highlighting inequities in GP practice prescribing rates for many drug therapies. The equity of prescribing is of central importance in the area of therapeutics since it explores the interface between those patients who should and those who actually do receive a drug therapy. Four primary care trusts (PCTs 1-4) in the North West of England, including 132 GP practices. Actual and expected prescribing rates for statins, beta-blockers, and ACE inhibitors were specifically developed for each GP practice. There were no statistically significant correlations between actual and expected prescribing rates in PCT2 and PCT3, although in PCT1 there were statistically significant correlations for statins (0.286, p < 0.05) and ACE inhibitors (0.381, p < 0.01). In PCT4, correlations were moderate to high for beta-blockers (0.693, p < 0.01), and moderate for statins (0.541, p < 0.05) and ACE inhibitors (0.585, p < 0.01). Scatterplots highlighted large variations between individual GP practices (both within and between PCTs) in terms of the relationship between actual and expected prescribing rates. This paper highlights variability between PCTs and GP practices in terms of the relationship between actual and expected prescribing rates. The findings from this paper may further advance the suggestion of inequities in prescribing rates for coronary heart disease (CHD) drugs, and studies such as this may be repeated in different therapeutic areas, healthcare settings, and countries.
 
WHO-ART preferred terms included in the groups assessed
rates (95% confidence interval [CI]) of spontaneous reports of adverse reactions with aceclofenac, meloxicam, and rofecoxib during the first year after introduction to the UK market
The objective was to compare the incidence of adverse reactions reported with three nonsteroidal anti-inflammatory drugs with different cyclo-oxygenase (COX)-2 selectivity. All spontaneous adverse reaction notifications in the pharmacovigilance database of the World Health Organisation Collaborating Centre for International Drug Monitoring with aceclofenac, meloxicam, and rofecoxib that were recorded during the first year of marketing were included. The incidence rate (adverse reactions/10(6) defined daily dose) and 95% confidence interval for total adverse reactions was 8.7 (6.1-12.0) for aceclofenac, 24.8 (23.1-26.6) for meloxicam, and 52.6 (49.9-55.4) for rofecoxib. Aceclofenac had a lower incidence of gastrointestinal bleeding, abdominal pain, and arterial hypertension than meloxicam and a lower incidence of gastrointestinal bleeding, abdominal pain, liver toxicity, thromboembolic cardiovascular events, arterial hypertension, and edema than rofecoxib. The incidence of total and gastrointestinal adverse reactions was significantly lower with aceclofenac than with meloxicam or rofecoxib, thus raising doubts about the hypothetical advantage of COX-2 selective inhibitors.
 
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Osama A Abu-Hammad
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