Cancer-Causing Effects of Orthopaedic Metal Implants in Total Hip Arthroplasty.

BACKGROUND: Metal implants have been preferentially used in THA due to its biocompatibility, mechanical stability and durability. Yet concerns have emerged regarding their potential to release metallic ions, leading to long-term adverse effects, including carcinogenicity. This study aimed to investigate the risk of cancer development in patients with orthopaedic metal implants in total hip arthroplasty (THA). METHODS: Patients with THA conducted at a local tertiary implant centre from 2001-2008 were linked to the local cancer registry and followed up to the end of 2023. Standardized incidence ratios (SIRs) for cancer incidence and its confidence interval by Poisson distribution were calculated. Survival analysis was depicted using the Kaplan-Meier method, and the log-rank test was used to assess the differences across groups. RESULTS: The study cohort included 388 patients and 53 cancers diagnosed during follow-up, at least 5 years post THA. All-site cancer risks were increased in patients with THA (SIR: 1.97; 95% CI: 1.48-2.46), validated with chi-square analysis (chi-square = 15.2551, N = 100,388, p < 0.01). A statistically significant increase in multiple site-specific cancers including haematological cancers were identified. CONCLUSIONS: Patients with THA were found to have an increased risk for cancer compared to the general population during a mean follow-up of 16 years.

A multiplex qPCR assay for transgenes detection: A novel approach for gene doping control in horseracing using conventional laboratory setup.

Illicit administration of transgene into horses is a form of gene doping that has been a key concern in equine sports. The large number of potential performance-enhancing transgenes has demanded a cost-effective and reliable detection method. Multiplex qPCR is a relevant technique, but the cross-talking between fluorophores and high background noise limits the method sensitivity and specificity. This study reports a simpler multiplexing approach by using the same fluorophore for four hydrolysis probes each targeting one of the four transgenes: human growth hormone, insulin-like growth factor 1, equine erythropoietin and interleukin-10. Any positive findings from this multiplex qPCR assay can then be confirmed by individual qPCR assays to identify potential transgene(s). This has effectively eliminated the cross-talking issue and allowed an improved signal-to-noise than conventional multiplex qPCR assay. It has also removed the limitation imposed by the available choice of fluorophores and optical channels of qPCR instruments on the number of transgenes that can be analysed in a multiplex qPCR assay. This novel multiplex qPCR has been successfully validated. The estimated limits of detection were ~1500-2500 copies/mL of blood, thus demonstrating comparable sensitivity with the corresponding duplex qPCR assays. Concurring results were obtained by analysing hundreds of official blood samples provided by racehorses with this multiplex qPCR assay and the accredited individual duplex qPCR assays. This novel multiplex qPCR assay for detecting multiple transgenes is a cost-effective screening method using a conventional laboratory setup and has opened up the potential to include the testing of additional transgenes in a single assay.

Paliperidone-Associated Sialorrhea: A Case Report With Review of Current Literature.

PURPOSE/BACKGROUND: Antipsychotic-associated sialorrhea is a problematic adverse effect with potentially negative consequences on quality of life and medication adherence. While clozapine is the antipsychotic that is most associated with sialorrhea, there have been published reports of other second-generation antipsychotics associated with sialorrhea, including aripiprazole, olanzapine, quetiapine, and risperidone. Although drooling is mentioned within the package insert for paliperidone, to date there have been minimal published reports in which paliperidone is implicated as the offending agent. METHODS/PROCEDURES: Here, we present a case of sialorrhea in a 56-year-old man with schizoaffective disorder who had a supratherapeutic paliperidone level after both oral and intramuscular paliperidone use. FINDINGS/RESULTS: Paliperidone was ultimately cross tapered to aripiprazole, and the patient was given atropine drops and benztropine with resolution of the sialorrhea. We provide a review of the literature regarding the other available reports of paliperidone-associated sialorrhea, possible mechanisms behind pathophysiology, as well as reports from the World Health Organization and Food and Drug Administration adverse event reporting systems. IMPLICATIONS/CONCLUSIONS: Clinicians should be aware of the potential for paliperidone and other nonclozapine second-generation antipsychotics to be associated with sialorrhea, especially given the increased frequency of their use for a variety of psychiatric disorders.

Development and Validation of a Rubric to Evaluate Diabetes SOAP Note Writing in APPE.

Objective. To develop and establish validity for a grading rubric to evaluate diabetes subjective, objective, assessment, plan (SOAP) note writing on primary care (PC) advanced pharmacy practice experiences (APPEs), and to assess reliability and student perceptions of the rubric. Methods. Ten PC APPE faculty members collaborated to develop a rubric to provide formative and summative feedback on three written SOAP notes per APPE student over a 10-month period. Correlation analyses were conducted between rubric scores and three criterion variables to assess criterion-related validity: APPE grades, Pharmaceutical Care Ability Profile Scores, and Global Impression Scores. Inter-rater and intra-rater reliability testing were completed using Cohen's kappa and Intraclass Correlation Coefficients (ICC). Student perceptions were assessed through an anonymous student survey. Results. Fifty-one students and 167 SOAP notes were evaluated using the final rubric. The mean score significantly increased from the first to second SOAP note and from the first to third SOAP note. Statistically significant positive correlations were found between final rubric scores and criterion variables. The ICC for inter-rater reliability was fair (.59) for final rubric scores and excellent for intra-rater reliability (.98 to1.00). Students responded that the rubric improved their ability (84.9%) and confidence (92.4%) to write SOAP notes. Conclusion. The rubric may be used to make valid decisions about students' SOAP note writing ability and may increase their confidence in this area. The use of the rubric allows for greater reliability among multiple graders, supporting grading consistency.

Ambulatory care preceptors' perceptions on SOAP note writing in advanced pharmacy practice experiences (APPEs).

INTRODUCTION: Descriptions of SOAP note requirements and assessment methods used during advanced pharmacy practice experiences (APPEs) are limited in the literature. This study aimed to gather information from preceptors regarding SOAP note writing and assessment methods utilized during ambulatory care APPEs. METHODS: A survey was developed and distributed to ambulatory care preceptors with data collected via Qualtrics and analyzed using descriptive statistics, Fisher's exact test to assess the significance for associations between dependent and independent variables, and the Gamma test to assess dependent variables in grading habits and feedback types. RESULTS: The survey response rate was 62% with 75% of preceptors having students write SOAP notes during APPEs. A majority of preceptors (84%) do not formally grade SOAP notes with full-time faculty being more likely to grade and provide written feedback. Half of the preceptors perceived students as either prepared or very prepared to write SOAP notes but the majority felt that students struggle with the assessment portion of the note. There were significant differences between schools in the percentage of preceptors that formally grade SOAP notes, ranging from 2 to 45%. CONCLUSIONS: Preceptors' perception of student preparedness to write SOAP notes on ambulatory APPEs was similar, despite assessment methods varying widely.

A 90-day subchronic gavage toxicity study in Fischer 344 rats with 3-methylfuran.

A 90-day gavage study was conducted with 0.0, 0.02, 0.075, 0.25, 1.0 and 4.0 mg/kg bw/day dose groups of 3-methylfuran to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including changes in gross anatomy, histopathology, clinical biochemistry and hematology. There were significant changes in the serum clinical biochemistry markers related to liver injury where males were more affected than the females for most parameters analysed. The serum liver injury marker γ-glutamyltransferase, alanine and aspartate aminotransferases were significantly increased in males in the 4.0 mg/kg dose group. Alkaline phosphatase was increased in females and males. There were increases in both gross and histological lesions in the liver of both sexes in addition to statistical differences in female liver weights at the 4.0 mg/kg bw/day dose. Significant increases in spleen weights were found in both genders. This was accompanied by a dose-dependent atrophy of both B- and T-cell regions in which the males were more affected. There were no significant changes in male kidney weights but there was microscopically decreased protein in the proximal tubules and crowding of their nuclei in the 4.0 mg/kg bw/day dose group. There were also significant changes in the kidney serum biomarkers including various electrolytes, blood urea nitrogen, creatinine and uric acid. A small, but significant increase in female kidney weights was observed and which increase was accompanied by changes in electrolytes, kidney specific markers and a dose-dependent increase in mineralization. In both genders, amylase decreased whereas lipase increased but these were not accompanied by any histological changes in the pancreas. Histopathological changes in the liver were observed consistently in male and female rats in the 0.25 mg/kg dose group and higher. Hence, a lowest observed adverse effect level (LOAEL) of 0.25 mg/kg bw/d and a no observed adverse effect level (NOAEL) of 0.075 mg/kg bw/day are proposed for 3-methylfuran-induced hepatic lesions in this study. Benchmark dose modelling based on a BMR of 10% change in lesion incidence, generated BMDLs10 of 0.08 mg/kg bw/day in male rats and 0.05-0.17 mg/kg bw/day in female rats for increased incidence of liver lesions.

Brominated diphenyl ether (BDE) levels in liver, adipose, and milk from adult and juvenile rats exposed by gavage to the DE-71 technical mixture.

Brominated diphenyl ethers (BDEs) are used as flame retardants in consumer products. Rodent studies indicate that the liver, thyroid, and nervous system of developing animals are targets of BDEs. To explore the relationship between exposure and health in developing animals, BDE accumulation in adult and juvenile rats was examined in conjunction with changes in liver weight and serum thyroxine (T4). Adult (F0) rats received the commercial BDE mixture DE-71 by gavage at doses of 0.5, 5, and 25 mg kg(-1) body weight (bw)/day for 21 weeks. F0 rats were mated and exposure continued throughout breeding, pregnancy, lactation, and postweaning until the pups (F1 generation) reached postnatal day (PND) 42. Milk was collected from lactating dams. Adipose and liver samples were collected from F0 and F1 males and females for BDE congener analysis. Congener prevalence in rat tissues mimicked congener prevalence in wildlife and humans. Tissue concentrations of all congeners except BDE-153 were lower than would be expected based on dose proportionality, confirming that BDE-153 has a high capacity for bioaccumulation. BDEs were transferred from maternal tissues to milk during lactation. Milk congener profiles differed from maternal tissue profiles indicating that degree of bromination and maternal sequestration influenced BDE transfer to milk. Female F1 rats accumulated more BDEs than F1 males, indicating that female rats were less able to metabolize and/or excrete BDEs. Significant effects on liver weight and serum T4 levels were observed in adults and juveniles in the middle and high dose groups, corresponding to BDE levels in the µg g(-1) range. Although it remains to be determined how human liver and thyroid are affected by exposure to much lower BDE levels, the present study confirmed that gender and reproductive status influence BDE accumulation in tissues and BDE transfer to the neonate via milk.

Ramelteon for Insomnia Related to Attention-Deficit/Hyperactivity Disorder (ADHD).

OBJECTIVES: This study evaluated the efficacy of ramelteon for insomnia in adult subjects with ADHD. EXPERIMENTAL DESIGN: For this randomized, double-blind, placebo-controlled crossover trial, 8 mg of ramelteon was given nightly, within three hours of bedtime, to ADHD-insomnia subjects confirmed by DSM-IV-TR, ADHD-RS, MINI, and clinical interview. All subjects underwent two weeks each of ramelteon and placebo. Objective sleep measures were obtained by actigraphy. Subjective measures included: the Epworth Sleepiness Scale (ESS) and ADHD-RS. PRINCIPAL OBSERVATIONS: Of 36 subjects entering the study, 58% met criteria for circadian rhythm sleep disorder (CRSD), delayed sleep phase type. During ramelteon period, mid-sleep time, an indicator of circadian phase, occurred significantly earlier, by ~45 minutes compared to placebo period. An association was noted between the magnitude of the sleep phase advance and the timing of ramelteon administration in relationship to sleep start time, but did not reach statistical significance; maximal efficacy was noted 1.5 hours before bedtime. Paradoxically, ramelteon marginally, but significantly increased sleep fragmentation and ESS scores compared to the placebo state. CONCLUSIONS: Ramelteon is efficacious in maintaining an earlier sleep/wake cycle in adults with ADHD and CRSD but can have paradoxical fragmenting effects on sleep and exacerbate daytime sleepiness. In the presence of a circadian rhythm disorder, the usual dosing and timing parameters for ramelteon need to be carefully considered.

Adjunctive use of atypical antipsychotics for treatment-resistant generalized anxiety disorder.

Generalized anxiety disorder (GAD) is a common, chronic mental illness that has a significant burden on the patient's quality of life. Treatment for GAD routinely consists of monotherapy with a proven anxiolytic such as an antidepressant or benzodiazepine, but many patients do not respond fully to these drugs, and additional treatment may be needed. Therefore, we reviewed the safety and efficacy of atypical antipsychotics as adjunct therapy to standard GAD pharmacotherapy in patients deemed treatment resistant. We performed a literature search of the MEDLINE database for English-language articles published from January 1966-May 2009. Identified articles were evaluated, and only open-label trials and randomized controlled trials (RCTs) were included in the review. Relevant references from the articles were also evaluated. Only a few reports of large-scale RCTs that assessed an atypical antipsychotic for treatment-resistant GAD have been published. Articles were found for five of the eight currently available atypical antipsychotics, but not for asenapine, clozapine, and paliperidone. Several open-label trials and smaller RCTs support the need for further evaluation of aripiprazole and quetiapine for treatment-refractory GAD, although one quetiapine trial demonstrated negative results. There is disparate data for risperidone, with one open-label trial and one small RCT showing positive results and one large RCT showing negative results. One open-label trial of ziprasidone and one RCT of olanzapine both showed beneficial effects of the drugs. Adverse effects were specific to each agent, with weight gain being the most common, but many studies did not monitor systematically for lipid level, weight, or glucose level changes. Although data suggest efficacy regarding the use of atypical antipsychotics for augmentation of treatment-refractory GAD, more rigorous studies (large, double-blind, placebo-controlled trials) on the safety and efficacy of these agents are needed in order to recommend their use in patients with GAD.

Metabolic consequences of using low-dose quetiapine for insomnia in psychiatric patients.

Quetiapine is frequently prescribed for insomnia that is comorbid with psychiatric disorders, but there has been no documentation of metabolic adverse effects associated with this practice. The objective of this study was to document changes in weight, body mass index, and waist circumference that occurred when low-dose quetiapine was used at bedtime for insomnia. The study was a retrospective chart review conducted at a community mental health center. Patients were non-elderly (19-65 years old) psychiatric patients who received quetiapine at < or =200 mg at bedtime for the explicit indication of insomnia. Forty-three patients were included in the study. Weight and BMI increased by an average of 4.9 lb. (P = 0.037) and 0.8 points (P = 0.048), respectively. Males experienced statistically significant increases in weight and BMI, and Caucasians experienced a statistically significant increase in BMI. There were no significant differences between baseline and endpoint metabolic parameters when examined by baseline BMI, age category, psychiatric diagnosis, or concomitant psychotropic medication. Despite the low doses typically used when quetiapine is prescribed for insomnia, metabolic adverse effects can occur and should be considered in the overall benefit to risk analysis.

A novel IL-1 family cytokine, IL-33, potently activates human eosinophils.

BACKGROUND: Eosinophils are likely key cells involved in the pathogenesis of asthma and allergic diseases; however, the mechanisms that regulate eosinophil dynamics and functions in mucosal tissues are incompletely understood. IL-33, which is produced by mucosal cells, is a new member of the IL-1 cytokine family. Mice injected with IL-33 display profound mucosal eosinophilia with associated pathologic changes. Although mast cells and T(H)2 cells express the IL-33 receptor, ST2, the roles of IL-33 and ST2 in eosinophil biology are unknown. OBJECTIVES: We investigated the effects of IL-33 on human eosinophils in vitro. METHODS: Eosinophils and neutrophils were isolated from blood of normal individuals and mildly atopic patients. Real-time RT-PCR and flow cytometry were used to detect ST2. Granulocyte responses to IL-33 were monitored by superoxide anion production and by degranulation; IL-5, IL-1beta, and TNF-alpha served as controls. Eosinophil survival and cytokine production were assessed by flow cytometry and ELISA, respectively. RESULTS: ST2 mRNA and protein were detected on eosinophils. IL-33 induced eosinophil superoxide anion production and degranulation as potently as IL-5. IL-33 also increased eosinophil survival and induced production of IL-8. Anti-ST2 inhibited eosinophil responses to IL-33. Neutrophils did not express ST2, nor did they respond to IL-33. CONCLUSION: IL-33 and its receptor, ST2, may play important roles in eosinophil-mediated inflammation; they may provide new therapeutic targets for controlling mucosal eosinophilic inflammation.

Chronic rhinosinusitis in adults.

There is no consensus on diagnostic criteria for chronic rhinosinusitis. By convention, the symptoms of chronic rhinosinusitis are similar to those of acute rhinosinusitis but last more than 8 weeks. Diagnosis is based on history, physical examination, and computed tomography scan of the sinuses or rhinoscopy. Treatment options are numerous and, for the most part, not evidence based. They include antibiotics, nasal or oral corticosteroids, antihistamines, naval lavage, decongestants, immunotherapy, and surgery. Which diagnostic and therapeutic options to exercise when, is the focus of this article.

The effect of voluntary trunk rotation and half-field eye-patching for patients with unilateral neglect in stroke: a randomized controlled trial.

OBJECTIVE: To investigate the effectiveness of voluntary trunk rotation and half-field eye-patching to treat patients with unilateral neglect in stroke. DESIGN: Pre-post, day 60 follow-up, single-blinded randomized controlled trial. SETTING: Single-centre inpatient rehabilitation hospital. SUBJECTS: Sixty subacute patients with right hemisphere stroke having unilateral neglect within eight weeks post stroke consented to participate between November 2003 and July 2005. They were randomly assigned to three comparison groups. INTERVENTIONS: Nineteen patients received daily experimental training in voluntary trunk rotation (TR) for 1 hour five times a week for 30 days. Twenty patients received the same kind of treatment together with half-field eye-patching (TR + EP). Fifteen patients in the control group received conventional training with the same contact time. MAIN OUTCOME MEASURES: Patients were assessed on days 0, 30 and 60 using the Behavioural Inattention Test, the Clock Drawing Test, and the Functional Independence Measure. RESULTS: No significant differences between voluntary trunk rotation (TR), voluntary trunk rotation and half-field eye-patching (TR + EP) and controls were found in functional performance and neglect measures at day 30 (P = 0.042-0.994) and follow-up (P = 0.052-0.911) at P = 0.005 using Bonferroni correction. CONCLUSIONS: The results of this study do not support the use of voluntary trunk rotation alone or with half-field eye-patching to improve functional performance or reduce unilateral neglect in subacute patients with stroke.

Evidence-based review of the black-box warning for droperidol.

PURPOSE: Data collected from the Food and Drug Administration (FDA) under the Freedom of Information Act are presented to help clinicians understand the data prompting the black-box warning for droperidol and to make educated decisions regarding the use of droperidol and alternative agents. SUMMARY: A written request was submitted to FDA to provide a report of any and all reports of cardiovascular adverse events related to droperidol that were part of the decision to add a black-box warning to the label of droperidol. The report listed 277 cases of adverse effects associated with droperidol since its introduction to the market in 1970. Many of the reports were duplicates, leaving a total of 65 individual cases. Of these cases, only 2 described adverse effects possibly caused by droperidol in dosages commonly used in the United States. In addition to these reports, the results of two European studies prompted FDA to make the decision for the black-box warning. Both studies used droperidol doses 50-100 times higher than those used in the United States. CONCLUSION: Studies show that there is a dose-dependent increase in the rate of adverse cardiovascular events when droperidol is used either alone or in combination with other medications that cause Q-T interval prolongation. At this time, there does not appear to be significant evidence to suggest that serotonin type 3-receptor (5-HT(3)) antagonists are safer than droperidol with regard to Q-T interval prolongation. More studies are needed to determine the safety and efficacy of droperidol when used in doses of 0.625-1.25 mg compared with the 5-HT(3) antagonists.

Further examination of the effects of nitrosylation on Alternaria alternata mycotoxin mutagenicity in vitro.

Previously, Alternaria extract and metabolite mutagenicities+/-nitrosylation were characterized using Ames Salmonella strains TA98 and TA100, which are both reverted at GC sites. To examine other targets for mutation, the metabolites Altertoxin I (ATX I), Altenuene (ALT), Alternariol (AOH), Alternariol monomethyl ether (AME), Tentoxin (TENT), Tenuazonic acid (TA) and Radicinin (RAD) were reexamined+/-nitrosylation, using Ames Salmonella strain TA97, sensitive to frameshift mutations at a run of C's, as well as strains TA102 and TA104, reverted by base pair mutations at AT sites and more sensitive to oxidative damage. ATX I was also assessed for mammalian mutagenicity at the Hprt gene locus in Chinese hamster V79 lung fibroblasts and rat hepatoma H4IIE cells. When tested from 1 to 100 microg/plate without nitrosylation, ATX I was mutagenic in TA102+/-rat liver S9 for activation and weakly mutagenic in TA104+/-S9, demonstrating direct-acting AT base pair mutagenicity. AOH was also directly mutagenic at AT sites in TA102+/-S9 while AME was weakly mutagenic in TA102+/-S9 and TA104+S9. Nitrosylation of ATX I enhanced mutagenicity at AT sites in TA104+/-S9 but produced little change in TA102+/-S9 compared to native ATX I. However, nitrosylated ATX I generated a potent direct-acting frameshift mutagen at C sites in TA97+/-S9. While ATX I was not mutagenic in either V79 cells or H4IIE cells, 5 and 10 microg/ml nitrosylated ATX I produced a doubling of 6-thioguanine resistant V79 colonies and 0.5 and 1 microg/ml were mutagenic to H4IIE cells, becoming toxic at higher concentrations. These results suggest ATX I, AME and AOH induce mutations at AT sites, possibly through oxidative damage, with nitrosylation enhancing ATX I frameshift mutagenicity at runs of C's. Nitrosylated ATX I was also directly mutagenic in mammalian test systems.

Rectus sheath hematoma: review of 126 cases at a single institution.

Rectus sheath hematoma (RSH) is an uncommon condition characterized by abdominal pain and an abdominal wall mass. We reviewed the clinical features, treatment, and outcomes of 126 patients treated for RSH at Mayo Clinic from January 1, 1992, to December 31, 2002. Most patients (64%) were women and the mean +/- SD age was 67.9 +/- 16.5 years. Most patients (69%) were on some form of anticoagulation therapy. The mean international normalized ratio was 2.6 +/- 2.4, and mean activated partial thromboplastin time was 64.2 +/- 42.7 seconds. No patients were pregnant or had a peritoneal dialysis catheter at the time of diagnosis. Approximately half of the patients (48%) had nonsurgical abdominal trauma around the time of diagnosis, with 37 patients (29%) having a cough. The most common presenting signs and symptoms were abdominal pain (84%) and an abdominal wall mass (63%). CT of the abdomen and pelvis was the most commonly used method to establish the diagnosis (83%). Most patients (86%) were successfully treated with symptom management and blood transfusion. Ten patients (7.9%) underwent surgery or endovascular embolization of bleeding vessels, and 2 patients (1.6%) died as a result of RSH bleeding. Although RSH is rarely fatal, the clinician should be aware of important risk factors that lead to RSH including female sex, older age, anticoagulation therapy, and cough or other abdominal trauma. Rapid diagnosis with directed history, physical examination, and CT of the abdomen and pelvis may help decrease unnecessary laparotomy and lead to better triage of patients who present with RSH.