Second tier non-invasive prenatal testing in a regional prenatal diagnosis service unit: a retrospective analysis and literature review.

INTRODUCTION: The Hong Kong Hospital Authority has newly introduced a new Down's syndrome screening algorithm that offers free-of-charge non-invasive prenatal testing (NIPT) to women who screen as high risk. In preparation for this public-funded second tier NIPT service, the present study was conducted to retrospectively analyse women eligible for NIPT and to review the local literature. METHODS: Our retrospective study included women screened as high risk for Down's syndrome (adjusted term risk ≥1:250) during the period of 1 January 2015 to 31 December 2016. We performed descriptive statistics and multivariable logistic regression to examine the factors associated with women's choice between NIPT and invasive testing. We also reviewed existing local literature about second tier NIPT. RESULTS: The study included 525 women who screened positive: 67% chose NIPT; 31% chose invasive diagnostic tests; and 2% declined further testing. Our literature review showed that in non-research (self-financed NIPT) settings, NIPT uptake rates have been increasing since 2011. Nulliparity, first trimester status, higher education, maternal employment, and conception by assisted reproductive technology are common factors associated with self-financed NIPT after positive screening. Among women choosing NIPT, the rates of abnormal results have typically been around 8% in studies performed in Hong Kong. CONCLUSION: Implementation of second tier NIPT in the public setting is believed to be able to improve quality of care. We expect that the public in Hong Kong will welcome the new policy.

Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP.

Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP-PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation.

Brain dose-sparing radiotherapy techniques for localized intracranial germinoma: Case report and literature review of modern irradiation.

We examined the effects of intensity-modulated radiation therapy with dose-sparing and avoidance technique on a pediatric patient with localized intracranial germinoma. We also reviewed the literature regarding modern irradiation techniques in relation to late neurocognitive sequelae. A patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland received a dose-sparing intensity-modulated radiation therapy. The planning was compared to the radiation oncologist's guide of organs at risk and dose constraints for dosimetric analyses. The patient received radiation therapy alone. The total dose was 54Gy delivered in 2.0Gy fractions to the primary tumour and 37Gy in 1.4Gy fractions to whole ventricles using a dose-sculpting plan. Dosimetry analyses showed that dose-sparing intensity-modulated radiation therapy delivered reduced doses to the whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With a follow-up of 22 months, failure-free survival was 100% for the patient and no adverse events during radiation treatment process. Intensity-modulated radiation therapy with dose sparing and avoidance technique can spare the limbic circuit, central nervous system, and hippocampus for pineal germ cell tumours. This technique reduces the integral dose delivered to the uninvolved normal brain tissues and may reduce late neurocognitive sequelae caused by cranial radiotherapy.

Pedestrian level wind environment assessment around group of high-rise cross-shaped buildings: Effect of building shape, separation and orientation.

Blockage of air circulation caused by the mutual sheltering effect of high-rise buildings in built-up areas in dense cities causes various health- and comfort-related problems. The combined effect of neighborhood geometry (e.g., re-entrant corners, wind incident angle, passage angle, and building separation) on wind flow at the pedestrian level is an active field of research. This study investigates the influence of the wind incident angle and passage width on the wind flow characteristics at the re-entrant corners of cross-shaped high-rise buildings. This study also examines the influence of stagnant zones and wake regions on ventilation potential and wind comfort around the case study arrangements at various wind incident directions. An investigation was performed from 16 wind directions using the standard k-ε turbulence model with revised closure coefficients. A wind tunnel experiment was conducted to validate the results, which revealed that wind circulation at re-entrant corners was substantially affected by the building orientations and separation. The wind catchment effect within the re-entrant corners and the sheltering effect of buildings at various wind incident directions and building separations are also discussed. Unstable vortices were formed in oblique wind directions; these vortices facilitate contaminant dispersion and wind comfort at re-entrant corners and near buildings.

Pharmacotherapy of critical asthma syndrome: current and emerging therapies.

The critical asthma syndrome (CAS) encompasses the most severe, persistent, refractory asthma patients for the clinician to manage. Personalized pharmacotherapy is necessary to prevent the next acute severe asthma exacerbation, not just the control of symptoms. The 2007 National Asthma Education and Prevention Program Expert Panel 3 provides guidelines for the treatment of uncontrolled asthma. The patient's response to recommended pharmacotherapy is highly variable which risks poor asthma control leading to frequent exacerbations that can deteriorate into CAS. Controlling asthma symptoms and preventing acute exacerbations may be two separate clinical activities with their own unique demands. Clinicians must be prepared to use the entire spectrum of asthma medications available but must concurrently be aware of potential drug toxicities some of which can paradoxically worsen asthma control. Medications normally prescribed for COPD can potentially be useful in the CAS patient, particularly those with asthma-COPD overlap syndrome. Immunomodulation with drugs like omalizumab in IgE-mediated asthma syndromes is one important approach. New and emerging drugs address unique aspects of airway inflammation and biology but at a significant financial cost. The pharmacology and toxicities of the agents that may be used in the treatment of CAS to control asthma symptoms and prevent severe exacerbations are reviewed.

Expression of E6AP and PML predicts for prostate cancer progression and cancer-specific death.

BACKGROUND: The promyelocytic leukemia (PML) tumor suppressor plays an important role in the response to a variety of cellular stressors and its expression is downregulated or lost in a range of human tumors. We have previously shown that the E3 ligase E6-associated protein (E6AP) is an important regulator of PML protein stability but the relationship and clinical impact of PML and E6AP expression in prostatic carcinoma is unknown. METHODS: E6AP and PML expression was assessed in tissue microarrays from a phase I discovery cohort of 170 patients treated by radical prostatectomy for localized prostate cancer (PC). Correlation analysis was carried out between PML and E6AP expression and clinicopathological variates including PSA as a surrogate of disease recurrence. The results were confirmed in a phase II validation cohort of 318 patients with associated clinical recurrence and survival data. RESULTS: Survival analysis of the phase I cohort revealed that patients whose tumors showed reduced PML and high E6AP expression had reduced time to PSA relapse (P = 0.012). This was confirmed in the phase II validation cohort where the expression profile of high E6AP/low PML was significantly associated with reduced time to PSA relapse (P < 0.001), clinical relapse (P = 0.016) and PC-specific death (P = 0.014). In multivariate analysis, this expression profile was an independent prognostic indicator of PSA relapse and clinical relapse independent of clinicopathologic factors predicting recurrence. CONCLUSION: This study identifies E6AP and PML as potential prognostic markers in localized prostate carcinoma and supports a role for E6AP in driving the downregulation or loss of PML expression in prostate carcinomas.

E6AP is required for replicative and oncogene-induced senescence in mouse embryo fibroblasts.

Cellular senescence is important for the maintenance of tissue homeostasis, and has recently been shown to pose a natural barrier to tumorigenesis. The E3 ubiquitin ligase, E6AP, has been linked to a number of protein regulators of the cell cycle as well as the cellular stress response. We therefore explored the role of E6AP in the cellular response to stress. We found that mouse embryo fibroblasts (MEFs) lacking E6AP escape replicative senescence, as well as Ras-induced senescence associated with impaired markers. E6AP-deficient MEFs exhibit a range of transformed phenotypes: these include the ability to grow under stress conditions (such as low serum and DNA damage), enhanced proliferation, anchorage independent growth and enhanced growth of xenografts in mice. The transformed phenotype of E6AP-deficient MEFs is associated with lower basal and stress-induced accumulation of p53. Overall, our study implicates E6AP as an important regulator of the cellular response to stress, in particular through the regulation of replicative and oncogene-induced senescence.

Pharmacist intervention in activated protein C therapy for severe sepsis: influence on health and economic outcomes.

OBJECTIVE: To assess the health and cost outcomes of pharmacist intervention versus non-intervention in activated protein C (drotrecogin alpha) therapy for patients with severe sepsis. METHOD: This is a retrospective study. We reviewed the medical records of patients aged 18 years and older who were admitted to our hospital for severe sepsis from January 1, 2003 to December 31, 2007. Only patients who are prescribed activated protein C for the treatment of severe sepsis according to the reimbursement criteria can be reimbursed by the Taiwan Bureau of National Health Insurance (BNHI). Our hospital stipulated that the criteria check list must be evaluated by a clinical pharmacist and the prescribing physician as to whether the patient is eligible to receive activated protein C. To assess the influence of pharmacist intervention on outcomes, we divided eligible patients into two groups, pharmacist-intervention group (Group A; n = 19) and non-pharmacist intervention group (Group B; n = 19). Both groups received a 96-h intravenous infusion of activated protein C at 24 microg/kg/h. We defined evident severe sepsis as concurrent antibiotic plus ventilator and/or vasopressor use. We compared group characteristics, 28-day in-hospital mortality, length of stay and direct medical costs between the two groups. One-way ANOVA was used for analysis. RESULTS: 50% of patients in each group met the reimbursement criteria of the BNHI. Activated protein C therapy was initiated within 1.37 +/- 0.4 days and 7.21 +/- 7.8 days of admission to the ICU in Group A and Group B, respectively (p < 0.01). All of the patients in Group A (19/19) and 42.1% of the patients in Group B (8/19) received activated protein C within 12 - 48 h of admission to the Intensive care unit (ICU) (p < 0.01). 28-day mortality was lower for Group A than for Group B (26.7% and 43.8%, respectively). The length of stay in the ICU for patients in Group A was shorter than that in Group B (14.1 +/- 7.7 vs. 19.7 +/- 11.1, respectively; p < 0.079). Total direct medical costs for survivors in Group A were less than those in Group B (US$ 20,632.3 vs. US$ 24,785.8, respectively; p < 0.05). CONCLUSIONS: Pharmacist intervention in prescribing activated protein C for patients with severe sepsis might reduce direct medical costs and promote earlier initiation of therapy. The potential impact of pharmacist intervention on the timing of activated protein C therapy and the direct medical costs of treatment warrant further study.

Effects of pharmaceutical care intervention by clinical pharmacists in renal transplant clinics.

Renal transplantation is an established treatment for end-stage renal disease. Most renal transplant patients take multiple medications for a long period of time to maintain immunosuppression as well as to treat concomitant chronic diseases. Since some medications prescribed for these patients have narrow therapeutic ranges, optimal pharmacotherapy is vital. However, pharmacists can qualify the role in assisting patients and physicians to solve and reduce drug-related problems. The purpose of this trial was to investigate the effects on treatment outcomes by clinical pharmacists joining renal transplant clinics to provide pharmaceutical care. We enrolled 37 renal transplant patients who visited the renal transplant clinic in our medical center from May 2005 through August 2006. The responsibility of the clinical pharmacist was to interview patients, review medication regimens, and make therapeutic recommendations for 3 hours every Tuesday morning. According to potential clinical impacts, pharmacist recommendations were divided into 6 scales, evaluating physician acceptance of pharmacist recommendations and impact on treatment outcomes. Fifty-five pharmacotherapy recommendations were made for the 37 renal transplant patients during the trial period, of which 81.8% were classified as clinically significant. The drug classes most commonly involved were cardiovascular medications, immunosuppressants, and antimetabolites (32.6%, 23.9%, and 26.1%, respectively). Physician acceptance rates of recommendation types and drug classes were 96.0% and 97.1%, respectively. Among the cases in which the recommendations were accepted, 94.2% of patients showed improved conditions. We concluded that clinical pharmacists joined to renal transplant clinics provide pharmaceutical care with a positive potential impact on physician prescriptions and patient outcomes.

Fatal amiodarone-induced hepatotoxicity: a case report and literature review.

OBJECTIVE: To report a fatal case of amiodarone-induced acute hepatotoxicity after intravenous amiodarone administration and similar fatal cases review. CASE SUMMARY: A 72-year-old woman with a history of hypertension, prior cardiovascular disease, atrial fibrillation and diabetes mellitus was admitted to the hospital with acute pyelonephritis and transferred to the intensive care unit due to cerebral infarction. An antidiabetic drug, a low dose of aspirin and intravenous amiodarone therapy was started. After receiving a second dose of amiodarone (1,200 mg; injection rate 1 mg/min), the woman developed ascites, jaundice, high levels of serum transaminases, decreased prothrombin time, and finally became unconscious. Immediately after treatment was discontinued, her extremely high hepatic parameters returned to normal. According to the Naranjo probability scale, this adverse reaction was highly probable. DISCUSSION: The occurrence of acute liver damage after intravenous amiodarone is rare but harmful. It can be induced by polysorbate 80, a solubilizer, by immunomediated centrilobular necrosis, or by the presence of a functional PPAR-I+/- gene. CONCLUSION: Amiodarone is an effective antiarrhythmic agent for preventing and treating atrial and ventricular arrhythmias. The molecular mechanism causing acute hepatic damage after amiodarone treatment is not clear. Therefore, amiodarone must be administered with care, and liver function should be monitored closely in patients treated with this drug.

Application of data mining to predict the dosage of vancomycin as an outcome variable in a teaching hospital population.

OBJECTIVE: Data mining is a process used to extract potentially valuable information hidden in large volumes of raw data. The aim of this study was to explore the possibility of using easy to implement and effective supervised learning techniques to predict the dosage of vancomycin. METHODS: To reach this goal, we considered the prediction of the dosage of vancomycin as a classification problem. We chose the C4.5 decision tree technique for the dosage prediction process and supplied it with a boosting technique to enhance its performance. RESULTS: The potential predictor variables were collected from 833 patients with methicillin-resistant Staphylococcus aureus, or penicillin intolerance who were being treated with vancomycin and undergoing therapeutic drug monitoring (TDM) after attainment of steady state blood concentrations. Attributes tested as potential predictors included age, sex, weight, serum creatinine concentration, dosing interval, and variables from 1-compartment model kinetics such as Kd, Vd, and t(1/2). CONCLUSIONS: The results showed that the proposed method can utilize a variety of parameters to predict the dosage of vancomycin in the population used and that it performs well over a range of patient ages and renal function. The method may offer an alternative to existing methods used to support decision-making in clinical practice.

Unusual primary lung neoplasms.

Bronchial carcinoids and hamartomas are, respectively, the most common malignant and benign unusual primary lung neoplasms. These tumors are often asymptomatic but can cause central airway obstruction. Helical computed tomographic and radionuclide scintigraphic advances in their detection and evolution, together with newer interventional bronchoscopy techniques such as neodymium:yttrium-aluminum-garnet laser phototherapy and cryotherapy, represent important improvements in the diagnosis and management of patients with such tumors.

Survival of patients undergoing Nd:YAG laser therapy compared with Nd:YAG laser therapy and brachytherapy for malignant airway disease.

Brachytherapy in combination with Nd:YAG laser therapy may add to the duration of survival of the palliative period when compared with laser alone. A retrospective study of patients with inoperable squamous cell carcinoma (SCC) was undertaken to determine if there was a difference in survival between those patients treated with Nd:YAG laser alone and those treated with Nd:YAG laser and brachytherapy. Twenty-two patients were treated with brachytherapy for malignant airway disease at our institution of which 13 had SCC. All patients had previously received treatment with Nd:YAG laser for exophytic disease. Survival was compared with those patients treated with Nd:YAG laser alone for SCC involving the airway. There was no statistical difference between the two groups with regard to age. The duration of survival of patients with SCC of the airway from the first Nd:YAG laser treatment was determined. A significant difference between those patients treated with Nd:YAG laser alone and those patients treated with combined therapy was found (p < 0.001). Brachytherapy may potentiate the duration of survival in patients with SCC involving the airway compared to palliation with Nd:YAG laser alone.

Silent myocardial ischaemia: the Tan Tock Seng experience.

The results of treadmill exercise stress test (TMX) for ischaemia is based on ST-segment depression. Patients with positive test may or may not be symptomatic. This study examines if there are any differences between these two groups of patients. A total of thirty-nine patients with coronary artery disease and positive TMX results in 1988 was studied. There were 16 patients with chest pain and 23 without. They were followed-up for a mean period of 16.9 and 15.2 months respectively. The following factors were found not to be statistically significant between these two groups of patients: age, sex, race, height, weight, history of hypertension, diabetes mellitus or smoking, indication for the test, use of drugs, total and HDL-cholesterol, exercise duration and the initial double product. The difference between the maximal double product of the two groups was statistically significant (p = 0.004). In the follow-up period, in the group of patients with silent myocardial ischaemia, one had a cardiac event and one underwent revascularisation. While in the symptomatic group, two had cardiac events and seven underwent revascularisation. There were no deaths in either group. The difference in overall outcome was significant statistically (p = 0.002). Therefore, patients with silent myocardial ischaemia have a higher maximal double product in TMX; hence a higher maximal workload and a less adverse outcome compared to symptomatic patients.

A novel sialylated N-acetylgalactosamine-containing oligosaccharide is the major complex-type structure present in Bowes melanoma tissue plasminogen activator.

We have employed fast atom bombardment mass spectrometry (FAB-MS) to screen the N-linked oligosaccharides of Bowes melanoma tissue plasminogen activator (mt-PA), and recombinant t-PAs produced by Chinese hamster ovary cells (rt-PA) and by a gene-enriched melanoma cell line (rmt-PA). These studies have confirmed the published structures for rt-PA, but are not in agreement with some of the structures reported for mt-PA. In the latter glycoprotein we have identified a novel structure as the major oligosaccharide attached to Asn-184 and Asn-448. This is a biantennary oligosaccharide consisting of a fucosylated trimannosyl core to which are attached two GalNAc(1----4)GlcNAc antennae, one of which carries a sialic acid linked at the 6-position of the GalNAc. Minor constituents are sialylated on both or neither antennae. The sialylated GalNAc moiety is unique in N-linked glycoproteins. The majority of complex structures in rmt-PA contain N-acetyllactosamine moieties at both the Asn-184 and Asn-448 sites with the novel oligosaccharide occurring as a minor component at the Asn-184 site. This study demonstrates the power of mass spectrometric strategies based on high-field two-sector FAB-MS for structure elucidations of natural and recombinant glycoproteins.

Nd:YAG laser bronchoscopy. Rigid or fiberoptic mode?

One hundred twenty four Nd:YAG laser procedures were performed on 79 patients (age range, 25 to 89 years) over a five-year period at our institution. Over 90 percent of patients had malignant tumors. The fiberoptic bronchoscope (FOB group) was used exclusively during the first two years (61 cases, 32 patients). All except four of these cases utilized conscious sedation and local anesthesia. Subsequent to this, the rigid bronchoscope (RB group) was used as the primary instrument under general anesthesia (51 cases, 42 patients). Twelve cases combined both bronchoscopic modalities (combined group, 12 patients). The percentage improvement in proximal airway lumen diameter post-Nd:YAG laser therapy was significantly greater using the RB (p less than 0.05). For distal lesions, the FOB was superior (p less than 0.05). There was no difference in the complication or survival rates between the groups. Our data suggest that whenever possible, the RB should be used to treat proximal lesions, and the FOB should be used for distal lesions. Both bronchoscopes are often used together. Hence, laser bronchoscopists should be proficient in both bronchoscopic techniques.

Closing of the nurse-midwifery service at Boston City Hospital: another perspective.

This paper is a response to an article previously published in JNM's Issues and Opinions column. It provides another perspective regarding the recent troubles of Boston City Hospital's nurse-midwifery service.

Coronary artery-left ventricular fistula.

Coronary artery-left ventricular fistulae are exceedingly rare and to date only 19 cases have been reported in the literature. We describe another four cases which we encountered recently. The first patient was a 10-year-old asymptomatic Indian male who was referred because of a to-and-fro murmur. Haemodynamic and angiographic studies revealed an aneurysmally enlarged right coronary draining into the left ventricle. The fistula was ligated and the patient has remained well over a 21/2-year follow-up period. The second patient was a 13-year-old asymptomatic Chinese female referred also because of a to-and-fro murmur. Haemodynamic and angiographic studies showed a grossly enlarged right coronary artery draining into the left ventricle. This patient refused operation and has remained well over a 2-year follow-up period. The third patient was a 43-year-old Chinese male who presented with a 3-year history of angina pectoris and was admitted to hospital because of crescendo angina. The resting electrocardiogram showed marked ischaemic changes and the treadmill exercise stress test was also positive. Selective coronary angiography showed markedly dilated right and left coronary arteries. Multiple fistulae from the three major coronary arteries were seen to communicate with the left ventricle. It was elected to treat this patient medically with propranolol. He has remained well over a 6-month follow-up period. The fourth patient was a 5-year-old asymptomatic Chinese girl. Cardiac catheterization and selective coronary angiography revealed marked dilatation of the branches of the left coronary artery which communicated via a maize of fine vessels into the left ventricle. This patient has remained well over a 5-year follow-up period. The clinical presentation, investigations and treatment of coronary artery-left ventricular fistula are discussed and the literature regarding this subject is reviewed.