Molecular epidemiology of multi- and extensively-drug-resistant Mycobacterium tuberculosis in Ireland, 2001-2014.

OBJECTIVES: The primary objective of this work was to examine the acquisition and spread of multi-drug resistant (MDR) tuberculosis (TB) in Ireland. METHODS: All available Mycobacterium tuberculosis complex (MTBC) isolates (n = 42), from MDR-TB cases diagnosed in Ireland between 2001 and 2014, were analysed using phenotypic drug-susceptibility testing, Mycobacterial-Interspersed-Repetitive-Units Variable-Number Tandem-Repeat (MIRU-VNTR) genotyping, and whole-genome sequencing (WGS). RESULTS: The lineage distribution of the MDR-TB isolates comprised 54.7% Euro-American, 33.3% East Asian, 7.2% East African Indian, and 4.8% Indo-Oceanic. A significant association was identified between the East Asian Beijing sub-lineage and the relative risk of an isolate being MDR. Over 75% of MDR-TB cases were confirmed in non-Irish born individuals and 7 MIRU-VNTR genotypes were identical to clusters in other European countries indicating cross-border spread of MDR-TB to Ireland. WGS data provided the first evidence in Ireland of in vivo microevolution of MTBC isolates from drug-susceptible to MDR, and from MDR to extensively-drug resistant (XDR). In addition, they found that the katG S315T isoniazid and rpoB S450L rifampicin resistance mutations were dominant across the different MTBC lineages. CONCLUSIONS: Our molecular epidemiological analyses identified the spread of MDR-TB to Ireland from other jurisdictions and its potential to evolve to XDR-TB.

Fixation of displaced femoral neck fractures in young adults: Fixed-angle devices or Pauwel screws?

BACKGROUND: We sought to compare the incidence of complications after fixation of displaced femoral neck fractures in young adults treated with fixed-angle devices versus multiple cancellous screws and a trochanteric lag screw (Pauwel screw). METHODS: We conducted a retrospective cohort study at a level I trauma centre. Sixty-two skeletally mature patients (age range, 16-60 years) with displaced femoral neck fractures were included in the study. Forty-seven were treated with a fixed-angle device (sliding hip plate with screw or helical blade) and 15 with multiple cancellous screws placed in a Pauwel configuration. The main outcome measure was postoperative complication of osteonecrosis or nonunion treated with a surgical procedure. RESULTS: Significantly fewer failures occurred in the fixed-angle group (21%) than in the screws group (60%) (p=0.008). Osteonecrosis was rare in the fixed-angle group, occurring in 2% of cases versus 33% of cases in the screws group (p=0.002). Consistent with previous studies, good to excellent reductions were associated with a failure rate of 25% and fair to poor reductions were associated with a failure rate of 55% (p=0.07). The best-case scenario of a good to excellent reduction stabilised with a fixed-angle device yielded a success rate of 85%. CONCLUSION: In young patients with displaced high-energy femoral neck fractures, fixed-angle devices resulted in fewer treatment failures than did Pauwel screws.

Tuberculosis incidence in the Irish Traveller population in Ireland from 2002 to 2013.

The health status of the Irish Traveller ethnic minority is low compared to the general population in Ireland in terms of infant mortality rates and life expectancies. Respiratory disease is an area of health disparity manifested as excess mortalities in Traveller males and females. In this study, we examined the available data with regard to tuberculosis (TB) notifications in Ireland from 2002 to 2013. We found an increase in TB notifications in Irish Travellers from 2010 onwards. This resulted in a crude incidence rate for TB in Irish Travellers that was approximately threefold higher than that of the white Irish-born population in 2011 and 2012. An outbreak of TB in Irish Travellers in 2013 increased this differential further, but when outbreak-linked cases were excluded, a higher incidence rate was still observed in Irish Travellers relative to the general population and to white Irish-born. The mean age of a TB patient was 26 years in Irish Travellers compared to 43 years in the general population, and 49 years in white Irish-born. Based on available data, Irish Travellers exhibit a higher incidence rate and younger age distribution of TB compared to white Irish-born and the general population. These observations emphasize the importance of routine use of ethnicity identifiers in the management of TB and other notifiable communicable illnesses in Ireland. They also have implications for the orientation of preventive services to address health disparities in Irish Travellers and other ethnic minority groups.

Phylogenetic lineages of tuberculosis isolates in New Zealand and their association with patient demographics.

SETTING: In New Zealand, the lineage genotypes of Mycobacterium tuberculosis clinical isolates and their role in the epidemiology of tuberculosis (TB) are currently unknown. OBJECTIVE: 1) To measure the relative frequency of each phylogenetic lineage of the M. tuberculosis complex in New Zealand, and 2) to examine its relationship with patient demographics and multidrug-resistant TB (MDR-TB). METHODS: All non-duplicate M. tuberculosis complex isolates recovered in 2010 and 2011 underwent large sequence polymorphism and/or single nucleotide polymorphism analyses. Mycobacterial interspersed repetitive units (MIRU) profiling was also performed for cluster identification. RESULTS: New Zealand isolates were dominated by lineage 4 (Euro-American: 37.8%, 95%CI 33.6-42.2), followed by lineage 1 (Indo-Oceanic: 22.6%, 95%CI 19.1-26.5), lineage 2 (East Asian: 19.5%, 95%CI 16.2-23.3) and lineage 3 (East-African Indian, which included Central Asian: 17.7%, 95%CI 14.5-21.3). Lineage 2 accounted for 58.1% of MDR-TB cases from 2002 to 2011. Among immigrants, the predominant lineages corresponded to high prevalence lineages in the country of origin. In New Zealand-born individuals, Maori and NZ Europeans share the same predominant lineage, lineage 4, with a higher proportion of non-unique MIRU types observed in Maori cases. Lineage 3 was more prevalent in Maori than in NZ Europeans. CONCLUSION: In New Zealand, M. tuberculosis complex phylogenetic lineage is associated with TB epidemiology in terms of ethnicity, country of origin and MDR-TB.

Clinical pregnancy from a vitrified/warmed human blastocyst.

The first pregnancy after vitrification of a human blastocyst (day 5 of embryo culture) was reported by Yokota et al. in 2000. Since then more attention has been given to the technique of vitrification and its safe application in ART. To the best of our knowledge, this is the first report of a clinical pregnancy resulting in a live birth from the transfer of a vitrified/ warmed human blastocyst in the Republic of Ireland.

Comparative bioactivation of the novel anti-tuberculosis agent PA-824 in Mycobacteria and a subcellular fraction of human liver.

BACKGROUND AND PURPOSE: PA-824 is a 2-nitroimidazooxazine prodrug currently in Phase II clinical trial for tuberculosis therapy. It is bioactivated by a deazaflavin (F(420) )-dependent nitroreductase (Ddn) isolated from Mycobacterium tuberculosis to form a des-nitro metabolite. This releases toxic reactive nitrogen species which may be responsible for its anti-mycobacterial activity. There are no published reports of mammalian enzymes bioactivating this prodrug. We have investigated the metabolism of PA-824 following incubation with a subcellular fraction of human liver, in comparison with purified Ddn, M. tuberculosis and Mycobacterium smegmatis. EXPERIMENTAL APPROACH: PA-824 (250 µM) was incubated with the 9000 × g supernatant (S9) of human liver homogenates, purified Ddn, M. tuberculosis and M. smegmatis for metabolite identification by liquid chromatography mass spectrometry analysis. KEY RESULTS: PA-824 was metabolized to seven products by Ddn and M. tuberculosis, with the major metabolite being the des-nitro product. Six of these products, but not the des-nitro metabolite, were also detected in M. smegmatis. In contrast, only four of these metabolites were observed in human liver S9; M3, a reduction product previously proposed as an intermediate in the Ddn-catalyzed des-nitrification and radiolytic reduction of PA-824; two unidentified metabolites, M1 and M4, which were products of M3; and a haem-catalyzed product of imidazole ring hydration (M2). CONCLUSIONS AND IMPLICATIONS: PA-824 was metabolized by des-nitrification in Ddn and M. tuberculosis, but this does not occur in human liver S9 and M. smegmatis. Thus, PA-824 was selectively bioactivated in M. tuberculosis and there was no evidence for 'cross-activation' by human enzymes.

Multidisciplinary approach for patients with pelvic fractures and hemodynamic instability.

The hemodynamically unstable patient with a pelvic fracture presents a diagnostic and therapeutic challenge. The care of these patients requires a unique multidisciplinary approach with input and expertise from many different specialists. An understanding of pelvic anatomy and fracture patterns can help guide the diagnostic evaluation and treatment plan. The initial management of these patients must focus on rapid airway and hemorrhage control while preparing for ongoing blood loss. Rapid temporary fracture stabilization with simple bedside modalities is crucial in limiting additional blood loss. An exhaustive search must also be performed to evaluate for concomitant injuries that commonly accompany major pelvic fractures and the treatment of these other injuries must be appropriately prioritized. For patients who are unresponsive to standard resuscitation and bedside attempts at limiting hemorrhage, angiographic embolization is often utilized as the next step to attain hemodynamic stability. The key to successful management of these patients lies in the careful coordination of different specialists and the expertise that each brings to the clinical care of the patient.

Role of motility in adherence to and invasion of a fish cell line by Vibrio anguillarum.

To understand further the role of the flagellum of Vibrio anguillarum in virulence, invasive and adhesive properties of isogenic motility mutants were analyzed by using a chinook salmon embryo cell line. Adhesion was unaffected but invasion of the cell line was significantly decreased in nonmotile or partially motile mutants, and the chemotactic mutant was hyperinvasive. These results suggest that active motility aids invasion by V. anguillarum, both in vivo and in vitro.

Teachers' recognition and reporting of child abuse: a factorial survey.

OBJECTIVE: The major aim of this study was to determine the effect of characteristics of the case, the teacher, and the organizational setting on recognition and reporting of child abuse. METHOD: A factorial survey design was employed in which a probability sample of teachers (N = 480) responded to vignettes in which case characteristics were systematically manipulated. RESULTS: Analysis using OLS regression showed that case characteristics alone accounted for 50.30% of the variance in recognition and 51.08% of the variance in reporting: the strongest effects were from type and seriousness of abuse, positive behavior of the victim and positive psychology of the perpetrator. The inclusion of variables describing the teachers and the school explained only a very small additional proportion of the variance in teacher's responses. CONCLUSIONS: Teachers responses to child abuse are relatively unbiased by either the extraneous characteristics of the perpetrator or victim, the responding teacher, or the school setting. The findings do not appear to support the problem of "overreporting." There is evidence for "underreporting," particularly in less serious cases involving physical and emotional abuse. Teachers are undeterred by the many problems and fears that may accompany a report of child abuse to Child Protective Services. Teachers use discretion in reporting abuse they recognize.

The chemotactic response of Vibrio anguillarum to fish intestinal mucus is mediated by a combination of multiple mucus components.

Chemotactic motility has previously been shown to be essential for the virulence of Vibrio anguillarum in waterborne infections of fish. To investigate the mechanisms by which chemotaxis may function during infection, mucus was isolated from the intestinal and skin epithelial surfaces of rainbow trout. Chemotaxis assays revealed that V. anguillarum swims towards both types of mucus, with a higher chemotactic response being observed for intestinal mucus. Work was performed to examine the basis, in terms of mucus composition, of this chemotactic response. Intestinal mucus was analyzed by using chromatographic and mass spectrometric techniques, and the compounds identified were tested in a chemotaxis assay to determine the attractants present. A number of mucus-associated components, in particular, amino acids and carbohydrates, acted as chemoattractants for V. anguillarum. Importantly, only upon combination of these attractants into a single mixture were levels of chemotactic activity similar to those of intestinal mucus generated. A comparative analysis of skin mucus revealed its free amino acid and carbohydrate content to be considerably lower than that of the more chemotactically active intestinal mucus. To study whether host specificity exists in relation to vibrio chemotaxis towards mucus, comparisons with a human Vibrio pathogen were made. A cheR mutant of a Vibrio cholerae El Tor strain was constructed, and it was found that V. cholerae and V. anguillarum exhibit a chemotactic response to mucus from several animal sources in addition to that from the human jejunum and fish epithelium, respectively.

Measuring and developing suturing technique with a virtual reality surgical simulator.

BACKGROUND: We have developed an interactive virtual reality (VR) surgical simulator for the training and assessment of suturing technique. The surgical simulator is comprised of surgical tools with force feedback, a 3-dimensional graphics visual display of the simulated surgical field, physics-based computer simulations of the tissues and tools, and software to measure and evaluate the trainee's performance. STUDY DESIGN: This study uses the simulator to measure and compare the skills of 8 experienced vascular surgeons versus 12 medical students when performing a virtual reality suturing task. Eight parameters of the suturing task were measured: total tissue damage, accuracy of needle puncture, peak tissue tearing force, time to complete the task, damage to the surface of the tissue, angular error in needle technique, total distance traveled by the tool tip, and a measure of overall error. Three test conditions (dominant hand, nondominant hand, and 3-dimensional needle guide) were tested. Statistical significance was defined as a univariate two-sided p value < or = 0.05. RESULTS: The surgeons' average performance was significantly better than the students' average performance for three of the measured parameters (total tissue damage, time to complete the task, and total distance traveled by the tool tip) for each of the test conditions. For the test condition most similar to surgery (using the dominant hand to suture) one additional parameter was also significantly different (the measure of overall error). The medical students showed improvements for 6 of the 7 parameters for which the users received feedback during the training process. The surgeons also had significant improvement for 4 of the 7 parameters. The students had a larger improvement than the surgeons for 6 of the parameters, but these differences were not statistically significant. CONCLUSIONS: Data indicate differences between surgeon and nonsurgeon performance and in improvement in performance with training. One possible explanation for the superior performance of the surgeons is that their suturing skills applied well to the simulated suturing task. Additional research is required to confirm or deny the similarity between actual and simulated surgical tasks and the relevance of virtual reality surgical simulation to surgical skill assessment and training.

Melanosis of the uterine cervix: a report of two cases and discussion of pigmented cervical lesions.

Two cases of cervical melanosis, an uncommon process characterized by hyperpigmentation of the basal epithelium, with or without accompanying basal melanocytes, are reported. The etiology of cervical melanosis is uncertain but may represent a metaplastic change in response to trauma or chronic irritation. On gross examination, it is not possible to reliably separate the different causes of cervical pigmentation; consequently, any pigmented cervical lesion should be biopsied.

Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.

BACKGROUND: Intravenous platinum-based chemotherapy is the standard primary therapy for advanced ovarian cancer. We conducted a phase 3 trial to compare the effects of intraperitoneal and intravenous cisplatin on the survival of women with previously untreated, stage III, epithelial ovarian cancer. METHODS: The patients underwent an initial exploratory laparotomy and resection of all tumor masses larger than 2 cm. Within four weeks after surgery, six courses of intravenous cyclophosphamide (600 mg per square meter of body-surface area per course) plus either intraperitoneal cisplatin (100 mg per square meter) or intravenous cisplatin (100 mg per square meter) were administered at three-week intervals. RESULTS: Of 654 randomized patients, 546 were eligible for the study. The estimated median survival was significantly longer in the group receiving intraperitoneal cisplatin (49 months; 95 percent confidence interval, 42 to 56) than in the group receiving intravenous cisplatin (41 months; 95 percent confidence interval, 34 to 47). The risk of death was lower in the intraperitoneal group than in the intravenous group (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Moderate-to-severe tinnitus, clinical hearing loss, and neuromuscular toxic effects were significantly more frequent in the intravenous group. CONCLUSIONS: As compared with intravenous cisplatin, intraperitoneal cisplatin significantly improves survival and has significantly fewer toxic effects in patients with stage III ovarian cancer and residual tumor masses of 2 cm or less.

Nurses' diagnostic work on possible physical child abuse.

The concept of diagnostic work (A. Strauss, S. Fagerhaugh, B. Suczek, & C. Wiener, 1985) is used to explore nurses' responses to potential child abuse. A total of 1,036 nurses (response rate of 67%) completed a mailed questionnaire that included open-ended qualitative-type questions about a hypothetical situation involving possible child abuse. We report their judgments regarding information presented in the hypothetical situation and additional information they requested to make the diagnosis. Nurses focused primarily on the child's injuries and behavior and wanted more information about the abuse event. Diagnostic work was then analyzed by specialty group: community health, school health, emergency, and pediatric nursing. Nurses' specialization influenced the choice of information that was determined to be decisive and the additional information desired to make a diagnosis.

Endometriosis with myxoid change simulating mucinous adenocarcinoma and pseudomyxoma peritonei.

A case of endometriosis with myxoid change is presented here which raised concern for metastatic adenocarcinoma and pseudomyxoma peritonei. This is the second case similar to the one described previously in the literature. A 51-year-old woman underwent repair for an umbilical hernia. The tissue sections of the hernia specimen contained isolated pools of mucin surrounded focally by cuboidal-type epithelium. Subsequent CT scan of the abdomen and pelvis revealed a large right adenexal mass. These clinicopathologic findings raised strong suspicion for adenocarcinoma and pseudomyxoma peritonei. Intraoperative frozen section of the right ovary showed an endometriotic cyst. She underwent hysterectomy, bilateral salpingoophrectomy, partial omentectomy, and lysis of adhesions. Permanent sections revealed foci of endometriosis in both ovaries and cervix. Pools of acellular mucin were present in the omentum and bladder peritoneum. There was no evidence of malignancy in any of the specimen. The case illustrates that endometriosis with myxoid change can simulate with mucinous adenocarcinoma and pseudomyxoma peritonei.

A phase II trial of piroxantrone in endometrial cancer: Southwest Oncology Group study 8918.

A phase II trial of the new anthrapyrazole piroxantrone was carried out by the Southwest Oncology Group in patients with advanced metastatic or recurrent endometrial cancer. A two-stage statistical design targeted accrual of 20 eligible patients. The starting dose of piroxantrone was 150 mg/m2 in patients without prior radiation therapy (RT) and 120 mg/m2 in patients with prior RT. There were 15 eligible patients, six of whom had received prior hormonal therapy while nine patients had not received prior hormonal therapy. Eight patients had received prior RT while seven patients had not received any prior RT. One to seven cycles of piroxantrone were administered. Dose escalation was feasible in four patients. No grade 5 toxicity was experienced by any patients. Most of the grade 4 (granulocytopenia in one) and grade 3 (leukopenia in three, granulocytopenia in three, anemia in two and thrombocytopenia in one) toxicity was related to myelosuppression. Grade 3 non-hematologic toxicities were nausea, fatigue and SGOT elevation. There was one partial response for a response rate of 7% (95% CI 0.2-32%) and median survival was 11 months (95% CI 3-13 months). The study was prematurely terminated due to lack of patient accrual.

Automated screening for quality control using PAPNET: a study of 638 negative Pap smears.

To determine if the PAPNET screening system can be used for quality control to lower false-negative rates for Pap smears 638 manually screened, "negative" Pap smears were subjected retrospectively to the PAPNET screening system. Twenty-nine of the smears came from 18 patients who subsequently had biopsyproven high-grade squamous intraepithelial lesions (SIL). The remaining 609 negative smears were arbitrarily selected as controls. One hundred twenty-eight (128) of the retrospectively reviewed smears (20%) were selected by PAPNET for microscopic referral because of potential abnormalities. Abnormalities were confirmed on 14 of these smears upon microscopic evaluation. Five of these 14 smears were from smears obtained from four of the 18 women with high-grade SIL. The incidence of manually screened false-negatives detected by PAPNET rescreening was 14/638 or 2.2% for the entire patient population in this study and 5/29 or 17.24% for the targeted patients known to have subsequently developed highgrade lesions. The 2.2% decrease in the false-negative rate in this experiment may be partly artificial as this study group was seeded with false-negative cases at high risk for containing missed abnormalities. The implementation of the PAPNET system for quality control may lower false-negative rates for Pap smears.

Intraperitoneal mitoxantrone or floxuridine: effects on time-to-failure and survival in patients with minimal residual ovarian cancer after second-look laparotomy--a randomized phase II study by theSouthwest Oncology Group.

A randomized phase II study of intraperitoneal (ip) mitoxantrone or floxuridine (FUDR) was performed for the treatment of minimal residual epithelial ovarian cancer found at second-look laparotomy after initial platinum-based chemotherapy. Entry was to take place within 30 days of reassessment laparotomies, with documentation of peritoneal metastases either microscopic or gross with cytoreduction to less than or equal to 1 cm in largest diameter. Patients were stratified by the site of the largest disease present (microscopic to 0.5 cm maximum diameter versus greater than 0.5 to 1 cm maximum diameter), by time of registration (< 14 days versus up to 30), and by serum CA-125 (< or = 35 versus >35 units/ml) prior to randomization to either ip mitoxantrone 10 mg/m2 every 2 weeks X 9 or ip floxuridine (FUDR) 3 g (total dose)/ day X 3 days every 3 weeks X 6 cycles. Implantable ip systems and 1.5-2 liters of normal saline were used to deliver the drugs of 83 patients registered between December 1988 and January 1994; there were 6 pathology exclusions and 9 surgical exclusions, and 1 nonevaluable patient for a total of 39 evaluable on mitoxantrone and 28 on FUDR being evaluable. FUDR is the choice for further study because of a progression-free survival exceeding 15% at 1 year over mitoxantrone and a median overall survival of 38 months. It should be emphasized again that the goal of a randomized phase II selection design is to select a winner for phase III testing should there be a substantial difference between the treatments with respect to the primary endpoint. Comparative conclusions between the treatment arms should not be attempted due to the inherently much smaller sample sizes. This should reemphasize the limitations in a comparison of efficacy; however, the toxicologic differences still emerge quite clearly.