Associations between maternal inflammation during pregnancy and infant birth outcomes in the Seychelles Child Development Study.

PROBLEM: Markers of maternal inflammation may determine infant birth outcomes. METHOD OF STUDY: Maternal serum samples were collected at 28 weeks gestation (n = 1418) in the Seychelles Child Development Study Nutrition Cohort 2 and analyzed for immune markers by MSD multiplex assay, including cytokines from the Th1 (IFN-γ, IL-1ß, IL-2 and TNF-α) and Th2 (IL-4, IL-5, IL-10) subsets, with IL-6, MCP-1, TARC, sFlt-1 and VEGF-D. Associations of log-transformed immune markers with birthweight, length, head circumference and gestational age were assessed by multiple linear regression models, which were adjusted for maternal age, BMI, parity, child sex, gestational age and socioeconomic status. RESULTS: Neither total Th1, Th2 nor Th1:Th2 were significantly associated with any birth outcome. However, the angiogenesis marker VEGF-D was predictive of a lower birthweight, (ß = -0.058, P = 0.017) and birth length (ß = -0.088, P = 0.001) after adjusting for covariates. Higher concentrations of CRP were predictive of a lower birthweight (ß = -0.057, P = 0.023) and IL-2 (ß = 0.073, P = 0.009) and the chemokine MCP-1 (ß = 0.067, P = 0.016) were predictive of a longer gestational age. CONCLUSIONS: In our cohort of healthy pregnant women, we found no evidence for associations between the Th1 or Th2 inflammatory markers with birth outcomes. However, VEGF-D and CRP appear to predict lower birthweight and IL-2 and MCP-1 a longer gestation. Greater understanding is required of the variation in these immune markers at different gestational stages, as well as the factors which may regulate their balance in healthy pregnancy. n = 233.

Migration of etonogestrel contraceptive implants: Implications for difficult removals services need in southern Africa.

The first difficult contraceptive implant removals clinic in sub-Saharan Africa was started 2 years ago at New Somerset Hospital in Cape Town, South Africa, and has seen two cases of implant migration. We report these cases here. The first was a case of fascial migration and the second one of migration via the cephalic vein, both to a site just anterior to the glenohumeral joint. Both implants were removed without complications. Even with correct insertion technique, migrations can occur. Healthcare providers need to know how to manage difficult removals, and how to access and refer to difficult removals services when necessary. These services must therefore be available in all settings where implants are offered, to ensure access to rights-based family planning services for all women in southern Africa.

The Somatic Curation and Interpretation Across Laboratories (SOCIAL) project-current state of solid-tumour variant interpretation for molecular pathology in Canada.

Background: Practices in somatic variant interpretation and classification vary between Canadian clinical molecular diagnostic laboratories, and understanding of current practices and perspectives is limited. To define gaps and future directions, including consensus guideline development, the Somatic Curation and Interpretation Across Laboratories (social) project examined the present state of somatic variant interpretation in Canadian molecular laboratories, including testing volumes and methods, data sources and evidence criteria, and application of published classification guidelines. Methods: Individuals who perform somatic variant interpretation in Canadian centres were invited to participate in an online survey. Invitees included laboratory directors (certified as Fellows of the Canadian College of Medical Geneticists or the American College of Medical Geneticists), md or md and phd molecular pathologists, and other phd experts, including phd specialists in variant annotation or bioinformatics. Current testing methods, volumes, and platforms in next-generation sequencing, use of variant annotation resources and evidence criteria, and preference for variant classification schemes were evaluated. Results: Responses were received from 37 participants in 8 provinces. A somatic variant classification scheme jointly supported by the Association for Molecular Pathology (amp), the American Society of Clinical Oncology (asco), and the College of American Pathologists (cap) was used by 47% of respondents; an alternative guideline or a combination of published guidelines was used by 35% of respondents. The remaining 18% did not use a published scheme. Only 41% of respondents used a published scheme without alteration. Although all respondents indicated that there is a need for Canadian laboratories to adopt a somatic variant classification guideline, only 38% of respondents felt that it should be mandatory to adopt the amp/asco/cap-endorsed guideline. Conclusions: Data from the social project identified high variability in current practice, yet strong support for standardization of solid-tumour somatic variant interpretation across Canadian institutions. Aligning classification methods will reduce variation in cross-institutional classification and reporting practices, aiding in consistent practice nationwide.

Inter-laboratory proficiency testing scheme for tumour next-generation sequencing in Ontario: a pilot study.

Background: A pilot inter-laboratory proficiency scheme for 5 Ontario clinical laboratories testing tumour samples for the Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) study was undertaken to assess proficiency in the identification and reporting of next-generation sequencing (ngs) test results in solid tumour testing from archival formalin-fixed, paraffin-embedded (ffpe) tissue. Methods: One laboratory served as the reference centre and provided samples to 4 participating laboratories. An analyte-based approach was applied: each participating laboratory received 10 ffpe tissue specimens profiled at the reference centre, with tumour site and histology provided. Laboratories performed testing per their standard ngs tumour test protocols. Items returned for assessment included genes and variants that would be typically reported in routine clinical testing and variant call format (vcf) files to allow for assessment of ngs technical quality. Results: Two main aspects were assessed:■ Technical quality and accuracy of identification of exonic variants■ Site-specific reporting practicesTechnical assessment included evaluation of exonic variant identification, quality assessment of the vcf files to evaluate base calling, variant allele frequency, and depth of coverage for all exonic variants. Concordance at 100% was observed from all sites in the technical identification of 98 exonic variants across the 10 cases. Variability between laboratories in the choice of variants considered clinically reportable was significant. Of the 38 variants reported as clinically relevant by at least 1 site, only 3 variants were concordantly reported by all participating centres as clinically relevant. Conclusions: Although excellent technical concordance for ngs tumour profiling was observed across participating institutions, differences in the reporting of clinically relevant variants were observed, highlighting reporting as a gap where consensus on the part of Ontario laboratories is needed.

Strategic planning in an academic radiation medicine program.

BACKGROUND: In this paper, we report on the process of strategic planning in the Radiation Medicine Program (rmp) at the Princess Margaret Cancer Centre. The rmp conducted a strategic planning exercise to ensure that program priorities reflect the current health care environment, enable nimble responses to the increasing burden of cancer, and guide program operations until 2020. METHODS: Data collection was guided by a project charter that outlined the project goal and the roles and responsibilities of all participants. The process was managed by a multidisciplinary steering committee under the guidance of an external consultant and consisted of reviewing strategic planning documents from close collaborators and institutional partners, conducting interviews with key stakeholders, deploying a program-wide survey, facilitating an anonymous and confidential e-mail feedback box, and collecting information from group deliberations. RESULTS: The process of strategic planning took place from December 2014 to December 2015. Mission and vision statements were developed, and core values were defined. A final document, Strategic Roadmap to 2020, was established to guide programmatic pursuits during the ensuing 5 years, and an implementation plan was developed to guide the first year of operations. CONCLUSIONS: The strategic planning process provided an opportunity to mobilize staff talents and identify environmental opportunities, and helped to enable more effective use of resources in a rapidly changing health care environment. The process was valuable in allowing staff to consider and discuss the future, and in identifying strategic issues of the greatest importance to the program. Academic programs with similar mandates might find our report useful in guiding similar processes in their own organizations.

Pulsed quantum cascade laser-based CRDS substance detection: real-time detection of TNT.

This paper presents experimental results from a pulsed quantum cascade laser based cavity ringdown spectrometer used as a high-throughput detection system. The results were obtained from an optical cavity with 99.8% input and output coupling mirrors that was rapidly swept (0.2s to 7s sweep times) between 1582.25 cm(-1) (6.3201µm) and 1697.00 cm(-1) (5.8928µm). The spectrometer was able to monitor gas species over the pressure range 585 torr to 1µtorr, and the analysis involves a new digital data processing system that optimises the processing speed and minimises the data storage requirements. In this approach we show that is it not necessary to make direct measurements of the ringdown time of the cavity to obtain the system dynamics. Furthermore, we show that correct data processing is crucial for the ultimate implementation of a wideband IR spectrometer that covers a range similar to that of commercial Fourier transform infrared instruments.

Real-time FPGA data collection of pulsed-laser cavity ringdown signals.

This paper presents results from a pulsed-laser cavity ring-down spectrometer with novel field programable gate array real-time data collection. We show both theoretically and experimentally that the data extraction can be achieved from a single cavity ringdown event, and that the absorbance can be determined without the need to fit the ringdown time explicitly. This methodology could potentially provide data acquisition rate up to 1 MHz, with the accuracy and precision comparable to nonlinear least squares fitting algorithms.

Frequency domain analysis for laser-locked cavity ringdown spectroscopy.

In this paper we report on the development of a Fourier-transform based signal processing method for laser-locked Continuous Wave Cavity Ringdown Spectroscopy (CWCRDS). Rather than analysing single ringdowns, as is the norm in traditional methods, we amplitude modulate the incident light, and analyse the entire waveform output of the optical cavity; our method has more in common with Cavity Attenuated Phase Shift Spectroscopy than with traditional data analysis methods. We have compared our method to Levenburg-Marquardt non linear least squares fitting, and have found that, for signals with a noise level typical of that from a locked CWCRDS instrument, our method has a comparable accuracy and comparable or higher precision. Moreover, the analysis time is approximately 500 times faster (normalised to the same number of time domain points). Our method allows us to analyse any number of periods of the ringdown waveform at once: this allows the method to be optimised for speed and precision for a given spectrometer.

Infrapopliteal angioplasty for critical limb ischemia: relation of TransAtlantic InterSociety Consensus class to outcome in 176 limbs.

OBJECTIVE: Recent data suggest that percutaneous transluminal angioplasty (PTA) may be appropriate primary therapy for critical limb ischemia (CLI). However, little data are available regarding infrapopliteal angioplasty outcomes based on TransAtlantic InterSociety Consensus (TASC) classification. We report our experience with infrapopliteal angioplasty stratified by TASC lesion classification. METHODS: From February 2004 to March 2007, 176 consecutive limbs (163 patients) underwent infrapopliteal angioplasty for CLI. Stents were placed for lesions refractory to PTA or flow-limiting dissections. Patients were stratified by TASC classification and suitability for bypass grafting. Primary outcome was freedom from restenosis, reintervention, or amputation. Primary patency, freedom from secondary restenosis, limb salvage, reintervention by repeat angioplasty or bypass, and survival were determined. RESULTS: Median age was 73 years (range, 39-94 years). Technical success was 93%. Average follow-up was 10 months (range, 1-41 months). At 1 and 2 years, freedom from restenosis, reintervention, or amputation was 39% and 35%, conventional primary patency was 53% and 51%, and freedom from secondary restenosis and reintervention were 63% and 61%, respectively. Limb salvage was 84% at 1, 2, and 3 years. Within 2 years, 15% underwent bypass and 18% underwent repeat infrapopliteal PTA. Postoperative complications occurred in 9% and intraprocedural complications in 10%. The 30-day mortality was 5% (9 of 181). Overall survival was 81%, 65%, and 54% at 1, 2, and 3 years. TASC D classification predicted diminished technical success (75% D vs 100% A, B, and C; P < .001), primary restenosis, reintervention, or amputation (hazard ratio [HR], 3.4; 95% confidence interval [CI], 2.1-5.5, P < .001), primary patency (HR, 2.2; 95% CI, 1.3-3.9, P < .004), secondary restenosis (HR, 3.2; 95% CI, 1.6-6.4, P = .001), and limb salvage (HR, 2.6; 95% CI, 1.1-6.3, P < .05). Unsuitability for surgical bypass also predicted restenosis, reintervention, or amputation, secondary restenosis, need for repeated angioplasty, and inferior primary patency and limb salvage rates. CONCLUSION: Infrapopliteal angioplasty is a reasonable primary treatment for CLI patients with TASC A, B, or C lesions. Restenosis, reintervention, or amputation was higher in patients who were unsuitable candidates for bypass; however, an attempt at PTA may be indicated as an alternative to primary amputation. Although restenosis, reintervention, or amputation is high after tibial angioplasty for CLI, excellent limb salvage rates may be obtained with careful follow-up and reinterventions when necessary, including bypass in 15%.

Diffuse alveolar hemorrhage syndrome due to 'silent' mitral valve regurgitation.

A variety of clinical diseases are associated with diffuse alveolar hemorrhage. Although mitral valve disease can cause hemoptysis, it rarely is associated with diffuse alveolar hemorrhage at presentation. A 49-year-old woman was admitted to the hospital with the abrupt onset of fever, anemia, dyspnea, azotemia, and diffuse alveolar infiltrates. Two-dimensional echocardiography done several months earlier to evaluate atypical chest pain had been unremarkable. Fiberoptic bronchoscopy 2 days after admission to the hospital revealed fresh blood throughout the tracheobronchial tree. The infiltrates resolved rapidly and completely during systemic steroid therapy only to reappear as the steroids were tapered, suggesting a beneficial therapeutic response. Results of serologic evaluation were negative. Transbronchial biopsies showed inflammation and hemosiderin-laden macrophages; no specific diagnosis was established. The patient was scheduled for open lung biopsy. The surgeon was concerned about the history of chest pain and requested placement of a pulmonary artery catheter, which revealed severe pulmonary hypertension. Transesophageal echocardiography and subsequent cardiac catheterization showed severe mitral regurgitation. Mitral valve replacement resulted in complete elimination of symptoms.

Cavity ringdown spectroscopy using mid-infrared quantum-cascade lasers.

Cavity ringdown spectra of ammonia at 10 parts in 10(9) by volume (ppbv) and higher concentrations were recorded by use of a 16-mW continuous-wave quantum-casacde distributed-feedback laser at 8.5 mum whose wavelength was continuously temperature tuned over 15 nm. A sensitivity (noise-equivalent absorbance) of 3.4x10(-9) cm(-1) Hz(-1/2) was achieved for ammonia in nitrogen at standard temperature and pressure, which corresponds to a detection limit of 0.25 ppbv.

Frequency-switched heterodyne cavity ringdown spectroscopy.

When the frequency of light coupled into a cavity is suddenly shifted, the radiation emanating from the input port of the previously excited cavity can beat with the reflection of the frequency-shifted input on the surface of a photodetector. When the beat frequency is stable, the time decay of the resulting optical heterodyne signal can be used to measure intracavity absorption spectra with near quantum-limited sensitivity.

Photoacoustic spectroscopy using quantum-cascade lasers.

Photoacoustic spectra of ammonia and water vapor were recorded by use of a continuous-wave quantum-cascade distributed-feedback (QC-DFB) laser at 8.5 mum with a 16-mW power output. The gases were flowed through a cell that was resonant at 1.6 kHz, and the QC-DFB source was temperature tuned over 35 nm for generation of spectra or was temperature stabilized on an absorption feature peak to permit real-time concentration measurements. A detection limit of 100 parts in 10(9) by volume ammonia at standard temperature and pressure was obtained for a 1-Hz bandwidth in a measurement time of 10 min.

Spontaneous resolution of a lung mass due to infection with Mycobacterium terrae.

A 61-year-old smoker had a large right lung mass suggestive of bronchogenic carcinoma. Bronchoscopy showed what appeared to be tumor occlusion of a right middle lobe subsegment. Biopsies were nondiagnostic for malignancy. A scheduled percutaneous needle aspiration biopsy 1 week later was canceled because of a significant reduction in size of the lung mass. Acid-fast bacilli were subsequently found in bronchoscopic specimens, and treatment was started with isoniazid, rifampin, pyrazinamide, and ethambutol. The organism was identified as Mycobacterium terrae. In vitro resistance was noted to isoniazid. The early reduction in size of the mass before antimycobacterial therapy suggested that spontaneous regression may be part of the natural history of pulmonary infection with Mycobacterium terrae.

Hemodynamic effects of amrinone in a canine model of massive pulmonary embolism.

Amrinone, an inotrope with vasodilating properties, is of potential use in managing the right ventricular failure and pulmonary vasoconstriction induced by massive pulmonary embolism (PE). Therefore, to determine the hemodynamic effects of amrinone in a canine model of massive PE, autologous blood clot was infused into ten dogs (eight treated and two control animals) in an amount sufficient to decrease mean systemic arterial pressure (MAP) by at least 25 percent. This resulted in an increase in mean pulmonary artery pressure (MPAP) from 13.4 +/- 3.7 mm Hg to 44.4 +/- 4.8 mm Hg (p less than 0.01), a decrease in MAP from 122 +/- 9.5 mm Hg to 35.6 +/- 9.8 mm Hg (p less than 0.01), and a decrease in cardiac output from 2.73 +/- 0.834 L/min to 1.22 +/- 0.61 L/min (p less than 0.01). Amrinone was administered in an initial bolus of 0.75 mg/kg followed by an infusion of 7.5 micrograms/kg/min, which resulted in significant hemodynamic improvement in all subjects, with a fall in MPAP to 35.3 +/- 5.1 mm Hg (p less than 0.01), an increase in MAP to 98.1 +/- 31.1 mm Hg (p less than 0.01), and an increase in cardiac output to 2.01 +/- 0.7 L/min (not significant) at 5 min. Cardiac output continued to increase to 2.56 +/- 0.16 L/min (p less than 0.01) at 35 min. We conclude that amrinone alleviated pulmonary hypertension, systemic hypotension, and low cardiac output in a canine model of massive PE.

Pulmonary embolism: improvement in hemodynamic function with amrinone therapy.

We have described a 57-year-old man who had had lower extremity vascular surgery complicated by PE. Dyspnea, hypotension, hypoxemia, and CHF developed, but thrombolytic therapy was not started because of the recent surgical procedure; instead, he had plication of the inferior vena cava. Because of persistent pulmonary artery hypertension and decreasing cardiac indices, amrinone therapy was begun, and resulted in marked hemodynamic improvement.

Rat lung glutathione release: response to oxidative stress and selenium deficiency.

We performed experiments to characterize the glutathione-dependent metabolism occurring during tert-butyl hydroperoxide infusion in isolated perfused rat lungs and to examine the effect of selenium deficiency on this metabolism. Selenium deficiency resulted in decreased lung glutathione peroxidase activity but normal glutathione reductase activity and glutathione content. Infusion of the hydroperoxide into control lungs caused a proportional increase in tissue glutathione disulfide (GSSG) concentration and release of GSSG into the perfusate up to an infusion rate of 250 nmol of tert-butyl hydroperoxide X min-1 X 100 g body wt-1. Infusion rates greater than this resulted in continued rise of tissue GSSG concentrations but GSSG release into the perfusate plateaued. Infusion of tert-butyl hydroperoxide into selenium-deficient rat lungs resulted in much lower concentrations of tissue GSSG and GSSG release into the perfusate; however, release in the selenium-deficient rat lung was also found to be saturable at infusion rates of 450 nmol of tert-butyl hydroperoxide X min-1 X 100 g of body wt-1. Selenium deficiency in the rat decreases the rate of reduction of infused tert-butyl hydroperoxide by glutathione and may predispose the lung to free radical damage.

Effects of bacterial endotoxin on protecting copper-deficient rats from hyperoxia.

The administration of very low doses of bacterial endotoxin protects rats during exposure to hyperoxia and is associated with the induction of lung antioxidant enzyme activities. Copper-deficient rats have increased susceptibility to O2 toxicity, which may be related to their decreased lung superoxide dismutase activity (SOD) or decreased plasma ceruloplasmin concentrations. To determine whether endotoxin can protect against hyperoxia in this susceptible model, we exposed copper-deficient and control rats to a fractional inspiratory concentration of O2 greater than 0.95 for 96 h after pretreatment with 500 micrograms/kg of bacterial endotoxin or phosphate-buffered saline (PBS). Mortality in the copper-deficient and control rats given PBS and exposed to O2 for 96 h was 100%. Copper-deficient rats died significantly earlier during the exposure than controls. No mortality occurred in either group treated with endotoxin and hyperoxia despite the decreased activity of copper-dependent enzymes in the copper-deficient rats. Copper-deficient rats treated with endotoxin and exposed to hyperoxia did increase lung Cu-Zn-SOD activity, but activity remained below levels found in air-exposed controls. Mn-SOD activity was found to be induced above air-exposed controls in the copper-deficient rats treated with endotoxin and exposed to hyperoxia. Hyperoxic exposure resulted in a marked increase in plasma ceruloplasmin concentrations in the control rats, but no increases in ceruloplasmin occurred in the copper-deficient animals. Endotoxin protects copper-deficient rats from hyperoxia despite their decreased lung Cu-Zn-SOD activity, and decreased plasma ceruloplasmin.

Transbronchial needle aspiration staging of bronchogenic carcinoma.

Transbronchial needle aspiration (TBNA) has been advocated as a reliable technique in the nonsurgical staging of patients with bronchogenic carcinoma. Some have questioned the reliability of TBNA, however. We used TBNA directed by computed tomography (CT) in 88 consecutive patients with bronchogenic carcinoma who had undergone chest CT. Chest CT was 94% sensitive, 79% specific, and 85% accurate in evaluating the mediastinum for malignant lymphadenopathy. There were 19 malignant aspirates in 44 patients with malignancy and apparent adenopathy evaluated by chest CT. No malignant carinal aspirates were obtained in any patient with a normal mediastinum evaluated by chest CT. There were 2 false positive needle aspirates. One patient with apparent right paratracheal adenopathy and malignant needle aspirate had no mediastinal neoplasm detected at surgery. The other false positive aspirate had been contaminated by tracheal debris. The overall sensitivity, specificity, and accuracy of TBNA mediastinal staging were 50, 96, and 78%, respectively. We conclude that CT scanning is a useful adjunct in the staging of patients with bronchogenic carcinoma, and that TBNA is a sensitive and highly specific staging technique that may negate the need for surgical staging in a large number of patients with bronchogenic carcinoma.

Tracheocarotid fistula secondary to laryngeal carcinoma presenting as massive hemoptysis.

Tracheovascular fistulas are not traditionally included in the differential diagnosis of massive hemoptysis. We report the first such case due to a tracheocarotid fistula produced by occult subglottic laryngeal cancer. Also described is the unusual role the cuffed endotracheal tube played in obscuring the diagnosis and palliating the hemorrhage.