Reliability of CE-marked NATs for HIV-1 subtype C detection and quantitation.

We compared seven CE-marked HIV-1 RNA nucleic acid amplification technology (NAT) based assays for their detection efficiency and quantitation concordance in regard to HIV-1 subtype C. We used 398 plasma samples from South African repeat blood donors identified as HIV positive at occasion of routine screening NAT performed mainly during the years 2010-2013, with most plasma samples reflecting recent HIV-1 infections. All HIV-1 subtype C specimens were detected, independent of mono- or dual-target assay design. In the same time period new variants of HIV-1 subtype B had been identified which were missed by some mono-target assays, a finding which was not corroborated for subtype C in our study. A high level of concordance of HIV-1 subtype C quantitation was determined for the HIV-1 NATs, showing successful standardization in this diagnostic field.

Cervical cancer prevention in Australia: Planning for the future.

The high rate of coverage that has been achieved to date by the Australian government's Human Papillomavirus (HPV) Vaccination Program has already led to profound reductions in the prevalence of biopsy-confirmed, high-grade abnormalities and of vaccine-preventable HPV types in Australia. Declines in the prevalence of vaccine preventable HPV have occurred not only in vaccinated women but also in unvaccinated women, suggesting a herd-immunity affect. These declines were anticipated on the basis of modelling and were the major drivers for the changes proposed to the Australian National Cervical Screening Program. The federal and state-based Australian governments established a "Renewal Steering Committee," which conducted a literature search and a review of the available evidence to assess its applicability and quality. Together with this information the committee also used modeling to determine the optimal screening pathway for cervical cancer screening and constructed a plan for implementing the changes that will be required to transition from the currently successful screening program to the renewed program. The committee recommended that Australia move to a screening program based on testing every 5 years using an HPV test with partial genotyping with reflex liquid-based cytology (LBC) triage for HPV-vaccinated and unvaccinated women ages 25 to 69 years, and an additional exit test for women up to age 74 years. Primary HPV testing and reflex LBC will be funded by government. Symptomatic women outside the screening program will also be able to access government funded testing. The new screening program, to be rolled out in 2017, will also provide a cost-effective framework for an evaluation of the national HPV vaccination program, enabling ongoing monitoring of HPV genotypes and cervical lesions in screened women.

Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study.

BACKGROUND: Australia was one of the first countries to introduce a publicly funded national human papillomavirus (HPV) vaccination program that commenced in April 2007, using the quadrivalent HPV vaccine targeting 12- to 13-year-old girls on an ongoing basis. Two-year catch-up programs were offered to 14- to 17- year-old girls in schools and 18- to 26-year-old women in community-based settings. We present data from the school-based program on population-level vaccine effectiveness against cervical abnormalities in Victoria, Australia. METHODS: Data for women age-eligible for the HPV vaccination program were linked between the Victorian Cervical Cytology Registry and the National HPV Vaccination Program Register to create a cohort of screening women who were either vaccinated or unvaccinated. Entry into the cohort was 1 April 2007 or at first Pap test for women not already screening. Vaccine effectiveness (VE) and hazard ratios (HR) for cervical abnormalities by vaccination status between 1 April 2007 and 31 December 2011 were calculated using proportional hazards regression. RESULTS: The study included 14,085 unvaccinated and 24,871 vaccinated women attending screening who were eligible for vaccination at school, 85.0% of whom had received three doses. Detection rates of histologically confirmed high-grade (HG) cervical abnormalities and high-grade cytology (HGC) were significantly lower for vaccinated women (any dose) (HG 4.8 per 1,000 person-years, HGC 11.9 per 1,000 person-years) compared with unvaccinated women (HG 6.4 per 1,000 person-years, HGC 15.3 per 1,000 person-years) HR 0.72 (95% CI 0.58 to 0.91) and HR 0.75 (95% CI 0.65 to 0.87), respectively. The HR for low-grade (LG) cytological abnormalities was 0.76 (95% CI 0.72 to 0.80). VE adjusted a priori for age at first screening, socioeconomic status and remoteness index, for women who were completely vaccinated, was greatest for CIN3+/AIS at 47.5% (95% CI 22.7 to 64.4) and 36.4% (95% CI 9.8 to 55.1) for women who received any dose of vaccine, and was negatively associated with age. For women who received only one or two doses of vaccine, HRs for HG histology were not significantly different from 1.0, although the number of outcomes was small. CONCLUSION: A population-based HPV vaccination program in schools significantly reduced cervical abnormalities for vaccinated women within five years of implementation, with the greatest vaccine effectiveness observed for the youngest women.

C-branched iminosugars: α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP, and isoDAB-L-isoDMDP compared to miglitol and miglustat.

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 µM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.

Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study.

BACKGROUND: Australia introduced a human papillomavirus (HPV) vaccination programme with the quadrivalent HPV vaccine for all women aged 12-26 years between 2007 and 2009. We analysed trends in cervical abnormalities in women in Victoria, Australia, before and after introduction of the vaccination programme. METHODS: With data from the Victorian Cervical Cytology Registry between 2003 and 2009, we compared the incidence of histopathologically defined high-grade cervical abnormalities (HGAs, lesions coded as cervical intraepithelial neoplasia of grade 2 or worse or adenocarcinoma in situ; primary outcome) and low-grade cytological abnormalities (LGAs) in five age groups before (Jan 1, 2003, to March 31, 2007) and after (April 1, 2007, to Dec 31, 2009) the vaccination programme began. Binary comparisons between the two periods were done with Fisher's exact test. Poisson piecewise regression analysis was used to compare incident rate trends. FINDINGS: After the introduction of the vaccination programme, we recorded a decrease in the incidence of HGAs by 0·38% (95% CI 0·61-0·16) in girls younger than 18 years. This decrease was progressive and significantly different to the linear trend in incidence before introduction of the vaccination (incident rate ratio 1·14, 1·00-1·30, p=0·05). No similar temporal decline was recorded for LGAs or in older age groups. INTERPRETATION: This is the first report of a decrease in incidence of HGAs within 3 years after the implementation of a population-wide HPV vaccination programme. Linkage between vaccination and screening registers is needed to confirm that this ecological observation is attributable to vaccination and to monitor participation in screening among vaccinated women. FUNDING: None.

Effect of study design and quality on unsatisfactory rates, cytology classifications, and accuracy in liquid-based versus conventional cervical cytology: a systematic review.

BACKGROUND: Liquid-based cytology is reported to increase the sensitivity of cervical cytology and the proportion of slides that are satisfactory for assessment, in comparison with conventional cytology. Although some countries have changed to liquid-based cytology for cervical screening, controversy remains. We reviewed the published work to assess the performance of liquid-based cytology relative to conventional cytology in primary studies assessed to be of low, medium, or high methodological quality. METHODS: 56 primary studies were reviewed and assessed with strict methodological criteria. Liquid-based cytology and conventional cytology were compared in terms of the percentage of slides classified as unsatisfactory, the percentage of slides classified in each cytology category, and the accuracy of detection of high-grade disease. Data were examined for studies overall and in strata to examine the effect of study quality on results. FINDINGS: The median difference in the percentage of unsatisfactory slides between liquid-based cytology and conventional cytology was 0.17%. Only one small study was a randomised controlled trial. The classification of high-grade squamous epithelial lesion varied according to study quality (p=0.04), with conventional cytology classifying more slides in this category than did liquid-based cytology in high-quality studies (n=3) only. In medium-quality (n=30) and high-quality studies, liquid-based cytology classified more slides as atypical squamous cells of unknown significance than did conventional cytology when compared with low-quality studies (n=17; p=0.05). Only four studies provided sufficient verified data to allow estimation of sensitivity and specificity and comparison of test accuracy. INTERPRETATION: We saw no evidence that liquid-based cytology reduced the proportion of unsatisfactory slides, or detected more high-grade lesions in high-quality studies, than conventional cytology. This review does not lend support to claims of better performance by liquid-based cytology. Large randomised controlled trials are needed.

NPB-75: A portable quantitative microstream capnometer.

A portable quantitative microstream capnometer (NPB-75) was tested in intubated children. The end-tidal CO(2) values measured by this device showed good agreement with concomitantly measured values of a stationary mainstream capnometer (N-6000). This lightweight device, with a 4-hour battery life, graphic capnogram display, and audiovisual alarms is well suited for the prehospital setting.

Occult nitric oxide inhalation improves oxygenation in mechanically ventilated children.

OBJECTIVES: Auto-inhalation of nitric oxide (NO) produced in the upper airways may have physiologic effects on lung function. For intubated patients, the upper airway source of NO is eliminated, but the hospital compressed air source from the environment is contaminated with varying levels of NO, creating an "occult" form of NO therapy. We examined the physiologic significance of occult inhaled NO in ventilator-dependent pediatric patients. We hypothesized that very low levels of NO contamination in inspired gas improve PaO2 in ventilator-dependent children. STUDY DESIGN: Inspired NO levels at the mouth were measured by chemiluminescence in 4 pediatric subjects with normal lungs and 3 with parenchymal lung disease. Subjects were sequentially ventilated with first standard hospital gas (H1), switched to pure nitrogen-oxygen at a similar FIO2 but with no NO contamination (A2), hospital gas again (H2), the nitrogen-oxygen (A2) to control for time and sequence, and finally the nitrogen-oxygen mixture with supplemental NO in an amount equal to the NO previously measured in hospital gas (A2 + NO). Inhaled NO levels and PaO2 were recorded 15 minutes into each of the 5 steps. Two patients were studied a second time, remote from their first examination. RESULTS: NO levels in inhaled hospital gas mixtures ranged from 13 to 79 ppb (mean H1 = 53.3 +/- 23.7 ppb, mean H2 = 53.2 +/- 20.7 ppb, mean A2 + NO = 45 +/- 15.3 ppb; P < .0001). Removing NO from ventilator gas decreased PaO2 in all subjects, whereas replacing NO in artificial gas restored PaO2 to baseline values (P < .0001). CONCLUSION: Concentrations of NO in hospital compressed air are variable and have physiologic effects. The long-term implications of these findings remain to be defined.

Accuracy of physiologic deadspace measurement in intubated pediatric patients using a metabolic monitor: comparison with the Douglas bag method.

OBJECTIVE: To evaluate the accuracy of physiologic deadspace (VD/VT) measurement, using a metabolic monitor. DESIGN: Prospective collection of data. SETTING: University-affiliated children's hospital with a 51-bed critical care area. PATIENTS: Infants and children who were sedated and paralyzed and were receiving mechanical ventilation through a cuffed endotracheal tube. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mixed expired carbon dioxide tension (PECO2) was measured. With the Douglas bag method, mixed expired gas was collected over 15 mins and was analyzed. With the metabolic monitor, FECO2 was measured for 15 mins and the results were averaged. The PECO2 was calculated by multiplying FECO2 by the barometric pressure. The PaCO2 was measured simultaneously. The PECO2 was corrected for the compressible volume in the ventilator circuit. All gas volumes were corrected for body temperature, pressure, and water vapor pressure. The physiologic deadspace/tidal volume ratio (VD/VT) was calculated for both techniques using the Enghoff modification of the Bohr equation. The accuracy of the VD/VT measured, by using the metabolic monitor, was assessed by comparing this measurement against the VD/VT measured by the Douglas bag method. This comparison was done by simple linear regression and correlation and by bias analysis (Bland and Altman method). The magnitude of compressible volume expressed as a fraction of the tidal volume delivered by the ventilator was compared with the error in VD/VT expressed as the difference between the uncorrected and corrected VD/VT. Sixteen paired measurements were made in 12 children. The VD/VT measured by the metabolic monitor correlated well with the VD/VT measured by the Douglas bag method (r2 = .99; p < .0001). There was no correlation between the bias of VD/VT and the average VD/VT. As the magnitude of compressible volume increased, the error in VD/VT increased (r2 =.61; p < .001). CONCLUSIONS: The VD/VT can be measured reliably and accurately in intubated pediatric patients using a metabolic monitor. The metabolic monitor method is a convenient and simple alternative to the standard Douglas bag method.

Continuous vs intermittent nebulized albuterol for emergency management of asthma.

OBJECTIVE: To compare the efficacy and safety of continuous nebulized (CN) albuterol therapy with those of intermittent nebulized (IN) albuterol therapy in the ED treatment of children with moderate to severe asthma exacerbations. METHODS: A prospective, randomized, single-blind study was conducted at a children's hospital ED. Patients aged 2 to 18 years with a moderate to severe asthma exacerbation (asthma score > or = 8) were enrolled. Patients were randomized to receive either IN albuterol (0.15 mg/kg/dose every 30 min) or CN albuterol (0.3 mg/kg/hr) for a maximum of 2 hours. All patients received prednisone at entry. All released patients were evaluated by telephone, 48 hours after the ED visit. Estimates of respiratory therapist (RT) time commitments for the 2 delivery systems were calculated. RESULTS: There were 35 patients assigned to IN therapy and 35 to CN therapy. Nine of the 35 patients (26%) in the IN group and 8 of the 35 patients (22%) in the CN group were hospitalized (p = NS). Although the durations of ED therapy were comparable in the 2 groups, the time spent by the RTs in delivering asthma therapy was significantly less for the CN group than it was for the IN group (30.3 min vs 51.9 min per patient; p < 0.001). There was no major adverse effect in either study group. CONCLUSION: There was no difference in efficacy or safety between CN therapy and IN therapy in the ED management of moderate to severe asthma exacerbations in children. Moreover, CN therapy provided a significant time savings in the delivery of asthma therapy to patients in a busy ED.

Validity of a disposable end-tidal CO2 detector in verifying endotracheal tube placement in infants and children.

STUDY OBJECTIVE: To examine the validity of a disposable, colorimetric end-tidal CO2 detector in verifying endotracheal tube (ETT) placement in infants and children. DESIGN: The detector was studied prospectively in 151 intubations. SETTING: Operating room, ICU, and emergency department of a children's hospital. PARTICIPANTS: One hundred thirty-seven children undergoing endotracheal intubation for anesthesia (52), respiratory support (76), or CPR (23). INTERVENTIONS: After endotracheal intubation, tube position was verified, the detector was attached, and readings were obtained. MEASUREMENTS AND RESULTS: The detector correctly identified tube position (trachea, 124; esophagus, four) in all 120 patients who were not in cardiac arrest (P less than .01). In the cardiac arrest setting, all six esophageal intubations were correctly identified, but two of the 17 tracheal intubations were incorrectly interpreted as esophageal intubations (P less than .01). CONCLUSION: The detector accurately identifies ETT position in children with spontaneous circulation who weigh more than 2 kg. During CPR, a positive test correctly indicates that the ETT is in the airway, but a negative result (suggesting esophageal placement) requires an alternate means of confirming ETT position.

Accuracy of expiratory carbon dioxide measurements using the coaxial and circle breathing circuits in small subjects.

Mass spectrometry is widely used to measure the end-tidal concentrations of inhalation anesthetics and other gases during surgery in order to estimate their arterial concentrations. When certain breathing circuits are used in newborns, however, fresh gas or ambient air may contaminate the expired sample, introducing a systematic error in the measurement of any end-tidal gas concentration. We estimated this error in newborn piglets using carbon dioxide as an indicator substance of expired gas. The capnograms and the difference between arterial carbon dioxide tension (PaCO2) and peak-expired carbon dioxide tension (PeCO2) were compared when either a coaxial (Bain) or circle breathing circuit was used. Gas was sampled from the proximal airway and distal trachea. No combination of circuit and sampling site produced a flat alveolar phase until the circle circuit was modified with diversion valves to reduce gas mixing. The mean PaCO2-PeCO2 gradients using the coaxial/proximal sampling, coaxial/distal sampling, and modified circle/proximal sampling circuits were 12.4, 9.2, and 8.8 mm Hg, respectively. The mean PeCO2 in each of these combinations was significantly different from the corresponding mean PaCO2 (p less than 0.05). Using the modified circle circuit with distal sampling, mean PeCO2 was not significantly different from mean PaCO2: the mean PaCO2-PeCO2 gradient was 2.2 +/- 0.2 mm Hg (SEM), range, 0 to 6 mm Hg, with 95% confidence limits less than or equal to 8 mm Hg. When a coaxial breathing circuit is used in small subjects, PaCO2 may be significantly underestimated regardless of sampling site, although the circle breathing circuit with distal tracheal sampling yields accurate results.