Liquid phase detection in the miniature scale. Microfluidic and capillary scale measurement and separation systems. A tutorial review.

Microfluidic and capillary devices are increasingly being used in analytical applications while their overall size keeps decreasing. Detection sensitivity for these microdevices gains more importance as device sizes and consequently, sample volumes, decrease. This paper reviews optical, electrochemical, electrical, and mass spectrometric detection methods that are applicable to capillary scale and microfluidic devices, with brief introduction to the principles in each case. Much of this is considered in the context of separations. We do consider theoretical aspects of separations by open tubular liquid chromatography, arguably the most potentially fertile area of separations that has been left fallow largely because of lack of scale-appropriate detection methods. We also examine the theoretical basis of zone electrophoretic separations. Optical detection methods discussed include UV/Vis absorbance, fluorescence, chemiluminescence and refractometry. Amperometry is essentially the only electrochemical detection method used in microsystems. Suppressed conductance and especially contactless conductivity (admittance) detection are in wide use for the detection of ionic analytes. Microfluidic devices, integrated to various mass spectrometers, including ESI-MS, APCI-MS, and MALDI-MS are discussed. We consider the advantages and disadvantages of each detection method and compare the best reported limits of detection in as uniform a format as the available information allows. While this review pays more attention to recent developments, our primary focus has been on the novelty and ingenuity of the approach, regardless of when it was first proposed, as long as it can be potentially relevant to miniature platforms.

Optimizing column-to-column retention time alignment in high-speed gas chromatography by combining retention time locking and correlation optimized warping.

We examine and then optimize alignment of chromatograms collected on nominally identical columns using retention time locking (RTL), an instrumental alignment tool, and software-based alignment using correlation optimized warping (COW). For this purpose, three samples are constructed by spiking two sets of analytes into a base test mixture. The three samples are analyzed by high-speed gas chromatography with four nominally identical columns and identical separation conditions. The data is first analyzed without alignment, then using COW alone, then RTL alone, and finally with RTL followed by COW to correct the severe column-to-column misalignment. Principal component analysis (PCA) is used to investigate how well each alignment method clustered the chromatograms into the three sample classes via a scores plot without being compromised by the specific column(s) used. The degree-of-class separation (DCS) is used as a classification metric, measured as the Euclidian distance between the centroids of two clusters in PC space in the scores plot, normalized by their pooled variance. With no alignment, the average DCS between sample classes (DCSsam) was 3.0, while the average DCS between the four nominally identical columns, i.e., column classes (DCScol) was 76.1 (ideally the DCScol should be 0), indicating the chromatograms were initially classified by the columns used. Using either COW or RTL alone also produced unsatisfactory results, with COW alone incorrectly aligning many peaks, leading to a DCSsam of only 1.9 and DCScol of 1.7, while RTL alone provided a DCSsam of 4.7 and DCScol of 4.2. Finally, using RTL followed by COW alignment, DCSsam increased to 32.5, indicating successful classification by chemical differences between sample classes, while the DCScol decreased to 0.4, indicating virtually no classification due to column-to-column differences, as desired. Thus, RTL provided a "first-order" correction of the initial retention mismatch observed for the nominally identical columns, while additional alignment via COW was required to optimize sample classification by PCA.

Gender differences in barriers to mental healthcare for UK military veterans: a preliminary investigation.

INTRODUCTION: Limited UK research focuses on female military veterans' gender-related experiences and issues when accessing civilian mental healthcare support. This study sought to illuminate a preliminary understanding of any gender differences in barriers that may discourage them accessing mental healthcare support. METHODS: A total of 100 participants completed an open online survey of UK triservice veterans who identified as having experienced postmilitary mental health problems. They completed a 30-item Barriers to Access to Care Evaluation scale and were asked to elaborate using free-text questions. Resulting quantitative data were analysed for gender-related differences, while the qualitative text was thematically explored. RESULTS: While stigma, previous poor experience of mental healthcare and a lack of trust in civilian providers were found to act as barriers to postmilitary support for both men and women, significantly more women reported that their gender had also impacted on their intention to seek help. Women also commented on the impact of gender-related discrimination during service on their help-seeking experiences. CONCLUSIONS: While efforts are being made by the UK Ministry of Defence to reduce barriers to mental healthcare for those still serving in the Armed Forces, it has been more difficult to provide a similar level of support to the veteran population. With little veteran research focusing on the specific experiences of women, this study suggests that female veterans encounter specific access barriers and issues related to their gender. Further research is therefore needed to ensure these findings are addressed.

Determination of the Signal-To-Noise Ratio Enhancement in Comprehensive Three-Dimensional Gas Chromatography.

We investigate the extent to which comprehensive three-dimensional gas chromatography (GC3) provides a signal enhancement (SE) and a signal-to-noise ratio enhancement (S/NRel) relative to one-dimensional (1D)-GC. Specifically, the SE is defined as the ratio of the tallest 3D peak height from the GC3 separation to the 1D peak height from the unmodulated 1D-GC separation. A model is proposed which allows the analyst to predict the theoretically attainable SE (SET) based upon the peak width and sampling density inputs. The model is validated via comparison of the SET to the experimentally measured SE (SEM) obtained using total-transfer GC3 (100% duty cycle for both modulators) with time-of-flight mass spectrometry detection. Two experimental conditions were studied using the same GC3 column set, differing principally in the modulation period from the 1D to 2D columns: 4 s versus 8 s. Under the first set of conditions, the average SEM was 97 (±22), in excellent agreement with the SET of 97 (±18). The second set of conditions improved the average SEM to 181 (±27), also in agreement with the average SET of 176 (±26). The average S/NRel following correction for the mass spectrum acquisition frequency was 38.8 (±11.2) and 59.0 (±27.2) for the two sets of conditions. The enhancement in S/N is largely attributed to moving the signal to a higher frequency domain where the impact of "low frequency" noise is less detrimental. The findings here provide strong evidence that GC3 separations can provide enhanced detectability relative to 1D-GC and comprehensive two-dimensional gas chromatography (GC×GC) separations.

Total-transfer comprehensive three-dimensional gas chromatography with time-of-flight mass spectrometry.

Although comprehensive two-dimensional (2D) gas chromatography (GC × GC) is a powerful technique for complex samples, component overlap remains likely. An intriguing route to address this challenge is to utilize the additional peak capacity and chemical selectivity provided by comprehensive three-dimensional (3D) gas chromatography (GC3), especially with time-of-flight mass spectrometry detection (GC3-TOFMS). However, the GC3-TOFMS instrumentation reported to date has employed one or both modulators with a duty cycle < 100%, making the potential gain in detection sensitivity over GC × GC modest, or perhaps even worse. Herein, we describe instrumentation for GC3-TOFMS in which both modulators provide total-transfer (100% duty cycle). Specifically, the instrument is based on the facile modification of a commercial thermally modulated comprehensive GC × GC-TOFMS platform for modulation from the 1D column to the 2D column, with recently described dynamic pressure gradient modulation (DPGM) as the second modulator from the 2D column to the 3D column, which is a total-transfer flow modulation technique. Area measurements of 1D peaks are compared to the sum of 3D peak areas to validate the assumption that total-transfer from 1D to 3D is accomplished. Additionally, peak heights were amplified by as high as a factor of 177 (x̅ = 130, s = 47) via comparison of 1D peak heights to the maximum 3D peak heights. Column selection is explored, with emphasis on the resulting peak width-at-base on each dimension and usage of 3D space as evaluation metrics. Using a nonpolar × polar × ionic liquid column combination, an effective peak capacity which considers modulation-induced broadening as high as 32,300 for select analytes was achieved (x̅ = 19,900, s = 10,700). The analytical benefits of employing three selective phases, mass spectrometry detection, and total-transfer modulation are explored with separations of a metabolomics-type sample, i.e., derivatized porcine serum, and a jet fuel spiked with various sulfur-containing compounds.

A systematic investigation of comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry with dynamic pressure gradient modulation for high peak capacity separations.

Dynamic pressure gradient modulation (DPGM) in full modulation mode is optimized for comprehensive two-dimensional (2D) gas chromatography (GC × GC) with time-of-fight mass spectrometry (TOFMS) detection to obtain high peak capacity separations and demonstrate broad applicability for complex samples. A pulse valve introduces an auxiliary carrier gas flow at a T-union connecting the first dimension (1D) column to the second dimension (2D) column. At a sufficiently high auxiliary pressure (Paux) the 1D flow is temporarily stopped. Then, during each modulation period (PM) the valve is turned off briefly, a period termed the pulse width (pw), allowing the 1D effluent to essentially be reinjected onto the 2D column for the modulated separations. Modifications to the modulator assembly are provided to improve performance. Method optimization is demonstrated for a 116-component test mixture by tuning the Paux and the pw. For a PM = 2 s and 1F of 0.10 ml/min, the optimal pw and initial Paux selected were 200 ms and 330.9 kPa (33 psig), respectively. The 30 min separation of the test mixture provided a 1D peak capacity of 1nc = 330 and a 2D peak capacity of 2nc = 15, hence an ideal 2D peak capacity nc,2D = 1nc × 2nc = 4950. Likewise, the 2D peak capacity corrected for undersampling of the 1D separation was 4500 and corrected for both undersampling and sampling variation via statistical overlap theory was 4090. These results provide a 2-fold improvement in peak capacity relative to the previous DPGM study in full modulation mode for GC × GC-TOFMS. The optimized conditions were applied for a variety of applications: diesel fuel, derivatized cow serum, solid phase microextraction (SPME) of coffee headspace, and SPME of river water headspace. Additionally, the fraction of 2D separation space utilized (fcoverage), as defined by the minimum convex hull method, ranged from 0.60 to 0.85. We observed that any fcoverage correction to 2D peak capacity is highly sample dependent, since all samples, except for the diesel sample, were run with the same separation conditions, and yet the fcoverage ranged from 0.60 to 0.80.

Discovery-based analysis and quantification for comprehensive three-dimensional gas chromatography flame ionization detection data.

Basic principles are introduced for implementing discovery-based analysis with automated quantification of data obtained using comprehensive three-dimensional gas chromatography with flame ionization detection (GC3-FID). The GC3-FID instrument employs dynamic pressure gradient modulation, providing full modulation (100% duty cycle) with a fast modulation period (PM) of 100 ms. Specifically, tile-based Fisher-ratio analysis, previously developed for comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry (GC×GC-TOFMS), is adapted and applied for GC3-FID where the third chromatographic dimension (3D) is treated as the "spectral" dimension. To evaluate the instrumental platform and software implementation, ten "non-native" compounds were spiked into a ninety-component base mixture to create two classes with a concentration ratio of two for the spiked analyte compounds. The Fisher ratio software identified 95 locations of potential interest (i.e., hits), with all ten spiked analytes discovered within the top fourteen hits. All 95 hits were quantified by a novel signal ratio (S-ratio) algorithm portion of the F-ratio software, which determines the time-dependent S-ratio of the 3D chromatograms from one class to another, thus providing relative quantification. The average S-ratio for spiked analytes was 1.94 ± 0.14 mean absolute error (close to the nominal concentration ratio of two), and 1.06 ± 0.16 mean absolute error for unspiked (i.e., matrix) components. The appearance of the S-ratio as a function of 3D retention time in the GC3 dataset, referred to as an S-ratiogram, provides indication of peak purity for each hit. The unique shape of the S-ratiogram for hit 1, α-pinene, suggested likely 3D overlap. Parallel factor analysis (PARAFAC) decomposition of the hit location confirmed that overlap was occurring and successfully decomposed α-pinene from a highly overlapped (3Rs = 0.1) matrix interferent.

Dynamic pressure gradient modulation for comprehensive two-dimensional gas chromatography.

We report the discovery, preliminary investigation, and demonstration of a novel form of differential flow modulation for comprehensive two-dimensional (2D) gas chromatography (GC×GC). Commercially available components are used to apply a flow of carrier gas with a suitable applied auxiliary gas pressure (Paux) to a T-junction joining the first (1D) and second (2D) dimension columns. The 1D eluate is confined at the T-junction, and introduced for 2D separation with a cyclic rhythm, dependent upon the relationship of the modulation period (PM) to the pulse width (pw), where pw is defined as the time interval when the auxiliary gas flow at the T-junction is off. We refer to this flow modulation technique as "dynamic pressure gradient modulation" (DPGM) since a pressure gradient oscillates with the PM along the 1D and 2D column ensemble providing temporary stop-flow conditions and fast 2D flow rates, resulting in 100% duty cycle and full modulation. A 90-component test mixture was used to evaluate the technique with a pw of 60 ms and a PM of 750 ms. The resulting peaks were narrow, with 2Wb ranging from about 20-180 ms. With an average 1Wb of 3 s and a 2nc of 10, a 2D peak capacity, nc,2D, for the 25 min separation was 5000. The detector response enhancement factor (DREF) is reported, defined as the peak height of the highest modulated 2D peak divided by the unmodulated 1D peak height (DREF = 2h/1h). The DREF ranged from about 7-87, depending on the 1Wb and 2Wb for a given analyte. A diesel sample was analyzed to demonstrate performance with a complex sample. Based upon the average 1Wb of 5 s and an average 2Wb of 168 ms, a nc,2D of 8640 was obtained for the 60 min diesel separation. Finally, the modulation principle was investigated as a function of PM, pw, and the volumetric flow rates, 1F and 2F. The measured 2Wb correlate well with the theoretical 2D injected width, given by 2Winj = (1F/2F) ·PM. However, the relevant 1F appears to be dictated by the 1D flow rate when no pressure is applied (during the pw interval), instead of 1F being the average flow rate on 1D (defined by the 1D dead time). The findings provide strong evidence for a differential flow modulation mechanism.

The effect of acute simulated moderate altitude on power, performance and pacing strategies in well-trained cyclists.

Athletes regularly compete at 2,000-3,000 m altitude where peak oxygen consumption (VO2peak) declines approximately 10-20%. Factors other than VO2peak including gross efficiency (GE), power output, and pacing are all important for cycling performance. It is therefore imperative to understand how all these factors and not just VO2peak are affected by acute hypobaric hypoxia to select athletes who can compete successfully at these altitudes. Ten well-trained, non-altitude-acclimatised male cyclists and triathletes completed cycling tests at four simulated altitudes (200, 1,200, 2,200, 3,200 m) in a randomised, counter-balanced order. The exercise protocol comprised 5 x 5-min submaximal efforts (50, 100, 150, 200 and 250 W) to determine submaximal VO2 and GE and, after 10-min rest, a 5-min maximal time-trial (5-minTT) to determine VO2peak and mean power output (5-minTT(power)). VO2peak declined 8.2 +/- 2.0, 13.9 +/- 2.9 and 22.5 +/- 3.8% at 1,200, 2,200 and 3,200 m compared with 200 m, respectively, P < 0.05. The corresponding decreases in 5-minTT(power) were 5.8 +/- 2.9, 10.3 +/- 4.3 and 19.8 +/- 3.5% (P < 0.05). GE during the 5-minTT was not different across the four altitudes. There was no change in submaximal VO2 at any of the simulated altitudes, however, submaximal efficiency decreased at 3,200 m compared with both 200 and 1,200 m. Despite substantially reduced power at simulated altitude, there was no difference in pacing at the four altitudes for athletes whose first trial was at 200 or 1,200 m; whereas athletes whose first trial was at 2,200 or 3,200 m tended to mis-pace that effort. In conclusion, during the 5-minTT there was a dose-response effect of hypoxia on both VO2peak and 5-minTT(power) but no effect on GE.

The ability of the community pharmacist to learn the proper actuation techniques of inhaler devices.

Today, greater responsibility is placed on community pharmacists for the education of patients than ever before. Thus community pharmacists were recruited for this study and asked to demonstrate the proper steps in the actuation sequences of 3 inhaler devices. Baseline measurements were followed by an instructional session on the proper actuation technique, and then a posttest was conducted 4 to 6 weeks later. The mean changes between baseline and postinstruction percentage scores for the metered-dose inhaler device, the Turbuhaler, and the Diskus were (mean +/- SD) 17.1% +/- 15.4%, 22.6% +/- 18.7%, and 38.4% +/- 19.6%, respectively. This study demonstrates that a single instructional session can dramatically improve a community pharmacist's ability to demonstrate the correct method of actuation.

Enhancing causal interpretations of quality improvement interventions.

In an era of chronic resource scarcity it is critical that quality improvement professionals have confidence that their project activities cause measured change. A commonly used research design, the single group pre-test/post-test design, provides little insight into whether quality improvement interventions cause measured outcomes. A re-evaluation of a quality improvement programme designed to reduce the percentage of bilateral cardiac catheterisations for the period from January 1991 to October 1996 in three catheterisation laboratories in a north eastern state in the USA was performed using an interrupted time series design with switching replications. The accuracy and causal interpretability of the findings were considerably improved compared with the original evaluation design. Moreover, the re-evaluation provided tangible evidence in support of the suggestion that more rigorous designs can and should be more widely employed to improve the causal interpretability of quality improvement efforts. Evaluation designs for quality improvement projects should be constructed to provide a reasonable opportunity, given available time and resources, for causal interpretation of the results. Evaluators of quality improvement initiatives may infrequently have access to randomised designs. Nonetheless, as shown here, other very rigorous research designs are available for improving causal interpretability. Unilateral methodological surrender need not be the only alternative to randomised experiments.

Granulomatous hepatitis due to sarcoidosis: a case report.

A Royal Australian Air Force transport pilot is discovered to have abnormal liver function tests during a routine aircrew medical examination. In the preceding 12 mo he had experienced minimal symptoms. Liver biopsy confirmed granulomatous hepatitis, the cause of which was determined to be sarcoidosis. Hilar and paratracheal lymphadenopathy were found on chest radiography. No overt evidence of other pulmonary, cardiac or ocular disease was found. This case illustrates the interesting problem of a clinically well aviator with biochemical abnormalities only, but at risk due to the potential presence of more widely disseminated sarcoidosis.

Wealth from Health: an incentive program for disease and population management: a 12-year project.

The future of healthcare is linked with its ability to face the challenges of consumerism. Disease and population management will represent the dominant style of healthcare delivery in the future. This article describes the Wealth from Health programs which utilize current and future technologies to help the healthcare system become a leader in healthcare delivery and to assist many communities at an affordable cost.

Effect of cholesterol levels on villous histology in colonic adenomas.

To date no studies have examined the relationship between cholesterol levels and the occurrence of specific colonic polyp histologies. Villous histology has a greater predilection for subsequent malignancies than other histologies. Consequently, we examined the effect of cholesterol levels on the occurrence of villous adenomas. Just under one in 10 (9.5%, 15/158) patients had polyps with villous histologies. Cholesterol levels were positively and nonlinearly associated with a greater likelihood of villous histology, suggesting that a threshold exists for the effect of cholesterol level on the likelihood of having polyps with villous histology [odds ratios (OR) for combined two variable quadratic effect: cholesterol OR, 1.18; 95% confidence interval (CI), 1.02-1.37 and cholesterol squared OR, 1.004; 95% CI, 1.00-1.02]. Our data suggest that, in patients with polyps, higher cholesterol levels increase the likelihood of having polyps with villous histology, but that the effect of cholesterol level reaches a threshold.

Pulmonary cyst and cerebral arterial gas embolism in a hypobaric chamber: a case report.

This is a report of an aircrew member who suffered a serious physiological incident in the form of pulmonary barotrauma and cerebral arterial gas embolism during hypobaric chamber training, and who subsequently was shown to have a cyst in the upper lobe of the left lung. The likely origin of the cyst is discussed, as well as the aeromedical disposition following thoracotomy and apical segmentectomy to remove the cyst.

Knowledge, attitudes, and practices of geriatricians regarding patients with dementia who are potentially dangerous automobile drivers: a national survey.

OBJECTIVES: To determine geriatrician knowledge regarding how to prevent a patient with dementia who is a potentially dangerous driver from driving and to determine their willingness to recommend license revocation against the wishes of both the patient and the patient's family. Included is a comparison of responses from geriatricians in California, where related legislation has existed for a decade, with responses from geriatricians from all other US states combined. DESIGN: Survey sample. SETTING: Geriatric practices. PARTICIPANTS: Probability sample of 467 geriatricians. MAIN OUTCOME MEASURES: Survey responses. RESULTS: More than 28% of all geriatricians (95% CI, 24.3%-32.7%) do not know how to report patients with dementia who are potentially dangerous drivers. A 22% difference (95% CI, 13.9%-30.8%) exists between California geriatricians and those in all other US states. More than 75% (95%, CI, 71.5%-79.5%) of all geriatricians agreed that physicians are responsible for reporting patients. More than 86% (95% CI, 83.2%-89.6%) of all geriatricians would contact state authorities despite the objections of the patient, and 72.9% (95% CI, 68.7%-77.1%) would contact authorities despite the objections of the patient's family. CONCLUSIONS: Although most geriatricians will act to protect the public from patients with dementia who are potentially dangerous drivers, many do not know how to report these drivers. Legislation can improve a physician's ability to report patients with dementia who are potentially dangerous drivers.

Hyperhomocysteinaemia and upper extremity deep venous thrombosis: a case report.

A case is presented of a 24 yr old military aircrew applicant who developed a right axillary subclavian deep venous thrombosis following physical exertion. Investigations revealed damage to the right axillary subclavian venous system and limitation to flow. Coagulation studies also showed an elevated plasma homocysteine level. Hyperhomocysteinemia has recently been recognized as a risk factor for venous thromboembolic disease. Damage caused by the thrombosis, the hyperhomocysteinemia and environmental factors encountered in flight, may predispose him to recurrent episodes of thrombosis. This complex case involves aspects of hematology and the nature of coagulation which are only just being elucidated and as yet are poorly understood, and highlights some serious aeromedical implications for pilots afflicted with these conditions.

Acute carbamate and organochlorine toxicity causing convulsions in an agricultural pilot: a case report.

Agricultural pilots are involved in a particularly hazardous occupation with a high occupational mortality rate. They face many risks, not least of which is exposure to the agricultural chemicals that they spray. Many accidents and illnesses have been reported previously in the literature, attributable to the acute and chronic effects of chemical exposure, most notably the organophosphate family of insecticides. There are few reports of post-crash exposure to carbamate and organochlorine insecticides. This report documents the case of a professional agricultural pilot who, following an emergency landing, was soaked with Methomyl (a carbamate) and Endosulfan (an organochlorine) leaking from his aircraft. He developed cholinergic symptoms within an hour of the accident, which settled spontaneously, but suffered a tonic-clonic seizure some 6 h later while in the hospital. The seizure was attributed to exposure to the organochlorine, however, subsequent EEG recordings demonstrated a non-specific epileptiform focus in the frontal lobes. The pilot made a full recovery and has remained seizure-free without treatment. The pathophysiology of carbamate and organochlorine poisoning is reviewed, and the differential diagnoses of seizures in this pilot discussed. The difficulty facing a licensing authority in determining the aeromedical disposition of a pilot who has suffered a provoked seizure is also highlighted.

A case of the Wolff-Parkinson-White ECG abnormality in a trainee military pilot.

Wolff-Parkinson-White (WPW) Syndrome is a disorder of cardiac conduction which may cause recurrent atrial and ventricular rhythm disturbances, and even sudden death. The diagnosis of this condition or, more frequently the associated electrocardiographic (ECG) abnormality, in a professional aircrew member has, until recently, been cause for disqualification of that individual from flying status. The recent use of electrophysiological studies (EPS) in patients with WPW, and the use of radiofrequency ablation (RFA) to the accessory pathway(s), offers aircrew a safe and effective treatment for their condition.