Pharmacokinetics and safety of first-line tuberculosis drugs rifampin, isoniazid, ethambutol, and pyrazinamide during pregnancy and postpartum: results from IMPAACT P1026s.

Physiological changes during pregnancy may alter the pharmacokinetics (PK) of antituberculosis drugs. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1026s was a multicenter, phase IV, observational, prospective PK and safety study of antiretroviral and antituberculosis drugs administered as part of clinical care in pregnant persons living with and without HIV. We assessed the effects of pregnancy on rifampin, isoniazid, ethambutol, and pyrazinamide PK in pregnant and postpartum (PP) persons without HIV treated for drug-susceptible tuberculosis disease. Daily antituberculosis treatment was prescribed following World Health Organization-recommended weight-band dosing guidelines. Steady-state 12-hour PK profiles of rifampin, isoniazid, ethambutol, and pyrazinamide were performed during second trimester (2T), third trimester (3T), and 2-8 of weeks PP. PK parameters were characterized using noncompartmental analysis, and comparisons were made using geometric mean ratios (GMRs) with 90% confidence intervals (CI). Twenty-seven participants were included: 11 African, 9 Asian, 3 Hispanic, and 4 mixed descent. PK data were available for 17, 21, and 14 participants in 2T, 3T, and PP, respectively. Rifampin and pyrazinamide AUC0-24 and C max in pregnancy were comparable to PP with the GMR between 0.80 and 1.25. Compared to PP, isoniazid AUC0-24 was 25% lower and C max was 23% lower in 3T. Ethambutol AUC0-24 was 39% lower in 3T but limited by a low PP sample size. In summary, isoniazid and ethambutol concentrations were lower during pregnancy compared to PP concentrations, while rifampin and pyrazinamide concentrations were similar. However, the median AUC0-24 for rifampin, isoniazid, and pyrazinamide met the therapeutic targets. The clinical impact of lower isoniazid and ethambutol exposure during pregnancy needs to be determined.

Efficacy and safety of three antiretroviral therapy regimens started in pregnancy up to 50 weeks post partum: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Drugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1. METHODS: In this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422. FINDINGS: Between Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per µL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups. INTERPRETATION: Safety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. TRIAL DESIGN: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. METHODS: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. RESULTS: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). CONCLUSIONS: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. TRIAL REGISTRATION: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Forty-Eight Week Outcomes of a Site-Randomized Trial of Combined Cognitive Behavioral Therapy and Medication Management Algorithm for Treatment of Depression Among Youth With HIV in the United States.

BACKGROUND: Studies suggest that manualized, measurement-guided, depression treatment is more efficacious than usual care but impact can wane. Our study among youth with HIV (YWH), aged 12-24 years at US clinical research sites in the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, found a significant reduction in depressive symptoms among YWH who received a manualized, measurement-guided treatment. This paper reports outcomes up to 24 weeks after the intervention. METHODS: Eligibility included diagnosis of ongoing nonpsychotic depression. Using restricted randomization, sites were assigned to either combination cognitive behavioral therapy and medication management algorithm tailored for YWH or to enhanced standard of care, which provided psychotherapy and medication management. Site-level mean Quick Inventory for Depression Symptomatology Self-Report (QIDS-SR) scores and proportion of youth with treatment response (>50% decrease from baseline) and remission (QIDS-SR ≤ 5) were compared across arms using t tests. RESULTS: Thirteen sites enrolled 156 YWH, with baseline demographic factors, depression severity, and HIV disease status comparable across arms. At week 36, the site-level mean proportions of youth with a treatment response and remission were greater at combination cognitive behavioral therapy and medication management algorithm sites (52.0% vs. 18.8%, P = 0.02; 37.9% vs. 19.4%, P = 0.05), and the mean QIDS-SR was lower (7.45 vs. 9.75, P = 0.05). At week 48, the site-level mean proportion with a treatment response remained significantly greater (58.7% vs. 33.4%, P = 0.047). CONCLUSIONS: The impact of manualized, measurement-guided cognitive behavioral therapy and medication management algorithm tailored for YWH that was efficacious at week 24 continued to be evident at weeks 36 and 48.

Pharmacokinetics of Tenofovir Alafenamide With Boosted Protease Inhibitors in Pregnant and Postpartum Women Living With HIV: Results From IMPAACT P1026s.

BACKGROUND: Tenofovir alafenamide (TAF) is a key component of HIV treatment, but pharmacokinetic data supporting the use of TAF during pregnancy are limited. In this study, we report pharmacokinetic, safety, and birth outcomes for TAF 25 mg with a boosted protease inhibitor in pregnant women living with HIV. METHODS: IMPAACT P1026s was a multicenter, nonrandomized, open-label, phase IV prospective study. Pregnant women living with HIV receiving TAF 25 mg with a boosted protease inhibitor were eligible. Intensive pharmacokinetic assessments were performed during the second and third trimesters and 6-12 weeks postpartum. Maternal and cord blood samples were collected at delivery. Infant washout samples were collected through 5-9 days postbirth. Comparisons of paired pharmacokinetic data between pregnancy and postpartum were made using geometric mean ratios (GMR) [90% confidence intervals (CIs)] and Wilcoxon signed-rank tests with P < 0.10 considered significant. RESULTS: Twenty-nine women were enrolled from the United States (median age 31 years and weight 84.5 kg during the third trimester; 48% Black, 45% Hispanic/Latina). TAF AUCtau did not significantly differ in the second [GMR 0.62 (90% CI: 0.29 to 1.34); P = 0.46] or third trimester [GMR 0.94 (90% CI: 0.63 to 1.39); P = 0.50] vs. postpartum and were comparable with historical data in nonpregnant adults. TAF was only quantifiable in 2/25 maternal delivery samples and below the limit of quantification in all cord blood and infant washout samples, likely because of the short half-life of TAF. CONCLUSION: TAF AUCtau did not significantly differ between pregnancy and postpartum. These findings provide reassurance as TAF use during pregnancy continues to expand.

Prolonged Wireless pH Monitoring in Patients With Persistent Reflux Symptoms Despite Proton Pump Inhibitor Therapy.

BACKGROUND & AIMS: Wireless pH monitoring measures esophageal acid exposure time (AET) for up to 96 hours. We evaluated competing methods of analysis of wireless pH data. METHODS: Adult patients with persisting reflux symptoms despite acid suppression (n = 322, 48.5 ± 0.9 years, 61.7% women) from 2 tertiary centers were evaluated using symptom questionnaires and wireless pH monitoring off therapy, from November 2013 through September 2017; 30 healthy adults (control subjects; 26.9 ± 1.5 years; 60.0% women) were similarly evaluated. Concordance of daily AET (physiologic <4%, borderline 4%-6%, pathologic>6%) for 2 or more days constituted the predominant AET pattern. Each predominant pattern (physiologic, borderline, or pathologic) in relation to data from the first day, and total averaged AET, were compared with other interpretation paradigms (first 2 days, best day, or worst day) and with symptoms. RESULTS: At least 2 days of AET data were available from 96.9% of patients, 3 days from 90.7%, and 4 days from 72.7%. A higher proportion of patients had a predominant pathologic pattern (31.4%) than control subjects (11.1%; P = .03). When 3 or more days of data were available, 90.4% of patients had a predominant AET pattern; when 2 days of data were available, 64.1% had a predominant AET pattern (P < .001). Day 1 AET was discordant with the predominant pattern in 22.4% of patients and was less strongly associated with the predominant pattern compared with 48 hour AET (P = .059) or total averaged AET (P = .02). Baseline symptom burden was higher in patients with a predominant pathologic pattern compared with a predominant physiologic pattern (P = .02). CONCLUSIONS: The predominant AET pattern on prolonged wireless pH monitoring can identify patients at risk for reflux symptoms and provides gains over 24 hours and 48 hours recording, especially when results from the first 2 days are discordant or borderline.

Crystal structure of the thortveitite-related M phase, (MnxZn1-x)2V2O7 (0.75 < x < 0.913): a combined synchrotron powder and single-crystal X-ray study.

The determination of the crystal structure of the M phase, (MnxZn1-x)2V2O7 (0.75 < x < 0.913), in the pseudobinary Mn2V2O7-Zn2V2O7 system for x ≃ 0.8 shows that the previously published triclinic unit-cell parameters for this thortveitite-related phase do not describe a true lattice for this phase. Instead, single-crystal X-ray data and Rietveld refinement of synchrotron X-ray powder data show that the M phase has a different triclinic structure in the space group P-1 with Z = 2. As prior work has suggested, the crystal structure can be described as a distorted version of the thortveitite crystal structure of ß-Mn2V2O7. A twofold superstructure in diffraction patterns of crystals of the M phase used for single-crystal X-ray diffraction work arises from twinning by reticular pseudomerohedry. This superstructure can be described as a commensurate modulation of a pseudo-monoclinic basis structure closely related to the crystal structure of ß-Mn2V2O7. In comparison with the distortions introduced when ß-Mn2V2O7 transforms at low temperature to α-Mn2V2O7, the distortions which give rise to the M phase from the ß-Mn2V2O7 prototype are noticeably less pronounced.

Diagnostic yield of high-resolution manometry with a solid test meal for clinically relevant, symptomatic oesophageal motility disorders: serial diagnostic study.

BACKGROUND: The use of high-resolution manometry (HRM) to diagnose oesophageal motility disorders is based on ten single water swallows (SWS); however, this approach might not be representative of oesophageal function during the ingestion of normal food. We tested whether inclusion of a standardised solid test meal (STM) to HRM studies increases test sensitivity for major motility disorders. Additionally, we assessed the frequency and cause of patient symptoms during STM. METHODS: Consecutive patients who were referred for investigation of oesophageal symptoms were recruited at Nottingham University Hospitals (Nottingham, UK) in the development study and at University Hospital Zürich (Zürich, Switzerland) in the validation study. HRM was done in the upright, seated position with a solid-state assembly. During HRM, patients ingested ten SWS, followed by a standardised 200 g STM. Diagnosis of oesophageal motility disorders was based on the Chicago Classification validated for SWS (CCv3) and with STM (CC-S), respectively. These studies are registered with ClinicalTrials.gov, numbers NCT02407938 and NCT02397616. FINDINGS: The development cohort included 750 patients of whom 360 (48%) had dysphagia and 390 (52%) had reflux or other symptoms. The validation cohort consisted of 221 patients, including 98 (44%) with dysphagia and 123 (56%) with reflux symptoms. More patients were diagnosed with a major motility disorder by use of an STM than with SWS in the development set (321 [43%] patients diagnosed via STM vs 163 [22%] via SWS; p<0·0001) and validation set (73 [33%] vs 49 [22%]; p=0·014). The increase was most evident in patients with dysphagia (241 [67%] of 360 patients on STM vs 125 [35%] patients on SWS in the development set, p<0·0001), but was also present in those referred with reflux symptoms (64 [19%] of 329 patients vs 32 [10%] patients in the development set, p=0·00060). Reproduction of symptoms was reported by nine (1%) of 750 patients during SWS and 461 (61%) during STM (p<0·0001). 265 (83%) of 321 patients with major motility disorders and 107 (70%) of 152 patients with minor motility disorders reported symptoms during the STM (p=0·0038), compared with 89 (32%) of 277 patients with normal motility as defined with CC-S (p<0·0001). INTERPRETATION: The diagnostic sensitivity of HRM for major motility disorders is increased with use of the STM compared with SWS, especially in patients with dysphagia. Observations made during STM can establish motility disorders as the cause of oesophageal symptoms. FUNDING: None.

Petiolate wings: effects on the leading-edge vortex in flapping flight.

The wings of many insect species including crane flies and damselflies are petiolate (on stalks), with the wing planform beginning some distance away from the wing hinge, rather than at the hinge. The aerodynamic impact of flapping petiolate wings is relatively unknown, particularly on the formation of the lift-augmenting leading-edge vortex (LEV): a key flow structure exploited by many insects, birds and bats to enhance their lift coefficient. We investigated the aerodynamic implications of petiolation P using particle image velocimetry flow field measurements on an array of rectangular wings of aspect ratio 3 and petiolation values of P = 1-3. The wings were driven using a mechanical device, the 'Flapperatus', to produce highly repeatable insect-like kinematics. The wings maintained a constant Reynolds number of 1400 and dimensionless stroke amplitude Λ* (number of chords traversed by the wingtip) of 6.5 across all test cases. Our results showed that for more petiolate wings the LEV is generally larger, stronger in circulation, and covers a greater area of the wing surface, particularly at the mid-span and inboard locations early in the wing stroke cycle. In each case, the LEV was initially arch-like in form with its outboard end terminating in a focus-sink on the wing surface, before transitioning to become continuous with the tip vortex thereafter. In the second half of the wing stroke, more petiolate wings exhibit a more detached LEV, with detachment initiating at approximately 70% and 50% span for P = 1 and 3, respectively. As a consequence, lift coefficients based on the LEV are higher in the first half of the wing stroke for petiolate wings, but more comparable in the second half. Time-averaged LEV lift coefficients show a general rise with petiolation over the range tested.

A Comparative Study on Graphene Oxide and Carbon Nanotube Reinforcement of PMMA-Siloxane-Silica Anticorrosive Coatings.

Carbon nanotubes (CNTs) and graphene oxide (GO) have been used to reinforce PMMA-siloxane-silica nanocomposites considered to be promising candidates for environmentally compliant anticorrosive coatings. The organic-inorganic hybrids were prepared by benzoyl peroxide (BPO)-induced polymerization of methyl methacrylate (MMA) covalently bonded through 3-(trimethoxysilyl)propyl methacrylate (MPTS) to silica domains formed by hydrolytic condensation of tetraethoxysilane (TEOS). Single-walled carbon nanotubes and graphene oxide nanosheets were dispersed by surfactant addition and in a water/ethanol solution, respectively. These were added to PMMA-siloxane-silica hybrids at a carbon (CNT or GO) to silicon (TEOS and MPTS) molar ratio of 0.05% in two different matrices, both prepared at BPO/MMA molar ratios of 0.01 and 0.05. Atomic force microscopy and scanning electron microscopy showed very smooth, homogeneous, and defect-free surfaces of approximately 3-7 µm thick coatings deposited onto A1020 carbon steel by dip coating. Mechanical testing and thermogravimetric analysis confirmed that both additives CNT and GO improved the scratch resistance, adhesion, wear resistance, and thermal stability of PMMA-siloxane-silica coatings. Results of electrochemical impedance spectroscopy in 3.5% NaCl solution, discussed in terms of equivalent circuits, showed that the reinforced hybrid coatings act as a very efficient anticorrosive barrier with an impedance modulus up to 1 GΩ cm(2), approximately 5 orders of magnitude higher than that of bare carbon steel. In the case of GO addition, the high corrosion resistance was maintained for more than 6 months in saline medium. These results suggest that both carbon nanostructures can be used as structural reinforcement agents, improving the thermal and mechanical resistance of high performance anticorrosive PMMA-siloxane-silica coatings and thus extending their application range to abrasive environments.

The effect of aspect ratio on the leading-edge vortex over an insect-like flapping wing.

Insect wing shapes are diverse and a renowned source of inspiration for the new generation of autonomous flapping vehicles, yet the aerodynamic consequences of varying geometry is not well understood. One of the most defining and aerodynamically significant measures of wing shape is the aspect ratio, defined as the ratio of wing length (R) to mean wing chord (c). We investigated the impact of aspect ratio, AR, on the induced flow field around a flapping wing using a robotic device. Rigid rectangular wings ranging from AR = 1.5 to 7.5 were flapped with insect-like kinematics in air with a constant Reynolds number (Re) of 1400, and a dimensionless stroke amplitude of 6.5c (number of chords traversed by the wingtip). Pseudo-volumetric, ensemble-averaged, flow fields around the wings were captured using particle image velocimetry at 11 instances throughout simulated downstrokes. Results confirmed the presence of a high-lift, separated flow field with a leading-edge vortex (LEV), and revealed that the conical, primary LEV grows in size and strength with increasing AR. In each case, the LEV had an arch-shaped axis with its outboard end originating from a focus-sink singularity on the wing surface near the tip. LEV detachment was observed for AR > 1.5 around mid-stroke at ~70% span, and initiated sooner over higher aspect ratio wings. At AR > 3 the larger, stronger vortex persisted under the wing surface well into the next half-stroke leading to a reduction in lift. Circulatory lift attributable to the LEV increased with AR up to AR = 6. Higher aspect ratios generated proportionally less lift distally because of LEV breakdown, and also less lift closer to the wing root due to the previous LEV's continuing presence under the wing. In nature, insect wings go no higher than AR ~ 5, likely in part due to architectural and physiological constraints but also because of the reducing aerodynamic benefits of high AR wings.

Investigation of Dysphagia After Antireflux Surgery by High-resolution Manometry: Impact of Multiple Water Swallows and a Solid Test Meal on Diagnosis, Management, and Clinical Outcome.

BACKGROUND & AIMS: Management of patients with dysphagia, regurgitation, and related symptoms after antireflux surgery is challenging. This prospective, case-control study tested the hypothesis that compared with standard high-resolution manometry (HRM) with single water swallows (SWS), adding multiple water swallows (MWS) and a solid test meal increases diagnostic yield and clinical impact of physiological investigations. METHODS: Fifty-seven symptomatic and 12 asymptomatic patients underwent HRM with SWS, MWS, and a solid test meal. Dysphagia and reflux were assessed by validated questionnaires. Diagnostic yield of standard and full HRM studies with 24-hour pH-impedance monitoring was compared. Pneumatic dilatation was performed for outlet obstruction on HRM studies. Clinical outcome was assessed by questionnaires and an analogue scale with "satisfactory" defined as at least 40% symptom improvement requiring no further treatment. RESULTS: Postoperative esophagogastric junction pressure was similar in all groups. Abnormal esophagogastric junction morphology (double high pressure band) was more common in symptomatic than in control patients (13 of 57 vs 0 of 12, P = .004). Diagnostic yield of HRM was 11 (19%), 11 (19%), and 33 of 57 (58%), with SWS, MWS, and solids, respectively (P < .001); it was greatest for solids in patients with dysphagia (19 of 27, 70%). Outlet obstruction was present in 4 (7%), 11 (19%), and 15 of 57 patients (26%) with SWS, MWS, and solids, respectively (P < .009). No asymptomatic control had clinically relevant dysfunction on solid swallows. Dilatation was performed in 12 of 15 patients with outlet obstruction during the test meal. Symptom response was satisfactory, good, or excellent in 7 of 12 (58%) with no serious complications. CONCLUSIONS: The addition of MWS and a solid test meal increases the diagnostic yield of HRM studies in patients with symptoms after fundoplication and identifies additional patients with outlet obstruction who benefit from endoscopic dilatation.

Devitrite-based optical diffusers.

Devitrite is a novel material produced by heat treatment of commercial soda-lime-silica glass. It consists of fans of needle-like crystals which can extend up to several millimeters and have interspacings of up to a few hundred nanometers. To date, only the material properties of devitrite have been reported, and there has been a distinct lack of research on using it for optical applications. In this study, we demonstrate that randomly oriented fans of devitrite crystals can act as highly efficient diffusers for visible light. Devitrite crystals produce phase modulation of light because of their relatively high anisotropy. The nanoscale spacings between these needles enable light to be diffused to large scattering angles. Experimentally measured results suggest that light diffusion patterns with beam widths of up to 120° are produced. Since devitrite is an inexpensive material to produce, it has the potential to be used in a variety of commercial applications.

X-ray powder diffraction and electron diffraction studies of the thortveitite-related L phase, (Zn,Mn)2V2O7.

The phase designated gamma-Zn3(VO4)2 reported as a minor second phase in zinc oxide-based varistor materials doped with vanadium oxide and manganese oxide is shown to be the L phase, (Zn(1-x)Mn(x))2V2O7 (0.188 < x < 0.538), in the pseudo-binary Mn2V2O7-Zn2V2O7 system. Analysis of X-ray powder diffraction patterns and electron diffraction patterns of this phase shows that the previously published a, c and beta values for this thortveitite-related phase are incorrect. Instead, Rietveld refinement of the X-ray powder pattern of the L phase shows that it has a monoclinic C lattice with Z = 6, with a = 10.3791 (1), b = 8.5557 (1), c = 9.3539 (1) A and beta = 98.467 (1) degrees. Although prior convergent-beam electron diffraction work of 'gamma-Zn3(VO4)2' confirmed the C Bravais lattice, the space group was found to be Cm rather than C2/m, the difference perhaps arising from the inability of the X-rays to detect small displacements of oxygen. Attempts to refine the structure in Cm did not produce improved R factors. The relationship between the crystal structure of the L phase and the high-temperature C2/m beta'-Zn2V2O7 thortveitite-type solid solution is discussed.

On mathematical modelling of insect flight dynamics in the context of micro air vehicles.

We discuss some aspects of mathematical modelling relevant to the dynamics of insect flight in the context of insect-like flapping-wing micro air vehicles (MAVs). MAVs are small flying vehicles developed to reconnoître in confined spaces. This requires power-efficient, highly-manoeuvrable, low-speed flight with stable hover. All of these attributes are present in insect flight and hence the focus on reproducing the functionality of insect flight by engineering means. Empirical research on insect flight dynamics is limited by experimental difficulties. Force and moment measurements require tethering the animal whose behaviour may then differ from free flight. The measurements are made when the insect actively tries to control its flight, so that its open-loop dynamics cannot be observed. Finally, investigation of the sensory-motor system responsible for flight is even more challenging. Despite these difficulties, much empirical progress has been made recently. Further progress, especially in the context of MAVs, can be achieved by the complementary information derived from appropriate mathematical modelling. The focus here is on a means of computing the data not easily available from experiments and also on making mathematical predictions to suggest new experiments. We consider two aspects of mathematical modelling for insect flight dynamics. The first one is theoretical (computational), as opposed to empirical, generation of the aerodynamic data required for the six-degrees-of-freedom equations of motion. For this purpose we first explain insect wing kinematics and the salient features of the corresponding flow. In this context, we show that aerodynamic modelling is a feasible option for certain flight regimes, focusing on a successful example of modelling hover. Such modelling progresses from the first principles of fluid mechanics, but relies on simplifications justified by the known flow phenomenology and/or geometric and kinematic symmetries. This is relevant to six types of fundamental manoeuvres, which we define as those flight conditions for which only one component of the translational and rotational body velocities is nonzero and constant. The second aspect of mathematical modelling for insect flight dynamics addressed here deals with the periodic character of the aerodynamic force and moment production. This leads to consideration of the types of solutions of nonlinear equations forced by nonlinear oscillations. In particular, the mechanism of synchronization seems relevant and should be investigated further.

Redo antireflux surgery--the importance of a tailored approach.

OBJECTIVE: Although several studies have examined early outcome following redo antireflux surgery, there is little data on the long-term efficacy of these procedures. We reviewed our experience of these operations in order to assess the long-term results which can be achieved by choosing redo antireflux procedures based on the results obtained from pre-operative oesophageal function testing. METHODS: The case notes of 26 patients who underwent a repeat antireflux procedure between 1981 and 2000 were reviewed. Clinical history, examination, endoscopy, pH studies, oesophageal manometry and video barium contrast studies were performed on all patients prior to re-operation. In all cases, a standardised pre-formulated algorithm, based on the results of the pre-operative oesophageal function tests, was used to determine the choice of surgical procedure. Post-operatively, patients were classified into three groups: Group A (those with no symptoms), Group B (symptoms controlled by medication) and Group C (symptoms refractory to medical treatment). Patients in Groups B and C underwent repeat oesophageal function studies. RESULTS: In all cases, the indication for re-operation was gastro-oesophageal reflux symptoms refractory to medical treatment. Twenty-one patients (81%) underwent a left thoracotomy, of whom 11 patients (42%) underwent a gastroplasty. The mean follow-up period was 8.27 years (range 1.5-19.8 years), after which 14 patients (54%) were classified as Group A; 10 patients (38%) as Group B; and 2 patients (8%) as Group C. Within Groups B and C, manometry showed that re-operation had increased basal lower oesophageal sphincter pressure (4.6 vs 12.7 mmHg, pre- vs post-operative P=0.03), and in all, but one case pH studies showed no evidence of recurrent acid reflux. CONCLUSIONS: Redo antireflux surgery can provide complete symptomatic relief in approximately 50% of patients and symptomatic improvement over 90% of patients. We advocate a tailored approach in the selection of re-operative procedures based on the results of pre-operative oesophageal function testing.