Cost estimation alongside a multi-regional, multi-country randomized trial of antenatal ultrasound in five low-and-middle-income countries.

BACKGROUND: Improving maternal health has been a primary goal of international health agencies for many years, with the aim of reducing maternal and child deaths and improving access to antenatal care (ANC) services, particularly in low-and-middle-income countries (LMICs). Health interventions with these aims have received more attention from a clinical effectiveness perspective than for cost impact and economic efficiency. METHODS: We collected data on resource use and costs as part of a large, multi-country study assessing the use of routine antenatal screening ultrasound (US) with the aim of considering the implications for economic efficiency. We assessed typical antenatal outpatient and hospital-based (facility) care for pregnant women, in general, with selective complication-related data collection in women participating in a large maternal health registry and clinical trial in five LMICs. We estimated average costs from a facility/health system perspective for outpatient and inpatient services. We converted all country-level currency cost estimates to 2015 United States dollars (USD). We compared average costs across countries for ANC visits, deliveries, higher-risk pregnancies, and complications, and conducted sensitivity analyses. RESULTS: Our study included sites in five countries representing different regions. Overall, the relative cost of individual ANC and delivery-related healthcare use was consistent among countries, generally corresponding to country-specific income levels. ANC outpatient visit cost estimates per patient among countries ranged from 15 to 30 USD, based on average counts for visits with and without US. Estimates for antenatal screening US visits were more costly than non-US visits. Costs associated with higher-risk pregnancies were influenced by rates of hospital delivery by cesarean section (mean per person delivery cost estimate range: 25-65 USD). CONCLUSIONS: Despite substantial differences among countries in infrastructures and health system capacity, there were similarities in resource allocation, delivery location, and country-level challenges. Overall, there was no clear suggestion that adding antenatal screening US would result in either major cost savings or major cost increases. However, antenatal screening US would have higher training and maintenance costs. Given the lack of clinical effectiveness evidence and greater resource constraints of LMICs, it is unlikely that introducing antenatal screening US would be economically efficient in these settings--on the demand side (i.e., patients) or supply side (i.e., healthcare providers). TRIAL REGISTRATION: Trial number: NCT01990625 (First posted: November 21, 2013 on https://clinicaltrials.gov ).

Optical transfer diagnosis differentiating benign and malignant pigmented lesions in a simulated primary care practice.

BACKGROUND: The detection of melanoma poses a substantial challenge, particularly for primary care providers (PCPs) who may have limited training in discriminating between suspicious and benign melanocytic lesions. The noninvasive optical transfer diagnosis (OTD) method was designed to be used by PCPs in their decision-making process. OBJECTIVES: To assess the potential of the OTD method by developing, training and validating an OTD indication algorithm for automated discrimination between benign melanocytic lesions and malignant lesions, based on a set of 712 lesions. METHODS: The authors performed in vivoOTD capture and subsequent analysis of 712 pigmented lesions. Of the lesions, 415 were clinically and dermoscopically benign and 297 were dermoscopically suspicious or equivocal. After image capture, all suspicious or equivocal lesions were biopsied and examined histopathologically. RESULTS: Of the 297 suspicious or equivocal lesions, histopathological findings revealed 80 to be malignant (64 melanomas, 13 basal cell carcinomas and 3 squamous cell carcinomas). OTD misdiagnosed one of the 80 malignant lesions as benign (sensitivity, 99%). OTD specificity was 93% for the dermoscopically benign lesions, 73% for all lesions included in the study and 36% for the clinically suspicious but histopathologically benign lesions. CONCLUSIONS: High sensitivity and specificity, as provided by OTD in this preliminary study, would help PCPs reduce the number of referrals for dermatology consultation, excision or biopsy. Further studies are planned for screening patients in a primary care setting, with comparisons of OTD results with biopsy or dermoscopy results.

Routine antenatal ultrasound in low- and middle-income countries: first look - a cluster randomised trial.

OBJECTIVE: Ultrasound is widely regarded as an important adjunct to antenatal care (ANC) to guide practice and reduce perinatal mortality. We assessed the impact of ANC ultrasound use at health centres in resource-limited countries. DESIGN: Cluster randomised trial. SETTING: Clusters within five countries (Democratic Republic of Congo, Guatemala, Kenya, Pakistan, and Zambia) METHODS: Clusters were randomised to standard ANC or standard care plus two ultrasounds and referral for complications. The study trained providers in intervention clusters to perform basic obstetric ultrasounds. MAIN OUTCOME MEASURES: The primary outcome was a composite of maternal mortality, maternal near-miss mortality, stillbirth, and neonatal mortality. RESULTS: During the 24-month trial, 28 intervention and 28 control clusters had 24 263 and 23 160 births, respectively; 78% in the intervention clusters received at least one study ultrasound; 60% received two. The prevalence of conditions noted including twins, placenta previa, and abnormal lie was within expected ranges. 9% were referred for an ultrasound-diagnosed condition, and 71% attended the referral. The ANC (RR 1.0 95% CI 1.00, 1.01) and hospital delivery rates for complicated pregnancies (RR 1.03 95% CI 0.89, 1.20) did not differ between intervention and control clusters nor did the composite outcome (RR 1.09 95% CI 0.97, 1.23) or its individual components. CONCLUSIONS: Despite availability of ultrasound at ANC in the intervention clusters, neither ANC nor hospital delivery for complicated pregnancies increased. The composite outcome and the individual components were not reduced. TWEETABLE ABSTRACT: Antenatal care ultrasound did not improve a composite outcome that included maternal, fetal, and neonatal mortality.

Educational and practice gaps in the management of volar melanocytic lesions.

BACKGROUND: The benign and malignant patterns of acral melanocytic naevi (AMN) and acral melanomas (AM) have been defined in a series of retrospective studies. A three-step algorithm was developed to determine when to biopsy acral melanocytic lesions. This algorithm has only been applied to a Japanese population. OBJECTIVES: Our study aimed to review the current management strategy of acral melanocytic lesions and to investigate the utility of the three-step algorithm in a predominately Caucasian cohort. METHODS: A retrospective search of the pathology and image databases at Mayo Clinic was performed between the years 2006 and 2016. Only cases located on a volar surface with dermoscopic images were included. Two dermatologists reviewed all dermoscopic images and assigned a global dermoscopic pattern. Clinical and follow-up data were gathered by chart review. All lesions with known diameter and pathological diagnosis were used for the three-step algorithm. RESULTS: Regular fibrillar and ridge patterns were more likely to be biopsied (P = 0.01). The majority of AMN (58.1%) and AM (60%) biopsied were due to physician-deemed concerning dermoscopic patterns. 39.2% of these cases were parallel furrow, lattice-like or regular fibrillar. When patients were asked to follow-up within a 3- to 6-month period, only 16.7% of the patients returned within that interval. The three-step algorithm would have correctly identified four of five AM for biopsy, missing a 6 mm, multicomponent, invasive melanoma. CONCLUSION: We found one major educational gap in the recognition of low-risk lesions with high rates of biopsy of the fibrillary pattern. Recognizing low-risk dermoscopic patterns could reduce the rate of biopsy of AMN by 23.3%. We identified two major practice gaps, poor patient compliance with follow-up and the potential insensitivity of the three-step algorithm to small multicomponent acral melanocytic lesions.

Small-aperture array processing for passive multi-target angle of arrival estimation.

Small aperture arrays (size less than a wavelength) can be used for passive angle of arrival (AOA) estimation of both broadband and narrowband signals in the frequency domain. Phase differences across the array are measured in the frequency domain and can be spectrally averaged if desired for stationary source AOA and frequencies. The array is capable of measuring multiple target AOAs so long as each target produces unique frequencies or radiates in unique frequency bandwidths. Broadband and narrowband signals from targets can be collected from the fast Fourier transform (FFT) bins and summed by arrival angle in elevation and azimuth using a bearing histogram where the amplitude is displayed in dB. This provides a very useful and intuitive display of received signal levels. The Cramer-Rao lower bound (CRLB) for bearing accuracy is presented as a function of frequency, aperture, and signal-to-noise ratio (SNR). The small aperture background noise includes any other coherent or incoherent signal other than the source of interest. Analysis of phase calibration requirements, nonstationary frequencies, and channel cross-talk are also presented, as well as a technique for generating broadband source signals with the fractional delays needed to simulate the correct AOA.

Spatial stratification of host-seeking Diptera in boreal forests of northern Europe.

The stratification of haematophagous Diptera was assessed in two boreal forests in northern Sweden by placing traps baited with carbon dioxide at 1.5 m, 5.0 m and 10.0 m above the ground. More than 40 000 specimens were captured, including 617 biting midges (Ceratopogonidae), 4029 mosquitoes (Culicidae) and 36 092 black flies (Simuliidae). Catches at the various trap heights reflected the general vertical distribution of the preferred hosts, with mammalophilic flies predominating (68.6%) in catches at 1.5 m and ornithophilic flies (42.4%) in catches at 10.0 m; however, most flies that use host birds at ground level were caught in the lowest traps (e.g. 85.1% of Simulium annulus were collected at 1.5 m). Within-species variation in vertical patterns between forests suggests plasticity in responses to environmental factors such as vegetative structure.

Comparison of blind tracheal intubation through the intubating laryngeal mask airway (LMA Fastrach™) and the Air-Q™.

This study assessed two disposable devices, the LMA Fastrach™ and the newly developed supraglottic airway device, the Air-Q™, as a conduit for tracheal intubation in 154 healthy adults undergoing elective surgery. Using a non-inferiority approach, the primary outcome measure was successful tracheal intubation within two blind insertion attempts. Successful blind intubation after two attempts was achieved in 75/76 (99%) of the patients in the LMA Fastrach group vs 60/78 (77%) in the Air-Q group (95% CI for the difference 12-32%, p<0.0001). Fibreoptic intubation was used to assist the third attempt. The rate of successful intubation after three attempts was 100% in the LMA Fastrach group and 95% in Air-Q group. The single-use LMA Fastrach appears superior compared with the Air-Q, as a conduit to facilitate blind tracheal intubation.

In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase.

Human embryonic stem cells (hESCs) provide a novel source of hematopoietic and other cell populations suitable for gene therapy applications. Preclinical studies to evaluate engraftment of hESC-derived hematopoietic cells transplanted into immunodeficient mice demonstrate only limited repopulation. Expression of a drug-resistance gene, such as Tyr22-dihydrofolate reductase (Tyr22-DHFR), coupled to methotrexate (MTX) chemotherapy has the potential to selectively increase the engraftment of gene-modified, hESC-derived cells in mouse xenografts. Here, we describe the generation of Tyr22-DHFR-GFP-expressing hESCs that maintain pluripotency, produce teratomas and can differentiate into MTXr-hemato-endothelial cells. We demonstrate that MTX administered to nonobese diabetic/severe combined immunodeficient/IL-2Rgammac(null) (NSG) mice after injection of Tyr22-DHFR-hESC-derived cells significantly increases human CD34(+) and CD45(+) cell engraftment in the bone marrow (BM) and peripheral blood of transplanted MTX-treated mice. These results demonstrate that MTX treatment supports selective, long-term engraftment of Tyr22-DHFR cells in vivo, and provides a novel approach for combined human cell and gene therapy.

A randomized, treat-to-target trial comparing insulin lispro protamine suspension and insulin detemir in insulin-naive patients with Type 2 diabetes.

AIMS: Insulin lispro protamine suspension (ILPS) and insulin detemir were compared in insulin-naive patients with Type 2 diabetes poorly controlled by oral glucose-lowering agents (OGLAs) to demonstrate non-inferior overall glycaemic control. METHODS: This was a 24-week, multinational, open-label, parallel-group, treat-to-target trial. Adults taking two or more OGLAs were randomized to ILPS (n = 223) or detemir (n = 219) once daily at bedtime. Doses were titrated to target fasting blood glucose (FBG) 5.0-7.2 mmol/l. A pre-breakfast dose was added up to week 8 per prespecified criteria. The primary objective was comparison of glycated haemoglobin (HbA(1c)) change from baseline (non-inferiority margin 0.4%). RESULTS: At end-point, HbA(1c) decreased from 8.8 +/- 0.7% in both groups to 7.3 +/- 0.9% (ILPS) and 7.5 +/- 1.1% (detemir). Least-squares mean difference (95% confidence interval) for HbA(1c) [-0.21% (-0.39, -0.03)] and glycaemic variability [0.10 mmol/l (-0.02, 0.23)] demonstrated non-inferiority. End-point mean FBG was 7.0 vs. 6.9 mmol/l (P = 0.85), and percentages of patients achieving H < 7.0% were 34.9% vs. 31.2% for ILPS vs. detemir. More ILPS patients used twice-daily dosing (59% vs. 49%). Mean daily insulin dose was 0.39 vs. 0.46 U/kg (P = 0.005) and weight gain was 1.88 vs. 0.36 kg (P < 0.001) for ILPS vs. detemir. Overall hypoglycaemia (episodes patient(-1) year(-1)) (24.2 +/- 33.0 vs. 16.2 +/- 26.1, P = 0.001) and nocturnal (6.3 +/- 12.1 vs. 3.8 +/- 13.2, P < 0.001) rates were higher for ILPS. CONCLUSIONS: At end-point, ILPS was non-inferior to detemir in HbA(1c) change from baseline. Patients using ILPS achieved lower end-point HbA(1c) with lower insulin doses but greater hypoglycaemia and weight gain.

Vertical distribution of haematophagous Diptera in temperate forests of the southeastern U.S.A.

The vertical distribution of blood-feeding flies in two temperate forests in the southeastern U.S.A. was determined by placing 15 Centers for Disease Control and Prevention miniature light traps (12 CO(2)-baited, three unbaited controls), without lights, at three heights (1.5 m, 5.0 m, 10.0 m). More than 6550 haematophagous flies, representing 49 species in four families, were collected. Eighteen species were taken almost exclusively (90-100%) at 1.5 m or 10.0 m, and the mean number of flies per trap differed significantly with height for another six species. Five species exhibited shifts in vertical distribution between the two forests, indicating that forest structure could influence the height of host searching. Most (52.5%) mammalophilic flies were collected at 1.5 m, whereas most (56.4%) ornithophilic flies were taken at 10.0 m, suggesting that host associations influence vertical distributions. The significant differences in the composition of haematophagous fly populations among forest strata emphasize the importance of trap placement in vector surveillance and of understanding the ecological relationships of blood-feeding flies.

Cumulative achievement testing: progress testing in reverse.

This collaborative project between the National Board of Medical Examiners (NBME) and Case Western Reserve University (CWRU) School of Medicine explored the design and use of cumulative achievement tests in basic science education. In cumulative achievement testing, integrative end-of-unit tests are deliberately constructed to systematically retest topics covered in previous units as well as material from the just-completed unit. CWRU faculty developed and administered a series of six web-based cumulative achievement tests using retired United States Medical Licensing Examination (USMLE) step 1 test material and tools provided by NBME's Customized Assessment Services, and trends in student performance were examined as the new CWRU basic science curriculum unfolded. This article provides the background information about test design and administration, as well as samples of score reporting information for students and faculty. While firm conclusions about the effectiveness of cumulative achievement testing are not warranted after a pilot test at a single school, preliminary results suggest that cumulative achievement testing may be an effective complement to progress testing, with the former used to encourage retention of already-covered material and the latter used to assess growth toward the knowledge and skills expected of a graduating student.

Collaboration across the pond: the multi-school progress testing project.

This collaborative project between the National Board of Medical Examiners and four schools in the UK is investigating the feasibility and utility of a cross-school progress testing program drawing on test material recently retired from the United States Medical Licensing Examination (USMLE) Step 2 Clinical Knowledge (CK) examination. This article describes the design of the progress test; the process used to build, translate (localize), review, and finalize test forms; the approach taken to (web-based) test administration; and the procedure used to calculate and report scores. Results to date have demonstrated that it is feasible to use test items written for the US licensing examination as a base for developing progress test forms for use in the UK. Some content areas can be localized more readily than others, and care is clearly needed in review and revision of test materials to ensure that it is clinically appropriate and suitably phrased for use in the UK. Involvement of content experts in review and vetting of the test material is essential, and it is clearly desirable to supplement expert review with the use of quality control procedures based on the item statistics as a final check on the appropriateness of individual test items.

Next generation tools for high-throughput promoter and expression analysis employing single-copy knock-ins at the Hprt1 locus.

We have engineered a set of useful tools that facilitate targeted single copy knock-in (KI) at the hypoxanthine guanine phosphoribosyl transferase 1 (Hprt1) locus. We employed fine scale mapping to delineate the precise breakpoint location at the Hprt1(b-m3) locus allowing allele specific PCR assays to be established. Our suite of tools contains four targeting expression vectors and a complementing series of embryonic stem cell lines. Two of these vectors encode enhanced green fluorescent protein (EGFP) driven by the human cytomegalovirus immediate-early enhancer/modified chicken beta-actin (CAG) promoter, whereas the other two permit flexible combinations of a chosen promoter combined with a reporter and/or gene of choice. We have validated our tools as part of the Pleiades Promoter Project (http://www.pleiades.org), with the generation of brain-specific EGFP positive germline mouse strains.

Metabolic Flexibility in Response to Within-Season Temperature Variability in House Sparrows.

The climatic variability hypothesis (CVH) posits that more flexible phenotypes should provide a fitness advantage for organisms experiencing more variable climates. While typically applied across geographically separated populations, whether this principle applies across seasons or other conditions (e.g., open vs. sheltered habitats) which differ in climatic variability remains essentially unstudied. In north-temperate climates, climatic variability in winter usually exceeds that in summer, so extending the CVH to within-population seasonal variation predicts that winter phenotypes should be more flexible than summer phenotypes. We tested this prediction of the within-season extension of the CVH by acclimating summer and winter-collected house sparrows (Passer domesticus) to 24, 5, and -10°C and measuring basal metabolic rate (BMR) and summit metabolic rate (Msum = maximum cold-induced metabolic rate) before and after acclimation (Accl). To examine mechanistic bases for metabolic variation, we measured flight muscle and heart masses and citrate synthase and ß-hydroxyacyl coA-dehydrogenase activities. BMR and Msum were higher for cold-acclimated than for warm-acclimated birds, and BMR was higher in winter than in summer birds. Contrary to our hypothesis of greater responses to cold Accl in winter birds, metabolic rates generally decreased over the Accl period for winter birds at all temperatures but increased at cold temperatures for summer birds. Flight muscle and heart masses were not significantly correlated with season or Accl treatment, except for supracoracoideus mass, which was lower at -10°C in winter, but flight muscle and heart masses were positively correlated with BMR and flight muscle mass was positively correlated with Msum. Catabolic enzyme activities were not clearly related to metabolic variation. Thus, our data suggest that predictions of the CVH may not be relevant when extended to seasonal temperature variability at the within-population scale. Indeed, these data suggest that metabolic rates are more prominently upregulated in summer than in winter in response to cold. Metabolic rates tended to decrease during Accl at all temperatures in winter, suggesting that initial metabolic rates at capture (higher in winter) influence metabolic Accl for captive birds.

Magma supply rate at kilauea volcano, 1952-1971.

The three longest Kilauea eruptions since 1952 produced lava at an overall constant rate of about 9 x 10(6) cubic meters per month (vesicle-free). This is considered to represent the rate of magma supply from a deep source, probably the mantle, because little or no summit deformation indicating high-level storage accompanied any of the three eruptions.

Predicting eruptions at mount st. Helens, june 1980 through december 1982.

Thirteen eruptions of Mount St. Helens between June 1980 and December 1982 were predicted tens of minutes to, more generally, a few hours in advance. The last seven of these eruptions, starting with that of mid-April 1981, were predicted between 3 days and 3 weeks in advance. Precursory seismicity, deformation of the crater floor and the lava dome, and, to a lesser extent, gas emissions provided telltale evidence of forthcoming eruptions. The newly developed capability for prediction reduced risk to life and property and influenced land-use decisions.

Deformation monitoring at mount st. Helens in 1981 and 1982.

For several weeks before each eruption of Mount St. Helens in 1981 and 1982, viscous magma rising in the feeder conduit inflated the lava dome and shoved the crater floor laterally against the immobile crater walls, producing ground cracks and thrust faults. The rates of deformation accelerated before eruptions, and thus it was possible to predict eruptions 3 to 19 days in advance. Lack of deformation outside the crater showed that intrusion of magma during 1981 and 1982 was not voluminous.

The 2018 rift eruption and summit collapse of Kilauea Volcano.

In 2018, Kilauea Volcano experienced its largest lower East Rift Zone (LERZ) eruption and caldera collapse in at least 200 years. After collapse of the Pu'u 'O'o vent on 30 April, magma propagated downrift. Eruptive fissures opened in the LERZ on 3 May, eventually extending ~6.8 kilometers. A 4 May earthquake [moment magnitude (M w) 6.9] produced ~5 meters of fault slip. Lava erupted at rates exceeding 100 cubic meters per second, eventually covering 35.5 square kilometers. The summit magma system partially drained, producing minor explosions and near-daily collapses releasing energy equivalent to M w 4.7 to 5.4 earthquakes. Activity declined rapidly on 4 August. Summit collapse and lava flow volume estimates are roughly equivalent-about 0.8 cubic kilometers. Careful historical observation and monitoring of Kilauea enabled successful forecasting of hazardous events.

Hypothesis Tests for Neyman's Bias in Case-Control Studies.

Survival bias is a long-recognized problem in case-control studies, and many varieties of bias can come under this umbrella term. We focus on one of them, termed Neyman's bias or "prevalence-incidence bias." It occurs in case-control studies when exposure affects both disease and disease-induced mortality, and we give a formula for the observed, biased odds ratio under such conditions. We compare our result with previous investigations into this phenomenon and consider models under which this bias may or may not be important. Finally, we propose three hypothesis tests to identify when Neyman's bias may be present in case-control studies. We apply these tests to three data sets, one of stroke mortality, another of brain tumors, and the last of atrial fibrillation, and find some evidence of Neyman's bias in the former two cases, but not the last case.

Targeted disruption of the methionine synthase gene in mice.

Alterations in homocysteine, methionine, folate, and/or B12 homeostasis have been associated with neural tube defects, cardiovascular disease, and cancer. Methionine synthase, one of only two mammalian enzymes known to require vitamin B12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. Human patients with methionine synthase deficiency exhibit homocysteinemia, homocysteinuria, and hypomethioninemia. They suffer from megaloblastic anemia with or without some degree of neural dysfunction and mental retardation. To better study the pathophysiology of methionine synthase deficiency, we utilized gene-targeting technology to inactivate the methionine synthase gene in mice. On average, heterozygous knockout mice from an outbred background have slightly elevated plasma homocysteine and methionine compared to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutritional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patients with methionine synthase deficiency have a complete absence of enzyme activity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase-deficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice.