External validation of prognostic models to predict stillbirth using International Prediction of Pregnancy Complications (IPPIC) Network database: individual participant data meta-analysis.

OBJECTIVE: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance. METHODS: MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit. RESULTS: Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes. CONCLUSIONS: The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of pre-eclampsia: review of reviews.

OBJECTIVE: Primary studies and systematic reviews provide estimates of varying accuracy for different factors in the prediction of pre-eclampsia. The aim of this study was to review published systematic reviews to collate evidence on the ability of available tests to predict pre-eclampsia, to identify high-value avenues for future research and to minimize future research waste in this field. METHODS: MEDLINE, EMBASE and The Cochrane Library including DARE (Database of Abstracts of Reviews of Effects) databases, from database inception to March 2017, and bibliographies of relevant articles were searched, without language restrictions, for systematic reviews and meta-analyses on the prediction of pre-eclampsia. The quality of the included reviews was assessed using the AMSTAR tool and a modified version of the QUIPS tool. We evaluated the comprehensiveness of search, sample size, tests and outcomes evaluated, data synthesis methods, predictive ability estimates, risk of bias related to the population studied, measurement of predictors and outcomes, study attrition and adjustment for confounding. RESULTS: From 2444 citations identified, 126 reviews were included, reporting on over 90 predictors and 52 prediction models for pre-eclampsia. Around a third (n = 37 (29.4%)) of all reviews investigated solely biochemical markers for predicting pre-eclampsia, 31 (24.6%) investigated genetic associations with pre-eclampsia, 46 (36.5%) reported on clinical characteristics, four (3.2%) evaluated only ultrasound markers and six (4.8%) studied a combination of tests; two (1.6%) additional reviews evaluated primary studies investigating any screening test for pre-eclampsia. Reviews included between two and 265 primary studies, including up to 25 356 688 women in the largest review. Only approximately half (n = 67 (53.2%)) of the reviews assessed the quality of the included studies. There was a high risk of bias in many of the included reviews, particularly in relation to population representativeness and study attrition. Over 80% (n = 106 (84.1%)) summarized the findings using meta-analysis. Thirty-two (25.4%) studies lacked a formal statement on funding. The predictors with the best test performance were body mass index (BMI) > 35 kg/m2 , with a specificity of 92% (95% CI, 89-95%) and a sensitivity of 21% (95% CI, 12-31%); BMI > 25 kg/m2 , with a specificity of 73% (95% CI, 64-83%) and a sensitivity of 47% (95% CI, 33-61%); first-trimester uterine artery pulsatility index or resistance index > 90th centile (specificity 93% (95% CI, 90-96%) and sensitivity 26% (95% CI, 23-31%)); placental growth factor (specificity 89% (95% CI, 89-89%) and sensitivity 65% (95% CI, 63-67%)); and placental protein 13 (specificity 88% (95% CI, 87-89%) and sensitivity 37% (95% CI, 33-41%)). No single marker had a test performance suitable for routine clinical use. Models combining markers showed promise, but none had undergone external validation. CONCLUSIONS: This review of reviews calls into question the need for further aggregate meta-analysis in this area given the large number of published reviews subject to the common limitations of primary predictive studies. Prospective, well-designed studies of predictive markers, preferably randomized intervention studies, and combined through individual-patient data meta-analysis are needed to develop and validate new prediction models to facilitate the prediction of pre-eclampsia and minimize further research waste in this field. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Predicción de la preeclampsia: revisión de revisiones OBJETIVO: Los estudios primarios y las revisiones sistemáticas proporcionan estimaciones de precisión variable para diferentes factores en la predicción de la preeclampsia. El objetivo de este estudio fue revisar las revisiones sistemáticas publicadas para recopilar evidencia sobre la capacidad de las pruebas disponibles para predecir la preeclampsia, identificar avenidas de investigación futura valiosas y minimizar el desperdicio futuro de investigación en este campo. MÉTODOS: Se realizaron búsquedas de artículos relevantes en bibliografías sobre el tema y en las bases de datos MEDLINE, EMBASE y The Cochrane Library, incluida DARE (Database of Abstracts of Reviews of Effects), desde el inicio de cada base de datos hasta marzo de 2017, sin restricciones de idioma, para obtener revisiones sistemáticas y metaanálisis sobre la predicción de la preeclampsia. La calidad de las revisiones incluidas se evaluó utilizando la herramienta AMSTAR y una versión modificada de la herramienta QUIPS. Se evaluó la amplitud de la búsqueda, el tamaño de la muestra, las pruebas y los resultados evaluados, los métodos de síntesis de datos, las estimaciones de la capacidad de predicción, el riesgo de sesgo relacionado con la población estudiada, la medición de los predictores y los resultados, la deserción del estudio y el ajuste por confusión. RESULTADOS: De las 2444 citas identificadas, se incluyeron 126 revisiones, que informaron sobre más de 90 predictores y 52 modelos de predicción para la preeclampsia. Alrededor de un tercio (n=37 (29,4%)) de todas las revisiones investigaron únicamente marcadores bioquímicos para predecir la preeclampsia, 31 (24,6%) investigaron asociaciones genéticas con la preeclampsia, 46 (36,5%) informaron sobre las características clínicas, cuatro (3,2%) evaluaron sólo marcadores ecográficos y seis (4,8%) estudiaron una combinación de pruebas; dos (1,6%) revisiones adicionales evaluaron los estudios primarios que investigaron cualquier prueba de diagnóstico de la preeclampsia. Las revisiones incluyeron entre dos y 265 estudios primarios, que incluyeron hasta 25 356 688 mujeres en la revisión más grande. Sólo aproximadamente la mitad (n=67 (53,2%)) de las revisiones evaluaron la calidad de los estudios incluidos. En muchas de las revisiones incluidas hubo un alto riesgo de sesgo, particularmente en relación con la representatividad de la población y la deserción de los estudios. Más del 80% (n=106 (84,1%)) resumió los hallazgos utilizando el metaanálisis. Treinta y dos (25,4%) estudios carecían de una declaración formal sobre la financiación. Los predictores con el mejor rendimiento de la prueba fueron el índice de masa corporal (IMC) >35 kg.m-2 , con una especificidad del 92% (IC 95%, 89-95%) y una sensibilidad del 21% (IC 95%, 12-31%); IMC >25 kg.m-2 , con una especificidad del 73% (IC 95%: 64-83%) y una sensibilidad del 47% (IC 95%: 33-61%); índice de pulsatilidad de la arteria uterina en el primer trimestre o índice de resistencia >90° percentil (especificidad del 93% (IC 95%: 90-96%) y sensibilidad del 26% (IC 95%: 23-31%)); factor de crecimiento placentario (especificidad 89% (IC 95%, 89-89%) y sensibilidad 65% (IC 95%, 63-67%)); y proteína placentaria 13 (especificidad 88% (IC 95%, 87-89%) y sensibilidad 37% (IC 95%, 33-41%)). Ningún marcador por sí solo tuvo un rendimiento de la prueba adecuado para el uso clínico rutinario. Los modelos que combinan marcadores son prometedores, pero ninguno fue sometido a una validación externa. CONCLUSIONES: Esta revisión de revisiones ha puesto en duda la necesidad de un metaanálisis agregado adicional en esta área, dado el gran número de revisiones publicadas sujetas a las limitaciones comunes de los estudios predictivos primarios. Se necesitan estudios prospectivos bien diseñados de marcadores predictivos, preferiblemente en estudios de intervención aleatorios, y combinados mediante el metaanálisis de datos de pacientes individuales, para desarrollar y validar nuevos modelos predictivos que faciliten la predicción de la preeclampsia y minimicen el desperdicio de investigación adicional en este campo.

From protection of privacy to control of data streams: a focus group study on biobanks in the information society.

Most people in Europe do not know what biobanks are. In this study, public perceptions of biobanks and collection of genetic and health data were analyzed in relation to other technologies and digital networks where personal information is compiled and distributed. In this setting, people contextualized biobanks in line with their daily experiences with other technologies and data streams. The analysis was based on 18 focus group discussions conducted in Austria, Finland and Germany. We examined the ways in which people frame and talk about problems and benefits of information distribution in digital networks and biobanks. People identify many challenges associated with collection of personal data in the information society. The study showed that instead of privacy - which has been the key term of bioethical debates on biobanks - the notions of control and controllability are most essential for people. From the viewpoint of biobanks, issues of controllability pose challenges. In the information society, people have become accustomed to controlling personal data, which is particularly difficult in relation to biobanks. They expressed strong concerns over the controllability of the goals and benefits of biobanks.

Mortality and implant revision rates of hip arthroplasty in patients with osteoarthritis: registry based cohort study.

OBJECTIVES: To examine mortality and revision rates among patients with osteoarthritis undergoing hip arthroplasty and to compare these rates between patients undergoing cemented or uncemented procedures and to compare outcomes between men undergoing stemmed total hip replacements and Birmingham hip resurfacing. DESIGN: Cohort study. SETTING: National Joint Registry. POPULATION: About 275,000 patient records. MAIN OUTCOME MEASURES: Hip arthroplasty procedures were linked to the time to any subsequent mortality or revision (implant failure). Flexible parametric survival analysis methods were used to analyse time to mortality and also time to revision. Comparisons between procedure groups were adjusted for age, sex, American Society of Anesthesiologists (ASA) grade, and complexity. RESULTS: As there were large baseline differences in the characteristics of patients receiving cemented, uncemented, or resurfacing procedures, unadjusted comparisons are inappropriate. Multivariable survival analyses identified a higher mortality rate for patients undergoing cemented compared with uncemented total hip replacement (adjusted hazard ratio 1.11, 95% confidence interval 1.07 to 1.16); conversely, there was a lower revision rate with cemented procedures (0.53, 0.50 to 0.57). These translate to small predicted differences in population averaged absolute survival probability at all time points. For example, compared with the uncemented group, at eight years after surgery the predicted probability of death in the cemented group was 0.013 higher (0.007 to 0.019) and the predicted probability of revision was 0.015 lower (0.012 to 0.017). In multivariable analyses restricted to men, there was a higher mortality rate in the cemented group and the uncemented group compared with the Birmingham hip resurfacing group. In terms of revision, the Birmingham hip resurfacings had a similar revision rate to uncemented total hip replacements. Both uncemented total hip replacements and Birmingham hip resurfacings had a higher revision rate than cemented total hip replacements. CONCLUSIONS: There is a small but significant increased risk of revision with uncemented rather than cemented total hip replacement, and a small but significant increased risk of death with cemented procedures. It is not known whether these are causal relations or caused by residual confounding. Compared with uncemented and cemented total hip replacements, Birmingham hip resurfacing has a significantly lower risk of death in men of all ages. Previously, only adjusted analyses of hip implant revision rates have been used to recommend and justify use of cheaper cemented total hip implants. Our investigations additionally consider mortality rates and suggest a potentially higher mortality rate with cemented total hip replacements, which merits further investigation.

Belonging and community: understandings of "home" and "friends" among the English poor, 1750-1850.

This article is based on unique 'narratives of the poor', that is, letters from poor people to their parishes of settlement, petitions to the London Refuge of the Destitute, and letters from mothers to the London Foundling Hospital, with supportive evidence from newspapers. These display fundamental concepts among the English poor, who were often poorly literate, and who comprised the majority of the population. Discussion focuses upon their understandings of 'home', 'belonging', 'friends', and 'community'. These key concepts are related here to modern discussions, to set important concerns into historical perspective. 'Friends', valuably studied by sociologists such as Pahl, had a wide meaning in the past. 'Home' meant (alongside abode) one's parish of legal settlement, where one was entitled to poor relief under the settlement/poor laws. This was where one 'belonged'. Ideas of 'community' were held and displayed even at a distance, among frequently migrant poor, who wrote to their parishes showing strong ties of attachment, right, and local obligation. This discussion explores these issues in connection with belonging and identity. It elucidates the meaning and working of poor law settlement, and is also an exploration of popular mentalities and the semi-literate ways in which these were expressed.

Class I and III polyhydroxyalkanoate synthases from Ralstonia eutropha and Allochromatium vinosum: characterization and substrate specificity studies.

Class I and III polyhydroxyalkanoate (PHA) synthases catalyze the conversion of beta-hydroxybutyryl coenzyme A (HBCoA) to polyhydroxybutyrate. The Class I PHA synthase from Ralstonia eutropha has been purified by numerous labs with reported specific activities that vary between 1 and 160 U/mg. An N-terminal (His)6-PHA synthase was constructed and purified with specific activity of 40 U/mg. The variable activity is shown to be related to the protein's propensity to aggregate and not to incomplete post-translational modification by coenzyme A and a phosphopantetheinyl transferase. The substrate specificities of this enzyme and the Class III PHA synthase from Allochromatium vinosum have been determined with nine analogs of varied chain length and branching, OH group position within the chain, and thioesters. The results suggest that in vitro, both PHA synthases are very specific and provide further support for their active site structural similarities. In vitro results differ from studies in vivo.

A case-control study of tattoos in young suicide victims as a possible marker of risk.

BACKGROUND: The goal was to examine tattooing in suicides, as tattoos have been associated with several risk factors for suicide. METHOD: A chart review of a three-year sample of 134 consecutive suicides in Mobile County, Alabama, was conducted. The prevalence of tattoos was compared between young (<30) white suicides and accidental deaths matched for age, gender and race, in a case-control study. RESULTS: Tattoos were found in 21% of suicides. Fifty-seven percent of young white suicides were tattooed compared to 29% of matched accidental deaths. LIMITATIONS: Findings are preliminary due to the small sample size. The study methodology precluded obtaining information of psychiatric diagnoses prior to death. CONCLUSIONS: Tattoos may be possible markers for lethality from both suicide and accidental death in young people, presumably because of shared risk factors such as substance abuse and personality disorder. Affective disorders should receive further, more specific studies. The clinical value of inquiring about tattoos in young people at risk of suicide needs further study.

Relationships among age-related differences in gap detection and word recognition.

The relationships among age-related differences in gap detection and word recognition in subjects with normal hearing or mild sensorineural hearing loss were explored in two studies. In the first study, gap thresholds were obtained for 40 younger and 40 older subjects. The gaps were carried by 150-ms, modulated, low-pass noise bursts with cutoff frequencies of 1 or 6 kHz. The noise bursts were presented at an overall level of 80 dB SPL in three background conditions. Mean gap thresholds ranged between 2.6 and 7.8 ms for the younger age group and between 3.4 and 10.0 ms for the older group. Mean gap thresholds were significantly larger for the older group in all six conditions. Gap thresholds were not significantly correlated with audiometric thresholds in either age group but the 1-kHz gap thresholds increased with age in the younger group. In the second study, the relationships among gap thresholds, spondee-in-babble thresholds, and audiometric thresholds of 66 subjects were examined. Compared with the older subjects, the younger group recognized the spondees at significantly lower (more difficult) spondee-to-babble ratios. In the younger group, spondee-in-babble thresholds were significantly correlated with gap thresholds in conditions of high-frequency masking. In the older group, spondee-in-babble thresholds, gap thresholds, and audiometric thresholds were not significantly correlated, but the spondee-in-babble thresholds and two audiometric thresholds increased significantly with age. These results demonstrate that significant age-related changes in auditory processing occur throughout adulthood. Specifically, age-related changes in temporal acuity may begin decades earlier than age-related changes in word recognition.

Remodeling of lung interstitium but not resistance vessels in canine pacing-induced heart failure.

We previously showed that pacing-induced heart failure in dogs results in an enhancement of pulmonary vascular reactivity. In the present study we hypothesized that enhanced matrix deposition and structural remodeling of lung resistance microvessels would underlie these functional changes. Using biochemical measures, we found no difference in the normalized lung content of hyaluronan, uronic acid, and collagen between control dogs and dogs paced for 1 mo, although lung dry weight and noncollagen protein content increased significantly in the paced group (P < 0.05). From separate Formalin-fixed lung lobes, 5-microm frozen sections were prepared and stained with Masson's trichrome, and vascular structure was evaluated using standard morphometric techniques. When perivascular fluid cuffs were excluded from the measure of wall thickness, collagen and media volume fractions in any size range did not differ between paced and control groups. Similarly, in the paced group, medial thickness in <400-microm arterial or venular microvessels did not vary significantly from that in the controls. In contrast, the relationship of interstitial fluid pressure to lung water was significantly shifted to the right in the paced group, such that normal tissue pressures were observed, despite the increased water content. We conclude that although 1 mo of pacing-induced heart failure results in altered interstitial function, the attendant pulmonary hypertension and/or hormonal responses are insufficient to induce medial hypertrophy or other remodeling of the extra-alveolar microvasculature.

The effect of temporal placement on gap detectability.

The detectability of a masked sinusoid increases as its onset approaches the temporal center of a masker. This study was designed to determine whether a similar change in detectability would occur for a silent gap as it was parametrically displaced from the onset of a noise burst. Gap thresholds were obtained for 13 subjects who completed five replications of each condition in 3 to 13 days. Six subjects were inexperienced listeners who ranged in age from 18 to 25 years; seven subjects were highly experienced and ranged in age from 20 to 78 years. The gaps were placed in 150-ms, 6-kHz, low-passed noise bursts presented at an overall level of 75 dB SPL; the bursts were digitally shaped at onset and offset with 10-ms cosine-squared rise-fall envelopes. The gated noise bursts were presented in a continuous, unfiltered, white noise floor attenuated to an overall level of 45 dB SPL. Gap onsets were parametrically delayed from the onset of the noise burst (defined as the first nonzero point on the waveform envelope) by 10, 11, 13, 15, 20, 40, 60, 110, 120, and 130 ms. Results of ANOVAs indicated that the mean gap thresholds were longer when the gaps were proximal to signal onset or offset and shorter when the gaps approached the temporal center of the noise burst. Also, the thresholds of the younger, highly experienced subjects were significantly shorter than those of the younger, inexperienced subjects, especially at placements close to signal onset or offset. The effect of replication (short-term practice) was not significant nor was the interaction between gap placement and replication. Post hoc comparisons indicated that the effect of gap placement resulted from significant decreases in gap detectability when the gap was placed close to stimulus onset and offset.

Inclusive instruction and learning for deaf students in postsecondary education.

This article explores how students who are deaf and their instructors experience mainstream college classes. Both quantitative and qualitative procedures were used to examine student access to information and their sense of belonging and engagement in learning. Instructors were asked to discuss their approach to teaching and any instructional modifications made to address the needs of deaf learners. Results indicate that deaf students viewed classroom communication and engagement in a similar manner as their hearing peers. Deaf students were more concerned about the pace of instruction and did not feel as much a part of the 'university family' as did their hearing peers. Faculty generally indicated that they made few if any modifications for deaf students and saw support service faculty as responsible for the success or failure of these students. We discuss results of these and additional findings with regard to barriers to equal access and strategies for overcoming these barriers.

The crystal structure of human cytosolic serine hydroxymethyltransferase: a target for cancer chemotherapy.

BACKGROUND: Serine hydroxymethyltransferase (SHMT) is a ubiquitous enzyme found in all prokaryotes and eukaryotes. As an enzyme of the thymidylate synthase metabolic cycle, SHMT catalyses the retro-aldol cleavage of serine to glycine, with the resulting hydroxymethyl group being transferred to tetrahydrofolate to form 5, 10-methylene-tetrahydrofolate. The latter is the major source of one-carbon units in metabolism. Elevated SHMT activity has been shown to be coupled to the increased demand for DNA synthesis in rapidly proliferating cells, particularly tumour cells. Consequently, the central role of SHMT in nucleotide biosynthesis makes it an attractive target for cancer chemotherapy. RESULTS: We have solved the crystal structure of human cytosolic SHMT by multiple isomorphous replacement to 2.65 A resolution. The monomer has a fold typical for alpha class pyridoxal 5'-phosphate (PLP) dependent enzymes. The tetramer association is best described as a 'dimer of dimers' where residues from both subunits of one 'tight' dimer contribute to the active site. CONCLUSIONS: The crystal structure shows the evolutionary relationship between SHMT and other alpha class PLP-dependent enzymes, as the fold is highly conserved. Many of the results of site-directed mutagenesis studies can easily be rationalised or re-interpreted in light of the structure presented here. For example, His 151 is not the catalytic base, contrary to the findings of others. A mechanism for the cleavage of serine to glycine and formaldehyde is proposed.

Purification, crystallization and preliminary X-ray analysis of human recombinant cytosolic serine hydroxymethyltransferase.

As an enzyme of the thymidylate synthase cycle, serine hydroxymethyltransferase (SHMT) has a key role in nucleotide biosynthesis. Elevated activities of SHMT have been correlated with the increased demand for nucleotide biosynthesis in tumors of human and rodent origin, making this enzyme a novel target for cancer chemotherapy. Here the purification and crystallization of recombinant human cytosolic SHMT are reported. Crystals belong to space group P6222 or P6422 with cell parameters a = b = 155.0, c = 235.5 A and diffract to at least 3.0 A resolution.

Tunable diode-pumped and frequency-doubled Cr:LiSAF lasers.

The performance of a diode-pumped Cr:LiSAF laser and its intracavity frequency-doubled operation is reported. Close to 1 W of quasi-cw power at 870 nm was obtained in multimode operation. Power in excess of 20-mW cw of TEM(00) second-harmonic power at 435 nm has also been obtained by using a lithium triborate crystal with an infrared-to-visible conversion efficiency of 33%. This result is believed to be the highest yet reported for a true cw blue output from a diode-pumped Cr:LiSAF system. However, the maximum attainable output power was limited by thermal fluorescence quenching. The effect of the pump size on the temperature rise and on the small-signal gain is investigated.

Age-related changes in temporal gap detection.

The purpose of this study was to clarify and extend the results of earlier studies of age-related effects on temporal resolution by precisely matching young and old subjects with normal hearing and measuring gap thresholds in a variety of listening conditions. Younger subjects were between 17 and 40 years of age, older subjects between 64 and 77 years. Signals were noisebursts which varied in upper-cutoff frequency, overall level, and sinusoidal-amplitude-modulation depth. Signals were presented in quiet, in a noise floor, and with a gated-high-frequency masker in a noise floor. Significant main effects were found for signal frequency, intensity, modulation, age, and background condition. Mean gap thresholds ranged between 2.1 and 10.1 ms and were larger for the older subjects in all 24 conditions. In some conditions, introduction of a noise floor increased the gap thresholds of the older subjects relative to those of the younger. Analyses of individual data support the conclusion that the mean differences between groups reflect shifts in the distributions of gap thresholds of the older subjects towards poorer temporal resolution.