Isoniazid urine spectrophotometry for prediction of serum pharmacokinetics in adults with TB.

BACKGROUND: Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. METHODS: We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0-4, 4-8, and 8-24 h intervals, with INH concentrations measured using colorimetric methods. RESULTS: The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak <3.0 mg/L) were as follows: 0-4 h interval (AUC 0.85, 95% CI 0.7-0.96), 0-8 h interval (AUC 0.85, 95% CI 0.71-0.96), and 0-24 h urine collection interval (AUC 0.84, 95% CI 0.68-0.96). CONCLUSION: Urine spectrophotometry may improve feasibility of personalized dosing in high TB burden regions but requires further study of target attainment following dose adjustment based on a urine threshold.

CONTEXTE: L'isoniazide (INH) est un médicament important dans de nombreux schémas thérapeutiques contre la TB, et des résultats thérapeutiques défavorables peuvent être dus à une pharmacocinétique sous-optimale. L'ajustement de la dose peut être personnalisé en mesurant les concentrations sériques maximales ; cependant, le processus implique la conservation de la chaîne du froid et des techniques de laboratoire telles que la chromatographie liquide (LC)/spectrométrie de masse (MS), qui ne sont pas disponibles dans de nombreuses régions à forte charge de morbidité. La spec-trophotométrie urinaire pourrait constituer une alternative peu coûteuse avec des méthodes d'échantillonnage et de quantification simples. MÉTHODES: Nous avons recruté 56 patients adultes sous traitement pour une TB active. Le sérum a été prélevé à 0, 1, 2, 4, 6 et 8 h pour mesurer les concentrations d'INH à l'aide de méthodes LC-MS/MS validées. L'urine a été prélevée à des intervalles de 0­4, 4­8 et 8­24 h, et les concentrations d'INH ont été mesurées à l'aide de méthodes colorimétriques. RÉSULTATS: La concentration sérique maximale médiane et l'exposition sérique totale sur 24 h étaient respectivement de 4,8 mg/L et de 16,4 mg*heure/L. L'aire sous les courbes caractéristiques de l'opérateur récepteur a été mesurée à l'aide de méthodes color-imétriques. Les aires sous les courbes caractéristiques des récepteurs pour les valeurs urinaires prédisant une concentration sérique sous-thérapeutique (pic <3,0 mg/L) étaient les suivantes : intervalle 0­4 h (AUC 0,85 ; IC 95% 0,7­0,96), intervalle 0­8 h (AUC 0,85 ; IC 95% 0,71­0,96), et intervalle de collecte d'urine 0­24 h (AUC 0,84 ; IC 95% 0,68­0,96). CONCLUSION: La spectrophotométrie urinaire peut améliorer la faisabilité d'un dosage personnalisé dans les régions à forte charge de TB, mais nécessite une étude plus approfondie de l'atteinte de la cible après l'ajustement de la dose sur la base d'un seuil urinaire.

A time series analysis of milk productivity in US dairy states.

As US dairy cow production evolves, it is important to characterize trends and seasonal patterns to project amounts and fluctuations in milk and milk components by states or regions. Hence, this study aimed to (1) quantify historical trends and seasonal patterns of milk and milk components production associated with calving date by parities and states; (2) classify parities and states with similar trends and seasonal patterns into clusters; and (3) summarize the general pattern for each cluster for further application in simulation models. Our data set contained 9.18 million lactation records from 5.61 million Holstein cows distributed in 17 states during the period January 2006 to December 2016. Each record included a cow's total milk, fat, and protein yield during a lactation. We used time series decomposition to obtain each state's annual trend and seasonal pattern in milk productivity for each parity. Then, we classified states and parities with agglomerative hierarchical clustering into groups according to 2 methods: (1) dynamic time warping on the original time series and (2) Euclidean distance on extracted features of trend and seasonality from the decomposition. Results showed distinguishable trends and seasonality for all states and lactation numbers for all response variables. The clusters and cluster centroid pattern showed a general upward trend for all yields [energy-corrected milk (ECM), milk, fat, and protein] and a steady trend for fat and protein percent for all states except Texas. We also found a larger seasonality amplitude for all yields (ECM, milk, fat, and protein) from higher lactation numbers and a similar amplitude for fat and protein percent across lactation numbers. The results could be used for advising management decisions according to farm productivity goals. Furthermore, the trend and seasonality patterns could be used to adjust the production level in a specific state, year, and season for farm simulations to accurately project milk and milk components production.

Multivariable time series classification for clinical mastitis detection and prediction in automated milking systems.

In this study, we developed a machine learning framework to detect clinical mastitis (CM) at the current milking (i.e., the same milking) and predict CM at the next milking (i.e., one milking before CM occurrence) at the quarter level. Time series quarter-level milking data were extracted from an automated milking system (AMS). For both CM detection and prediction, the best classification performance was obtained from the decision tree-based ensemble models. Moreover, applying models on a data set containing data from the current milking and past 9 milkings before the current milking showed the best accuracy for detecting CM; modeling with a data set containing data from the current milking and past 7 milkings before the current milking yielded the best results for predicting CM. The models combined with oversampling methods resulted in specificity of 95 and 93% for CM detection and prediction, respectively, with the same sensitivity (82%) for both scenarios; when lowering specificity to 80 to 83%, undersampling techniques facilitated models to increase sensitivity to 95%. We propose a feasible machine learning framework to identify CM in a timely manner using imbalanced data from an AMS, which could provide useful information for farmers to manage the negative effects of CM.

A stochastic animal life cycle simulation model for a whole dairy farm system model: Assessing the value of combined heifer and lactating dairy cow reproductive management programs.

This analysis introduces a stochastic herd simulation model and evaluates the estimated reproductive and economic performance of combinations of reproductive management programs for both heifers and lactating cows. The model simulates the growth, reproductive performance, production, and culling for individual animals and integrates individual animal outcomes to represent herd dynamics daily. The model has an extensible structure, allowing for future modification and expansion, and has been integrated into the Ruminant Farm Systems model, a holistic dairy farm simulation model. The herd simulation model was used to compare outcomes of 10 reproductive management scenarios based on common practices on US farms with combinations of estrous detection (ED) and artificial insemination (AI), synchronized estrous detection (synch-ED) and AI, timed AI (TAI, 5-d CIDR-Synch) programs for heifers; and ED, a combination of ED and TAI (ED-TAI, Presynch-Ovsynch), and TAI (Double-Ovsynch) with or without ED during the reinsemination period for lactating cows. The simulation was run for a 1,000-cow (milking and dry) herd for 7 yr, and we used the outcomes from the final year to evaluate results. The model accounted for incomes from milk, sold calves, and culled heifers and cows, as well as costs from breeding, AI, semen, pregnancy diagnosis, and calf, heifer, and cow feed. We found that the interaction between heifer and lactating dairy cow reproductive management programs influences herd economic performance primarily due to heifer rearing costs and replacement heifer supply. The greatest net return (NR) was achieved when combining heifer TAI and cow TAI without ED during the reinsemination period, whereas the lowest NR was obtained when combining heifer synch-ED with cow ED.

Investigating the effect of temporal, geographic, and management factors on US Holstein lactation curve parameters.

We fit the Wood's lactation model to an extensive database of test-day milk production records of US Holstein cows to obtain lactation-specific parameter estimates and investigated the effects of temporal, spatial, and management factors on lactation curve parameters and 305-d milk yield. Our approach included 2 steps as follows: (1) individual animal-parity parameter estimation with nonlinear least-squares optimization of the Wood's lactation curve parameters, and (2) mixed-effects model analysis of 8,595,413 sets of parameter estimates from individual lactation curves. Further, we conducted an analysis that included all parities and a separate analysis for first lactation heifers. Results showed that parity had the most significant effect on the scale (parameter a), the rate of decay (parameter c), and the 305-d milk yield. The month of calving had the largest effect on the rate of increase (parameter b) for models fit with data from all lactations. The calving month had the most significant effect on all lactation curve parameters for first lactation models. However, age at first calving, year, and milking frequency accounted for a higher proportion of the variance than month for first lactation 305-d milk yield. All parameter estimates and 305-d milk yield increased as parity increased; parameter a and 305-d milk yield rose, and parameters b and c decreased as year and milking frequency increased. Calving month estimates parameters a, b, c, and 305-d milk yield were the lowest values for September, May, June, and July, respectively. The results also indicated the random effects of herd and cow improved model fit. Lactation curve parameter estimates from the mixed-model analysis of individual lactation curve fits describe well US Holstein lactation curves according to temporal, spatial, and management factors.

Synthetic amyloid beta does not induce a robust transcriptional response in innate immune cell culture systems.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aß) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aß is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e., microglia), which culminates in neuronal damage and cognitive decline. To test this hypothesis, many in vitro systems have been established to study Aß-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale. METHODS: We used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aß or LPS and INFγ. RESULTS: We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell model that best resembles primary microglia. Surprisingly, synthetic Aß does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aß formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes that resemble many, but not all, aspects of the transcriptomic profiles of disease associated microglia (DAM) present in the AD brain. CONCLUSIONS: These results suggest that synthetic Aß treatment of innate immune cell cultures does not recapitulate transcriptional profiles observed in microglia from AD brains. In contrast, treating IMGL with LPS and INFγ induces transcriptional changes similar to those observed in microglia detected in AD brains.

The application of nonlinear programming on ration formulation for dairy cattle.

The objective of this study was to compare the application of iterative linear programming (iteLP), sequential quadratic programming (SQP), and mixed-integer nonlinear programming-based deterministic global optimization (MINLP_DGO) on ration formulation for dairy cattle based on Nutrient Requirements of Dairy Cattle (NRC, 2001). Least-cost diets were formulated for lactating cows, dry cows, and heifers. Nutrient requirements including energy, protein, and minerals, along with other limitations on dry matter intake, neutral detergent fiber, and fat were considered as constraints. Five hundred simulations were conducted, with each simulation randomly selecting 3 roughages and 5 concentrates from the feed table in NRC (2001) as the feed resource for each of 3 animal groups. Among the 500 simulations for lactating cows, 57, 45, and 21 simulations did not yield a feasible solution when using iteLP, SQP, and MINLP_DGO, respectively. All the simulations for dry cows and heifers were feasible when using SQP and MINLP_DGO, but 49 and 11 infeasible simulations occurred when using iteLP for dry cows and heifers, respectively. The average ration costs per animal per day of the feasible solutions obtained by iteLP, SQP, and MINLP_DGO were $4.78 (±0.71), $4.45 (±0.65), and $4.44 (±0.65) for lactating cows; $2.39 (±0.52), $1.48 (±0.26), and $1.48 (±0.26) for dry cows; and $0.98 (±0.72), $0.97 (±0.15), and $0.91 (±0.14) for heifers, respectively. The average computation time of iteLP, SQP, and MINLP_DGO were 0.59 (±1.87) s, 1.15 (±0.62) s, and 58.69 (±68.45) s for lactating cows; 0.041 (±0.070) s, 0.76 (±0.37) s, and 14.84 (±39.09) s for dry cows; and 1.60 (±2.90) s, 0.51 (±0.19) s, and 16.45 (±45.56) s for heifers, respectively. In conclusion, iteLP had limited capability of formulating least-cost diets when nonlinearity existed in the constraints. Both SQP and MINLP_DGO handled the nonlinear constraints well, with SQP being faster, whereas MINLP_DGO was able to return a feasible solution under some situations where SQP could not.

The stress in a dispersion of mutually polarizable spheres.

Dispersions of dielectric and paramagnetic nanoparticles polarize in response to an external electric or magnetic field and can form chains or other ordered structures depending on the strength of the applied field. The mechanical properties of these materials are of interest for a variety of applications; however, computational studies in this area have so far been limited. In this work, we derive expressions for two important properties for dispersions of polarizable spherical particles with dipoles induced by a uniform external field-the isothermal stress tensor and the pressure. Numerical calculations of these quantities, evaluated using a spectrally accurate Ewald summation method, are validated using thermodynamic integration. We also compare the stress obtained using the mutual dipole model, which accounts for the mutual polarization of particles, to the stress expected from calculations using a fixed dipole model, which neglects mutual polarization. We find that as the conductivity of the particles increases relative to the surrounding medium, the fixed dipole model does not accurately describe the dipolar contribution to the stress. The thermodynamic pressure, calculated from the trace of the stress tensor, is compared to the virial expression for the pressure, which is simpler to calculate but inexact. We find that the virial pressure and the thermodynamic pressure differ, especially in suspensions with a high volume fraction of particles.

Diagnostic applications of molecular and serological assays for bluetongue and African horse sickness.

The availability of rapid, highly sensitive and specific molecular and serologic diagnostic assays, such as competitive enzyme-linked immunosorbent assay (cELISA), has expedited the diagnosis of emerging transboundary animal diseases, including bluetongue (BT) and African horse sickness (AHS), and facilitated more thorough characterisation of their epidemiology. The development of assays based on real-time, reverse-transcription polymerase chain reaction (RT-PCR) to detect and identify the numerous serotypes of BT virus (BTV) and AHS virus (AHSV) has aided in-depth studies of the epidemiology of BTV infection in California and AHSV infection in South Africa. The subsequent evaluation of pan-serotype, real-time, RT-PCR-positive samples through the use of serotype-specific RT-PCR assays allows the rapid identification of virus serotypes, reducing the need for expensive and time-consuming conventional methods, such as virus isolation and serotype-specific virus neutralisation assays. These molecular assays and cELISA platforms provide tools that have enhanced epidemiologic surveillance strategies and improved our understanding of potentially altered Culicoides midge behaviour when infected with BTV. They have also supported the detection of subclinical AHSV infection of vaccinated horses in South Africa. Moreover, in conjunction with whole genome sequence analysis, these tests have clarified that the mechanism behind recent outbreaks of AHS in the AHS-controlled area of South Africa was the result of the reversion to virulence and/or genome reassortment of live attenuated vaccine viruses. This review focuses on the use of contemporary molecular diagnostic assays in the context of recent epidemiologic studies and explores their advantages over historic virus isolation and serologic techniques.

La disponibilité d'essais diagnostiques moléculaires et sérologiques rapides, hautement sensibles et spécifiques tels que l'épreuve immuno-enzymatique de compétition (ELISAc), a accéléré le diagnostic des maladies animales transfrontalières émergentes, dont la fièvre catarrhale ovine (FCO) et la peste équine, et contribué à dresser un tableau épidémiologique plus complet de ces maladies. Grâce à la mise au point d'essais basés sur l'amplification en chaîne par polymérase en temps réel couplée à une transcription inverse (RT­PCR) qui permettent de détecter et d'identifier les nombreux sérotypes du virus de la fièvre catarrhale du mouton et du virus de la peste équine, des études approfondies ont pu être conduites sur l'épidémiologie de l'infection par le virus de la fièvre catarrhale du mouton en Californie et de l'infection par le virus de la peste équine en Afrique du Sud. L'évaluation postérieure des échantillons positifs à une RT­PCR en temps réel de groupe (détectant le virus quel que soit le sérotype) au moyen de RT­PCR spécifiques de chaque sérotype permet d'identifier rapidement le sérotype causal et de limiter le recours à des méthodes classiques onéreuses et chronophages comme l'isolement viral ou les essais de neutralisation virale spécifiques de chaque sérotype. Les outils fournis par ces essais moléculaires et par les plateformes ELISAc ont renforcé les stratégies de surveillance épidémiologique et permis de mieux connaître les altérations potentielles de comportement chez les tiques Culicoides infectées par le virus de la fièvre catarrhale du mouton. Ils ont également contribué à détecter les cas d'infection asymptomatique par le virus de la peste équine chez des chevaux vaccinés en Afrique du Sud. En outre, associés avec l'analyse de séquences du génome entier, ces tests ont révélé que le mécanisme sous-jacent aux récents foyers de peste équine dans la zone de contrôle en Afrique du Sud correspondait à une réversion vers la virulence et/ou à un réassortiment du génome des souches de vaccin à virus vivant atténué. Les auteurs passent en revue l'utilisation des essais de diagnostic moléculaire de nouvelle génération dans le contexte de récentes études épidémiologiques et cherchent à établir leurs avantages par rapport aux techniques classiques d'isolement viral et de recherche sérologique.

La existencia de ensayos moleculares y serológicos de diagnóstico rápidos y de gran sensibilidad y especificidad, como el ensayo inmunoenzimático de competición (ELISAc), ha acelerado el diagnóstico de enfermedades animales transfronterizas emergentes, como la lengua azul o la peste equina, y facilitado una caracterización más exhaustiva de su epidemiología. La creación de ensayos basados en la reacción en cadena de la polimerasa acoplada a transcripción inversa (RT?PCR) en tiempo real para detectar y caracterizar los numerosos serotipos de los virus de la lengua azul y la peste equina ha ayudado a estudiar a fondo la epidemiología de sendos episodios infecciosos causados por el virus de la lengua azul en California y por el virus de la peste equina en Sudáfrica. El subsiguiente análisis de las muestras positivas a la prueba de RT?PC en tiempo real de cualquier serotipo con empleo de ensayos RT?PCR dirigidos específicamente contra uno u otro serotipo permite identificar rápidamente los serotipos víricos, lo que hace menos necesario el uso de métodos convencionales más caros y largos, como el aislamiento del virus o técnicas de neutralización vírica adaptadas específicamente a un serotipo. Estos dispositivos de ensayo molecular o de ELISAc ponen a nuestra disposición herramientas que potencian las estrategias de vigilancia epidemiológica y ayudan a conocer mejor las eventuales alteraciones del comportamiento de los jejenes Culicoides al ser infectados por el virus de la lengua azul. Estas técnicas han ayudado también a detectar en Sudáfrica casos de infección asintomática por el virus de la peste equina en caballos vacunados. Estas pruebas, además, empleadas en combinación con el análisis de secuencias genómicas completas, han servido para aclarar que el mecanismo subyacente a los recientes brotes de peste equina surgidos en la zona de Sudáfrica donde la enfermedad estaba bajo control fue fruto de la reversión a la virulencia y/o el reordenamiento genómico de virus vacunales atenuados. Los autores, centrándose en el uso de modernos ensayos moleculares de diagnóstico como parte de recientes estudios epidemiológicos, examinan las ventajas que ofrecen en comparación con las tradicionales técnicas serológicas y de aislamiento vírico.

Twin chorionicity-specific population birth-weight charts adjusted for estimated fetal weight.

OBJECTIVES: To construct chorionicity-specific birth-weight reference charts for dichorionic diamniotic (DCDA) and monochorionic diamniotic (MCDA) twin pregnancies, incorporating estimated-fetal-weight (EFW) data in order to adjust for the relationship between suboptimal growth and preterm delivery. An additional aim was to determine if the inclusion of complicated twin pregnancies impacts on the reference charts produced. METHODS: The inclusion criteria for this retrospective cohort study were twin pregnancy of known DCDA or MCDA chorionicity, known pregnancy outcome, last ultrasound scan within 14 days before birth and delivery between 25 and 38 weeks' gestation (Analysis A). An analysis was also conducted excluding pregnancies with complications recorded (Analysis B). Previously published twin EFW reference ranges were used in the analysis. A joint statistical model for EFW and observed birth weight for each pregnancy was created in order to estimate population birth-weight reference ranges corresponding to the distribution expected if all pregnancies delivered at any given gestational age. It was not assumed that the median EFW was equal to birth weight for any given gestational age. The models were fitted using a Bayesian approach. RESULTS: We retrieved data on 1664 twin pregnancies, of which 707 DCDA and 241 MCDA pregnancies met the inclusion criteria. In Analysis A, the estimated population median birth weight was similar to the median EFW at around 27 weeks' gestation but fell below the EFW values with increasing gestation, being 156 g lower in both DCDA and MCDA pregnancies at 35 weeks; this finding was confirmed by direct comparison of the last EFW and birth-weight values in each pregnancy. When the analysis was repeated after excluding complicated twin pregnancies (Analysis B), compared with Analysis A, there was very little difference in the median birth-weight results obtained across gestation. The largest absolute difference between Analyses A and B for DCDA twins was at 31, 32 and 33 weeks, with a 9-g lower median birth weight in Analysis A compared with Analysis B. The largest absolute difference for MCDA twins was greater than that for DCDA twins, with a 21-g lower median birth weight at 25 weeks in Analysis A compared with Analysis B. CONCLUSIONS: We have established population chorionicity-specific birth-weight reference charts for DCDA and MCDA twin pregnancies, corresponding to the range expected were all pregnancies to deliver at any given gestational age. In this population of twins, the median birth weight was consistently lower than that reported for singletons, and there was variation in the median birth weight at different gestational ages according to chorionicity. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. - Legal Statement: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Perinatal outcome of pregnancy complicated by twin anemia-polycythemia sequence: systematic review and meta-analysis.

OBJECTIVE: To report the perinatal outcome of monochorionic diamniotic (MCDA) twin pregnancies complicated by twin anemia-polycythemia sequence (TAPS), according to the type of TAPS (spontaneous or postlaser) and the management option adopted. METHODS: MEDLINE, EMBASE and The Cochrane Library databases were searched for studies reporting on the outcome of twin pregnancies complicated by TAPS. Inclusion criteria were non-anomalous MCDA twin pregnancies with a diagnosis of TAPS. The primary outcome was perinatal mortality; secondary outcomes were neonatal morbidity and preterm birth (PTB). The outcomes were stratified according to the type of TAPS (spontaneous or following laser treatment for twin-twin transfusion syndrome) and the management option adopted (expectant, laser surgery, intrauterine transfusion (IUT) or selective reduction (SR)). Random-effects meta-analysis of proportions was used to analyze the data. RESULTS: Perinatal outcome was assessed according to whether TAPS occurred spontaneously or after laser treatment in 506 pregnancies (38 studies). Intrauterine death (IUD) occurred in 5.2% (95% CI, 3.6-7.1%) of twins with spontaneous TAPS and in 10.2% (95% CI, 7.4-13.3%) of those with postlaser TAPS, while the corresponding rates of neonatal death were 4.0% (95% CI, 2.6-5.7%) and 9.2% (95% CI, 6.6-12.3%), respectively. Severe neonatal morbidity occurred in 29.3% (95% CI, 25.6-33.1%) of twins after spontaneous TAPS and in 33.3% (95% CI, 17.4-51.8%) after postlaser TAPS, while the corresponding rates of severe neurological morbidity were 4.0% (95% CI, 3.5-5.7%) and 11.1% (95% CI, 6.2-17.2%), respectively. PTB complicated 86.3% (95% CI, 77.2-93.3%) of pregnancies with spontaneous TAPS and all cases with postlaser TAPS (100% (95% CI, 84.3-100%)). Iatrogenic PTB was more frequent than spontaneous PTB in both groups. Perinatal outcome was assessed according to the management option adopted in 417 pregnancies (21 studies). IUD occurred in 9.8% (95% CI, 4.3-17.1%) of twins managed expectantly and in 13.1% (95% CI, 9.2-17.6%), 12.1% (95% CI, 7.7-17.3%) and 7.6% (95% CI, 1.3-18.5%) of those treated with laser surgery, IUT and SR, respectively. Severe neonatal morbidity affected 27.3% (95% CI, 13.6-43.6%) of twins in the expectant-management group, 28.7% (95% CI, 22.7-35.1%) of those in the laser-surgery group, 38.2% (95% CI, 18.3-60.5%) of those in the IUT group and 23.3% (95% CI, 10.5-39.2%) of those in the SR group. PTB complicated 80.4% (95% CI, 59.8-94.8%), 73.4% (95% CI, 48.1-92.3%), 100% (95% CI, 76.5-100%) and 100% (95% CI, 39.8-100%) of pregnancies after expectant management, laser surgery, IUT and SR, respectively. CONCLUSIONS: The present meta-analysis provides pooled estimates of the risks of perinatal mortality, neonatal morbidity and PTB in twin pregnancies complicated by TAPS, stratified by the type of TAPS and the management option adopted. Although a direct comparison could not be performed, the results from this systematic review suggest that spontaneous TAPS may have a better prognosis than postlaser TAPS. No differences in terms of mortality and morbidity were observed when comparing different management options for TAPS, although these findings should be interpreted with caution in view of the limitations of the included studies. Individualized prenatal management, taking into account the severity of TAPS and gestational age, is currently the recommended strategy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Transcriptional response of human articular chondrocytes treated with fibronectin fragments: an in vitro model of the osteoarthritis phenotype.

OBJECTIVE: Fibronectin is a matrix protein that is fragmented during cartilage degradation in osteoarthritis (OA). Treatment of chondrocytes with fibronectin fragments (FN-f) has been used to model OA in vitro, but the system has not been fully characterized. This study sought to define the transcriptional response of chondrocytes to FN-f, and directly compare it to responses traditionally observed in OA. DESIGN: Normal human femoral chondrocytes isolated from tissue donors were treated with either FN-f or PBS (control) for 3, 6, or 18 h. RNA-seq libraries were compared between time-matched FN-f and control samples in order to identify changes in gene expression over time. Differentially expressed genes were compared to a published OA gene set and used for pathway, transcription factor motif, and kinome analysis. RESULTS: FN-f treatment resulted in 3,914 differentially expressed genes over the time course. Genes that are up- or downregulated in OA were significantly up- (P < 0.00001) or downregulated (P < 0.0004) in response to FN-f. Early response genes were involved in proinflammatory pathways, whereas many late response genes were involved in ferroptosis. The promoters of upregulated genes were enriched for NF-κB, AP-1, and IRF motifs. Highly upregulated kinases included CAMK1G, IRAK2, and the uncharacterized kinase DYRK3, while growth factor receptors TGFBR2 and FGFR2 were downregulated. CONCLUSIONS: FN-f treatment of normal human articular chondrocytes recapitulated many key aspects of the OA chondrocyte phenotype. This in vitro model is promising for future OA studies, especially considering its compatibility with genomics and genome-editing techniques.

Phosphorylation state of pyruvate dehydrogenase and metabolite levels in turkey skeletal muscle in normal and pale, soft, exudative meats.

1. Turkey production has increased dramatically as genetic selection has succeeded in increasing body weight and muscle yield to fulfil increasing consumer demand. However, producing fast-growing, heavily muscled birds is linked to increased heat stress susceptibility and can result in pale, soft, exudative (PSE) meat. Previous studies indicated that pyruvate dehydrogenase kinase 4 (PDK4) is significantly reduced in PSE samples, suggesting this as a candidate gene associated with the development of this problem.2. The objective of this study was to determine whether pre-market thermal challenge results in PSE meat as a result of differential expression of PDK4. Two genetic lines of turkeys were used in this study; the Randombred Control Line 2 (RBC2) and a commercial line. Turkeys were exposed to a pre-market thermal challenge of 12 h at 35°C followed by 12 h at 27°C for 5 d. Birds were slaughtered and processed according to industry standards. Pectoralis major samples were categorised as PSE or normal based on marinade uptake and cook loss indicators. In the first experiment, the relative expression of pyruvate dehydrogenase (PDH) and the phosphorylation state of PDH in normal and PSE turkey meat were analysed by western blotting. In the second experiment, the same samples were used to measure metabolite levels at 5 min post-mortem, comparing the normal to the PSE samples.3. The results of the first experiment showed that PSE samples had significantly lower total PDH (P = 0.029) compared to normal meat. However, there was no significant difference in the degree of phosphorylation of sites 1, 2 or 3. In the second experiment, there were no significant differences in glycogen, lactate, glycolytic potential or ATP when comparing PSE to control samples.4. These results suggested that a reduction in PDK4 expression alone does not explain the development of PSE meat.

Forecasted attribution of the human influence on Hurricane Florence.

Changes in extreme weather, such as tropical cyclones, are one of the most serious ways society experiences the impact of climate change. Advance forecasted conditional attribution statements, using a numerical model, were made about the anthropogenic climate change influence on an individual tropical cyclone, Hurricane Florence. Mean total overland rainfall amounts associated with the forecasted storm's core were increased by 4.9 ± 4.6% with local maximum amounts experiencing increases of 3.8 ± 5.7% due to climate change. A slight increase in the forecasted storm size of 1 to 2% was also attributed. This work reviews our forecasted attribution statement with the benefit of hindsight, demonstrating credibility of advance attribution statements for tropical cyclones.

Core outcome set for studies investigating management of selective fetal growth restriction in twins.

OBJECTIVE: Selective fetal growth restriction (sFGR) occurs in monochorionic twin pregnancies when unequal placental sharing leads to restriction in the growth of just one twin. Management options include laser separation of the fetal circulations, selective reduction or expectant management, but what constitutes the best treatment is not yet known. New trials in this area are urgently needed but, in this rare and complex group, maximizing the relevance and utility of clinical research design and outputs is paramount. A core outcome set ensures standardized outcome collection and reporting in future research. The objective of this study was to develop a core outcome set for studies evaluating treatments for sFGR in monochorionic twins. METHODS: An international steering group of clinicians, researchers and patients with experience of sFGR was established to oversee the process of development of a core outcome set for studies investigating the management of sFGR. Outcomes reported in the literature were identified through a systematic review and informed the design of a three-round Delphi survey. Clinicians, researchers, and patients and family representatives participated in the survey. Outcomes were scored on a Likert scale from 1 (limited importance for making a decision) to 9 (critical for making a decision). Consensus was defined a priori as a Likert score of ≥ 8 in the third round of the Delphi survey. Participants were then invited to take part in an international meeting of stakeholders in which the modified nominal group technique was used to consider the consensus outcomes and agree on a final core outcome set. RESULTS: Ninety-six outcomes were identified from 39 studies in the systematic review. One hundred and three participants from 23 countries completed the first round of the Delphi survey, of whom 88 completed all three rounds. Twenty-nine outcomes met the a priori criteria for consensus and, along with six additional outcomes, were prioritized in a consensus development meeting, using the modified nominal group technique. Twenty-five stakeholders participated in this meeting, including researchers (n = 3), fetal medicine specialists (n = 3), obstetricians (n = 2), neonatologists (n = 3), midwives (n = 4), parents and family members (n = 6), patient group representatives (n = 3), and a sonographer. Eleven core outcomes were agreed upon. These were live birth, gestational age at birth, birth weight, intertwin birth-weight discordance, death of surviving twin after death of cotwin, loss during pregnancy or before final hospital discharge, parental stress, procedure-related adverse maternal outcome, length of neonatal stay in hospital, neurological abnormality on postnatal imaging and childhood disability. CONCLUSIONS: This core outcome set for studies investigating the management of sFGR represents the consensus of a large and diverse group of international collaborators. Use of these outcomes in future trials should help to increase the clinical relevance of research on this condition. Consensus agreement on core outcome definitions and measures is now required. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Consensus diagnostic criteria and monitoring of twin anemia-polycythemia sequence: Delphi procedure.

OBJECTIVES: Twin anemia-polycythemia sequence (TAPS) is associated with increased perinatal morbidity and mortality. Inconsistencies in the diagnostic criteria for TAPS exist, which hinder the ability to establish robust evidence-based management or monitoring protocols. The main aim of this study was to determine, by expert consensus using a Delphi procedure, the key diagnostic features and optimal monitoring approach for TAPS. METHODS: A Delphi process was conducted among an international panel of experts on TAPS. Panel members were provided with a list of literature-based parameters for diagnosing and monitoring TAPS. They were asked to rate the importance of the parameters on a five-point Likert scale. Consensus was sought to determine the cut-off values for accepted parameters, as well as parameters used in the monitoring of and assessment of outcome in twin pregnancy complicated by TAPS. RESULTS: A total of 132 experts were approached. Fifty experts joined the first round, of whom 33 (66%) completed all three rounds. There was agreement that the monitoring interval for the development of TAPS should be every 2 weeks and that the severity should be assessed antenatally using a classification system based on middle cerebral artery (MCA) peak systolic velocity (PSV), but there was no agreement on the gestational age at which to start monitoring. Once the diagnosis of TAPS is made, monitoring should be scheduled weekly. For the antenatal diagnosis of TAPS, the combination of MCA-PSV ≥ 1.5 MoM in the anemic twin and ≤ 0.8 MoM in the polycythemic twin was agreed. Alternatively, MCA-PSV discordance ≥ 1 MoM can be used to diagnose TAPS. Postnatally, hemoglobin difference ≥ 8 g/dL and intertwin reticulocyte ratio ≥ 1.7 were agreed criteria for diagnosis of TAPS. There was no agreement on the cut-off of MCA-PSV or its discordance for prenatal intervention. The panel agreed on prioritizing perinatal and long-term survival outcomes in follow-up studies. CONCLUSIONS: Consensus-based diagnostic features of TAPS, as well as cut-off values for the parameters involved, were agreed upon by a panel of experts. Future studies are needed to validate these diagnostic features before they can be used in clinical trials of interventions. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.