'Getting control of Corona takes many angles': COVID-19 vaccine knowledge, attitudes and beliefs among refugee/immigrant/migrant communities in four US cities.

The objectives of the study were to (i) document refugee, immigrant and migrant (RIM) communities' knowledge, attitudes and beliefs (KABs) related to the Coronavirus disease (COVID-19) vaccine and (ii) identify best practices for developing and disseminating culturally and linguistically responsive health messaging addressing those KABs. Thirteen online focus groups (OFGs) in 10 languages were conducted. Each OFG was conducted in the participants' native language. OFGs were recorded, transcribed, translated and uploaded to qualitative software for coding. A thematic analysis was conducted. Results suggest that while there was some variation between different language groups (e.g. whether religious leaders were seen as trusted sources of information about COVID), there were also important commonalities. Most language groups (i) alluded to hearing about or having gaps in knowledge about COVID-19/the COVID-19 vaccine, (ii) reported hearing negative or conflicting stories about the vaccine and (iii) shared concerns about the negative side effects of the vaccine. There continues to be a need for health messaging in RIM communities that is culturally and linguistically concordant and follows health literacy guidelines. Message content about the COVID-19 vaccine should focus on vaccine importance, effectiveness and safety, should be multimodal and should be primarily delivered by healthcare professionals and community members who have already been vaccinated.

Prefrontal neuronal assemblies temporally control fear behaviour.

Precise spike timing through the coordination and synchronization of neuronal assemblies is an efficient and flexible coding mechanism for sensory and cognitive processing. In cortical and subcortical areas, the formation of cell assemblies critically depends on neuronal oscillations, which can precisely control the timing of spiking activity. Whereas this form of coding has been described for sensory processing and spatial learning, its role in encoding emotional behaviour remains unknown. Fear behaviour relies on the activation of distributed structures, among which the dorsal medial prefrontal cortex (dmPFC) is known to be critical for fear memory expression. In the dmPFC, the phasic activation of neurons to threat-predicting cues, a spike-rate coding mechanism, correlates with conditioned fear responses and supports the discrimination between aversive and neutral stimuli. However, this mechanism does not account for freezing observed outside stimuli presentations, and the contribution of a general spike-time coding mechanism for freezing in the dmPFC remains to be established. Here we use a combination of single-unit and local field potential recordings along with optogenetic manipulations to show that, in the dmPFC, expression of conditioned fear is causally related to the organization of neurons into functional assemblies. During fear behaviour, the development of 4 Hz oscillations coincides with the activation of assemblies nested in the ascending phase of the oscillation. The selective optogenetic inhibition of dmPFC neurons during the ascending or descending phases of this oscillation blocks and promotes conditioned fear responses, respectively. These results identify a novel phase-specific coding mechanism, which dynamically regulates the development of dmPFC assemblies to control the precise timing of fear responses.

Tendon-derived extracellular matrix induces mesenchymal stem cell tenogenesis via an integrin/transforming growth factor-ß crosstalk-mediated mechanism.

Treatment of tendon injuries is challenging. To develop means to augment tendon regeneration, we have previously prepared a soluble, low immunogenic (DNA-free), tendon extracellular matrix fraction (tECM) by urea extraction of juvenile bovine tendons, which is capable of enhancing transforming growth factor-ß (TGF-ß) mediated tenogenesis in human adipose-derived stem cells (hASCs). Here, we aimed to elucidate the mechanism of tECM-driven hASC tenogenic differentiation in vitro, focusing on the integrin and TGF-ß/SMAD pathways. Our results showed that tECM promoted hASC proliferation and tenogenic differentiation in vitro based on tenogenesis-associated markers. tECM also induced higher expression of several integrin subunits and TGF-ß receptors, and nuclear translocation of p-SMAD2 in hASCs. Pharmacological inhibition of integrin-ECM binding, focal adhesion kinase (FAK) signaling, or TGF-ß signaling independently led to compromised pro-tenogenic effects of tECM and actin fiber polymerization. Additionally, integrin blockade inhibited tECM-driven TGFBR2 expression, while inhibiting TGF-ß signaling decreased tECM-mediated expression of integrin α1, α2, and ß1 in hASCs. Together, these findings suggest that the strong pro-tenogenic bioactivity of tECM is regulated via integrin/TGF-ß signaling crosstalk. Understanding how integrins interact with signaling by TGF-ß and/or other growth factors (GFs) within the tendon ECM microenvironment will provide a rational basis for an ECM-based approach for tendon repair.

Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression.

Synchronization of spiking activity in neuronal networks is a fundamental process that enables the precise transmission of information to drive behavioural responses. In cortical areas, synchronization of principal-neuron spiking activity is an effective mechanism for information coding that is regulated by GABA (γ-aminobutyric acid)-ergic interneurons through the generation of neuronal oscillations. Although neuronal synchrony has been demonstrated to be crucial for sensory, motor and cognitive processing, it has not been investigated at the level of defined circuits involved in the control of emotional behaviour. Converging evidence indicates that fear behaviour is regulated by the dorsomedial prefrontal cortex (dmPFC). This control over fear behaviour relies on the activation of specific prefrontal projections to the basolateral complex of the amygdala (BLA), a structure that encodes associative fear memories. However, it remains to be established how the precise temporal control of fear behaviour is achieved at the level of prefrontal circuits. Here we use single-unit recordings and optogenetic manipulations in behaving mice to show that fear expression is causally related to the phasic inhibition of prefrontal parvalbumin interneurons (PVINs). Inhibition of PVIN activity disinhibits prefrontal projection neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. Our results identify two complementary neuronal mechanisms mediated by PVINs that precisely coordinate and enhance the neuronal activity of prefrontal projection neurons to drive fear expression.

Host-specific differences in the contribution of an ESBL IncI1 plasmid to intestinal colonization by Escherichia coli O104:H4.

Objectives: To assess stability and contribution of a large ESBL-encoding IncI1 plasmid to intestinal colonization by Escherichia coli O104:H4 in two different mammalian hosts. Methods: Specific-pathogen-free 3-4-day-old New Zealand White rabbits and conventionally reared 6-week-old weaned lambs were orally infected with WT E. coli O104:H4 or the ESBL-plasmid-cured derivative, and the recovery of bacteria in intestinal homogenates and faeces monitored over time. Results: Carriage of the ESBL plasmid had differing impacts on E. coli O104:H4 colonization of the two experimental hosts. The plasmid-cured strain was recovered at significantly higher levels than WT during late-stage colonization of rabbits, but at lower levels than WT in sheep. Regardless of the animal host, the ESBL plasmid was stably maintained in virtually all in vivo passaged bacteria that were examined. Conclusions: These findings suggest that carriage of ESBL plasmids has distinct effects on the host bacterium depending upon the animal species it encounters and demonstrates that, as for E. coli O157:H7, ruminants could represent a potential transmission reservoir.

Large intercalated neurons of amygdala relay noxious sensory information.

Various GABAergic neuron types of the amygdala cooperate to control principal cell firing during fear-related and other behaviors, and understanding their specialized roles is important. Among GABAergic neurons, the so-called intercalated cells (ITCcs) are critically involved in the expression and extinction of fear memory. Tightly clustered small-sized spiny neurons constitute the majority of ITCcs, but they are surrounded by sparse, larger neurons (L-ITCcs) for which very little information is known. We report here a detailed neurochemical, structural and physiological characterization of rat L-ITCcs, as identified with juxtacellular recording/labeling in vivo. We supplement these data with anatomical and neurochemical analyses of nonrecorded L-ITCcs. We demonstrate that L-ITCcs are GABAergic, and strongly express metabotropic glutamate receptor 1α and GABAA receptor α1 subunit, together with moderate levels of parvalbumin. Furthermore, L-ITCcs are innervated by fibers enriched with metabotropic glutamate receptors 7a and/or 8a. In contrast to small-sized spiny ITCcs, L-ITCcs possess thick, aspiny dendrites, have highly branched, long-range axonal projections, and innervate interneurons in the basolateral amygdaloid complex. The axons of L-ITCcs also project to distant brain areas, such as the perirhinal, entorhinal, and endopiriform cortices. In vivo recorded L-ITCcs are strongly activated by noxious stimuli, such as hindpaw pinches or electrical footshocks. Consistent with this, we observed synaptic contacts on L-ITCc dendrites from nociceptive intralaminar thalamic nuclei. We propose that, during salient sensory stimulation, L-ITCcs disinhibit local and distant principal neurons, acting as "hub cells," to orchestrate the activity of a distributed network.

Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.

BACKGROUND: Gestational trophoblastic disease (GTD) represents a heterogeneous group of disorders. Wide variations in incidence rates are reported worldwide, probably explained by a lack of centralized databases and heterogeneity in case definition. The aim of the present study was to determine the trends in incidence of GTD in the last 20 years with the use of population-based data. PATIENTS AND METHODS: Data on patients with pathologically confirmed diagnosis of GTD between 1994 and 2013 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. RESULTS: In the 20-year period 6343 cases were registered with GTD, representing an overall incidence rate of 1.67 per 1000 deliveries per year. An initial rise in incidence rate was seen over the first 10 years (0.075 per year, 95% CI 0.040-0.109), followed by a stabilization from 2004 to 2013 (increase per year 0.011, 95% CI -0.017-0.040). Although partial hydatidiform mole (HM) was more common in earlier years, complete and partial HM reached comparable incidence rates of 0.68 and 0.64 per 1000 deliveries respectively from 2009 onwards. In the last decade, unspecified HM diagnosis declined significantly from 0.14 per 1000 deliveries in 2003 to 0.03 per 1000 deliveries (per year -0.011, CI -0.016-0.06), suggesting improved diagnostic analyses. CONCLUSION: After an initial rise in GTD incidence in the Netherlands rates remained steady from 2004 onwards. As pathological confirmation is currently the norm and advanced pathological techniques are now widely available, true steady incidence rates may have been reached.

Correlates of physical activity in children and adolescents with physical disabilities: A systematic review.

BACKGROUND: The benefits of physical activity (PA) for children with disabilities are well documented, and children with physical disabilities (PD) are often less active than peers with other disability types. Various correlates associated with PA in children with PD have been identified in separate studies, and a thorough analysis of these correlates could aid in understanding and designing interventions that promote children with PD to be more physically active. The purpose of this systematic review was to provide a comprehensive summary of the correlates of PA in children with PD. METHOD: A systematic search using PubMed, CINAHL, Cochrane Library, PsychINFO, Eric, and EMbase was initiated in October 2014 to identify studies examining the correlates of PA in children with PD aged 6-18years. Two researchers independently screened studies, assessed their methodological quality, and extracted relevant data. The correlates were synthesized and further assessed semi-quantitatively. RESULTS: A total of 45 articles were included in the detailed review. Several modifiable physical, psychological, and environmental correlates were consistently and positively associated with PA in children with PD. Some non-modifiable correlates (e.g., intellectual ability, parents' ethnicity) were found to be consistently and negatively associated with PA. CONCLUSIONS: The correlates of PA in children with PD are multifaceted and along many dimensions. This review can have implications for future studies and these may confirm the consistency of variables related to PA. Insights derived from the outcomes may also foster the measurement of the magnitude of associations that could assist the development of future interventions.

Enhancing spatial inference of air pollution using machine learning techniques with low-cost monitors in data-limited scenarios.

Ensuring environmental justice necessitates equitable access to air quality data, particularly for vulnerable communities. However, traditional air quality data from reference monitors can be costly and challenging to interpret without in-depth knowledge of local meteorology. Low-cost monitors present an opportunity to enhance data availability in developing countries and enable the establishment of local monitoring networks. While machine learning models have shown promise in atmospheric dispersion modelling, many existing approaches rely on complementary data sources that are inaccessible in low-income areas, such as smartphone tracking and real-time traffic monitoring. This study addresses these limitations by introducing deep learning-based models for particulate matter dispersion at the neighbourhood scale. The models utilize data from low-cost monitors and widely available free datasets, delivering root mean square errors (RMSE) below 2.9 µg m-3 for PM1, PM2.5, and PM10. The sensitivity analysis shows that the most important inputs to the models were the nearby monitors' PM concentrations, boundary layer dissipation and height, and precipitation variables. The models presented different sensitivities to each road type, and an RMSE below the regional differences, evidencing the learning of the spatial dependencies. This breakthrough paves the way for applications in various vulnerable localities, significantly improving air pollution data accessibility and contributing to environmental justice. Moreover, this work sets the stage for future research endeavours in refining the models and expanding data accessibility using alternative sources.

Lactobacillus reuteri-specific immunoregulatory gene rsiR modulates histamine production and immunomodulation by Lactobacillus reuteri.

Human microbiome-derived strains of Lactobacillus reuteri potently suppress proinflammatory cytokines like human tumor necrosis factor (TNF) by converting the amino acid l-histidine to the biogenic amine histamine. Histamine suppresses mitogen-activated protein (MAP) kinase activation and cytokine production by signaling via histamine receptor type 2 (H2) on myeloid cells. Investigations of the gene expression profiles of immunomodulatory L. reuteri ATCC PTA 6475 highlighted numerous genes that were highly expressed during the stationary phase of growth, when TNF suppression is most potent. One such gene was found to be a regulator of genes involved in histidine-histamine metabolism by this probiotic species. During the course of these studies, this gene was renamed the Lactobacillus reuteri-specific immunoregulatory (rsiR) gene. The rsiR gene is essential for human TNF suppression by L. reuteri and expression of the histidine decarboxylase (hdc) gene cluster on the L. reuteri chromosome. Inactivation of rsiR resulted in diminished TNF suppression in vitro and reduced anti-inflammatory effects in vivo in a trinitrobenzene sulfonic acid (TNBS)-induced mouse model of acute colitis. A L. reuteri strain lacking an intact rsiR gene was unable to suppress colitis and resulted in greater concentrations of serum amyloid A (SAA) in the bloodstream of affected animals. The PhdcAB promoter region targeted by rsiR was defined by reporter gene experiments. These studies support the presence of a regulatory gene, rsiR, which modulates the expression of a gene cluster known to mediate immunoregulation by probiotics at the transcriptional level. These findings may point the way toward new strategies for controlling gene expression in probiotics by dietary interventions or microbiome manipulation.

Water filtration by endobenthic sandprawns enhances resilience against eutrophication under experimental global change conditions.

Identifying processes that confer resilience against global change is a scientific challenge but is central to managing ecosystem functionality in future. Detecting resilience-enhancing mechanisms is especially relevant in coastal ecosystems, where multi-stressor interactions can drive degradation over time. Here, we quantify the resilience-conferring potential of endobenthic sandprawns against eutrophication, including under high temperatures. We show using a global change mesocosm experiment that sandprawn presence was associated with declines in phytoplankton biomass, particularly under eutrophic conditions, where sandprawns reduced phytoplankton biomass by approximately 74% and prevented a shift to extreme eutrophy. Eutrophic waters were nanophytoplankton-dominated, but sandprawn presence countered this, resulting in even contributions of pico- and nanophytoplankton. Our findings highlight the potential for sandprawns to increase resilience against eutrophication by limiting phytoplankton blooms, preventing extreme eutrophy and counteracting nanophytoplankton dominance. Incorporating endobenthic crustaceans into resilience-based management practices can assist in arresting future water quality declines in coastal ecosystems.

Axo-axonic cells in neuropsychiatric disorders: a systematic review.

Imbalance between excitation and inhibition in the cerebral cortex is one of the main theories in neuropsychiatric disorder pathophysiology. Cortical inhibition is finely regulated by a variety of highly specialized GABAergic interneuron types, which are thought to organize neural network activities. Among interneurons, axo-axonic cells are unique in making synapses with the axon initial segment of pyramidal neurons. Alterations of axo-axonic cells have been proposed to be implicated in disorders including epilepsy, schizophrenia and autism spectrum disorder. However, evidence for the alteration of axo-axonic cells in disease has only been examined in narrative reviews. By performing a systematic review of studies investigating axo-axonic cells and axo-axonic communication in epilepsy, schizophrenia and autism spectrum disorder, we outline convergent findings and discrepancies in the literature. Overall, the implication of axo-axonic cells in neuropsychiatric disorders might have been overstated. Additional work is needed to assess initial, mostly indirect findings, and to unravel how defects in axo-axonic cells translates to cortical dysregulation and, in turn, to pathological states.

Prediction of Total Knee Arthroplasty Sizes with Demographics, including Hand and Foot Sizes.

Anticipating implant sizes before total knee arthroplasty (TKA) allows the surgical team to streamline operations and prepare for potential difficulties. This study aims to determine the correlation and derive a regression model for predicting TKA sizes using patient-specific demographics without using radiographs. We reviewed the demographics, including hand and foot sizes, of 1,339 primary TKAs. To allow for comparison across different TKA designs, we converted the femur and tibia sizes into their anteroposterior (AP) and mediolateral (ML) dimensions. Stepwise multivariate regressions were performed to analyze the data. Regarding the femur component, the patient's foot, gender, height, hand circumference, body mass index, and age was the significant demographic factors in the regression analysis (R-square 0.541, p < 0.05). For the tibia component, the significant factors in the regression analysis were the patient's foot size, gender, height, hand circumference, and age (R-square 0.608, p < 0.05). The patient's foot size had the highest correlation coefficient for both femur (0.670) and tibia (0.697) implant sizes (p < 0.05). We accurately predicted the femur component size exactly, within one and two sizes in 49.5, 94.2, and 99.9% of cases, respectively. Regarding the tibia, the prediction was exact, within one and two sizes in 53.0, 96.0, and 100% of cases, respectively. The regression model, utilizing patient-specific characteristics, such as foot size and hand circumference, accurately predicted TKA femur and tibia sizes within one component size. This provides a more efficient alternative for preoperative planning.

Neurogliaform cells of amygdala: a source of slow phasic inhibition in the basolateral complex.

Synaptic inhibition in the amygdala actively participates in processing emotional information. To improve the understanding of interneurons in amygdala networks it is necessary to characterize the GABAergic cell types, their connectivity and physiological roles. We used a mouse line expressing a green fluorescent protein (GFP) under the neuropeptide Y (NPY) promoter. Paired recordings between presynaptic NPY-GFP-expressing (+) cells and postsynaptic principal neurons (PNs) of the basolateral amygdala (BLA) were performed. The NPY-GFP+ neurons displayed small somata and short dendrites embedded in a cloud of highly arborized axon, suggesting a neurogliaform cell (NGFC) type. We discovered that a NPY-GFP+ cell evoked a GABA(A) receptor-mediated slow inhibitory postsynaptic current (IPSC) in a PN and an autaptic IPSC. The slow kinetics of these IPSCs was likely caused by the low concentration and spillover of extracellular GABA. We also report that NGFCs of the BLA fired action potentials phase-locked to hippocampal theta oscillations in anaesthetized rats. When this firing was re-played in NPY+-NGFCs in vitro, it evoked a transient depression of the IPSCs. Presynaptic GABA(B) receptors and functional depletion of synaptic vesicles determined this short-term plasticity. Synaptic contacts made by recorded NGFCs showed close appositions, and rarely identifiable classical synaptic structures. Thus, we report here a novel interneuron type of the amygdala that generates volume transmission of GABA. The peculiar functional mode of NGFCs makes them unique amongst all GABAergic cell types of the amygdala identified so far.

Human chorionic gonadotropin (hCG) regression normograms for patients with high-risk gestational trophoblastic neoplasia treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) chemotherapy.

BACKGROUND: We present normograms for human chorionic gonadotropin (hCG) regression in patients with high-risk gestational trophoblastic neoplasia (GTN) successfully treated with multiagent chemotherapy in order to predict treatment resistance. PATIENTS AND METHODS: We collected data for 46 patients with high-risk GTN treated with EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine) who had hCG values available. Patients were classified as having methotrexate (MTX)-resistant disease (n = 22) or primary high-risk disease (n = 24). The 10th, 50th and 90th percentiles of the hCG before every chemotherapy course were calculated and plotted in normograms. RESULTS: Half of the patients treated for MTX-resistant disease and primary high-risk disease had normal hCG levels before the third and sixth course of chemotherapy, respectively. In patients with MTX-resistant disease, the 90th percentile line fell below normal before the start of the fourth course, whereas in patients with primary high-risk disease this was not the case until the eighth course of chemotherapy. CONCLUSION: Resistance to EMA/CO treatment for high-risk GTN, as illustrated by examples, could be predicted using normograms for hCG resistance. Normograms differed depending on the indication for multiagent chemotherapy due to much higher initial hCG values in patients with primary high-risk disease compared with those treated for MTX-resistant disease.

Identification of C-terminal hydrophobic residues important for dimerization and all known functions of ParB of Pseudomonas aeruginosa.

The ParB protein of Pseudomonas aeruginosa is important for growth, cell division, nucleoid segregation and different types of motility. To further understand its function we have demonstrated a vital role of the hydrophobic residues in the C terminus of ParB(P.a.). By in silico modelling of the C-terminal domain (amino acids 242-290) the hydrophobic residues L282, V285 and I289 (but not L286) are engaged in leucine-zipper-like structure formation, whereas the charged residues R290 and Q266 are implicated in forming a salt bridge involved in protein stabilization. Five parB mutant alleles were constructed and their functionality was defined in vivo and in vitro. In agreement with model predictions, the substitution L286A had no effect on mutant protein activities. Two ParBs with single substitutions L282A or V285A and deletions of two or seven C-terminal amino acids were impaired in both dimerization and DNA binding and were not able to silence genes adjacent to parS, suggesting that dimerization through the C terminus is a prerequisite for spreading on DNA. The defect in dimerization also correlated with loss of ability to interact with partner protein ParA. Reverse genetics demonstrated that a parB mutant producing ParB lacking the two C-terminal amino acids as well as mutants producing ParB with single substitution L282A or V285A had defects similar to those of a parB null mutant. Thus so far all the properties of ParB seem to depend on dimerization.

Functional mixture regression.

In functional linear models (FLMs), the relationship between the scalar response and the functional predictor process is often assumed to be identical for all subjects. Motivated by both practical and methodological considerations, we relax this assumption and propose a new class of functional regression models that allow the regression structure to vary for different groups of subjects. By projecting the predictor process onto its eigenspace, the new functional regression model is simplified to a framework that is similar to classical mixture regression models. This leads to the proposed approach named as functional mixture regression (FMR). The estimation of FMR can be readily carried out using existing software implemented for functional principal component analysis and mixture regression. The practical necessity and performance of FMR are illustrated through applications to a longevity analysis of female medflies and a human growth study. Theoretical investigations concerning the consistent estimation and prediction properties of FMR along with simulation experiments illustrating its empirical properties are presented in the supplementary material available at Biostatistics online. Corresponding results demonstrate that the proposed approach could potentially achieve substantial gains over traditional FLMs.

Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis.

PPT1-related neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder caused by deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Enzyme replacement therapy (ERT) has not been previously examined in a preclinical animal model. Homozygous PPT1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5 months of age and death by around 8 months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3 mg, corresponding to 12 mg/kg or 180 U/kg for a 25 g mouse) administered intravenously weekly either 1) from birth; or 2) beginning at 8 weeks of age. The treatment was surprisingly well tolerated and neither anaphylaxis nor antibody formation was observed. In mice treated from birth, survival increased from 236 to 271 days (p<0.001) and the onset of motor deterioration was similarly delayed. In mice treated beginning at 8 weeks, no increases in survival or motor performance were seen. An improvement in neuropathology in the thalamus was seen at 3 months in mice treated from birth, and although this improvement persisted it was attenuated by 7 months. Outside the central nervous system, substantial clearance of autofluorescent storage material in many tissues was observed. Macrophages in spleen, liver and intestine were especially markedly improved, as were acinar cells of the pancreas and tubular cells of the kidney. These findings suggest that ERT may be an option for addressing visceral storage as part of a comprehensive approach to PPT1-related NCL, but more effective delivery methods to target the brain are needed.

Relapse rates after two versus three consolidation courses of methotrexate in the treatment of low-risk gestational trophoblastic neoplasia.

OBJECTIVE: Methotrexate (MTX) alternating with folinic acid is a commonly used treatment regimen for low-risk gestational trophoblastic neoplasia (GTN). In The Netherlands, two courses of MTX are administered after normalization of serum human chorionic gonadotrophin (hCG) levels (consolidation courses), whereas in the United Kingdom, three consolidation courses are given. In a retrospective setting we compared relapse rates of women completing MTX therapy for low-risk GTN in The Netherlands and the UK. METHODS: From 1980 to 2008, 351 patients were collected from the Dutch Central Registry for Hydatidiform Moles and records from the Dutch Working Party on Trophoblastic Disease. From the Charing Cross Hospital Trophoblast Disease Centre (London), 600 low-risk GTN patients were identified from 1992 to 2008. RESULTS: In 4.0% of patients relapse occurred after MTX treatment with three consolidation courses, whereas 8.3% of patients relapsed after MTX treatment with two consolidation courses (p=0.006). Although patients from The Netherlands had a higher level of hCG (p<0.001) and more patients had metastases before the start of treatment (p=0.012), the number of courses of MTX to achieve a normal hCG did not differ significantly between patients from The Netherlands and the UK (p=0.375). CONCLUSIONS: Relapse rates were higher in patients treated with two consolidation courses of MTX. Although other factors might have influenced the observed difference in relapse rates, three courses of consolidation chemotherapy may be preferable to two in the treatment of low-risk GTN in order to decrease the risk of disease relapse. A prospective randomized study would be required to confirm these findings.

Fatal cases of gestational trophoblastic neoplasia over four decades in the Netherlands: a retrospective cohort study.

OBJECTIVE: To describe fatal cases of gestational trophoblastic neoplasia (GTN) over four decades and evaluate whether treatment was given according to the protocol and reveal possible implications for future management. DESIGN: Retrospective cohort study. SETTING: The Netherlands. POPULATION: Women who died from GTN from 1971 to 2011. METHODS: Records from the Dutch Central Registry for Hydatidiform Moles and the Working Party on Trophoblastic Disease were used to identify fatal cases of GTN. MAIN OUTCOME MEASURES: Disease extent, risk classification, treatment regimens and cause of death. RESULTS: Twenty-six women died from GTN. In five cases GTN developed after a hydatidiform mole and in 19 cases following term pregnancy. Half of the women died between 1971 and 1980, when women were not yet classified as having low-risk or high-risk disease and were therefore not yet treated accordingly. A major decline in the number of deaths was seen after the first decade, with a further decrease from 1981 to 2011. Early death occurred in nine women. In four of these women, death was treatment-related. Women who died more than 4 weeks after the start of treatment mostly died from metastatic tumour (n = 14). CONCLUSIONS: The yearly number of women who died from GTN decreased considerably over the last four decades. Appropriate risk classification is essential to start optimal initial therapy and to prevent therapy resistance. Women with post-term choriocarcinoma represented a large proportion of the dead women and we propose that these women are considered as having high-risk disease.